bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of serum brain-specific protein fragments and brain metastases in patients with metastatic breast cancer.
Authors: Damaso Sara , Willumsen Nicholas , Cavaco Ana C. Martins , Corredeira Patrícia , Pacheco Teresa Raquel Duarte , Costa Ana Lucia , Faria Claudia C , Tzara Ourania , Henriksen Kim , Karsdal Morten A. , Ali Suhail M. , Leitzel Kim , Lipton Allan , Costa Luis
Published: June 2021

e14007

Background: Brain metastases (BrMs) occur frequently in patients with breast cancer (BC) and represent one of the most difficult-to-treat events. Novel clinical tools are needed to identify BC patients at high risk of developing BrMs. Blood-based liquid biopsies represent a minimally invasive procedure that may detect surrogate markers of pathological changes occuring in the brain as a result of BrMs. Here we evaluated serum levels of a panel of brain-specific protein fragments in metastatic BC patients with BrMs, with no-BrMs and controls. Methods: Our cohort includes stage IV BC patients with BrMs (n= 27; median age 51 y.o.) and no-BrMs (n=50; median age 53.5 y.o.), and healthy controls (H) (n=23, median age 50 y.o.). Serum levels of 5 brain-specific protein fragments were measured by immunoassays and compared between groups. No-BrMs samples were collected at the time of metastatic disease diagnosis; BrMs samples were collected at BrMs diagnosis and before local treatment. Association with overall survival (OS) was evaluated by univariate Cox regression analysis. Results: All markers were significantly higher in patients with no-BrMs compared to H. Only Neurocan, Tenascin-R and GFAP were significantly higher in patients with BrMs compared to H. When comparing metastatic BC patients, significantly higher levels of Tau-A, Tau-C, Neurocan and GFAP were found in no-BrMs patients versus BrMs (Table). Association with OS was not found in BrMs patients, although a trend for high Tau-A levels to predict poor OS was detected in the no-BrMs group (HR 4.4, 95%CI 0.9-21.3, p=0.068). Conclusions: Protein fragments expected to be derived from brain remodeling consequent to BrMs were elevated in BC patients both with BrMs and no-BrMs at the time of sampling, with an overall trend for the highest levels to be found in patients with no-BrMs. This may suggest that brain remodeling processes are associated with BC and could partly explain the relatively high incidence of BrMs relapse in BC. Further studies requiring samples collected pre- and post-treatment are needed to further validate the diagnostic and prognostic value of these non-invasive biomarkers in BC BrMs setting. [Table: see text]
Prognostic value of methylation status of MGMT gene promoter in patients with glioblastoma after combination treatment.
Authors: Vlasov Stanislav G. , Gvaldin Dmitry Yu. , Pushkin Anton A. , Kit Oleg I. , Engibaryan Marina A. , Sakun Pavel G. , Voshedskiy Vitaliy I. , Gusareva Marina A. , Komandirov Maksim A. , Kultysheva Yulia A. , Solntseva Anna A. , Rodionova Olga G. , Karnaukhova Elena A. , Khatyushin Vladislav E. , Teplyakova Maria A. , Kecheryukova Takhmina M. , Zbrailova Ekaterina S. , Rogova Tatiana S.
Published: June 2021

e14025

Background: The effectiveness of radiation therapy in the classical and stereotactic treatment regimens of the primary glioblastoma multiforme was analyzed and compared. Methods: 87 patients with primary glioblastoma multiforme were hospitalized during the study period. 17 patients of them were in the treatment group (stereotactic radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.1 cm - group 1), and 70 patients were in the control group (conventionally fractionated radiotherapy, dose per fraction 2 Gy, 60 Gy total dose, CTV 2.0 cm, PTV 0.5 cm - group 2). Patients of both groups were treated with alkylating agents as the third stage of complex treatment. MGMT methylation was evaluated by pyrosequencing. Results: The use of stereotactic radiation therapy allowed to conduct a full course of treatment without interruption, whereas in the second group, due to the development of adverse reactions, the course was interrupted for 7 patients (10%). The advantage of stereotactic radiation therapy was a less pronounced increase and rapid regression of neurological deficits during treatment, manifested by better local control for 6 months. Hypermethylation of MGMT was detected in 39% of glioblastoma cases and was not detected in non-tumor tissue. The presence of promoter methylation disrupts DNA repair and is associated with longer survival in glioblastoma patients receiving alkylating agents. Note that the median survival of patients with MGMT hypermethylation in the group 1 was 285 days (IQR = 323.75), and in the group without hypermethylation was significantly more than 338.5 days (IQR = 476) (p = 0.045). A similar trend was observed in the second group: in patients with hypermethylated MGMT, the median survival was 271 days (IQR = 337), the result is different from patients without hypermethylated MGMT – 342 days (IQR = 493) (p = 0.039). Conclusions: As a result, the application of the stereotactic approach of radiation therapy in the complex treatment of patients with glioblastoma and their classification by the MGMT methylation status with a cut-off point of 10% has the basis for improving the effectiveness and tolerability of radiation therapy and contributes to the overall survival of patients.
MGMT gene polymorphisms in patients with severe hematological toxicity treated with temozolomide for adult diffuse gliomas: Results from a tertiary-care comprehensive cancer center.
Authors: Moitra Prithwijit , Chatterjee Abhishek , Kota Priti Khatri , Kowtal Pradnya , Dasgupta Archya , Sastri Jayant , Sahay Ayushi , Shridhar Epari , Patil Vijay Maruti , Moiyadi Aliasgar , Sarin Rajiv , Gupta Tejpal
Published: June 2021

