bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I dose escalation study of PCUR-101 in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kyriakopoulos Christos , Paller Channing Judith , Verma Ajit , Kader Karim , Kittrelle Jeff , Borgström Per G , Vaishampayan Ulka N.
Published: May 2019

e16517

Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.
Evaluation of monovalent versus biparatopic CD3xPSMA bispecific antibodies for t-cell mediated killing of prostate tumor cells with minimal cytokine release.
Authors: Buelow Ben , Clarke Starlynn , Dang Kevin , Li Jacky , Rancan Chiara , Li Yuping , Sankaran Preethi , Pham Duy , Balasubramani Aarti , Davison Laura , Harris Katherine , Jorgensen Brett , Schellenberger Ute , Trinklein Nathan , Ugamraj Harshad , Fong Lawrence , Van Schooten Wim , Force Aldred Shelley
Published: May 2019

e16519

Background: Castration resistant prostate cancer (CRPC) remains an incurable disease and new treatments are needed. Therapies directed against Prostate specific membrane antigen (PSMA) -such as radiolabeled antibodies, chimeric antigen receptor T cells (CAR-Ts) and T-cell engaging bispecific antibodies (T-BsAbs)- have shown promising efficacy but also induce significant toxicity. In particular T-cell redirection leads to efficient killing of tumor cells but induces cytokine release-related toxicities. We have developed a panel of monovalent and biparatopic CD3xPSMA bispecific antibodies that eliminate prostate tumor cells while minimizing cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated in transgenic rats (UniRat™, OmniFlic™) followed by deep sequencing of the antibody repertoire from draining lymph nodes in immunized animals, and high-throughput gene assembly/expression. PSMA x CD3 T-BsAbs were assembled and evaluated for stability, pharmacokinetics, and T cell activation and ability to eliminate PSMA+ tumor cells in vitro and in vivo. Results: Bispecific CD3xPSMA Abs. incorporating either monovalent or biparatopic anti-PSMA binding domains activated T-cells in the presence of PSMA (plate-bound or cell surface), while no T cell activation occurred in the absence of either PSMA antigen or bispecific antibody. Potent/selective cytotoxicity against PSMA+ cells was observed in co-cultures of primary human T cells and tumor cells treated with CD3xPSMA T-BsAbs. Similar results were observed in in vivo Xenograft models of prostate cancer. Strikingly, CD3xPSMA bispecifics containing a novel low affinity anti-CD3 domain produced similar levels of tumor cytotoxicity compared to those with a traditional high affinity anti-CD3 domain, but with reduced cytokine production. Conclusions: We have created novel CD3xPSMA bispecific antibodies incorporating both monovalent and biparatopic anti-PSMA binding domains that mediate T-cell killing of PSMA+ tumor cells with minimal production of cytokines. Such T-BsAbs may improve safety, efficacy, and opportunities for combination therapy to treat CRPC.
Are there any significant impacts of patient age and prior treatment profile with docetaxel on the efficacy of cabazitaxel in patient with castration-resistant prostate cancer?
Authors: Kosaka Takeo , Hongo Hiroshi , Mizuno Ryuichi , Tanaka Nobuyuki , Takaeda Toshikazu , Matshumoto Kazuhiro , Oya Mototsugu
Published: May 2019

e16522

Background: The correlation of the oncological outcomes of patient age in metastatic castration resistant prostate cancer (mCRPC) patients have not been unclear. Materials and Methods: This study included a total of 56 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the prognostic significance of cabazitaxel at Keio University Hospital from 2014 to 2019 were included., focusing on patient age and the correlation of efficacy between docetaxel and cabazitaxel. All patients received cabazitaxel at 20-25 mg/m2 administered intravenously on day 1 of each treatment cycle, together with prednisone 5 mg twice daily. Prophylactic administration of G-CSF was prescribed to all the patients. Results: The median overall survival (OS) periods after the introduction of cabazitaxel was 16.1 months. A 30% PSA response to cabazitaxel was achieved in 5 (50.0%) patients with ≧75 years (n = 10) and 19 (41.3%) patients with less than 75 years (n = 46). There was no significant correlation between the PSA response and patients’ age (p = 0.087). A 30% PSA response to cabazitaxel was achieved in 25 (43.9%) patients. A 30% PSA response to cabazitaxel was achieved in 15 (57.6%) and 10 (33.3%) patients with and without that to docetaxel, respectively. There was no significant correlation of the PSA response between docetaxel and cabazitaxel (p = 0.106). Univariate and multivariate analysis revealed that there were no significant correlation of patient age, the response to prior docetaxel therapyor cycles of docetaxel therapy with shorter OS. Conclusions: These results indicate that the introduction of cabazitaxel for mCRPC patients could result in oncological outcomes without any association with patient’s age and the profiles of previous docetaxel therapy.
Immune-stimulatory gene expression in stroma cells of African-American prostate cancer tissues.
Authors: Mercola Dan , Rahmatpanah Farah , Agrawal Anshu , Jia Zhenyu (Arthur) , Zi Xiaolin , Lilly Michael B. , McClelland Michael
Published: May 2019

