bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting patient response to cancer therapy via histopathology images.
Authors: Hoang Danh-Tai , Ben-Zvi Doreen , Hermida Leandro C. , Dinstag Gal , Elis Efrat , SInha Sanju , Sinha Neelam , Aharonov Ranit , Beker Tuvik , Stone Eric , Ruppin Eytan 
Published: June 2022

e13561 Background: Histopathology has long been considered the gold standard of clinical diagnosis and prognosis in cancer. In recent years, molecular markers including tumor gene expression have proven increasingly valuable for enhancing diagnosis and precision oncology. Here we ask if we can predict tumor gene expression from its histopathology images and based on the latter, predict patient survival and treatment response. Methods: We developed DeepPT (Deep Pathology for Treatment), a deep learning framework that predicts gene expression directly from histopathology tumor images. DeepPT is composed of three main components: a pre-trained convolutional neural network model for feature extraction, an auto-encoder for feature compression, and a multiple-layer perceptron for regression. This architecture enables the model to capitalize on the similarity among the gene expressions and benefit from the advantages of multitask learning. Results: DeepPT was trained with haematoxylin and eosin stained (H&E) tumor slides from lung and breast cancer patients and their corresponding gene expression profiles. The models were then used to predict gene expression from five different held-out datasets, using nested cross validation. A total of approximately 23,000 genes were considered in this study; out of these, over 99% had a positive correlation between predicted and actual values, commonly for lung and breast cancer. Furthermore, a record number of genes (2,541 and 1,197 genes for lung and breast cancer, respectively) had a correlation above 0.4, well over the results of the current state-of-the-art approach (1,550 and 786 genes, respectively). We next studied if the inferred gene expression could be used for H&E-based personalized medicine. To this end, we used the predicted tumor transcriptomics generated by DeepPT as input to ENLIGHT, a platform that predicts a patient’s response to treatment from their tumor transcriptomics. We found that ENLIGHT matching scores based on DeepPT outputs were indeed associated with response to treatment. Conclusions: DeepPT is the first computational approach for building response predictors that can infer therapy response directly from whole slide images of patient biopsies. Importantly, its future application promises to make precision oncology more accessible to physicians and patients in the developing world.
Phenotypic and endotypic features of COPD associated with lung cancer development.
Authors: Lee Kyeryoung , Cohn David , Liu Zongzhi , Ai Lei , Paek Hunki , Jin Lan , Raja Kalpana , Li Minghao , Zhang Xingmin , Jun Tomi , Higashi Mitchell , Oh William , Calay Ediz S. , Savic Radoslav , Ghosh Krish , Kasarskis Andrew , Mullaney Tommy , Pan Qi , Schadt Eric , Wang Xiaoyan 
Published: June 2022

e13563 Background: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with multiple phenotypes and endotypes and associated with lung cancer development. In this study, we analyzed the clinical features of COPD including various phenotypic and endotypic features from the electronic health records (EHR) as the potential risk factors for lung cancer development in a large cohort of COPD patients. Methods: We identified a COPD cohort based on electronic Medical Records and Genomics (eMERGE) network COPD cohort identification algorithms with minor modifications from the Mount Sinai Data Warehouse (2000-2020) and followed the patients on the first diagnosis of lung cancer. The development of lung cancer in COPD patients was confirmed by manual chart review. We retrieved the clinical features from EHRs and conducted Kaplan Meier (KM) analysis and multivariable Cox-regression modeling for hazard ratio (HR) analysis. Results: We found that 3.8 % of COPD patients (824 out of 21,658) developed lung cancer. While COPD patients with emphysema and smoking history (former or current) showed an increased risk of lung cancer onset, patients with concurrent asthma and corticosteroid (ICS) inhalation history showed a reduced risk of lung cancer onset (adjusted HR in Table). Interestingly, COPD patients with higher eosinophil counts showed late onset of lung cancer (>300 cells/ul, cancer rate at 5y=2.4%, p=< 0.002; 150-300 cells/ul, cancer rate at 5y=2.9%, p=0.003) when compared to patients with low eosinophils count (<150 cells/ul, cancer rate at 5y=3.4%) in a KM analysis. A multivariable analysis adjusted for age, gender, race, smoking status, COPD sub-phenotypes, severe exacerbation history, and ICS inhalation history showed a significantly lower risk of lung cancer in COPD patients with higher eosinophils count (150-300 cells/ul; HR: 0.82, 95% CI: 0.69-0.97, p=0.021 and >300 cells/ul; HR:0.72, 95% CI: 0.57-0.89, p=0.003) when compared to those with low eosinophils count (<150 cells/ul). Conclusions: Our study shows that many phenotypic and endotypic features of COPD are differentially associated with lung cancer development. High eosinophil levels, ICS usage, and concurrent asthma in COPD patients may reduce the risk of lung cancer development. [Table: see text]
Post-radiation cisplatin and etoposide as systemic treatment in newly diagnosed adult medulloblastomas: A retrospective, single institution, longitudinal evaluation of clinical outcomes and toxicity.
Authors: Komlodi-Pasztor Edina , Holdhoff Matthias , Ozer Byram Hirsch , Munjapara Vasu 
Published: June 2022

