bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety profile and disease stabilization in late stage, heavily pretreated, solid tumor patients in a first-in-human (FIH) study of ATX-101, a drug targeting proliferating cell nuclear antigen (PCNA).
Authors: Lemech Charlotte Rose , Kichenadasse Ganessan , Marschner Jens-Peter , Alevizopoulos Kostas , Otterlei Marit , Millward Michael 
Published: June 2021

3067 Background: PCNA is a conserved scaffold protein orchestrating DNA replication, repair or bypass pathways as well as cellular signaling and apoptosis. More than 500 protein-PCNA interactions have been identified which are mediated via two binding motifs, the PIP-box and APIM. Cellular stress, to which cancer cells and cells of tumor microenvironment are exposed, increases the affinity of the APIM motif. APIM-containing proteins bind to PCNA and mediate processes of escape mechanisms and survival of cancer cells. ATX-101 is a cell penetrating peptide containing APIM. It inhibits protein binding via APIM, resulting in cancer cell death and altered cellular signaling. Anticancer effects of ATX-101 have been demonstrated in vitro and in vivo. Methods: A FIH study using a 3+3 dose escalation design was conducted. Patients with late-stage solid tumors received weekly infusions of 20, 30, 45 and 60 mg/m² over 6 weeks. Primary objective was safety, secondary objectives were PK and efficacy. Patients with stable disease (SD) after 6 weeks could continue treatment in a long-term follow-up (LTFU) study. Results: As of January 2021, 22 patients have been treated. All patients received in average 3.8 [1-9] prior treatment lines, all but one had progressive disease at study entry and 80% were refractory to the last therapy. No dose limiting toxicity or death and no treatment related Grade 3/4 or serious adverse events were reported. The maximum tolerated dose was not reached. Mild to moderate infusion related reactions (IRR) were observed in 73% of patients. They were not dose dependent and resolved completely after treatment interruption and/or symptomatic treatment. IRRs occurred despite premedication and could cause infusion interruptions with extended infusion duration. Experiments in dogs indicate that transiently increased histamine levels may cause IRRs. However, elevated histamine and tryptase levels could not be measured in patients so far. ATX-101 exposure was dose-dependent. Cmax was reached either at the middle or at the end of infusion. ATX-101 disappeared quickly from plasma and was not detectable 5 - 60 minutes post infusion. 13 patients finished the FIH study, 10 had SD after 6 weeks. 9 of 10 patients moved into the LTFU study. The treatment duration in the LTFU study varied from 2.1 to 15.6 months (median 4.2 months). Conclusions: ATX-101 is well tolerated at all dose levels with IRRs being the most frequent AEs. Drug exposure is dose dependent with rapid plasma clearance, which confirms in vivo data demonstrating the quick uptake by cells of all organs. The observed duration of SD may be attributed to ATX-101 activity. Proof of concept combination studies are being initiated. Clinical trial information: 375262.
Association of low RKIP expression with poor prognosis in non-small cell lung cancer.
Authors: Meng Lingbin , Ji Rui , Laber Damian A. , Yan Xuebo , Xu Xiaochun 
Published: June 2021