e16544

Background: Prostate cancer (PCa) of African Americans (AA) has a two-fold higher mortality compared to PCa of European Americans (EA). PCa-adjacent stroma cells from these two populations were examined for differences in their cytokine secretion and gene transcription. Methods: Primary PCa-adjacent stroma cells (carcinoma-associated fibroblasts (CAFs)) and PCa-distant normal fibroblasts of the same gland (dNFs) from 15 AA and 27 EA patients were grown to passage 5. A multiplex immunoassay was then used to measure the secretion of 30 cytokines/chemokines in conditioned medium. In addition, RNA-Seq was performed on four AA and four EA CAF lines, and on PCa-adjacent stroma FFPE tissues of seven AA and five EA patients. Self-identified ethnicity was confirmed using the LASER program and SNPs present in the RNA-Seq. Results: Conditioned media from 42 AA and EA CAFs and dNFs were assayed for 30 immuno-regulatory cytokines/chemokines and growth factors, 20 of which (66%) were secreted at lower levels ( p < 0.05) in AA vs. EA CAFs. Remarkably, dNFs did not show this difference. RNA-Seq analysis of AA vs EA CAFs in culture identified 413 upregulated and 893 downregulated genes (FDR < 0.05, ≥ ±1.5 fold). Several interleukins, interferons, and 120 of 154 differentially transcribed interferon-stimulated genes were downregulated in AA vs. EA CAFs. RNA-Seq of PCa-adjacent stroma from FFPE tissues of seven AA and five EA patients revealed significantly reduced transcription of many immunomodulatory genes in AA stroma, including type I IFN-stimulated genes (ISGs). CIBERSORT analysis of the FFPE RNA-Seq data indicated the presence of significantly less numbers of dendritic cells and higher levels of naïve CD4 Th cells in AA vs. EA stroma. Conclusions: We observed reduced transcription of immunomodulators in CAFs of AA vs. EA, accompanied by profound decreases in the levels of many secreted cytokines and chemokines. These differences may indicate reduced innate and adaptive immune responses in AA PCa, compared to EA PCa. The differences observed here in primary cell lines may permit functional studies of the underlying mechanism(s) of the striking dissimilarity in disease outcome of AA PCa compared to EA PCa
Outcomes of men with prostate cancer managed with active surveillance and tested with clinical cell-cycle risk score.
Authors: Ehdaie Behfar , Kaul Sanjeev , Wojno Kirk , Evans Brent , Bernhisel Ryan , Meek Stephanie , D'Anna Richard , Ferguson Jeffrey , Glaser Jeffrey , Morgan Todd Matthew , Lieb Jeremy , Yan Robert , Stone Steven , Cohen Todd
Published: May 2019

e16566

Background: The indolent nature of many prostate cancers (PC) makes some men eligible to undergo active surveillance (AS) rather than immediate definitive treatment. Accurate risk classification is critical for selection of appropriate candidates for AS. The clinical cell-cycle risk (CCR) score, a combined clinical and molecular score, provides improved prognostic information about tumor aggressiveness over clinical parameters alone. This study aimed to evaluate the clinical outcomes of men with low-risk PC by NCCN guidelines and CCR score who selected AS. Methods: This study retrospectively reviewed men with localized PC who received CCR testing (2013-2017) and had low-risk disease according to NCCN guidelines and CCR score (N = 664). Low-risk by CCR score was defined as having a risk of disease-specific mortality < 3.2%. Men selected AS (no definitive treatment within 6 months of diagnosis) or underwent immediate definitive treatment. Durability of AS was evaluated beginning from diagnosis. Clinical outcomes were determined by reporting adverse events (biochemical recurrence (BCR), progression to metastasis as confirmed by radiographic imaging, prostate cancer specific mortality). Results: In this study, 547 men (82%) selected AS (median follow-up time 2.2 years [1.5, 3.1]). Of those managed by AS, two (0.4%) men experienced an adverse event. One man experienced BCR 3.7 years after diagnosis, and the other experienced metastasis 0.9 years after diagnosis. There were no reported cases of disease-specific mortality. The probability of remaining on AS for 3 years was 69.6%. Common reasons for exiting AS were patient choice (27.1%), increase in Gleason score (23.3%), and change in prostate specific antigen (PSA) (10.5%). Of those patients that left AS due to change in PSA (N = 14), only 4 exhibited a clinically significant increase in PSA ( > 10 ng/mL). Conclusions: The majority of men with molecularly-confirmed (CCR), NCCN low-risk PC selected AS in both academic and community settings. The incidence of metastatic disease or BCR after definitive treatment for disease progression was rare. The majority of men who selected AS remained on AS for the duration of the study.
Association of disease prognostic model (PM) with baseline quality of life (QOL) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Prizment Anna , Halabi Susan , McSweeney Sean , Eisenberg Amy , Rao Arpit , Gupta Shilpa , Morgans Alicia K. , Ryan Charles J.
Published: May 2019

