bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the various predictive values of TP53 mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.
Authors: Li Xiaoguang , Zhang Xin , Niu Yanling , Ma Tonghui 
Published: June 2022

e14581 Background: TP53, a well-known tumor suppressor gene that encodes p53.The mutations of TP53 have been shown to be associated with higher tumor mutation burden (TMB). And patients with TP53 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between TP53 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of TP53 mutations in some cancer types. Methods: The ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of TP53 mutations with ICIs efficacy. The patients were classified into two groups: TP53 mutation (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with the Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with TP53 mutations had significantly shorter median OS after ICIs therapy (14.00 vs 23.00 months, P < 0.0001), indicating that TP53 mutations were associated with worse immunotherapy outcome. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of TP53 mutations with longer median OS in bladder cancer (27.00 vs 14.00 months, P = 0.0359). However, the associations between TP53 mutations and ICIs efficacy were not observed in breast cancer, esophagogastric cancer, glioma, head and neck cancer, melanoma, non-small cell lung cancer and renal cell carcinoma. We found the associations of TP53 mutations with shorter median OS in colorectal cancer (13.00 vs 34.00 months, P = 0.0368). Furthermore, the data showed that the median TMB was significantly lower in the Mut group for colorectal cancer (17.63 vs 35.98 muts/Mb, P = 0.0086) and higher in the Mut group for bladder cancer (14.25 vs 10.81 muts/Mb, P = 0.1588). Conclusions: Although TP53 mutations were associated with better ICIs efficacy in previous studies, the prolonged OS was only found in the Mut group for bladder cancer. Although TP53 mutations were associated with worse ICIs efficacy for all the enrolled patients, the poor outcome was only found in the Mut group for colorectal cancer. These data suggested that TP53 mutations may be a useful predictor for ICIs efficacy in these two types of cancer.
Genomic characterization of immune checkpoint inhibitor resistance genes and hyperprogression genes in advanced solid tumors.
Authors: Xu Libin , Zhang Ge , Mu Tianhao , Wang Zhizheng 
Published: June 2022

e14582 Background: Immune checkpoint inhibitors have been widely used in the systematic treatment of various advanced solid tumors, but they show poor efficacy or lead to hyperprogression in some patients. Some studies reported that EGFR mutations, ALK fusion, interferon pathway or Wnt signal pathway gene mutations might reduce the efficacy of immunotherapy and lead to tumor hyperprogression. The aim of this study was to determine the frequency of gene variations associated with immunotherapy resistance or hyperprogression in advanced solid tumors. Methods: The tumor tissues or blood samples of 111 patients with advanced solid tumors were collected. The tumor tissues were sequenced by targeted next-generation sequencing (55 genes, Illumina novaseq 6000), MSI (PCR) and PD-L1 detection (IHC). Blood cfdna was extracted and sequenced by targeted next-generation sequencing (55 genes, Illumina novaseq 6000). Results: A total of 111 patients with advanced solid tumors were included in the study, including 34 patients with colorectal cancer, 27 patients with hepatobiliary tumors, 18 patients with gastric cancer, 15 patients with urothelial carcinoma, and 17 patients with other solid tumors. Among the 82 samples tested for MSI, there were 77 cases of MSS (93.9%), 1 case of MSI-L (1.2%), and 4 cases of MSI-H (4.9%). 44 samples were tested for PD-L1 expression. 33 (75%) had PD-L1 expression < 1%, and 11 (25%) had PD-L1 expression greater than 1% but less than 49%. Among the genes related to immunotherapy, the mutations of genes related to cell growth or cell cycle regulation (EGFR, ALK, CDKN2A and CCND1) accounted for 3 (2.7%), 5 (4.5%), 12 (10.8%) and 5 (4.5%), respectively. The mutation of antigen presentation related gene (B2M) accounted for 3 (2.7%). The mutations of interferon signaling pathway related genes (JAK1, JAK2, JAK3 and IFNGR1) accounted for 2 (1.8%), 5 (4.5%), 1 (0.9%) and 1 (0.9%), respectively. The mutations in Wnt signaling pathway related genes (APC, AXIN1, CTNNB1) accounted for 41 (36.9%), 5 (4.5%) and 7 (6.3%). The mutations of tumor suppressor genes (PTEN, STK11 and PTPN2) accounted for 9 (8.1%), 1 (0.9%) and 3 (2.7%). Mutations in other genes (APLNR, DNMT3a, MDM2) accounted for 1 (0.9%), 6 (5.4%) and 7 (6.3%). Conclusions: Our study shows that in patients with advanced solid tumors, there are multiple gene variants related to drug resistance or hyperprogression of tumor immune checkpoint inhibitor treatment, suggesting that it may be the reason for the difference in the efficacy of immunotherapy. It is necessary to further study the efficacy of immunotherapy in patients with different gene mutations and the combination of immune checkpoint inhibitors for patients with different pathway mutations.
Radiologic features of immune checkpoint inhibitor-related nephritis with clinical correlation in biopsy-proven cases.
Authors: Awiwi Muhammad , Abudayyeh Ala , Abdel-Wahab Noha , Diab Adi , Gjoni Migena , Xu Guofan , Vikram Raghu , Elsayes Khaled M. 
Published: June 2022