e14032

Background: Polymorphisms in MGMT gene have been implicated in temozolomide (TMZ)-induced hematological toxicity in patients with adult diffuse gliomas. We aimed to investigate the association of three single nucleotide polymorphisms (SNPs) in the MGMT gene viz. L84F, I143V/K178R with severe hematological toxicity in patients of adult diffuse glioma treated with TMZ at an academic neuro-oncology unit of a tertiary-care comprehensive cancer centre from India. Methods: Thirty-three patients of adult diffuse glioma treated with multi-modality adjuvant therapy including TMZ who developed CTCAE V5.0 grade 2-4 hematological toxicity were included after written informed consent. Genomic DNA was extracted from peripheral blood mononuclear cells for SNP analysis. Correlation of MGMT SNP with patient demographics and hematological toxicity was assessed using the Chi-square and Fisher’s exact test. Results: Twenty-four patients (72.7%) developed grade 3-4 hematological toxicity with TMZ with a distinct female predilection. The variant T allele of L84F was expressed in 28.7% of the total 66 analyzed alleles which was markedly higher than previously reported in the general population of South Asian ancestry. The variant G allele of I43V/K178R was expressed in 9.3% (6/64) of 64 analyzed alleles. Persistent myelosuppression lasting beyond 2 months after cessation of TMZ correlated with I143V/K178R hetero/homozygous compared to wild type allele (p = 0.03). However, no significant correlation could be seen between any of the tested MGMT SNPs and grade of hematological toxicity. Conclusions: There is a higher prevalence of the L84F polymorphism in Indian patients with severe hematological toxicity than previously reported in the literature. The variant G allele of I143V/K178R is associated with prolonged and persistent myelosuppression induced by TMZ. A larger case-control is being planned to further elucidate the causal relationship between MGMT gene polymorphisms and TMZ-induced severe hematological toxicity.
Association of inoperable glioblastoma with a heterogeneous functional and survival outcome.
Authors: Harlay Vincent , Loundou Anderson , Boucard Celine , Petrirena Gregorio , Barrie Maryline , Campello Chantal , Autran Didier , Padovani Laetitia , Figarella Dominique , Boissonneau Sebastien , Dufour Henry , Baumstarck Karine , Tabouret Emeline , Chinot Olivier L.
Published: June 2021

e14036

Background: “Biopsy only” GBM patients is an understudied group of patients associated to a poor outcome, which has been reported to represent 21% of histologically confirmed GBM in the US National Cancer Data Base. Pattern of care included radiotherapy-temozolomide (RT-TMZ) standard regimen completed in 15% of patients, any other form of oncologic treatment in 60%, and supportive care alone in 25% of patients (Kole, Cancer 2016). Our objective was to explore heterogeneity of inoperable GBM patients group, both for patients characteristics, pattern of care planned and completed, functional and survival outcome. Methods: Patients with inoperable GBM included in a prospective regional glioma cohort initiated in 2014 were retrospectively reviewed for patients characteristics, MRI finding, treatment allocation and delivery. Functional independency analyzed as a cumulative time of KPS≥70, PFS and OS were analyzed. Results: Of 535 patients referred to our center, 449 patients were included at initial surgery, of which 158 patients (35%) underwent biopsy only. 18 patients were excluded for missing data leaving 139 patients for the present analysis. 54 (39%) were referred to RT-TMZ (50 patients completed concomitant treatment), 68 (49%) considered unfitted for RT received chemotherapy upfront (CT-UF) (of which 3 were subsequently referred to RT), 17 (12%) referred to palliative care only (PC). Groups differed at baseline for age (mean 60, 68, 69y for RT-TMZ, CT-UF, PC respectively); for KPS (70, 60, 50 for RT-TMZ, CT-UF, PC respectively); for mean tumor surface (793, 1420, 1412 cm2 for RT-TMZ, CT-UF, PC); for tumor extension (bilateral in 6.4% and 29.3% for RT-CT and CT-UF respectively); for steroid intake (45, 60, 100 mg daily respectively). Median OS was 14 months (95% CI, 9.65-18.71), 8 months (95% CI, 4.62-7.67), 2 months (95% CI, 0.67-3.33) for RT-TMZ, CT-UF, PC respectively. Of importance, mean duration of functional independence was of 8.3 months, 2.1 months, and 0.1 month for RT-TMZ, CT-UF, and PC respectively; 33/139 (24%) of the patients experienced functional independency for more than 40% of their life time. Conclusions: Inoperable GBM constitute a large and heterogeneous population in which more than 1/3 of the patients are amenable to standard of care, with survival outcome similar to the one of patients who underwent surgery. Patients considered unfit for RT-CT at diagnosis fail to be referred subsequently to RT after CT and exhibit a poor survival outcome that deserve new effective treatments. Cumulative duration of functional independence is limited and should be considered as part of treatment evaluation.
Biosimilar trastuzumab active post marketing surveillance real world 2020 data update: Results from a patient support program for patients under treatment with the first biosimilar trastuzumab approved in Brazil.
Authors: Silva Allisson Monteiro da , Watanabe Thais Tiemi Wepeck Oliveira , Honda Eimy , Yamaguchi Juliana
Published: June 2021