e14046 Background: Medulloblastomas are malignancies of the posterior fossa with metastatic potential to the central nervous system. While a common pediatric malignancy, they are rare in adults. Extrapolating treatment regimens from pediatrics to adults is fraught as adults can developmentally tolerate higher radiation doses, but have less bone marrow reserve and therefore risk higher myelosuppressive toxicities with adjuvant systemic therapy. A standard systemic regimen for adults has not been delineated, though craniospinal radiation alone is likely insufficient in most cases. In the absence of well-established guidelines, our institution has historically used a combination of cisplatin (60 mg/m2 on Day 1) and etoposide (60-120 mg/m2 on Days 1-3 or 1-5) repeated in three-week cycles for three to a maximum of six cycles, but the literature to support this regimen is scant. Methods: In this retrospective chart evaluation, we reviewed the medical information of patients who were seen for newly diagnosed adult medulloblastoma between 1995 and 2020 at Johns Hopkins Hospitals. Those who met our pre-specified criteria (adjuvant treatment with etoposide/cisplatin within six months of craniospinal irradiation, sufficient data on toxicity before and after radiation, during chemotherapy, and one month after completion of the regimen, as well as sufficient clinical follow-up) were included in the analysis. Hematological toxicities were graded by NCI CTCAE guidelines. Follow-up for progression and survival were calculated from the end of the last chemotherapy administration and plotted on swimmers plots. Results: Ten out of 74 total adult medulloblastoma patients had adequate data about the tolerability of the regimen and clinical follow-up. Median time to follow-up was 46 months (range 4.5-164 months). Eight patients experienced Grade 3 and 4 hematological toxicities. Seven patients completed their planned treatment course, while two patients discontinued treatment prematurely because of hematological toxicities and one due to ototoxicity and fatigue. Three out of the ten patients progressed post-chemotherapy at 1 month, 24.5 months, and 44 months. Both early-progression patients died (7 and 29.5 months respectively), while the remaining eight are alive without evidence of progression. Conclusions: The data suggest a combination regimen of cisplatin and etoposide after craniospinal radiation in newly diagnosed adult medulloblastoma patients has acceptable toxicity and survival outcomes in this small patient cohort and compare favorably to other limited datasets in the literature. Further study is warranted to validate this as a recommended regimen.
Damage-associated molecular patterns (DAMPS) in patients with advanced cancer undergoing systemic treatment.
Authors: Valenti Vicente , Capdevila Laia , Ruiz Isabel , Badia Joan , Ramos Pascual Francisco Javier , Blázquez Susana , Villuendas Óscar , Pérez Cristina , Flores Gemma , Córdoba Mónica , Alonso Carlos 
Published: June 2022