3068 Background: Raf1 kinase inhibitor protein (RKIP) is able to bind Raf1 to inhibit Ras-Raf-MEK-ERK signaling, a major oncogenic pathway. It has been reported that reduced RKIP expression associates with poor prognosis in many cancers, including gastric adenocarcinoma, gliomas and bladder cancer. However, there are only several studies on its role in non-small cell lung cancer (NSCLC) and the conclusion is still controversial. Hence, we performed this study to assess the prognostic significance of RKIP in our NSCLC population. Methods: Between June 2017 and June 2020, 156 NSCLC patients treated at our hospital were included for the present study. None of the patients had received chemotherapy, radiotherapy or surgery before. Their tumor tissues and surrounding normal lung tissues were collected for immunostain and western blot analysis of RKIP expression and ERK signaling. We collected information about gender, age, histological differentiation, tumor size, TNM stage, and lymph node status. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic value of various variables in a univariate and multivariate setting. Results: Immunostain and western blot results showed a lower RKIP expression and a higher p-ERK level in cancer tissues compared with the surrounding normal tissues. A reduced RKIP expression with high level of p-ERK was also observed in TNM stages III and IV as compared with I and II. Pearson's chi-squared test confirmed low RKIP expression associated with poorer TNM stage ( p< 0.001) and N-stage ( p< 0.05). No significant correlation was observed between RKIP expression level and gender, age, histological type or tumor size. Kaplan-Meier survival analysis revealed that patients with low RKIP expression had significantly worse overall survival than patients with high RKIP expression ( p= 0.019, log-rank). This conclusion was consistent in the stage I&II patients ( p= 0.011, log-rank) but not in the stage III&IV patients ( p= 0.711, log-rank). Univariate Cox proportional hazards regression analysis indicated Tumor size, TNM stage and RKIP expression significantly affected overall survival of the NSCLC patients. Multivariate Cox proportional hazards regression analysis confirmed RKIP expression remained a significant predictor of survival after correcting for the effects of Tumor size and TNM stage (hazard ratio = 1.730, 95% confidence interval = 1.017 – 2.942, p = 0.043). Conclusions: In this study, low RKIP expression was a poor prognostic indicator in NSCLC as it significantly correlated with poorer TNM stage, N-status, and overall survival. Our findings suggest that by inhibiting Ras-Raf-MEK-ERK pathway RKIP may play an anti-tumor role in NSCLC.
Preliminary efficacy from an ongoing phase 1 dose escalation study of seclidemstat (SP-2577) in patients (pts) with advanced solid tumors (AST).
Authors: Chawla Sant P. , Chua-Alcala Victoria S. , Sachdev Jasgit C. , Wages David S. , Stenehjem David D. , Santiesteban Daniela Y. , Mirza Nadeem Q. , Gordon Michael S. 
Published: June 2021

3073 Background: Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that is aberrantly expressed in many solid tumors. High levels of LSD1 expression are often correlated with poor patient prognosis due to LSD1’s role in cancer cell proliferation, metastasis, and chemoresistance. Seclidemstat is a novel, selective, reversible and oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. We report preliminary efficacy in AST from an ongoing phase 1 trial. Methods: SALA-003-AC19 (NCT03895684) is a phase 1 trial of single agent SP-2577 in pts with AST. All pts had progressive disease (PD) at time of study entry. Pts received oral SP-2577 twice a day under fasting condition, in 28-day cycles (C). The primary objective is safety and tolerability. Secondary objectives are to determine maximum-tolerated dose, preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 19 pts with AST (10 sarcoma, 2 prostate, 2 ovarian, 2 pancreatic, 1 renal, 1 cervical, 1 breast) were enrolled. Pts received escalating doses of SP-2577 from 150 to 600 mg BID and the dose escalation is ongoing. The median age was 63 years (range, 21–79). 42% were male, and pts had received a median of 4 (range, 1–8) prior systemic therapies. The most common (>5%) grade 3 treatment-related adverse events were GI related including diarrhea (5.3%) and abdominal pain (5.3%). No grade 4 events were reported and there were no treatment-related deaths. Safety data will be presented after completion of phase 1. Three pts had at least one dose reduction. Among the 13 pts who were evaluable for response at end of C2, 7 pts (54%) had best response of stable disease (SD) with median time to progression (TTP) of 4.3 months (range, 2.1–11.5). Four of the 7 pts had genetic abnormalities that may demonstrate increased sensitization to SP-2577 according to preclinical studies. Characteristics of 7 pts with SD at C2 and beyond are shown in the table. Conclusions: Seclidemstat has shown activity among advanced sarcoma pts with a manageable safety profile. The dose escalation is ongoing and preliminary clinical data supports further exploration in FET-translocated sarcoma as single agent and in combination therapy. Clinical trial information: NCT03895684. [Table: see text]
High-intensity focused ultrasound ablation for treatment of chemotherapy-induced thrombocytopenia and hypersplenism.
Authors: Yuan Min , Xu Qing , Zhu Zhongzheng , Mao Wei , Guo Xianling , Wang Hui , Qian Hong , Wu Jianguo 
Published: June 2021