e14504

Background: In 2017, biosimilar trastuzumab (Zedora) became the first biosimilar trastuzumab approved in Brazil. In May 2018 an active postmarketing surveillance program was instituted. Data from this program was presented in ASCO in 2019 and 2020. Now, with an extended follow up (May 2018 to December 2020) and more patients included, we present updated data from the surveillance program. Methods: This is a prospective observational study to evaluate data from the patient support program. Patients who received prescription for biosimilar trastuzumab were invited to participate. After agreement of informed consent, they were followed by periodical phone calls after each infusion and up to 3 months after the end of treatment. Treatment related data and adverse events (AEs) were collected. Results: A total of 74 reports containing 656 adverse events (AEs) were received from the active postmarketing surveillance program between May 2018 and December 2020. Of the 74 reports, 73 are female patients with HER2+ breast cancer (BC) and 1 is a male patient with gastric adenocarcinoma. The patients mean age was 52 years (31 to 79 years). Regarding to AEs severity and expectedness, 588 (89.63%) were non-serious AE (413 expected / 175 unexpected) and 68 (10.37%) were serious AE (51 expected / 17 unexpected). Considering all serious unexpected AEs (17), 13 were assessed as not related to trastuzumab therapy and 4 were assessed as related to therapy. For the 175 non-serious unexpected AEs, 56 were assessed as not related to therapy and 119 were assessed as related to therapy. The three most frequently reported AEs according to SOC (System Organ Classification) were general disorders and administration site conditions 111 (16.92%), gastrointestinal disorders 98 (14.93%) and nervous system disorders 88 (13.41%). The five most commonly reported adverse events (MedDRA PT - Preferred term) were diarrhea 27 (4.11%), fatigue 24 (3.66%), nausea 22 (3.35%), weight decreased 18 (2.74%) and infusion related reaction 17 (2.59%). Further monitoring is continued. Conclusions: Nature of AEs noted in patients with breast cancer and gastric cancer treated with biosimilar trastuzumab (Zedora) were consistent with the known safety profile of Trastuzumab. The risk benefit remains consistent with the reference safety information and no new safety signals were detected.[Table: see text]
The correlation between tumor microenvironment and the clonality of the T-cell repertoire in lung cancer and colorectal cancer.
Authors: Cao Hua , Duan Jingxian , Jiang Shunda , Mu Tianhao , Xu Ruilian
Published: June 2021

e14524

Background: The tumor microenvironment has been shown to affect the responsiveness of immunotherapy. Effective anti-tumor immune response requires the activation and expansion of specific antigen-reactive T cell clones. It was reported that increased T cell clonality was associated with improved response to immunotherapy. However, what type of tumor microenvironment facilitates T cell clonal expansion remained controversial. The study aims to investigate the correlation between tumor microenvironment and the clonality of the T cell repertoire in lung cancer and colorectal cancer. Methods: 4 lung cancer patients and 4 colorectal cancer patients were enrolled in this study. Tumor tissues and peripheral blood samples were collected for RNA sequencing and T cell receptor CDR3 sequencing. The infiltration levels of 28 immune cells were estimated based on the mRNA expression of the genetic markers. The T cell clonality was defined as 1-Peilou’s evenness. Data were presented as mean± S.E.M. Results: The mean T cell clone counts in the blood samples of the 8 patients were 25676±4782 (ranging from 10259 to 45016), and the mean clonality of the TCR repertoires was 0.20±0.02 (ranging from 0.11 to 0.27). The clonality of T cells in colorectal cancer patients was similar to that of the lung cancer patients (0.22±0.02 versus 0.18±0.03, p = 0.31), showing comparable potentials of antigenic responses. The tumor infiltration of regulatory T cells, type 17 T helper cells, CD56bright natural killer cells, and natural killer cells varied greatly among patients, the coefficient of variation of those cells were 54.61%, 54.61%, 54.43%, and 55.62% respectively. In contrast, the coefficient of variation of monocytes was 23.34%, displaying a relatively even distribution among patients. The Pearson’s correlation coefficient was calculated to show the correlation between T cell clonality and the infiltration level of all 28 types of immune cells. Notably, only the infiltration of type 17 T helper cells significantly associated with T cell clonality, the positive correlation gave an R square value of 0.68 (r = 0.82, 95% confidence interval of 0.04-0.98, p = 0.04). The infiltration levels of CD4+ T cells, CD8+ T cells, regulatory T cells, type 1 and type 2 T cells, and gamma delta T cells were not affected by T cell clonal expansion. The expression of B cells, dendritic cells, macrophages, natural killer cells, and monocytes did not correlate with T cell clonal expansion. However, the abundance of neutrophils appears to positively correlate with T cell clonality (p = 0.09). Conclusions: The clonal expansion was significantly associated with the infiltration of type 17 T helper cells but not other subtypes of T cells, showing that the type 17 T helper cells are crucial to the antigenic responses in lung cancer and colorectal cancer. A neutrophil enriched tumor microenvironment may facilitate T cell clonal expansion.
Unaltered IL-2 encapsulated in acoustically active lipid microspheres for systemic but targeted microdose delivery to tumor microenvironment.
Authors: Larsen Clayton , Keltner Llew , Redmond William L , Li Rhodemann
Published: June 2021