e14524 Background: Immunogenic cell death (ICD) is known for the release of DAMPS from tumor cells. We aimed to find signals of ICD by assessing the variation of plasma DAMPS (HMGB1 and S100A8) after vs. before standard of care (SoC) systemic treatment in patients with advanced solid tumors. Methods: Patients scheduled to start a new line of systemic treatment were included. Plasma concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. CD44 immunohistochemical (IHC) expression was determined in tumor tissue. After vs. before variation of paired median concentrations was analyzed with the Wilcoxon signed-rank test for the whole population and selected subgroups according to RECIST response, baseline plasmatic iron levels, CD44 expression, and platinum-based treatment. Results: Fifty-two patients were included. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment as first-line. Thirty-six patients (69%) received chemotherapy (CT) alone, ten (19%) CT plus targeted therapy (7 FOLFOX or XELOX plus bevacizumab, and one each FOLFOX plus cetuximab, FOLFOX plus panitumumab, docetaxel-trastuzumab-pertuzumab), two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Overall response rate (RECIST) was 42%, rate of patients with low baseline plasmatic iron levels was 53%, and CD44 expression was positive in 35% of the patients. Results on plasma concentration of DAMPS are shown in the table. Conclusions: Signals of ICD were not observed in these patients. HMGB1 variation was not significant while plasma concentration of S100A8 significantly decreased after treatment, more markedly in those patients who experienced tumor response.[Table: see text]
Combination of immune checkpoint inhibitors plus chemotherapy and risk of pneumonitis: A worldwide retrospective pharmacovigilance study.
Authors: Zheng Yi-Fan , Xu Pei-Hang , Li Zi-mu , Kuang Yu-Kun , Li Jia , He Jun-Hao , Chen Xiao , Tang Ke-Jing 
Published: June 2022

e14587 Background: Pneumonitis is one of the most common fatal pulmonary adverse events that stem from immune checkpoint inhibitors (ICIs). Although the combination of ICI plus chemotherapy has become the standard first-line treatment regiments for various tumors, how the risk of pneumonitis changes during the combination treatments remains unclear. We used the World Health Organization pharmacovigilance database (VigiBase) to compare the risk of pneumonitis from the combinations of ICI plus chemotherapy with ICI in other regimens, including monotherapy. Methods: This observational, retrospective, pharmacovigilance study is a disproportionality analysis based on the individual case safety reports (ICSRs) extracted from the VigiBase from 1997 to 2020. The disproportionality analysis (known as case-non-case analysis) was conducted to compare the reporting of pneumonitis from the combination of ICI plus chemotherapy with ICI in other drug regimens, including monotherapy. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated. Results: From 1994 to 2020, A total of 93,623 ICI-associated ICSRs were reported in Vigibase, including 3,453 reports of pneumonitis (3.7%), among which 274 were associated with the combinations of ICI plus chemotherapy. The median time to event onset occurred about 2 months after therapy either in ICI without chemotherapy group or in the combination with chemotherapy group (61.5 days vs 74 days, respectively, p > 0.05). The ICI plus chemotherapy combination demonstrated a significant association with pneumonitis (ROR 1.35, 95% Cl 1.18-1.52). Among all the ICIs, anti-PD-1 antibodies combinations and anti-CTLA-4 antibodies combinations demonstrated a significant association with pneumonitis (PD-1+chemotherapy: 1.76, 95 % CI 1.52-2.05; CTLA-4+chemotherapy: 2.36, 95% Cl 1.67-3.35), while anti-PD-L1 antibodies plus chemotherapy combinations did not show similar association (ROR 0.37, 95% Cl 0.28-0.47). Conclusions: The combination of ICI plus chemotherapy is associated with higher risk of pneumonitis toxicity compared to other ICI-containing regimens (including ICI monotherapy) based on real-world data. The anti-PD-L1 plus chemotherapy combination has different pneumonitis profiles compared to anti-PD-1/CTLA-4 combinations. It suggests that a close monitoring for pneumonitis may be needed when using ICI plus chemotherapy combinations.[Table: see text]
A next generation site-specific ADC targeting breast and gastric cancer.
Authors: Italia James , Li Zhi , Hussain Myer , Boyce John , Warner Audrey 
Published: June 2022

