bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 416: Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in patients with locally advanced resectable esophageal squamous carcinoma: An open-label, single arm phase 2 trial
Authors: He Wenwu , Peng Lin , Bao Yu , Xiao Wenguang , Fang Qiang , Leng Xuefeng , Yan Jiaxin , Mao Tianqin , Shen Xudong , Huang Depei , Zhang Hushan , She Xueke , Han Yongtao 
Published: July 2021

Abstract
Background: Immune checkpoint inhibitors (ICIs) have shown promising results in patients with advanced esophageal squamous carcinoma (ESCC), while their efficacy for locally advanced patients is unclear. We conducted a neoadjuvant immunotherapy trial, investigating the safety and feasibility of toripalimab, a PD-1 inhibitor, combined with paclitaxel and carboplatin in patients with resectable ESCC (ClinicalTrials.gov identifier: NCT04177797).
Methods: Between May 2020 and June 2020, 18 patients with histopathologically diagnosed ESCC, clinically staged as T3N1-3M0, ECOG PS 0, received toripalimab 240 mg IV, D1, Q3W and paclitaxel 135 mg/m2, IV, D1, Q3W and carboplatin AUC 5 mg/mL per min, IV, D1, Q3W for two cycles, followed by McKeown esophagectomy 4-6 weeks later. The primary endpoint were safety and major pathological response (MPR) rate, and the secondary point were pathological complete response (pCR) rate, DFS and OS.
Results: Sixteen patients received surgery with no treatment-related surgical delay, and the R0 resection rate was 87.5% (14/16). Two patients refused surgery due to the clinical assessment as complete response. Among 16 patients undergoing surgery, 3 (16.6%) were pCR and 7 (43.8%) were MPR. Treatment-related adverse events occurred in all patients (100%), and 4 patients (22.2%) experienced grade 3 or higher treatment-related adverse events including neutropenia (2, 12.5%), leukopenia (1, 6.2%), diarrhea (1, 6.2%), fatigue (1, 6.2%). No surgery-related adverse events or treatment-related death occurred.
Conclusions: The combination of toripalimab, paclitaxel and carboplatin for patients with locally advanced resectable ESCC is well tolerated and shows antitumor activity, which might be a potential neoadjuvant therapy regimen.
Citation Format: Wenwu He, Lin Peng, Yu Bao, Wenguang Xiao, Qiang Fang, Xuefeng Leng, Jiaxin Yan, Tianqin Mao, Xudong Shen, Depei Huang, Hushan Zhang, Xueke She, Yongtao Han. Toripalimab plus paclitaxel and carboplatin as neoadjuvant therapy in patients with locally advanced resectable esophageal squamous carcinoma: An open-label, single arm phase 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 416.
Abstract 421: Characteristics of melanoma diagnosed in patients with underlying HIV infection
Authors: Wei Grace , Sinha Sweta , Messina Jane , Coghill Anna E. 
Published: July 2021

Abstract
Background: Melanoma is diagnosed more frequently in patients living with HIV (PLWH) compared to the general US population and HIV-infected melanoma patients also experience higher cancer-specific mortality. The mechanisms underlying these outcome disparities are poorly understood, and data describing tumor pathology and non-mortality outcomes for melanoma patients with HIV are lacking.
Objective: To describe differences in tumor presentation and disease course among melanoma patients presenting with or without underlying HIV infection in the era of effective HIV therapy.
Methods: We conducted an initial retrospective chart review of 29 HIV+ and 29 HIV- patients, matched as possible to HIV+ patients on age and disease stage, who presented to Moffitt Cancer Center between 2004 and 2019. Data abstracted included patient demographics, tumor pathology, treatment details, and clinical outcomes.
Results: Certain melanoma pathology features differed by HIV status, with a higher prevalence of elevated mitotic rate (78.9% vs 41.2%, p=0.02) and vertical growth phase (90% vs 55%, p=0.02) in melanoma patients with HIV. Nearly all patients underwent lesion excision, but post-treatment complications were greater in PLWH (44.8% vs 24%, p=0.09). Among 16 patients who received systemic therapy after excision (HIV+ 6; HIV- 10), progressive disease was more frequent in PLWH (100% vs 30%, p=0.01), with further suggestion of higher severe side effect rates, defined as events interrupting systemic therapy (66.7% vs 30%; p=0.18). Despite these differences in progression, overall survival rate were similar in PLWH (79.3%) and uninfected patients (82.8%).