e14535

Background: In order to take local advantage of exogenous interleukin-2 (IL-2) on effector T-cells within the tumor microenvironment while simultaneously avoiding systemic Treg immunosuppressive effects, microdoses of recombinant human IL-2 (rhIL-2) were encapsulated in gas-filled lipid microspheres (eIL-2), then activated with ultrasound. This novel therapeutic agent (eIL-2) was selectively delivered to the tumor via sonoporation and its anti-tumor effects were determined alone and in combination with PD-1 blockade. Methods: In an MC38 colon cancer model, jugular button catheters (Instech) were surgically implanted in a total of 56 animals (8 animals per arm) prior to tumor inoculation to facilitate repeatable IV injection of both anti-PD-1 (RMP1-14; BioXCell) and microspheres. Imagent perflexane lipid microspheres were incubated with rhIL-2 and the high concentration infranatant was separated, discarded, and replaced with sterile saline to resuspend microspheres to formulate eIL-2 on-site. Tumor-bearing mice were dosed on Days 1, 4, 8, and 12. Ultrasound (US) settings used were 2.2 MHz frequency, and 0.339 mechanical index (MI) during insonation. Once every 10 seconds a microbubble destruct pulse of 1.304 MI lasting 1,100 milliseconds was applied. Total insonation time was 5 minutes using a commercial ultrasound scanner (Mindray TE7) operating within diagnostically safe exposure limits. Study groups included Group 1: no treatment; Group 2: aPD-1, 3 mg/kg; Group 3: aPD-1, 3 mg/kg, Imagent + US; Group 4: Free rhIL-2, 10,000 IU (0.61μg)/animal; Group 5: eIL-2, approximately 0.2 μg encapsulated/animal; Group 6: Free rhIL-2, 10,000 IU (0.61μg)/animal, aPD-1, 3 mg/kg; Group 7: eIL-2, approximately 0.1 μg encapsulated/animal, aPD-1, 3 mg/kg. Results: The anti-PD-1 dose of 3 mg/kg demonstrated an expected tumor growth inhibition over control of -38.2% on Day 6, -35.6% on Day 8 and -30.3% on Day 12. Adding eIL-2 + ultrasound external stimuli approximately doubled the tumor inhibition effect of RMP1-14 to -68.1% on Day 6, -69.2% on Day 8 and -62.0% on Day 12. We also analyzed cytokine levels in the peripheral blood (Day 12) using a multiplex ELISA and observed elevated levels of pro-inflammatory cytokines including IFN-g, IL-12, and IL-1a, which likely serve to enhance anti-tumor immunity. IL-15 was also increased following treatment, which supports effector T cell survival. Conclusions: Using a novel form of recombinant human interleukin-2 encapsulated within a gas-filled lipid microsphere, we demonstrated that ultrasound-activated local delivery via sonoporation plus systemic PD-1 blockade led to improved tumor control and increased expression of pro-inflammatory cytokines. This novel approach enhances the efficacy of checkpoint blockade for the treatment of solid tumors. Further experiments are underway to interrogate mechanisms of action.
Updated safety and efficacy of MSB2311 (an anti-programmed death-ligand 1 antibody) in Chinese patients with advanced solid tumors and hematological malignancies from a phase 1 study.
Authors: Shen Lin , Gong Jifang , Zhang Jian , Ji Dongmei , Zhong Haijun , Yuan Ying , Yang Lei , Zhang Qingyuan , Li Yufeng , Wang Mengde , Qi Chuan , Xia Zhenzhong , Lu Lingmin , Huang John , Sun Ling , Xu Li , Shi Michael , Hu Xichun
Published: June 2021