e16579

Background: PM’s in mCRPC accurately predict survival, but little is known about their association with QOL. We hypothesize that pre-treatment QOL is inversely correlated with PM derived scores. Our study explored associations between baseline Halabi PM derived risk score (including metastatic site, opioid use, ECOG performance status (ECOG PS), Alk phos, albumin, hemoglobin, LDH, and PSA) and multiple QOL domains at treatment initiation with docetaxel and prednisone (DP). Methods: The DP arm of MAINSAIL, a multicenter, randomized Phase 3 study of DP +/- lenalidomide in mCRPC, was analyzed via ProjectDataSphere. Halabi PM score was computed as continuous with higher score reflecting worse survival and classified as low- ( < 140 points), intermediate- (140-194.96) or high-risk groups ( > 194.96 points). QOL tests included FACT-P (higher score = better QOL), BPI-SF Severity score (BPI-SFSS; higher score = higher pain severity); and BPI-SF Interference score (BPI-SFIS, higher score = worse pain). General linear regression model was used to calculate beta estimates and 95% confidence intervals. Results: The sample included 526 mCPRC pts (median 68 years, White: 91.9%, Black: 5.3%, median PSA 75.95 ng/ml). Median [range] for FACT-P, BPI-SFSS and BPI-SFIS were 111 [0-152], 1.8 [0-9.3], and 1.4 [0-10], respectively. PM score was correlated with BPI-SFIS and BPI-SFSS and inversely correlated with FACT-P with correlation of 0.36, 0.31 and -0.33, respectively (all p < 0.0001). For each unit increase in the PM score, BPI-SFIS increased by 2.1 points), BPI-SFSS increased by 1.5 points, and FACT-P decreased by 16.4 points. Using the three-risk groups, pts in the intermediate and high-risk groups had worse FACT-P QOL and higher BPI-SFIS and BPI-SFSS than pts in the low-risk group. In multivariate analysis, factors negatively impacting FACT-P QOL, BPI-SFSS and BPI-SFIS were higher ECOG PS, visceral metastases and opioid use. Declining hemoglobin levels were associated with increased BPI-SFSS and BPS-SFIS. Conclusions: Higher PM scores are associated with a lower baseline QOL overall, higher pain and higher pain interference. These results should be validated prospectively.
NT5E expression and the immune landscape of prostate cancer (PC): An analysis from The Cancer Genome Atlas database.
Authors: Tripathi Abhishek , Lin Edwin , Nussenzveig Roberto , Yandell Mark , Pal Sumanta K. , Agarwal Neeraj
Published: May 2019

e16591

Background: Immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 pathway have shown modest activity in patients with advanced PC. Additional immunosuppressive mechanisms in the PC tumor microenvironment need to be investigated. Increased CD73 (encoded by NT5E) expression results in generation of immunosuppressive adenosine in the tumor microenvironment and has been associated with metastasis and poor survival in PC. Utilizing the TCGA dataset, we investigated the association of NT5E expression with the immune landscape of PC. Methods: RNA-seq data for 331 PC tumor samples and 51 normal adjacent tissue (NAT) samples was downloaded and log2 transformed. Patients were split into low, intermediate, and high expression groups based on NT5E expression (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean) in tumor and NAT. A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged tumor expression of 18 previously validated genes (Ayers et al, 2017). Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes (Charoentong et al, 2017). Immune cell abundance scores and TIS were compared between NT5E expression groups using the Mann-Whitney U test and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression in NAT was not associated with the TIS or expression of immune cell marker genes. In contrast, NT5E expression in tumor tissue correlated positively with TIS (P < 0.001). Compared to tumors with low NT5E expression, those in high NT5E expression group had higher expression of central memory CD4+, effector memory CD8+, type 1 helper, NK and regulatory T (Treg) cell markers. Conclusions: In our analysis, NT5E expression correlated with markers of inflamed tumor phenotype in PC. Although NT5E expression was associated with higher CD8+and CD4+ T cells, concurrent increase in Tregs could inhibit the infiltrating lymphocytes and promote tumor growth. Our findings indicate a possible role for the adenosine pathway as a mediator of immunosuppression in PC and a potential therapeutic target. AT and EL: Equal contribution
30-year extrapolations of overall survival (OS) and metastasis-free survival (MFS) from the SPCG-4 trial of radical prostatectomy (RP) versus watchful waiting (WW) in patients (pts) with early prostate cancer (ePCa).
Authors: Alrawashdh Neda , Oh Mok , Almutairi Abdulaali , Alkhatib Nimer S , Babiker Hani M. , MacDonald Karen , McBride Ali , Abraham Ivo
Published: May 2019

e16597

Background: Bill-Axelson et al (NEJM, 2014) reported 18 year (y) mortality and metastasis (mets) data on ePCa pts randomized in the SPCG-4 trial to RP (n = 347) vs WW (n = 348) for all pts and by age < 65y (nRP= 157 nWW= 166) vs ≥65y (nRP= 190 nWW= 182). Using the 18y data, we estimated the cumulative incidence, OS and MFS curves, and absolute risk reduction (ARR) for death and mets up to 30y for all pts and pts < 65y vs ≥65y. Methods: Published 18y SPCG-4 cumulative incidence curves for death and mets were digitized and parametric regression models were tested to fit the data. From these we estimated, for death and mets, the respective 30y cumulative incidences, OS and MFS curves with 95%CI; and ARR. ARRs for < 65y and ≥65y were compared using the chi-squared test. Results: The exponential regression model fit the data best. Over the 18 to 30y period, OS in all pts decreased from .81 to .69 in RP and from .72 to .56 in WW; in pts < 65y from .81 to .69 in RP and from .67 to .49 in WW; in pts ≥65y from .83 to .72 in RP and from .78 to .64 in WW. Over the same period, MFS in all pts decreased from .81 to .69 in RP and from .73 to .56 in WW; in pts < 65y from .81 to .69 in RP and from .67 to .49 in WW; in pts ≥65y from .78 to .64 in RP and from .75 to .59 in WW. OS and MFS 95%CI curves overlapped in pts ≥65y but not in pts < 65y. ARRs for death and mets of RP over WW are shown below by 2y interval. ARRs for death and mets were statistically different in pts < 65y but not in pts ≥65y. Conclusions: Extrapolated to 30y post randomization, RP shows better gains in OS and MFS over WW. RP is associated with significant reductions of death and mets: 19 more surviving pts and 20 more metastasis free pts per 100 pts among pts < 65y but not among pts ≥65y. These data enable clinicians to provide ePCA pts considering RP vs WW with up to 30y prognostic information. This facilitates informed patient decision making, especially among those age < 65y. [Table: see text]
Physician benefit-risk preferences for non-metastatic castration-resistant prostate cancer treatment (nmCRPC).
Authors: Srinivas Sandy , Mohamed Ateesha F. , Appukkuttan Sreevalsa , Botteman Marc , Ng Xinyi , Joshi Namita , Horodniceanu Erica , Waldeck Reg , Simmons Stacey J.
Published: May 2019