e15024 Background: Antibody drug conjugates are entering a renaissance period as a promising treatment option for a variety of cancers. Despite some success in the past few decades, developing effective ADCs remains a challenge due to extensive inefficiencies of industry standard conjugation technologies. Industry available methods can be limited by lack of site-specificity, inflexibility on the site of conjugation, and poor overall biophysical characteristics which can alter the efficacy, safety, and bioavailability of these therapeutics. BrickBio’s unique bioconjugation methodology enables precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates which overcome these limitations and achieve the full potential of this highly promising class of therapeutics. Methods: In this work, we incorporate an azide-containing UAA (unnatural amino acid) into full-length antibodies targeting receptors overexpressed in breast and gastric cancer. Specifically, we have engineered variants of IgG1 antibodies to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as auristatins, via click chemistry to generate ADCs with homogeneous DARs. Results: The resulting BrickADCs exhibit high therapeutic efficacy against receptor-positive cell lines, particularly lines expressing low levels of HER2, in vitro as well as in mouse xenograft models. Not only are the BrickADCs 100x more potent in demonstrated cell lines, but current research indicate that they have an improved safety profile over T-DM1 and extended half-life. Conclusions: It is conclusive that the BrickADC platform enables an increased therapeutic window. In other efforts, the BrickADC platform is leveraging a new Modular Multisite Platform to address the unmet need of eventual ADC resistance by conjugating multiple distinct payloads in a homogenous fashion. Continued preclinical work is underway for these pipeline candidates as well as investigation into other target areas.
Mechanisms of anticancer activity of bacteria in enhancing cancer immunotherapy.
Authors: Im Sin-Hyeog , Sharma Garima , Sharma Amit , Kim Inhae , Lee Soo-Woong , Lee Hye-Na , Park ChangWook , Rudra Dipayan 
Published: June 2022

e15047 Background: Numerous studies indicate that selective microbiota could enhance anti-tumor immunity with checkpoint inhibitors. However, it is arduous to identify the best candidate bacteria strains and understand their underlying action mechanisms. Methods: We have developed Avatiome platform technology, an innovative pre-clinical model system that mimics the human body's immune system and microbiome. Avatiome incorporates up-to-date technologies such as immunophenotyping, single-cell transcriptomics, and an Artificial Intelligence system to develop novel therapeutics targeting neuronal, systemic inflammatory diseases, and cancers. Results: We have identified Lp IMB19 as an LBP candidate that can enhance anti-cancer immunity through this technology. Lp IMB19 suppresses tumor progression in pre-clinical models of melanoma, renal cancer, and NSCLC. Lp IMB19 efficiently potentiates the therapeutic effect of anti-PD-L1 in murine tumor models by enhancing the effector function of CD8+ T cells via altering the phenotypes of tumor-infiltrating macrophages with inflammatory M1 type. We have identified rhamnose-rich heteropolysaccharides (RHP) as key effector molecules to induce M1 macrophage in a TLR2 dependent manner. Lp IMB19 also limits the amount of iron availability via Lipocalin 2 (LCN2) to capture trace iron from the microenvironment and switch to an iron sequestration phenotype, subsequently inhibiting tumor growth. No side effect or toxicity is observed in pre-clinical toxicity studies. Conclusions: We are currently developing Lp IMB19 as an onco-biotics for clinical investigation as a live biotherapeutic product (LBP) combined with immune checkpoint inhibitors.
Hormonal indicator of effective mobilization of antitumor mechanisms in the experiment.
Authors: Zhukova Galina V. , Shikhlyarova Alla I. , Frantsiyants Elena M. , Kaplieva Irina V. , Engibaryan Marina A. , Volkova Viktoriya L. , Ulianova Yulia V. , Chernogorov Pavel V. , Ausheva Tatiana V. , Kit Oleg I. 
Published: June 2022