e14585 Background: Radiologic findings associated with biopsy proven immune checkpoint inhibitor (ICI) related nephritis have not been described. The objective of this study is to describe the radiologic features of immunotherapy related nephritis on computerized tomography (CT) and positron emission tomography (PET). A secondary objective is to investigate the association of these radiologic features with renal outcomes. Methods: A retrospective review of all biopsy proven ICI-related nephritis between February 2017 and April 2021 was performed and 34 patients were identified. CT and PET-CT scans before the initiation of immune checkpoint inhibitors (baseline), at nephritis and after resolution of nephritis were reviewed. Total kidney volume, renal parenchymal SUVmax, renal pelvis SUVmax and blood pool SUVmean were obtained. Results: The total kidney volume was significantly higher at nephritis compared to baseline (464.7±96.8 mL vs. 371.7±187.7 mL; p < 0.001). Fifteen patients (44.1%) had > 30% increase in total kidney volume at nephritis. A > 30% increase in total kidney volume was associated with significantly higher renal toxicity grade (p = 0.007), higher peak creatinine level (p = 0.004) and more aggressive medical treatment (p = 0.011). New/increasing perinephric fat stranding was noted in 10 patients (29.4%) at nephritis. Among 8 patients with contrast-enhanced CT at nephritis, 1 patient (12.5%) developed bilateral wedge-shaped hypoenhancing cortical lesions that healed with focal scarring on subsequent scans. On PET-CT, the renal parenchymal SUVmax-to-blood pool SUVmean ratio was significantly higher at nephritis compared to baseline (2.13 vs. 1.68; p = 0.035). The renal pelvis SUVmax-to-blood pool SUVmean ratio was significantly lower at nephritis compered to baseline (3.47 vs. 8.22; p = 0.011). Conclusions: Bilateral increase in kidney size, new/increasing perinephric stranding and bilateral wedge-shaped hypoenhancing cortical lesions can occur in immunotherapy-related nephritis. On PET-CT, diffuse bilateral increase in radiotracer uptake throughout the renal cortex and decrease in radiotracer activity in the renal pelvis can be seen. A > 30% increase in total kidney volume was associated with significantly higher renal toxicity grade and more aggressive medical treatment in a subset of patients. Acknowledgment: National Institute of Health K01 Award (N.A.: K01AI163412).
Correlation of BRAF genomic alterations with higher mutation burden and predictive response to immune checkpoint inhibitors among human malignancies.
Authors: Kuan Feng-Che , Shi Chung-Sheng , Lin Meng-Hung 
Published: June 2022