3082 Background: Chemotherapy-induced thrombocytopenia (CIT) contributes to treatment dose delay and/or modification, often resulting in poorer survival and disease progression. Compared with partial splenic embolization (PSE) and drugs, high-intensity focused ultrasound has the advantages as following: (1) it is a noninvasive treatment modality with potentially fewer adverse effects and complications; (2) the hospital stay and recovery time after treatment are short; (3) its cost is relatively low compared to surgery. The purpose of this work was to preliminarily investigate the efficacy and safety of high intensity focused ultrasound treatment of chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. Methods: 26 patients with chemotherapy-induced thrombocytopenia and hypersplenism (15 male and 11 female; median age, 56 years; range, 51-66 years) were treated with ultrasound guided high-intensity focused ultrasound. Complications were recorded. Laboratory examination and magnetic resonance imaging were used to evaluate the efficacy. The spleen volume and ablation volume rate of the spleen were calculated by MRI after treatment. They were followed closely for at least 6 months. Results: After high-intensity focused ultrasound treatment, the MRI showed that the ablation area had turned into a non-perfused volume, the mean percent spleen ablation volume was 18.76% ± 6.1% (range, 11.17%-32.34%). After 6 months of HIFU ablation, the ablated area shrank evidently; the sunken spleen formed a lobulated shape and the splenic volume decreased. The platelet count increased 3-7 days after treatment and remained for 1-2weeks higher than baseline (53.33 ± 15.80 × 109/L). The white blood cell count and platelet count of the patients were substantially improved during the follow-up period. No substantial difference was observed in RBC counts between baseline and after treatment. In addition, symptoms such as epistaxis and gingival bleeding were ameliorated or even eliminated, and the quality of life was improved. Follow-up imaging showed a nonperfused volume in the spleen. Conclusions: For the first time to our knowledge, high-intensity focused ultrasound ablation was used to treat Chemotherapy-induced thrombocytopenia (CIT) and hypersplenism. High-intensity focused ultrasound ablation of the spleen may cause damage to a certain volume of the spleen parenchyma to achieve the purpose of hypersplenism treatment. High intensity focused ultrasound may be an effective and safe alternative for treatment of CIT and hypersplenism.
Partitioning of cancer therapeutics in nuclear condensates.
Authors: Klein Isaac , Boija Ann , Afeyan Lena , Hawken Susana , Fan Mengyang , Taatjes Dylan , Chakraborty Arup , Sharp Phillip , Chang Young Tae , Hyman Anthony , Gray Nathanael , Young Richard 
Published: June 2021

3131 Background: The molecules of the cell are compartmentalized into membrane- and non-membrane-bound organelles. Many non-membrane-bound organelles are phase-separated biomolecular condensates with distinct physicochemical properties that can absorb and concentrate specific proteins and nucleic acids involved in discrete biochemical processes. We reasoned that selective condensate partitioning might also occur with small molecule drugs whose targets occur within condensates, and that the therapeutic index and efficacy of such compounds might therefore relate to their ability to partition into condensates. Methods: To study the behavior of drugs within condensates, these were modeled in cells and in vitro with purified proteins and visualized by fluorescent confocal microscopy. The functional outcomes of condensate partitioning were queried in cells. Results: We found that cisplatin, tamoxifen, JQ1, THZ1, and mitoxantrone are concentrated in specific protein condensates in vitro, and that this occurs through physicochemical properties independent of the drug target. A screen of a chemically diverse fluorescent probes and mutant-protein condensates demonstrated that pi-system interactions between aromatic moieties in the protein and small molecule govern concentration in condensates. These results show that clinically important drugs partition into specific protein condensates in vitro by virtue of defined chemical properties, thereby altering their local concentration. In vitro droplet assays revealed that cisplatin is selectively concentrated in transcriptional condensates, and that this ability is required for efficient platination of target DNA. In cell studies revealed that cisplatin preferentially targets DNA contained within MED1 condensates, and disrupts the genetic regulatory elements that compose phase-separated transcriptional condensates. Live cell imaging demonstrated that transcriptional condensates are dissolved by cisplatin, whereas other condensates remain intact. Conclusions: Our results show that antineoplastic drugs partition selectively into biomolecular condensates, that this can occur through physicochemical properties independent of their molecular targets, and that drug activity may occur through condensate-related mechanisms. These results have implications for development of efficacious cancer therapeutics; effective target engagement will depend on factors such as drug partitioning in condensates. Assays of the type described here may thus help optimize condensate partitioning, target engagement, and the therapeutic index of drugs for cancer treatment.
Prevalence of fertility discussions between young adult colorectal cancer survivors and their providers.
Authors: Stal Julia , Yi Serena , Cohen-Cutler Sally , Gallagher Phuong , Barzi Afsaneh , Milam Joel , Freyer David R. , Lenz Heinz-Josef , Miller Kimberly Ann 
Published: June 2021