e15054 Background: Previously, the antitumor efficacy of low intensity complex impacts, including electromagnetic radiation (EMR) of the extremely high frequency range (EHF) in combination with factors of electromagnetic or biochemical nature, was shown. The questions about systemic antitumor mechanisms and the role of the thyroid system in them are opened. The aim of the study was to evaluate changes in the levels of thyroid hormones and their ratio in the blood in the cases of tumor regression under the influence of complex impacts including EMR EHF. Methods: The experiments were carried out on outbred male rats of young (8-9 months) and senile (24-26 months) age with subcutaneously transplanted sarcoma 45 (S-45). EMR EHF (42.2 GHz, 10 mW/cm2) with previously developed regime of modulation was applied on the head. In young males (21), the tumor was additionally exposed to the electric field with neuron-like impulses (SCENAR-97.1 device); in 20 old animals, complexes of essential L-amino acids were used per os 260 mg/kg/day. The impact course lasted for 3 weeks. After its completion, the levels of thyroxine (T4) and triiodothyronine (T3) in the blood were assessed by radioimmunoassay and the T3/T4 ratio was calculated. The results were compared with the values in intact animals (n=9-10), control group rats (S-45, n=11-15) and animals of the main groups without tumor regression. The Kruskal-Wallis and Mann-Whitney criteria were used, and the coefficient of variation (cv) was determined. Results: The tumor growth was accompanied by a decrease in T3 by 1.7-2 times (p <0.05) without changes in T4. The studied impacts caused a complete regression of S-45 in 38% (8) of young males, as well as a regression by 75-100% in 25% (5) of old animals. Young rats with S-45 regression showed no decrease in T3, while in old animals the T3 decrease was 1.3 times less pronounced than in the control group (p <0.05). In young males without S-45 regression, a decrease in T3 at the tendency level was observed (p <0.1), and T3 in old rats did not differ from the control group. The level of T4 did not change. In all cases of S-45 regression, despite the variability of T3 and T4 separately (cv=31-68%), practically constant value of the T3/T4 ratio was noted (cv=2-4%). It was 16x10-5 in young animals and 13x10-5 in old ones. It differed by 12-94% from the T3/T4 in the comparison groups and in rats without tumor regression (p <0.05-0.01). In the latter cases, the T3/T4 ratio had significant variability (cv = 25-84%) and was outside the range of values in rats with tumor regression. Conclusions: The results indicate the participation of the thyroid gland in the effective mobilization of systemic antitumor mechanisms, the marker of which is the ratio of the thyroid hormone levels in the blood.
An alpha-fetoprotein-maytansine conjugate for the treatment of AFP receptor expressing tumors.
Authors: Sherman Igor A. , Boohaker Rebecca J , Stinson Karr , Griffin Patricia , Hill Wendy 
Published: June 2022

e15056 Background: The alpha fetoprotein (AFP) receptor is an oncofetal antigen and a novel target for cancer therapeutics. It is highly expressed on the surfaces of many cancers and myeloid derived suppressor cells (MDSCs) but absent on normal tissues. By conjugating a novel maytansinoid toxin to a recombinant form of human AFP (ACT-101), we can selectively deliver the toxin to cancer and MDSC cells while sparing normal cells, thereby enabling a combination of targeted and immune activating approaches against the tumor. Methods: Four ACT-101-maytansinoid conjugates with different protein-toxin ratios and different linker chemistries were initially investigated in a mouse COLO-205 xenograft model, resulting in the selection of ACT-903 as the lead candidate for further development. A second study performed in the same tumor model compared the effects of single intravenous doses of ACT-903 (10-50 mg/kg) to control groups receiving either vehicle or the unconjugated protein, ACT-101 (25 mg/kg). Tumor growth, survival and clinical observations were assessed for 60 days post tumor implantation. Both serum ACT-101 and maytansinoid levels were measured following the single dose. Results: In the first study, a statistically significant reduction in tumor volume was seen for all four conjugates compared to vehicle control (p < 0.05). For ACT-903, tumors continued shrinking even after treatment completion, becoming undetectable in 9 of 10 animals. All 10 mice in this group survived through Day 60 with no obvious signs of toxicity. In contrast, there were no survivors in the control group. In the single dose study of ACT-903, a significant reduction of tumor burden compared to vehicle was achieved by Day 14 (p < 0.05) in both the 40 and 50 mg/kg dose groups. Mice in these 2 groups received a second dose 15 days after the first dose, based on observed tumor re-growth. Survival was significantly prolonged in the 50 mg/kg (p = 0.0037) and 40 mg/kg group (p < 0.0001) with 7 of 10 in the 50 mg/kg group and 9 of 10 animals in the 40 mg/kg group surviving to Day 60. Similar doses of ACT-101 and ACT-903 produced comparable ACT-101 serum levels, suggesting that the pharmacokinetic profile of the conjugate is driven primarily by the protein component. Free maytansinoid levels at 4 hours were less than 0.01% of the injected dose of the conjugate, indicating that the conjugate is stable in circulation. Conclusions: The efficacy and tolerability of ACT-903 in an animal tumor model supports advancing this conjugate toward clinical use with a regimen of either once a week or once every other week administration.