e16610

Background: Second-generation androgen receptor inhibitors (SGARIs) are now available for the management of nmCRPC based on improvements in metastasis-free survival. We used a discrete choice experiment (DCE) to explore how U.S. oncologists and urologists may balance different SGARIs’ risks (i.e., adverse events [AEs]) against survival, when treating an otherwise asymptomatic patient population. Methods: We invited oncologists and urologists treating nmCRPC patients via online panels to participate. The survey included 14 treatment choice questions, each comparing 2 hypothetical medication profiles, which varied in terms of 5 safety and 2 efficacy attributes. These attributes were selected via qualitative interviews and pre-testing with physicians, patients, and caregivers. We described safety attributes (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency and efficacy attributes (overall survival [OS] and time to pain progression) in terms of duration of effect. We used a main-effects random parameters logit model to estimate preference weights and importance scores for each attribute. Results: 74 oncologists and 75 urologists completed the survey. Among safety attributes, physicians were most concerned with cognitive problems, fractures, and fatigue. Physicians placed 36% more importance on reducing cognitive problems from severe to none compared to improving OS by 12 months instead of 3 months. On average, physicians were willing to trade off 7.1 months of OS for a reduction in fatigue severity from severe to mild/moderate and 0.8 months of OS for a reduction in fatigue from mild/moderate to none. Physicians were willing to trade off approximately 4.2 and 5.0 months of OS for reduction in fracture risk from 8% to 5%, and 5% to 0%, respectively. Conclusions: As shown in this DCE, physicians making treatment decisions for largely asymptomatic nmCRPC patients, were willing to trade substantial amounts of survival to avoid AEs. These results emphasize the importance of carefully balancing the risk-benefit profiles of SGARI therapy when treating this patient population, to ultimately optimize the overall quality of the patients’ survival.
Race as a prognostic factor in high-risk prostate cancer: An NCDB analysis.
Authors: Kodiyan Joyson , Guirguis Adel , Yanagihara Theodore , Ashamalla Hani
Published: May 2019

e16611

Background: It is commonly held that race serves as a significant prognosticator in prostate cancer. However, it is unclear if race affects all risk groups similarly. We sought to analyze whether race, either African American (AfA) or Caucasian (C), impacted overall survival of men receiving standard of care treatment using a large national database. Materials and Methods: All data was obtained from the NCDB (National Cancer Database), a collaborative effort between the American Cancer Society and Commission on Cancer. The database initially contained 1,294,126 cases of prostate cancer diagnosed between 2004 and 2014. Those with documented race and minimum follow up of 4 years were analyzed in this study. Patients were eliminated from the study if they had metastatic or nodal disease, received chemotherapy, or had non-invasive disease. Patients were grouped into two cohorts as per NCCN criteria: favorable risk and unfavorable risk. All patients received definitive therapy appropriate for their risk group. AfA and C men were matched 1:1 within each risk cohort using propensity scores, and multivariate analysis was conducted on these matched cohorts. Results: The final analyzed cohort included 75,217 patients with median follow-up time of 5 years. 10-year OS for favorable risk and unfavorable risk cohorts were 78% and 73% respectively (log rank, p < 0.001). In the favorable risk cohort, 5,422 C cases were matched to 5,422 AfA cases. C men had superior OS compared to AfA men, 89% versus 86% at 8 years and 79% versus 79% at 10 years (HR 0.688, 95% CI 0.571-0.872, p = 0.0025). In the unfavorable risk cohort, 3,870 C cases were matched to 3,870 AfA cases. Race was not a significant prognostic factor for OS, 83% versus 83% at 8 years and 73% versus 71% at 10 years in C and AfA men, respectively (HR 0.961, 95%CI 0.837-1.103, p = 0.572). Conclusions: Race has no effect on overall survival in unfavorable disease while AfA race is a predictor for worse survival in favorable risk prostate cancer, independent of socioeconomic and demographic factors. This suggests that the biology of disease plays a significant role in favorable risk cohorts, but with more advanced higher risk disease, other factors besides race may play a more significant role.
Dynamics of the immune status in patients with cervical cancer receiving complex treatment with dendritic cell vaccine.
Authors: Menshenina Anna P. , Kit Oleg I. , Zlatnik Elena Yu. , Bondarenko Elena S. , Novikova Inna A. , Moiseenko Tatiana I. , Frantsiyants Elena M. , Verenikina Ekaterina V. , Selezneva Olga G. , Adamyan Meri L. , Cherkasova Anna A.
Published: May 2019