e14547

Background: MSB2311 is a novel humanized PD-L1 antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. Methods: Patients with metastatic solid tumors or selected lymphoma progressed on or after standard treatments were enrolled in this phase I study. In dose escalation part, MSB2311 was given at dose levels of 3, 10, and 20 mg/kg intravenously every 3 weeks. At the dose expansion part, patients with enriched biomarker expression, including EBV+, PD-L1+ (TPS≥50%), MSI-High or TMB-High (≥10muts/Mb), were dosed at 20mg/kg Q3W or 10mg/kg Q2W. Primary objectives are to evaluate the safety and tolerability and to identify MTD and RP2D. Secondary objectives include the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-cancer activity per RECIST1.1. Results: As of data cutoff by Aug 31, 2020, 33 Chinese patients had been treated, including 27 heavily pre-treated solid tumor patients and 6 lymphoma patients. No dose limiting toxicity was reported and MTD has not been reached. The most common AEs (>20%) included: anemia, hypothyroidism, aspartate aminotransferase elevated, proteinuria, weight loss. 13 patients (39.4%) experienced grade 3 AEs, and 6 patients (18.2%) experienced SAEs. No treatment related grade 4 or 5 event was reported. Of the 17 efficacy evaluable solid tumor patients with biomarker selection, 6 achieved confirmed partial response with 35% ORR: 2/8 (25%) at 10 mg/kg Q2W and 4/9 (44%) at 20 mg/kg Q3W. Additionally, one patient achieved sustained iPR via iRECIST. 4 out of 7 responding patients (including one iPR) achieved tumor shrinkage of more than 50%, 3 of them got durable response (≥24 weeks).1 out of 6 lymphoma patients achieved PR. Conclusions: MSB2311 demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors and selected lymphomas. Clinical trial information: NCT04272944.
Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.
Authors: Adhikari Amit , Macauley Juliete , Johnson Yoshimi , Connolly Mike , Coleman Tim , Heiland Teri
Published: June 2021

e14565

Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.
Safety of immune checkpoint inhibitors in patients with preexisting autoimmune disorders.
Authors: Kumar Rohit , Chan Abigail Sy , Bandikatla Sudeepthi , Mudra Sarah , Ranjan Smita , Ngo Phuong
Published: June 2021

e14568

Background: In recent years, immune checkpoint inhibitors (ICIs) have been approved for a growing number of cancer types. Approximately 10-30% of cancer patients have a concomitant diagnosis of autoimmune disorders (AID). Activation of the immune system with ICIs poses a potential risk of AID worsening. The majority of the ICI clinical trials excluded these patients from the study. There is a paucity of data regarding the benefits and risks of ICIs in cancer patients with AIDs. The primary objectives of this study were to determine the incidence of immunotherapy related AID worsening and all immunotherapy related adverse events (irAEs). Secondary outcomes were time to AID worsening and survival difference. Methods: All adult patients (age ≥18 years) with solid malignancy who received ICIs between Jan 2016 to June 2019 were identified using the University of Louisville pharmacy database. Medical records were reviewed to include all the patients with preexisting AIDs. Descriptive statistics were used to determine the incidence of AID worsening and all irAEs. Baseline characteristics were compared between cancer patients with versus without AID worsening using Pearson chi2 and Student’s t-test, where appropriate. Multivariate Cox regression analysis was used to compared survival between the 2 groups. Results: A total of 40 patients with AIDs were identified during the study period. The cancer types were melanoma (57.5%), lung (15%), breast (5%), and others (22.5%). AIDs were rheumatological (52.5%), gastroenterological (12.5%), neurological (12.5%), dermatological (20%) and hematological (2.5%). The incidence of all irAEs was 60% (grade ≥3 in 20%) and AID worsening was 40% (grade ≥3 in 15%). Baseline characteristics of the 2 comparison groups are shown in table. The median time from ICI initiation to AID worsening was 94.5 (range 21-431) days. In multivariate Cox regression analysis, adjusted for demographics, cancer type, and stage, survival was similar for patients who had AID worsening versus those who did not (HR 0.30 (95%CI 0.06-1.40, p=0.128). Conclusions: In our single-institution study, cancer patients with preexisting AID do have an increased risk of irAEs with high-grade toxicities in 20% compared to historically reported 5% in the general cancer population; about 15% of patients reported grade ≥3 worsening of their AIDs. However, though the risk of irAEs is numerically higher in patients with AID, it may be acceptable to the patients if the potential benefits of ICIs outweigh the risks. Baseline demographics and clinical characteristics.[Table: see text]
Combination therapy with vincristine, immunoglobulin and glucocorticosteroid (VIG regimen) is very effective for the management of grade 3/4 or steroid-refractory immune-related adverse events (irAE) secondary to PD-1 blockade.
Authors: Chen Zhan-Hong , Wei Li , Wang Tian-tian , Lin Qu , Wu Xiangyuan
Published: June 2021