Conclusions: These preliminary results suggest that PLWH and melanoma experience a unique disease course. Higher prevalence of post-excision complications and disease progression following systemic therapy in particular warrant further attention as age-related cancers, such as melanoma, are expected to grow in the US HIV population in coming years.
Citation Format: Grace Wei, Sweta Sinha, Jane Messina, Anna E. Coghill. Characteristics of melanoma diagnosed in patients with underlying HIV infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 421.
Abstract 432: Sarcopenia predicts dose-limiting toxicity in metastatic pancreatic cancer treated with gemcitabine plus nab-paclitaxel
Authors: Youn Susie , Chen Angela , Ha Vincent , Chambers Carole , Eurich Dean T. , McCall Michael , Sawyer Michael B. 
Published: July 2021

Abstract
Introduction: Gemcitabine (GEM) plus nab-paclitaxel (nab) has been shown to improve overall survival (OS) compared to GEM monotherapy in patients with metastatic pancreatic cancer. However, GEM/nab is associated with increased toxicity. Our study evaluated whether sarcopenia increased the likelihood of chemotherapy toxicity in pancreatic cancer treated with GEM/nab.
Methods: A retrospective review was performed of all patients who received GEM/nab as first-line therapy for metastatic pancreatic cancer at a northern Alberta cancer institute (Canada) from 2014-2017. Patients were included if a computed tomography (CT) scan of the abdomen and pelvis was performed within 60 days of starting chemotherapy. Skeletal muscle surface area was measured at L3 on baseline CT scans and normalized for height to determine skeletal muscle index (SMI, cm2/m2). Dose-limiting toxicity (DLT) was defined as dose reduction or treatment discontinuation due to toxicity. Optimal stratification was used to establish sex-specific SMI cut-offs with DLT as an outcome.
Results: 152 patients were included in the study. 88 patients (57.8%) were male and median age was 66.5 years (range 34-95). 62 patients (40.8%) experienced DLT. SMI cut-offs were determined as &lt;48.0 cm2/m2 in males and &lt;39.55 cm2/m2 in females. Sarcopenia prevalence using these cut-offs was 54.6%. DLT incidence was significantly higher in sarcopenic versus non-sarcopenic patients (55.4 vs. 23.2% respectively, p&lt;0.001). In multivariate logistic regression accounting for advanced age (&gt;65), sex, BMI category, and performance status (PS), sarcopenia significantly increased the likelihood of DLT (OR 7.21, 95% CI 3.02-17.24, p&lt;0.001). Sarcopenia did not impact OS (HR 1.30, 95% CI 0.94-1.80, p=0.118) or progression-free survival (HR 0.66, 95% CI 0.42-1.03, p=0.071).
Conclusion: In pancreatic cancer treated with GEM/nab, sarcopenic patients are significantly more likely to experience DLT, independent of age, sex, BMI, and PS. These findings could have implications for reduced chemotherapy dosing in sarcopenic patients.
Citation Format: Susie Youn, Angela Chen, Vincent Ha, Carole Chambers, Dean T. Eurich, Michael McCall, Michael B. Sawyer. Sarcopenia predicts dose-limiting toxicity in metastatic pancreatic cancer treated with gemcitabine plus nab-paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 432.
Abstract 457: A comparison of IDH1 R132H [H09] and [IHC132] antibodies on diffuse gliomas
Authors: Figueroa Sara , Vargas Joseph , Ramos Jason 
Published: July 2021

Abstract
Introduction In the 2016 World Health Organization Central Nervous System Tumor Classification, diffuse gliomas were reclassified to include astrocytic tumors (grade II and III), oligodendrogliomas (grade II and III), and grade IV glioblastomas with diffuse astrocytoma being distinct from the diffuse gliomas. This reclassification is due to the abundance of IDH1 mutations in many of these tumors. A much better outcome has been observed in these patients than those without this mutation. IDH1 mutation of the R132H type constitutes more than 90% of all IDH1 and IDH2 mutations. Further, IDH1 IHC is now widely applied for the differential diagnosis of these tumors. There are two distinct IDH1 R132H clones on the market, the H09 and IHC132. Comparing these markers for the IDH1 R132H mutations by IHC can help determine if one is superior for diagnostics.