e17005

Background: The purpose of the study was to determine the influence of complex treatment with dendritic cell vaccine on the dynamics of the immune status of patients with cervical cancer. Methods: 17 patients with cervical cancer (CC) T2b-4аN0-1M0-1 received chemotherapy with combined radiotherapy to the pelvic area. Between courses of cytostatic treatment, patients underwent dendritic cell vaccination (DCV) planned individually depending on the treatment effect, which was evaluated by the results of examination, US, CT and MRI. A control group included 19 patients with locally advanced CC receiving standard polychemotherapy (PCT) and radiotherapy. Immune status of patients was evaluated by flow cytometry (FACSCantoII BD) including T, B, NK cells, Tregs (CD4+CD25+CD127dim), memory T cells (Тm) and naïve T lymphocytes (Th0) was determined in the dynamics of the treatment. Results were calculated as a percentage from the total number of lymphocytes, for Tregs – in % from CD3+CD4+ cells, for Тm and Th0 – in % from CD3+CD4+ and CD3+CD8+ cells. Results: 1 to 4 cycles of PCT with DCV caused a transient increase in Tregs after the 1st cycle, with further regression to the initial levels; other studied lymphocyte subsets remained unchanged. Only after 8 or more DCV cycles, a favorable immunological dynamics developed; however, it was not observed in controls. DCV increased levels of lymphocytes with potential cytotoxicity: CD3+CD8+ (from 19.0±2.0 to 28.8±1.5%), NK cells (from 12.0±2.0 to 21.2±1.9%). During DCV courses helper-inducer Tm amount rose from 51.7±6.3 to 69.7±4.3%, while in remission – CD8+Tm grew from 28.5±2.1 to 40.4±5.3% (p < 0.05 for all cases). Repeated DCV was satisfactorily tolerated by CC patients and, when used in complex treatment, caused a pronounced clinical effect. DCV did not lead to serious adverse events. Patients in remission are still observed. Conclusions: Treatment for CC with DCV causes a positive dynamics of the immune status, with the maximal effect after 8 and more DCV cycles. Remission is apparently maintained due to an increase in the level of TmCD8+ cells.
A single-center retrospective analysis to evaluate the prognostic role of lymph node density in patients with lymph node-positive cervical cancer.
Authors: Polasik Arkadius A. , Janni Wolfgang , Scholz Christoph , De Gregorio Nikolaus , Schochter Fabienne , Friedl Thomas W. P. , Widschwendter Peter
Published: May 2019

e17013

Background: The aim of this retrospective analysis is to evaluate the prognostic role of lymph node density (LND), i.e. the ratio of positive lymph nodes to the total number of lymph nodes removed during surgery, in nodal-positive cervical cancer patients. Methods: Out of 266 patients with cervical cancer that underwent surgery including lymphonodectomy between 2000 and 2017 at the Department for Gynecology and Obstetrics of the University Hospital Ulm, 86 patients with positive lymph nodes were included in the analysis. According to former study results, patients were divided into two groups with LND < 10% vs. ≥ 10%. Univariable and multivariable cox-regression models (adjusted for age, histological subtype, grading, body mass index, R-status, lymphangiosis, histologically confirmed FIGO-status and chemotherapy) were used to evaluate the association between LND and both overall survival (OS) and disease-free survival (DFS). Results: In the 86 patients, a median of 42 lymph nodes were removed (range 11 – 107), and a median of 2 lymph nodes (range 1 – 25) were found positive. 57 (66.3%) patients had a LND < 10% and 29 (33.7%) patients had a LND ≥ 10%. There was no significant association between LND (≥ 10% vs. < 10%) and OS in both univariable (hazard ratio[HR] 1.49, 95% CI 0.72 – 3.07, p = 0.280) and multivariable survival analysis (HR 1.46, 95% CI 0.64 – 3.32, p = 0.372), respectively. However, LND was significantly associated with DFS in univariable analysis (HR 2.11, 95% CI 1.10 – 4.03, p = 0.024) and was found to be an independent predictor for DFS in adjusted multivariable analysis (HR 2.30, 95% CI 1.08 – 4.91, p = 0.031). Conclusions: LND ≥ 10% in patients with lymph node-positive cervical cancer is associated with a worsened DFS compared to patients with a LND < 10%. Thus, LND may be used as an independent prognostic marker and/or for risk stratification in these patients.
A phase I trial evaluating the safety and efficacy of weekly paclitaxel or cisplatin with electro-hyperthermia in patients with recurrent or persistent epithelial ovarian, fallopian tubal or primary peritoneal carcinoma (KGOG 3030).
Authors: Kim Kidong , Suh Dong-Hoon , No Jae Hong , Kim Yong Beom , Kim Jae Hoon , Kim Seung Cheol , Ju Woong , Kim Yun Hwan
Published: May 2019