3518 Background: Clinical guidelines indicate that oncologists should discuss potential treatment-induced infertility with patients with reproductive potential. Due to tumor location and use of multimodal therapies, young adults with colorectal cancer (CRC) are at heightened risk for treatment-related infertility. Methods: An online, cross-sectional survey was administered in collaboration with a national patient advocacy organization for young adult CRC survivors (currently under age 50). Survivors were asked to indicate if a doctor had ever talked to them about potential problems with their ability to have children after treatment and if they banked eggs/embryos (females) or sperm (males) prior to their cancer therapy. Those who reported that they did not preserve fertility were asked to indicate why ( not sure; I chose not to; I did not know this was an option; I wanted to, but could not afford it; and I wanted to, but my treatment would not allow it). Results: A total of 234 colon (N=86) or rectal (N=148) cancer survivors were included in the study (male [61.9%] and White [77.9%; table]). Most respondents were diagnosed with stage 2 cancer (55.8% colon, 61.6% rectal). Over half of male and female survivors reported that their doctor did not talk to them about problems with their ability to have children after treatment, and 75% did not bank eggs/embryos or sperm prior to their cancer therapy. Of those, over 20% endorsed ‘I wanted to, but could not afford it’ and over 20% endorsed ‘I did not know this was an option’. Conclusions: Most CRC survivors in this study reported never having a fertility discussion with their provider, suggesting that survivors are not receiving, or cannot recall, comprehensive and guideline-concordant cancer care. In addition, one-fifth were not aware of preservation options, suggesting potential healthcare and/or provider-level barriers to appropriate fertility counseling. Fertility preservation cost is another barrier to the appropriate delivery of care. Providers must ensure that patients receive timely fertility discussions covering options to preserve fertility to mitigate this late effect of cancer treatment to ensure optimal quality of life for CRC patients with reproductive potential.[Table: see text]
Association of HER2 expression with pathologic features and prognosis in stage II and III colon cancer.
Authors: Wu Zehua , Hu Huabin , Deng Yanhong 
Published: June 2021

3524 Background: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression in stage II and III colon cancer after curative resection. Methods: Paraffin-embedded tumors from consecutive primary stage II and III colon cancer patients were analyzed for HER2 protein expression by immunohistochemistry between April, 2013 and May, 2020. HER2 determination of immunohistochemistry scores (0/1+/2+/3+) was according to HERACLES diagnostic criteria. Results: A total of 2088 stage II and III colon cancer patients were included (53.8% stage II, 46.3% stage III). HER2 scored positive (3+) was detected in 48(2.3%) tumors, and was correlated with younger age (P < 0.001), well/moderate differentiation (P = 0.026), proficient mismatch repair (pMMR) (P = 0.045) and KRAS wild-type (P < 0.001). HER2 scored positive (3+) was not significantly associated with disease-free survival (DFS) compared with HER2 scored negative (0/1+), neither in stage III patients (multivariable HR, 0.86; 95CI, 0.38 to 1.94; P = 0.717), nor in stage II patients (multivariable HR, 1.68; 95CI, 0.74 to 3.84; P = 0.218). In a separate analysis involving stage II patients without any high-risk factor (n = 741), those with HER2 scored positive (3+) tumors (n = 16) showed significantly reduced DFS (multivariable HR, 2.91; 95CI, 1.04 to 8.81; P = 0.041) compared with patients with HER2 scored negative (0/1+) tumors, independent of sex, age and MMR status. Conclusions: HER2 scored positive (3+) was independently associated with poor DFS in stage II colon cancer patients without high-risk factors. HER2 expression determination may help to judge the prognosis of those patients and guide adjuvant chemotherapy.
Patient-reported quality of life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: Interim results of the TALLISUR study.
Authors: Karthaus Meinolf , Kretzschmar Albrecht , Fuxius Stefan , Riera Knorrenschild Jorge , Kaiser Florian , Mahlberg Rolf , Welslau Manfred , Pelz Henning , Heinemann Volker ,   on behalf of the TALLISUR Study Group
Published: June 2021