Materials and Methods IHC was performed on 3-5 um thick formalin-fixed, paraffin-embedded (FFPE) brain tissue arrays containing glioblastoma, astrocytoma, oligoastrocytoma, oligodendroglioma with adjacent normal tissue (US Biomax, Derwood, USA). These slides were deparaffinized, and peroxidase blocked in the usual manner. Slides were then subjected to HIER in a pressure cooker using a citrate-based buffer at 110°C for 15 minutes before being stained on a semi-automated instrument. The slides were stained with rabbit monoclonal IDH1 R132H antibody H09 (Dianova, Hamburg, Germany) and mouse monoclonal IDH1 R132H antibody IHC132 (GenomeMe, Richmond, Canada) at concentrations and protocols predetermined to match staining intensity.
Results The mouse monoclonal anti-IDH1 R132H IHC132 has shown that it is analogous to the current IDH1 R132H [H09]. Upon review of the data, IHC132 marker stains a higher percentage of cases in glioblastoma compared to H09 (11%, n=36) and equal in astrocytoma (73%, n=15), oligoastrocytoma (75%, n=4), oligodendroglioma (100%, n=8). Neither clone stained normal brain tissue per negative controls.
Conclusion Mouse monoclonal anti-IDH1 R132H [IHC132] compared with that of the rabbit monoclonal anti-IDH1 R132H [H09] showed equal sensitivity for astrocytoma, oligodendroglioma, and oligoastrocytomas with higher sensitivity for glioblastoma. The results provide evidence to support a higher percentage of positive staining and equal or greater intensity for clone IHC132 versus H09.
Citation Format: Sara Figueroa, Joseph Vargas, Jason Ramos. A comparison of IDH1 R132H [H09] and [IHC132] antibodies on diffuse gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 457.
Abstract 46: A new class of precision therapeutics that inhibit prostate cancer mediated bone destruction
Authors: Gordon Ryan R. , Pattanayak Abhinandan , Li Wenqi , Bergan Raymond 
Published: July 2021

Abstract
The destructive nature of bone metastases dominates the clinical management of advanced prostate cancer (PCa) and is a common cause of morbidity and mortality. Our current ability to therapeutically target this process is limited. Here we describe the synthesis and functional characterization of the first-in-class Dual Acting Bone Defending agents (DABDs), which couple a small molecule therapeutic that inhibits cell movement to bone trophic bisphosphonates. Upfront in-vitro screens assessed DABD efficacy at inhibiting PCa cell migration and invasion and osteoclast mediated bone destruction. Systemic models of PCa metastasis, inclusive of intracardiac (IC) and intratibial (IT) injection models, were deployed to characterize tolerance and efficacy in-vivo. Finally, in-vitro characterization of DABD molecular mechanism of action was performed, as guided by the existing knowledge base related to the parental compounds. Results demonstrated that DABDs inhibit PCa cell migration and invasion, chemically bind hydroxyappetite, and inhibit osteoclast mediated bone destruction in vitro. Following IC injection of PCa cells, a model where cells are placed into circulation, metastasize to bone, grow and induce bone destruction, emulating the clinical scenario in humans, DABD treatment inhibited circulating PCa cells from forming new bone metastasis and prolonged life in a dose-dependent fashion. In the IT mouse models of established metastatic lesions, DABDs induce reversion of PCa cell growth and disrupt further bone destruction. DABDs at doses 1000 fold higher than those associated with efficacy are well tolerated. At the molecular level, DABDs retain the molecular mechanisms of action of their constituent chemicals. They inhibit farnesyl diphosphate synthase (FDPS), in the mevalonate pathway, leading to decreased prenylation of small GTPases, including the Ras related protein, Rap-1A, as well as inhibit Raf1 activation, inducing apoptosis and impaired cell movement, respectively. DABDs are a new class of agents that inhibit formation of new bone metastasis, revert growth of established metastasis, prolong life, and have a high potential for improving clinical outcome in humans.
Citation Format: Ryan R. Gordon, Abhinandan Pattanayak, Wenqi Li, Raymond Bergan. A new class of precision therapeutics that inhibit prostate cancer mediated bone destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 46.