e14577

Background: The management of grade 3/4 or steroid-refractory immune related adverse events (irAE) is based on a paucity of retrospective data analysis. Our initial experience with the combination therapy with Vincristine (VCR), immunoglobulin (IVIG) and glucocorticosteroid (VIG regimen) showed clinical improvement in a wide variety of irAEs. As a result, we recommend the use of VIG regimen for the management of grade 3/4 or steroid-refractory irAEs. Methods: The character and clinical course of irAEs were abstracted from the medical record and analyzed. The components of VIG regimens are as follows: Methylprednisolone (MP) 2-10mg/kg for 3days, VCR 1.4mg/m2 (≤2mg) continuous infusion for 4-8 hours on day 3 once a week with Immunoglobulin (IVIG) 0.4g/kg for 3-5 days. The dose of MP and IVIG will be reduced quickly after irAE improves. VCR 1.4mg/m2 once a week will be used for 1 to 3 times according to the improvement. Clinical improvement was defined as either: documentation of resolution of symptoms and normalisation of biochemical tests or hospital discharge within 14 days. Results: A total of 25 patients had grade3/4 or steroid-refractory irAEs after receiving immune checkpoint inhibitors and then received VIG regimen. Among them, 22 patients have been significantly improved, with an improvement rate of 88%. Twenty-three patents were treated in the inpatient setting (92%). The index grade 3/4 irAE was pneumonitis in 28%, immune mediated hepatotoxicity(IMH) in 28%, rash/SJS/TEN in 24%, cerebritis in 8 % and one case each of ITP, Near blindness and severe oral mucositis. In 7 patients with severe IMH, the range of total bilirubin was 80-481umol/L and ALT 35-5000u/L. Six patients with IMH recover well but one patient did not recover to normal due to IMH complicated with pneumonitis and TEN . Clinical improvement was noted in 22/25 patients (88%), 11 patients (44%) required a single dose, while 12 patients (48%) required two doses, 2 patients(8%) required three doses of VCR 1.4mg/m2 continuous infusion for 4-8 hours. What is impressive is that the two patients with encephalitis were significantly relieved within 2 weeks after using the VIG regimen. One patient with TEN (SCORETEN 3)was significantly improved and discharged from our hospital 11 days after using the VIG regimen. A patient with near-blind eyesight recovered to normal 3 days after using the VIG regimen. Conclusions: VIG regimen may be an effective therapeutic option for the management of grade3/4 or steroid-refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the efficacy and safety of VIG regimen.
Identification and analysis of immune microenvironment characterization and key signal pathways in liver metastasis.
Authors: Zhu Xiaoxia , Zheng Zhihao , Jiang Yuhang , Li Luyao
Published: June 2021

e15004

Background: The liver represents a common site for metastatic disease, patients with advanced malignancies were usually associated with worse prognostic outcomes once liver metastasis has occurred. The aim of this study was to explore the immune microenvironment characterization and key signal pathways of liver metastasis in colorectal cancer (CRC) and breast cancer (BRCA), and to provide potential targets and decision-making basis for the diagnosis and treatment of patients with liver metastasis. Methods: Two datasets (GSE49355 and GSE58708) were downloaded from the Gene Expression Omnibus (GEO) database, and patients with primary tumors and paired liver metastases were enrolled. Data were processed by the limma and Deseq2 package and the differentially expressed genes (DEGs) were identified. Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG) and Reactome pathway analysis was performed using clusterProfiler package. Prognosis markers were identified via survival analysis of The Cancer Genome Atlas (TCGA) databases. CIBERSORT algorithm was used to calculate the proportions of 22 types of infiltrated immune cells. We used Spearman’s correlation analysis to describe the correlation between gene expression and microsatellite instability (MSI) or tumor mutational burden (TMB) score. Results: We investigated 16 patients with paired specimens (3 patients with BRCA and 13 patients with CRC). A total of 424 and 49 DEGs were identified in the BRCA and CRC samples. Only 26 DEGs were shared by the two kinds of cancers. The functional enrichment analysis suggested that the functions of DEGs were mainly related to cholesterol metabolism, complement and coagulation cascades, platelet activation etc. The survival analysis indicated that high expression levels of SERPINA3 was associated with a better prognosis in TCGA-BRCA (P = 0.01), while high ITIH2 and COLEC11 expression correlated with poor prognosis in TCGA-COAD (P = 0.045 and P = 0.013, respectively). CIBERSORT analysis revealed a significantly increased proportion of M2-macrophages and decreased proportion of activated mast cells in liver metastases. The Spearman correlation analysis showed that the SERPINA3 expression had a significantly negative relationship with the TMB (r = -0.26, P＜0.001) in TCGA-BRCA, but not significantly associated with the MSI (r = -0.02, P = 0.520), while the COLEC11 expression was significantly correlate negatively with the MSI and TMB (r = -0.15, P < 0.001 and r = -0.23, P < 0.001, respectively) in TCGA-COAD. Conclusions: The immune microenvironment of liver metastases exhibits a significant increase in the proportion of M2-macrophages and a significant decrease in the proportion of activated mast cells, and the key signal pathways implicate cholesterol metabolism and platelet activation. The specific mechanism needs to be further elucidated. Support: 81972853, 81572279, LC2019ZD009.
MosaicNeedles: A tool for multi-omic liquid biopsy sensitivity and specificity enhancement.
Authors: Quan Qimin , Wilkinson Joe , Ritchey Joshua , Kaiser Alaina , Geanacopoulos John , Boyce John
Published: June 2021