e14589 Background: The treatment of BRAF-mutated melanoma leads the evolution of management in BRAF-mutated human malignancies from targeted agents to immune checkpoint inhibition. The correlation between BRAF genomic alterations and mutation burden is not well-studied as well as its prognostic role and predictive role to immune checkpoint inhibitors. Methods: Three Public genomic database (AACR GENIE v.11 [N = 119,058], MSKCC pan-cancer [10,080], MSKCC ICI [1,608]) were retrieved from cBioPortal ( https://www.cbioportal.org ). Raw data of cancer types, BRAF status, mutation counts (MC), exposure to immune checkpoints inhibitors (ICIs), and survival were analyzed. Violin plots were used to compare the distribution of MC among BRAF-altered and -wild tumors, and the Kaplan-Meier method was used to estimate survival rates. Statistical significance was set at a two-sided P < 0.05. Results: BRAF genomic alterations exist in 7,361 (6.2%, AACR GENIE v.11), 560 (5.6%, MSKCC pan-cancer) and 165 patients (10.3%, MSKCC ICI). There are 4,851 (4.1%), 357 (3.6%), and 312 (19.4%) patients with melanoma in these database, respectively. AACR GENIE v.11 includes the other two MSKCC databases, and 10.7% (N = 1,074) patients in MSKCC pan-cancer databases are also cases in MSKCC ICI. The median MCs were 7/Mb and 4/Mb, with interquartile ranges of 1 to 1,467 and 1 to 821 in the BRAF-altered and -wild tumors in AACR GENIE v.11. In this three databases, the distribution of MC was different between the BRAF-altered and -wild tumors (p < 0.001). In MSKCC pan-cancer cohort, the median overall survival in BRAF-altered and -wild tumors are 22.8 vs. 26.3 months (logrank p = 0.005). In MSKCC ICI cohort, the median overall survival of BRAF-altered and -wild tumors are 47.0 vs. 17.0 months (logrank p < 0.001). Conclusions: BRAF genomic alterations are associated with higher mutation counts, represent a poor prognostic factor and positively predictive to immune checkpoint inhibition among human malignancies.
Personalized multimodality therapy with immune checkpoint inhibitors, chemotherapy, and targeted treatment (ICTriplex) in advanced/refractory cancer.
Authors: Salem Philip A. , Jabboury Khaled W. , McCallum William G.B. , Stenoien Randall A. , Wheeler Thomas M. 
Published: June 2022

e14590 Background: Advanced/refractory malignancies are associated with poor prognosis and their treatment remains a major challenge. The combination of immune checkpoint inhibitors (ICI) and chemotherapy (CT) has been shown in some cancers to be superior to chemotherapy alone. In our treatment program (ICTriplex), targeted therapy (TT) was added to this combination for the treatment of these diseases, as these three approaches have convergent efficacy but divergent toxicity. Our initial data was previously reported in ASCO 2019 (abstract e14254) and ASCO 2020 (abstract e15150). Methods: Treatment was highly personalized and was tailored to the individual patient depending on diagnosis, prior therapy, and genomic profiling. Between April 2016 and January 2022, 41 patients with advanced malignancies were treated. The median age was 59 years (range 17-78). 24 patients were female. The Median Eastern Cooperative Oncology Group Performance Status was 2 (range 0-4). Tumor types included; lung (10), pancreas (7), colorectal (4), cholangiocarcinoma (3), breast (3), ovarian (2), Glioblastoma (2), cervical (2), sarcoma (2), melanoma (2), Hodgkin’s (1), gallbladder (1), thymoma (1), and gastric (1). PDL-1 status was positive in 10, negative in 16 and unknown in 15. 32 patients received prior therapy. Of these, 9 received ICI, 14 received TT, and 31 received chemotherapy for a median of 2 regimens (range 1-11). In ICTriplex, the ICIs used were Pembrolizumab in 14, Nivolumab in 12, and Atezolizumab in 7. 8 patients received dual ICI with ipilimumab. Combination chemotherapy including platinum was used in 21 patients, taxanes in 17, and gemcitabine in 24. TT included 18 agents with erlotinib in 9 and bevacizumab in 8. Response was evaluated by both PET/CT and CT scans. A complete response was achieved when all metabolic activity had resolved. Results: A complete response (CR) was achieved in 19 patients (46.3%), and a partial response (PR) in 16 (39%), with a total response rate of 85.3%. All but 2 patients had response. Of the 10 patients with lung cancer, 7 had CR, and 3 of them had a duration of response of more than 30 months. Also, 3 of the complete responders with brain metastases achieved intracranial CR by MRI without radiation. 2 patients with pancreatic cancer had a response duration of more than 30 months. Regarding side effects, 2 patients died of pulmonary complications possibly due to treatment. There were no other unexpected side effects. Conclusions: ICTriplex therapy is highly effective in advanced/refractory cancer and therefore should be considered when standard therapy fails, as well as for patients for whom standard therapy is not available.
Exosome in ascites can be a potential therapeutic target for gastric cancer with malignant ascites.
Authors: Hyung Sujin , Ko Jihoon , Kim Seung , Kang Won Ki , Lee Jeeyun ,   Samsung Medical Center Group
Published: June 2022