Abstract 479: mRNA in situ expression of candidate genes for progression risk tissue biomarkers, in premalignant cervical lesions
Authors: Benedetti Ines , Ruiz Felipe , Rodríguez Reinhard 
Published: July 2021

Abstract
Background Comparing the in situ differences in mRNA expression of candidate genes between normal cervical tissue and premalignant lesions, could contribute to detect progression risk biomarkers. Use of RNAscope chromogenic in situ hybridization (CISH) that amplifies specific mRNA signals and detects molecules as points that can be quantified, could help the detection of these biomarkers.
Methods A tissue microarray was constructed from cervical samples (conization and histerectomy). Representative areas of normal cervix, low-grade (LSIL), and high-grade squamous intraepithelial lesions (HSIL) were chosen. RNAscope 2.5HD Red HPV-HR18 assay that detect E6/E7 mRNA for eighteen high-risk (HR) HPV genotypes, and RNAscope 2.5HD Red assays to detect mRNA from: KRT16, TMEM45A and RBP1, were performed. The stainings were scored by two pathologist from 0 to 4 in a semi-quantitative analysis based on the average number of dots per cell; mean score values were compared using GraphPad Prism 7.0. A p&lt;0.05 was considered statistically significant.
Results A total of 390 cervical tissues cores from 169 patients with mean age 36.08 years (SD ±10.48) were included. Mean mRNA expression of HR-HPV E6/E7, TMEM45A and RBP1 were significantly higher in HSIL compared to LSIL and normal cervix squamous epithelium. KRT16 mRNA expression scores in normal cervix squamous epithelium, LSIL, and HSIL, were not significantly different (Table 1).
Conclusions CISH allowed to detect E6/E7 mRNA molecules for eighteen HR-HPV genotypes in routinely processed tissues, and to evaluate the expression of the described candidate genes in their context without destroying the tissue morphology. Identification of differential expression between normal cervical tissue and HSIL supports the possible role of TMEM45A and RBP1 in cervical cancer progression and its potential use as progression risk tissue biomarkers.
Table 1.Biomarkers candidate genes expression profiles in normal cervix, LSIL and HSILCISH scoresMean (±SD)95% CINormal cervixLSILHSILp valueHR-HPV E6/E7 mRNAn=640.4098(±0.7611)0.2149-0.6048n=640.4098 (±0.7611)0.2149-0.6048n=1381.294 (±1.189)1.078-1.51&lt;0.0001*TMEM45A mRNAn=761.105 (± 1.322)0.8031-1.407n=691.232 (±1.477)0.8771-1.587n=2381.514(± 1.491)1.264-1.7650.046*RBP1 mRNAn=660.4242(±0.7658)0.236-0.6125n=740.5135 (±0.9826)0.2859-1.159n=1301.3 (±1.186)1.094-1.506&lt;0.0001*KRT16 mRNAn=840.9524(±1.15)0.7028-1.202n=770.8831 (±1.214)0.6076-1.159n=1571.115 (±1.41)0.8924-1.3370.573*
Citation Format: Ines Benedetti, Felipe Ruiz, Reinhard Rodríguez. mRNA in situ expression of candidate genes for progression risk tissue biomarkers, in premalignant cervical lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 479.