e17032

Background: To evaluate the safety and efficacy of weekly paclitaxel or cisplatin with electro-hyperthermia in patients with recurrent or persistent epithelial ovarian, fallopian tubal or primary peritoneal carcinoma. Methods: This prospective trial employed ‘3+3 design’ with no dose escalation. Initially, patients were randomized to weekly paclitaxel (70mg/m2) or weekly cisplatin (40mg/m2) with electro-hyperthermia until three patients in each arm were evaluable for dose-limiting toxicities (DLTs). A cycle was 4 weeks long and paclitaxel or cisplatin was administered at day 1, 8, 15. Targeting tumor beds, electro-hyperthermia was administered semi-weekly (8 time/cycle) for 1 hour per session. DLT was defined as any adverse event possibly or probably related to therapy, that required intensive care or was not recovered to grade 2 or lower within 3 weeks. If ≤1 patient in an arm experienced DLT, additional 3 patients were enrolled to that arm. Unevaluable patients (n = 4) were replaced. Finally, 12 patients (6 in each arm) were evaluated for toxicities, response rate, progression-free survival (PFS) and overall survival (OS). Results: Nine patients had high grade serous histology. Median number of previous regimen was 2 (range 1- 5) and median treatment-free interval from previous chemotherapy was 6 months (range 0 – 27). Nine patients were platinum resistant or refractory. No DLT was observed. Four grade 3 toxicities were observed (nausea 1, hematologic 3) in cisplatin arm. Overall response rate was 42% (5/12), median PFS was 4.3 months (range 1.7 – 11.8), and median OS was over 13.8 months (range 3.9 – > 38.5). Conclusions: Both weekly paclitaxel and cisplatin with electro-hyperthermia are safe enough to be tested in further studies. Chemotherapy with electro-hyperthermia was seems to be an effective treatment strategy for recurrent or persistent epithelial ovarian, fallopian tubal or primary peritoneal carcinomas. No significant differences in oncologic outcomes and toxicities were observed between paclitaxel and cisplatin arms. Clinical trial information: NCT02344095.
Impact of a structured quality management program on survival of patients with advanced (AOC) and relapsed ovarian cancer (ROC) treated in a dedicated tertiary gynecologic-oncology (GO) center.
Authors: Harter Philipp , Heitz Florian , Ataseven Beyhan , Prader Sonia , Schneider Stefanie , Baert Thaïs , Alesina Pier , Groeben Harald , Traut Alexander , Du Bois Andreas
Published: May 2019

e17048

Background: Treatment of AOC needs interdisciplinary and specialized skills and structures. We report the impact of a dedicated quality management program over 2 decades from learning curve and specialization process started in 1998-2004 when the surgical department was separated from a general clinic of obstetrics and gynecology. The next period from 2005-2010 covers the data after implementation of the first step of our ovarian cancer quality assurance program. In 2011, a dedicated department of GO was founded. Additionally, we investigated the role of subsequent centralized versus decentralized treatment when patients relapsed after they had primary therapy at our institution. Methods: Descriptive analysis of our prospective tumor registry including all consecutive patients with primary diagnosis of AOC FIGO IIB-IV treated from 1998-2004, 2005-2010 and 2011-2017. All patients having started any therapy outside of our center were excluded. Results: The number of patients with untreated AOC increased from 10 to 147 per year from 1998 to 2017. In total, 1,663 pts were analyzed. The annual percentage of FIGO IV increased from 14% in 1998 to 54-61% in recent years (2013-2017). The complete resection rate of upfront surgery was 50%, 67%, and 69% in the periods 1997-2004, 2005-2010, and 2011-2017, respectively. Correspondingly, median PFS increased from 19 to 21 and 26 months (p < 0.001) and median OS increased from 33 to 42 and 56 months, respectively (p < 0.001). Altogether, 893 pts (53.7%) experienced a relapse. 490/893 pts (54.9% of all ROC pts) were treated again in our center, the remaining 45.1% were treated somewhere else. Median OS calculated from first relapse was 43 months for patients re-treated in our institution versus 32 months for others (p < 0.001). Conclusions: We demonstrate a correlation between specialization and improved outcome in AOC. Focusing and implementing a quality assurance program including structural evolution from a department of general obstetrics/gynecology to a department of GO led to an improvement although systemic primary treatment standards did not change during this period.
Delay in time to adjuvant chemotherapy and its impact on outcome in completely resected advanced ovarian malignancies treated with CRS, CRS+IP and CRS +HIPEC.
Authors: Rajgopal Ashwin K , Somashekhar S.P. , C Rohit Kumar , Yethadka Ramya , Ahuja Vijay , Rauthan Amit , Patil Poonam
Published: May 2019