e15008 Background: Recently, exosomes widely distributed in body fluids, including blood, urine, saliva, and ascites, serve as an essential biomarker in cancers. Exosomes are considered as a cargo of potential oncogenic protein such as MET during cancer progression. Methods: Exosomes from the malignant ascites (exoAscites) of four patients with stage IV gastric cancers (GCs) were isolated by different serial centrifugation steps (300 g, 2000 g, 10,000 g, and 110,000 g at 4). After ultracentrifugation, nanoparticle tracking analysis, western blotting, and immunocytochemistry were performed for characterization of the exoAscites. Results: In this study, we enrolled 4 patients with malignant ascites which needed to be drained for symptom control. In all 4 patients, we successfully isolated highly concentrated exosomes in 50 ml of ascites (range, 55108 – 260 108exosomes/ml). (pt#1, 140108 particles/ml; pt#2, 138 108, pt#3, 55.6 108; pt#4, 260 108 exosomes/ml). In twopatients with MET amplification (METamp) in tumor specimens, exoAscites retrieved from the ascites harbored cMET protein in exosomes. In addition, the in-vitro cancer microenvironment model showed that tropism of exoAscitesharboring cMET oncogenic protein had the potential to induce cancer progression (EpCAM immunofluorescent intensity value; a 2.4-fold increase compared to control). In this model, the cancer invasiveness and angiogenesis were significantly enhanced by treatment with exoAscites with over time. (2.4-(EpCAM immunofluorescent intensity) and 3.6-(CD31 immunofluorescent intensity) fold increase, respectively). Furthermore, the cancer invasiveness was substantially increased as the exosome concentration increased from 0, 101, 103, 105, 107 exosome particles/ml. Cancer invasiveness measured by EpCAM immunofluorescent intensity was significantly decreased upon exosiMET treatment in MET amplified GC cells when compared to the control. Conclusions: For the first time, we demonstrated that exosomes from malignant ascites carry MET protein in their exosomes. Exosomes may be early mediators of cancer spread in GC.
Development of blood components samples collection as a source for new biomarkers search in multiple myeloma.
Authors: Gnennaya Nadezhda V. , Kit Oleg I. , Filippova Svetlana Yu , Sitkovskaya Anastasia O. , Mezhevova Irina V. , Shamova Tatiana V. , Timofeeva Sofia V. , Novikova Inna A. , Lysenko Irina B. , Nikolaeva Nadezhda V. , Samaneva Natalia Yu. , Gaysultanova Yakha S. , Kamaeva Inna A. , Tishina Anna V. , Pushkareva Tatiana F. , Kapuza Elena A. 
Published: June 2022

e15009 Background: Multiple myeloma (MM) is a B-cell malignancy resulting from the abnormal proliferation of neoplastic plasma cells that produce monoclonal immunoglobulin (Ig). The high variability of the course of this disease, its genetic clonal heterogeneity, is due to chromosomal deletions, chromosomal hyperploidy involving an odd number of chromosomes, as well as genetic aberrations, such as rearrangement of the Ig heavy chain gene loci. Since the available biomarkers do not take into account this feature of MM, there is a need to develop more advanced biomarkers that will more accurately predict the course of the disease and response to treatment. Methods: The collection of MM samples included biological samples obtained from patients over 18 years of age with a diagnosis of MM, who received treatment in the National Medical Research Center of Oncology since 2019. Only patients who signed an informed consent for the use of their biomaterial for scientific purposes were included in the project. The material was collected according to the developed algorithm of clinical information and biological material collection, sample preparation, quality control and storage in the cryostorage of the National Medical Research Centre for Oncology of the Ministry of Health of Russia (Rostov-on-Don). Results: As of December 23, 2021, collection consists of 387 samples of whole blood, serum, plasma and mononuclear cells obtained from 42 MM patients of both sexes, whose average age was 59.7 ± 1.49 (±SD) years. Each patient was assigned a unique identification number. Freezing of the obtained samples occurred in accordance with the low-temperature storage protocol. Registration, accounting and certification of the material were carried out in a specialized database for recording and storing information about biological samples. Conclusions: The identification of MM biomarkers is important for increasing the sensitivity of molecular monitoring, which makes it possible to stratify patients into risk groups for early relapses and treatment resistance development. Thanks to the accumulated experience, the Biobank of the National Medical Research Centre for Oncology of the Ministry of Health of Russia serves as a valuable resource for providing research in the development of new predictive molecular markers.
Performance and clinical utility of homologous recombination deficiency (HRD) determined by genome-wide loss of heterozygosity (LOH).
Authors: Li Chien-Feng , Chen Shu-Jen , Tan Kien Thiam , Tse Ka-Po , Wang Woei-Fuh 
Published: June 2022