e15019

Background: Liquid biopsy has evolved to be an important method complementary to tissue biopsy. It is not only non-invasive, but also has the potential to detect cancer in its earliest stages and monitor patients in remission. The integration of proteomics into liquid biopsy may transform the molecular diagnostics of cancer and accelerate basic and clinical oncology research. A recent study showed that adding just 8 protein biomarkers to a panel of circulating DNA biomarkers increased the diagnostic accuracy up to 98% sensitivity and 99% specificity. Proteomics also bridges the gaps of functional information lost due to post-transcriptional and post-translational modifications in the genomic approach. However, the proteogenomic approach normally requires the use of multiple different assay technologies and laboratory workflows, including mass spectrometry. Methods: NanoMosaic’s Tessie platform employs a densely integrated nanoneedle sensor array (thus named MosaicNeedles) which can be used to detect both nucleic acids and proteins in a single assay process with reduced workflow complexity, without the need for mass spectrometry. Results: The NanoMosaic platform is a label-free, digital, single molecule counting technology using nanoneedles. It achieves sub-pg/ml (̃fM) level sensitivity with 7 logs of dynamic range. An array of nanoneedles is densely integrated and manufactured with CMOS-compatible nanofabrication processes. Each nanoneedle is a single molecule biosensor that is functionalized with capture probes. The capture probe can be either an antibody for protein detection or an oligonucleotide with a specific target sequence to a DNA fragment, mRNA, or miRNA of interest. The scattering spectrum of each nanoneedle changes when an analyte binds to its surface. At low abundance, analytes that are captured can be quantitated by counting the presence or absence of a color change on each individual nanoneedle in a binary fashion. As an analyte concentration increases the binding events increase accordingly and achieve saturation. In this range, an analog analysis on the spectrum shift will be performed, thus providing a wider dynamic range, up to 7 logs. Ultrahigh level multiplex can be achieved by parallelizing each analyte specific sensing area without loss of sensitivity or dynamic range. A 10,000-plex study can be achieved with a total of 2.5 billion nanoneedles on a 50mm by 50mm consumable. In this consumable, a 2,000-plex proteome and 8,000 cell-free DNA fragments can be detected. Conclusions: In conclusion, a full proteogenomic quantification can be performed on the NanoMosaic platform in one reaction, with higher sensitivity, lower cost and higher throughput than is currently possible by traditional methods. In addition, the high-plexibility of the NanoMosaic platform allows the discovery of new biomarkers across the whole proteome without the need for mass spectrometry.
Polydatin reduces cardiotoxicity of tyrosine kinase inhibitor sunitinib by decreasing pro-oxidative stress, pro-inflammatory cytokines and NLRP3 inflammasome expression.
Authors: Berretta Massimiliano , Quagliariello Vincenzo , Buccolo Simona , Iovine Martina , De Laurentiis Michelino , Cavalcanti Ernesta , Di Francia Raffaele , Taibi Rosaria , Montopoli Monica , Botti Gerardo , Maurea Nicola
Published: June 2021

e15065

Background: : Polydatin has anticancer and anti-inflammatory properties, however no studies investigated on its putative cardioprotective effects against anticancer therapies. Sunitinib, a recently-approved, multi-targeted tyrosine kinases inhibitor, prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. We investigated on the reduction of cytokines and growth factors of polydatin resulting in putative cardioprotective effects. Methods: Human fetal cardiomyocytes were untreated (control) or treated for 48 h with polydatin (50,100,200 and 400 µM) or sunitinib (5,10,25 and 50 µM) alone or combined to polydatin. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Exposure of adult cardiomyocytes to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly intracellular reactive oxygen species, lipid peroxidation and cytochrome c release from mitochondria leading to a reduction in cell death compared to cells exposed to sunitinib alone. Polydatin reduces expression of pro-inflammatory cytokines and growth factors involved in myocardial damages and down-regulates the signaling pathway of NLRP3 inflammasome and NF-κB, increasing cellular resistance to sunitinib-mediated damages. Conclusions: Data of the present study, although in vitro, indicate that polydatin, besides reducing oxidative stress, has cardioprotective and anti-inflammatory properties, thus indicating one the mechanism(s) by which this metabolite of resveratrol might decrease sunitinib-mediated cardiotoxicity.
Integration of molecular cancer classification and next-generation sequencing to identify metastatic patients eligible for PARP inhibitors.
Authors: Hart Lowell L. , Treuner Kai , Ma Li , Wong Jenna , Schnabel Catherine A. , Reeves James Andrew
Published: June 2021