e17051

Background: The relationship between initiation time of adjuvant chemotherapy in ovarian cancer and prognosis has remained controversial. This study was done to determine whether time from optimal cytoreductive surgery (CRS) to initiation of adjuvant chemotherapy impacts disease free & overall survival in advanced ovarian carcinoma. Methods: Total of 185 patients with primary advanced epithelial ovarian carcinoma (Stage IIIc or selected Stage IV), underwent optimal cytoreduction (either as upfront or interval) & adjuvant chemotherapy. The analysis of interval between day of surgery and start of adjuvant chemotherapy and its impact on outcome was done. Results: CRS with intraperitoneal (IP) chemotherapy either in the form of IP port or hyperthermic intraperitoneal chemotherapy (HIPEC) was done in 135patients (60+ 75) and CRS alone in 50 patients. The median delay in starting adjuvant chemotherapy was 35 days for the whole cohort (32 days in the CRS group, 34 days in CRS+ IP group and 41 days in CRS+ HIPEC group). Delay in chemotherapy, as defined by more than 42 days had significant impact on DFS in CRS alone group (36 months vs 17 months: p = 0.02) had some impact in patients receiving intraperitoneal chemotherapy (38 versus 28 months; p = 0.78) & no impact on CRS+HIPEC group (35 vs 32 months; p = 0.17). In comparison to HIPEC vs non HIPEC group (CRS & CRS+IP), there was a meaningful impact on DFS with reference to delay in non HIPEC group ( 38 vs 22 months p = .08 whereas in the HIPEC group delay didn’t have any impact(35vs 32 months p = 017). There was trend towards better OS (88 vs 71 months p = 0.49). Conclusions: Delay in starting adjuvant chemotherapy certainly had impact on outcome with respect to CRS & CRS + IP arm (non HIPEC group) whereas the delay didn’t have an impact in the HIPEC group owing to the fact that single dose of chemotherapy during surgery in heated environment may substitute for the delay. However well designed clinical studies needs to be designed to evaluate the impact of single dose of intraperitoneal heated therapy & its interplay in delay on starting adjuvant chemotherapy.
Factors associated with extended survival for patients with platinum-resistant ovarian cancer treated with modified vaccinia oncolytic virotherapy.
Authors: Manyam Madhavi , Stephens Amanda J. , Kennard Jessica A. , Fitzsimmons Christine K. , Kendrick James Erasmus , McKenzie Nathalie Dauphin , LeBlanc Jane , Smith Jamie L. , Ahmad Sarfraz , Holloway Robert W.
Published: May 2019

e17070

Background: VIRO-15 phase IB trial included 11 patients (pts) with platinum-resistant ovarian cancer (PROC), extensive tumor burden and a median of 5 prior lines of therapy who were given intra-peritoneal Olvi-Vec (GL-ONC1), a modified vaccinia oncolytic virus (OV). Four pts had apparent clinical benefit with > 5 mos progression-free survival (PFS) following OV. This analysis aimed to determine factors that predict clinical benefit from OV. Methods: Comparative analyses included: anti-vaccinia neutralizing antibody (NA) as a measure of immune-competence, virus-encoded glucuronidase activity (GA) indicating viral replication, tumor shrinkage by RECIST 1.1, tumor burden (serum LDH), PD-L1 status, Prognostic Nutritional Index (PNI), absolute lymphocyte count, C-reactive protein, albumin, ECOG performance score (PS), no. of prior lines of therapy and platinum therapies, BRCA status, CA125 tumor marker, & circulating tumor cells (CTCs). Results: Mean age was 66.3±9.3 years and BMI 24.8±4.7 kg/m2. Median prior chemotherapy lines = 5 (range 2-10), median prior platinum lines = 3 (range 2-6), and 9 pts had prior Avastin. Following OV, 4 pts (Group A) had mean PFS 10.9±5.1 (range 5.4-16.4) mos compared to 7 pts (Group B), with mean PFS 2.4±1.1 (range 1.3-4.1) mos ( p< 0.05). Mean OS for Group A was 21.7±8.2 (range 7.8-28.3) mos vs 3.6±1.5 (range 1.6-6.2) mos for Group B ( p< 0.05). 3 Group A pts are alive with PS 0, and one with stable disease died at 8 mos from pulmonary embolism. Factors that predicted clinical benefit were: i) PNI [mean 49.0±5.7 vs 42.1±4.3 ( p< 0.05)], ii) Week-5 CA125 values < Week-2 [4/4 vs 0/7 (p < 0.01)], iii) absence of CTC [3/4 vs 1/7 pts ( p< 0.05)]. Baseline PD-L1 expression and BRCA status were not predictive markers. Conclusions: Factors associated with clinical benefit using GL-ONC1 monotherapy in PROC include PNI > 44.5, absence of CTCs, and Week-5 CA125 less than Week-2 levels. Absent these factors, cytotoxic therapy should be considered by Week-6 following GL-ONC1. Three patients are currently alive at 22.8-28.2 mos, following additional therapies. A multi-institutional phase II trial is currently enrolling. Clinical trial information: NCT02759588.
A 3D micro-tumor model capturing tumor heterogeneity of a patient's primary tumor biopsy.
Authors: Nikolov Katya , Sampson Ellen , Apfel Christian
Published: May 2019