e15025 Background: Homologous recombination deficiency (HRD) status plays an important role in identifying patients with ovarian cancer likely to benefit from Poly (ADP-ribose) polymerase inhibitor (PARPi) and platinum-based chemotherapies. Methods: ACTHRD is an NGS-based assay was designed to determine the homologous recombination deficiency (HRD) status based on the extent of genome-wide loss of heterozygosity (gLOH) and the detection of BRCA1/2 genes alteration. More than that, ACTHRD also assesses the mutational status of 22 homologous recombination repair (HRR) genes. We evaluated the performance and clinical utility of the ACTHRD and compared it with the FDA-approved companion test myChoice CDx. Results: Of the 36 specimens assayed, 24 were determined to be HRD, and 10 were determined to be homologous recombination repair proficient (HRP). The results showed high concordance with myChoice CDx with 100% positive percent agreement (PPA) and 90.91% negative percent agreement (NPA) in the HRD status estimation. Except one case showed HRD in the ACTHRD but showed homologous recombination proficiency (HRP) in the comparator panel. This patient responded to platinum-based chemotherapy and remained disease-free for up to 56 months. One BRCA1/2 wild-type patient was identified as HRD by myChoice CDx but not eligible for ACTHRD test due to low tumor cellularity experienced refractory 13 months after the initiation of the treatment. We further found that ovarian cancer patients identified as HRD by ACTHRD had significantly prolonged progression-free survival (PFS) after being treated with platinum-containing chemotherapies, regardless of BRCA1/2 mutational status. Conclusions: The ACTHRD assay provides high accuracy for identifying deleterious BRCA1/2 alterations and determining the HRD status of ovarian cancers. The analytical robustness of the test has been validated and indicates its suitability for clinical use. Notably, the prognosis data demonstrates that ACTHRD can predict eligible patients for platinum-based chemotherapy and may also be sensitive to PARPi treatment.
Bedside to benchtop translational development: Targeting the S1P/ceramide axis may alleviate symptoms of chemical induced peripheral neuropathy.
Authors: Takigiku Ray , Wesolowski Robert , Rixe Olivier , Morris John Charles , Yilmaz Emrullah , Villano John L. , Muller Carolyn , Curry Richard Charles , Puduvalli Vinay K. , Wise-Draper Trisha Michel , Wolfe Darren , Tapolsky Gilles 
Published: June 2022

e15045 Background: Chemical Induced Peripheral Neuropathy (CIPN) is a debilitating and serious side-effect associated with many chemotherapeutic treatments. Often, CIPN is a dose-limiting toxicity, and its effects can be long-lasting in some patients. The pathology of CIPN is thought to involve not only cytotoxicity of neuronal cells, but also inflammation and immune responses. Hence, it is not surprising that the sphingolipid sphingosine-1-phosphate (S1P) is thought to be a key contributor to CIPN. Methods: BXQ-350, a nanovesicle comprised of recombinantly expressed Saposin C and dioleoylphosphatidylserine, has broad anticancer activity. It modulates sphingolipid metabolism and signaling, lowers S1P and increases pro-apoptotic ceramides, and induces an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 )*. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetics, efficacy profile and to elucidate potential biomarkers. Results: Interestingly, several patients with established CIPN spontaneously reported improvement of their neuropathy-related symptoms following BXQ-350 administration. Plasma samples from those patients revealed changes in circulating levels of sphingolipids and cytokines, including reduction of circulating levels of S1P and of IL-6, IL-8, cytokines, following BXQ-350 dosing. These properties of BXQ-350 were subsequently investigated in a murine oxaliplatin-CIPN preclinical model; results showed a dose-dependent prevention/resolution of CIPN, which also correlated with decreasing systemic S1P levels. Additional plasma based CIPN specific biomarkers were investigated, and preclinical results suggest that BXQ-350 may also favorably inhibit specific immune cells that favor CPIN. Conclusions: These preclinical and clinical observations related to CIPN, coupled with the fact that BXQ-350 acts synergistically with many chemotherapies and radiation, warrant further its investigation into preventing or improving CIPN related symptoms in cancer patients. Clinical trial information: 02859857.