Abstract 497: Human CD73 knock-in mice facilitate evaluation of in vivo efficacy of anti-human CD73 cancer immunotherapies
Authors: Shang Chengzhang , Li Huilin , Zhang Jing , Lin Eugene , Yu Luke (Zhaoxue) , Shen Yuelei 
Published: July 2021

Abstract
In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, most patients with solid cancers do not respond to the current ICIs against PD-1/PD-L1 or CTLA-4 alone. Stimulating an effective anti-tumor immune response may require countering additional immunosuppressive pathways in the tumor microenvironment (TME). Adenosinergic pathways are critical to maintain normal immune system homeostasis, and tumors could exploit them to avoid immune attack. CD73 (NT5E) is a surface enzyme that catalyzes the final hydrolysis of AMP to adenosine, which impairs immune function through adenosine receptors like A2AR (see our poster on humanized A2AR mice) on immune cells. Some tumors overexpress CD73 driven by hypoxia in the TME, which associates with poor prognosis in some cases. It is also expressed on the surface of multiple immune cells that infiltrate tumors, including T-cells, B-cells, NK cells, macrophages, and myeloid-derived suppressor cells. Several anti-CD73 antibodies have started early stage clinical trials as a treatment for advanced cancers. Combined anti-CD73, anti-PD-1, and anti-CTLA4 therapies synergize to reduce tumor burden and extend survival. Thus, there is a need for pre-clinical models to evaluate the safety and efficacy of CD73-targeted therapeutics before they enter human trials. Biocytogen has generated a human CD73 knock-in (KI) mouse (B-hCD73) and a human CD73-expressing MC38 cell line (MC38-hCD73) for both in vitro functional validation and in vivo efficacy evaluation of CD73-specific antibodies. Human CD73 (hCD73) whole coding sequence was inserted following exon 2 of the mouse Cd73 gene. B-hCD73 mice did not exhibit any immune or developmental abnormalities compared to wild-type mice, but splenic Tregs of B-hCD73 mice and not wild-type expressed hCD73. Anti-hCD73 antibodies bound well only to splenocytes of hCD73 KI mice and also blocked the enzyme activity of CD73. Using our MC38-hCD73 tumor model, we showed robust efficacy of anti-hCD73 antibodies in inhibiting tumor growth in vivo. Furthermore, in PD-1/PD-L1/CD73 triple KI humanized mice implanted with MC38 tumors, combined CD73 and PD-1/PD-L1 blockade showed greater tumor inhibition than monotherapies. Taken together, CD73 humanized mice and their variants are useful tools for in vivo efficacy evaluation of candidate human CD73 antibodies and combination therapies being considered for clinical trials.
Citation Format: Chengzhang Shang, Huilin Li, Jing Zhang, Eugene Lin, Luke (Zhaoxue) Yu, Yuelei Shen. Human CD73 knock-in mice facilitate evaluation of in vivo efficacy of anti-human CD73 cancer immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 497.
Abstract 501: Double-humanized 4-1BB/4-1BBL mouse is an advanced model for liver toxicity and efficacy evaluation of 4-1BB therapeutic antibodies
Authors: Zhao Lei , Wang Linlin , Li Dirui , Hui Li , Lin Qingcong 
Published: July 2021

Abstract
4-1BB is an activation-induced costimulatory TNF receptor family member which is expressed on a variety of cell types such as activated T cells, NK cells, DCs, B cells, monocytes and Neutrophils. 4-1BB/4-1BBL interaction leads to a series of activation effects including increased cytotoxic T lymphocytes (CTL) activity, cytokine induction, prevention of activation-induced cells death (AICD). Agonistic monoclonal antibodies targeting 4-1BB have shown robust anti-tumor activity but has also caused substantial liver toxicity which hampered their clinical development. To better assist the efficacy and toxicity evaluation of anti 4-1BB antibodies, Biocytogen developed a 4-1BB/4-1BBL double humanized knock in mice, which is the second generation of humanized 4-1BB mice. In the double humanized mouse, the exons of mouse 4-1BBL and 4-1BB genes that encode the transmembrane domain and extracellular domain were replaced by human counterpart exons. The expression of knocked in exons were confirmed by both RT-PCR and Flow cytometry. In vivo efficacy study showed that 4-1BB antibodies significantly inhibited tumor growth in mice bearing the colon cancer cell line MC38 and this effect was dose-dependent. The tumor growth inhibition (TGI) reached approximately 70% in the mice group dosed 1mg/kg. More importantly, Toxicity study showed that compared to the single humanized 4-1BB mice, double humanized 4-1BB/4-1BBL mice have higher sensitivity on liver toxicity testing, reflected by sera AST and ALT level as well as liver pathological analysis. These results indicate that the double humanized B-h4-1BB/h4-1BBL mouse model, by mimicking a more human like 4-1BB and 4-1BBL interaction, has been proved to be a more advanced option for preclinical toxicity and efficacy evaluation for 4-1BB therapeutic antibodies compared to single humanized 4-1BB mice.
Citation Format: Lei Zhao, Linlin Wang, Dirui Li, Li Hui, Qingcong Lin. Double-humanized 4-1BB/4-1BBL mouse is an advanced model for liver toxicity and efficacy evaluation of 4-1BB therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 501.