e17076

Background: Cancer is a genetic disease. However, because of the randomness of mutations, less than 20% of patients have known driver mutations and it is estimated that in the United States, less than 5% of patients benefit from genome-driven targeted therapy. [1] Thus, treatment for millions of cancer patients is still today a hit or miss experiment. Therefore, we have developed a developed a genome-free and mechanism agnostic 3D micro-tumor platform (SAGE Direct Test™) to help oncologists and patients alike to directly identify the treatment that is most effective for an individual patient. Methods: The SAGE Direct Test™ works as follows with actionable results within 1 week: Disaggregation of the patient’s tumor tissue and recreation of 3D microtumors that resemble the tumor biology and heterogeneity of the patient’s primary tumor biopsy. Exposure of those 3D microtumors to a panel of potential treatment options. Measuring the metabolic or image-based response of such 3D microtumors, for example as EC50. Results: We created hundreds of 3D micro-tumors from biopsies of 7 ovarian cancer patients. Not surprisingly, when these microtumors were exposed to various cytotoxic chemotherapies such as cisplatin, paclitaxel or gemcitabine or targeted therapies such as erlotinib or crizotinib, the median EC50 varied significantly from drug to drug. However, for any given drug, the EC50 varied significantly from patient to patient, with an interquartile range spreading often by more than one order of magnitude. Values in the table are standardized means with their standard deviations. Conclusions: We have developed a 3D micro-tumor model that can measure the sensitivity of a patient’s cancer biopsy tissue within one week. Furthermore, we found that the sensitivities of those 3D microtumors differed significantly from patient to patient. These results have not yet established a correlation between this 3D micro-tumor model and patients’ tumor responses, which is one of the next steps towards establishing clinical utility for the millions of patients where genomic testing remains non-informative. [Table: see text]
Real time FTIR spectroscopy of tissue smears from gynecologic cancer tissues: A preliminary study.
Authors: Bruchim Ilan , Malonek Dov , Dekel Ben Zion , Reens Carmel Renat , Groisman Gabi , Hallak Mordechai
Published: May 2019

e17089

Background: Women with suspected Gynecologic cancer undergo surgical procedures during which tissue from suspected areas is excised. Fast histopathology analysis is performed intra-operatively using frozen section (FS) analysis, results of which are available within less than an hour. However, the accuracy of the FS test ranges between 75% and 100% when compared to final histopathology diagnoses. Fourier transform Infrared (FTIR) spectroscopy, utilized for classification of tissue samples into malignant and benign tumors, has shown comparable results to those of FS histopathology analysis. However, the sample preparation time and the effects of tissue preparation on the measured spectra have been a concern for the utilization of this technique in clinical practice. In this study we used attenuated total reflection (ATR) FTIR spectroscopy to examine fresh tissue impression smears as an alternative to the FS technique for rapid classification of tissue samples obtained during surgery. Methods: The study was approved by relevant ethics committees and was conducted in accordance with the Declaration of Helsinki. All patients provided written, informed consent. In total, 23 biopsies (ovarian and uterine) were extracted from suspected tumor sites during surgical procedures and sent to the histopathology laboratory for both pathological and FTIR analyses. Results of the histopathology analysis classified 15 samples as benign and 8 samples as malignant. Prior to the histopathologic analysis, tissue samples from these tumors were lightly pressed against the surface of an ATR crystal, leaving on its' surface impression smears. These smears were air dried for ~5 minutes. Mid-IR absorbance spectra were collected using an ATR-FTIR spectrometer. Machine learning techniques (PCA-LDA and SVM) were utilized to build discrimination models from the absorbance data of the measured smears. Sensitivity and specificity were calculated. Results: IR absorbance spectra of malignant smears were consistently higher from spectra of benign smears in the 850cm-1 to 1450 cm-1 range and they were consistently lower in the 3200cm-1 to 3600cm-1 range. The PCA-LDA discrimination model correctly classified the samples with a sensitivity and specificity of 100%, and the SVM showed a training accuracy of 100% and a cross validation accuracy of 91.3%. Conclusions: These preliminary results suggest that ATR-FTIR spectroscopy of tissue smears may have an important role in the development of next-generation techniques for intra-operative tumor classification.
The role of macrophage production of transforming growth factor-ß in epithelial ovarian cancer progression.
Authors: Roane Brandon , Birrer Michael J. , Goldsberry Whitney , Arend Rebecca Christian
Published: May 2019

e17100

Background: Increased Transforming Growth Factor- ß (TGF-ß) signaling is associated with poorer prognosis in advanced stage epithelial ovarian carcinoma (EOC). Macrophages are known to produce high amounts of TGF-ß which plays a significant role in immune suppression in the tumor microenvironment Methods: A syngeneic mouse model was created using ID8 cell lines with p53 knocked out. These cells were injected intraperitoneally to establish tumor challenge. One mouse model was treated with TGF-ß monoclonal antibody at the time of tumor inoculation. A second model utilized a mouse line that was engineered to eliminate production of TGF-ß from macrophages specifically. Tumors were harvested and weighed after 42 days of tumor challenge. Flow cytometry was used to analyze differences in CD8 T-cell and T regulatory cell populations. Results: Tumor weights were significantly reduced in mice treated with anti-TGF-ß monoclonal antibody (p = 0.02). Average tumor weights were 125mg vs 101mg comparing non-treated to treated mice. Also, ascites volume was measured using syringe aspiration from peritoneal cavity at the time of sacrifice. Mean ascites volume was 4.7mL vs 2.9 mL (p = 0.004) in untreated mice versus mice treated with monoclonal antibody. In mice with macrophages specific deletion of TGF-ß production, tumors were unable to be established in these mice and omental weights were comparable to tumor naive mice with a mean weight of 34mg compared to 115 mg in wild type mice. In both mouse models there was a significant difference in CD8 : Tregs ratio in omental tumor microenvironment. Conclusions: Increased amounts of TGF-ß contribute to increased tumor invasion and migration, while loss of TGF-ß results in both a decrease in tumor burden and a decrease in suppressors of T cell activity. Inhibition of TGF-ß, demonstrated with a monoclonal antibody can effectively reduce TGF-β signaling. The macrophages within the omental tumor microenvironment are a source of large amounts of TGF-ß and when lost result in an inability to establish tumors in intraperitoneal tumors.