3526 Background: Compared to placebo, trifluridine/tipiracil (FTD/TPI) significantly improved overall and progression-free survival in patients (pts) with pre-treated metastatic colorectal cancer (mCRC) in the phase III RECOURSE trial. Although time to deterioration of ECOG performance status (PS) from 0/1 to ≥ 2 was significantly longer in pts treated with FTD/TPI, health-related quality of life (HRQoL) was not formally assessed by direct means. Therefore, a two-arm trial with best supportive care (BSC) as appropriate comparative treatment was designed to specifically address the effect of FTD/TPI on HRQoL. Methods: In this prospective, multi-center, German, open-label, phase IV study, pts with pre-treated mCRC could choose between BSC or oral FTD/TPI (35 mg/m2 bid on days 1-5 and 8-12 of each 28-day cycle). EORTC QLQ-C30 and EQ-5D-5L questionnaires were employed to assess HRQoL. Primary endpoint was the rate of responders with stabilized ( > -10 and < 10 scores) or improved (≥ 10 scores) response (RR). Response was calculated as the mean score of the EORTC QLQ-C30 global health status/ QoL scale from the 2nd cycle until the end of treatment/ observation compared to the baseline score. Results: Of 194 eligible pts, 185 pts chose treatment with FTD/TPI (median 3 cycles), while 9 pts decided to receive BSC only. Questionnaires from 109 pts receiving FTD/TPI and from 6 pts with BSC were evaluable for RR. The primary endpoint (RR) was 59.6% (95% CI 49.8 – 68.9) in FTD/TPI-treated pts and 50.0% (95% CI 11.8 – 88.2) in pts receiving BSC. Analysis of the extended follow-up period, demonstrated that RR was 67.0% (95% CI 57.3 – 75.7) in FTD/TPI-treated pts. In the FTD/TPI-group, median time to deterioration of HRQoL was 121 days ( n = 61; 95% CI 87 – 151) according to EORTC QLQ-C30 and 119 days ( n = 63; 95% CI 85 – 138) according to EQ-5D-5L. Conclusions: If pts can choose between treatment and BSC in late-stage CRC, the vast majority opts for treatment. According to the present results, FTD/TPI-treatment induced prolonged stabilization of HRQoL, a highly desired attribute of therapies for pts with late-stage cancer. Clinical trial information: No 2017-000292-83.
A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer.
Authors: van Den Berg Inge , Smid Marcel , Coebergh van den Braak Robert R.J. , van de Wiel Mark A , Van Deurzen Carolien H. M. , de Weerd Vanja , Martens John W.M. , IJzermans Jan N.M. , Wilting Saskia M 
Published: June 2021

3545 Background: Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). Currently available assays can identify CMS1 and CMS4 cases well, while a dedicated test to distinguish CMS2 and 3 is lacking. This study aimed to identify a panel of methylation markers to distinguish between CMS2 and 3 in patients with CRC. Methods: Fresh-frozen tumor tissue of 239 patients with stage I-III CRC was included. CMS classification was performed on RNA-seq data using the single-sample-prediction parameter from the “CMSclassifier” package. Methylation profiles were obtained using the Infinium HumanMethylation450 BeadChip. We performed adaptive group-regularised logistic ridge-regression with post-hoc group-weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3 based on 15, 10 or 5 markers. Data from TCGAwas used for validation. Results: Overall methylation profiles differed between CMS2 and CMS3. Group-regularisation of the probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier resulting in two different prediction models and subsequently different marker panels. For both panels, even when using only 5 markers, sensitivity, specificity, and accuracy were > 90%. Validation showed comparable performances. Conclusions: Our highly sensitive and specific methylation marker panel can be used to distinguish CMS2 and 3. This enables development of a qPCR DNA methylation assay in patients with CRC to provide a specific and non-invasive classification tool.