e15080

Background: Olaparib, rucaparib, and niraparib are 3 poly-ADP-ribose polymerase inhibitors (PARPi) approved by the FDA for ovarian, breast, pancreatic, prostate, fallopian tube and peritoneal cancers with BRCA mutations. Several ongoing clinical trials aim to determine the efficacy of PARPi in various other cancer types, including specific cancer subtypes, such as clear cell renal cell carcinoma and cholangiocarcinoma either as monotherapy or combination therapy; however, eligibility for PARPi therapy requires the identification of the primary tumor type and confirmation of BRCA mutation. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor types and subtypes for metastatic patients with unknown or uncertain diagnoses. Multimodal biomarker testing, including next-generation sequencing (NGS), enables identification of actionable biomarkers to guide targeted therapy selection. In the current study, a database of metastatic cases that integrates tumor type with biomarker analysis was characterized to identify those eligible for PARPi treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of cases submitted for CancerTYPE ID testing with tissue-guided multimodal biomarker testing by NGS, including tumor mutational burden (TMB) fluorescent in situ hybridization (FISH), and microsatellite instability (MSI), and immunohistochemistry (IHC) (NeoTYPE profiles, Neogenomics). For the current study, metastatic cancers classified as ovarian, breast, pancreatic, or prostate were identified in the database, followed by NGS analysis to detect mutations in BRCA1 or BRCA2. Results: The current analysis included 2151 CancerTYPE ID cases, from which 71 ovarian, 47 breast, 12 pancreatic and 15 prostate cancer cases were identified. Out of 46 cases of ovarian cancer with molecular biomarker results, NGS identified 7 (15.3%) cases with BRCA1 mutation and 4 (8.7%) cases with BRCA2 mutation. Additionally, 4 (10.5%) cases with BRCA1 mutation and 1 (2.6%) case with BRCA2 mutation out of 38 cases of breast cancer with BRCA results were detected. No cases of prostate cancer or pancreatic cancer with mutations in BRCA1 or BRCA2 were detected. Conclusions: These findings in metastatic patients demonstrate the clinical utility of tumor type identification combined with molecular biomarker profiling, leading to additional options for patients with advanced disease. Specifically, analysis of the MOSAIC database identified a subset of patients with metastatic cancers eligible for PARPi therapy based on tumor type and BRCA mutation status. As new and approved PARPi are evaluated for efficacy in additional tumor types, patients can be identified that may be eligible for these targeted cancer drugs.
The clinicopathological characteristics, gene mutation characteristics and survival analysis of carcinoma of unknown primary origin.
Authors: Cui Yanzhi , Jiang Da , Hou Ran , Zhang Xue , Song Wenya , Zhou Xinliang , Hu Zexian
Published: June 2021

e15098

Background: Analyze the characteristics of CUPS clinicopathology and gene mutation spectrum, and discuss CUPS drug treatment strategies. Methods: A retrospective analysis of the data of 30 patients with metastatic cancer of CUP admitted to our department from April 2015 to April 2020. Including clinicopathological characteristics, treatment process and methods, gene molecular information, follow-up survival period. The follow-up was until February 1, 2021 or the patient died. Results: The pathological types of these cases were adenocarcinoma (14/30,46.7%), squamous cell carcinoma (5/30, 16.7%), neuroendocrine carcinoma (3/30,10%), small cell carcinoma (2/30,6.7%), sarcomatoid carcinoma (2/30,6.7%), large cell carcinoma (1/30,3.3%), lymphoepithelial carcinoma (1/30,3.3%), and poorly differentiated carcinoma (2/30,6.7%) . The most predilection site was lymph nodes, accounting for 70%. Primary lesions were not found in 23 cases in the course of diagnosis and treatment. They were head and neck in 1 case, lung in 1 case, mammary gland in 1 case, digestive tract in 3 cases and thymus in 1 case. 23 patients received chemotherapy alone or combined with antiangiogenic therapy, 2 patients received molecular targeted agents, 1 patient received ICI combined with antiangiogenic therapy, and the remaining 4 patients died without antitumor therapy or gave up treatment. The survival time of 26 patients was between 1 to 143 months, and the median survival time was 8.6 months. The 1-year, 2-year, 3-year and 5-year OS rate were 40%, 20%, 6.7% and 3.3%, respectively. Mean survival time was significantly longer among patients without visceral metastasis vs. with visceral metastasis (15.6m vs. 7.3m, P = 0.023). OS rate were 70% vs. 25%, 30% vs. 15%, 20% vs. 0% and 10% vs. 0%, respectively. The median survival time were 18.3m (with targeted therapy), 8.8m (without targeted therapy), 23.2m (with primary lesion), 8.4m (without primary lesion), The 1-year, 2-year, 3-year and 5-year OS were 53.3% vs. 26.7%, 40% vs. 0%, 23.3% vs. 0% and 6.7% vs. 0% for patients with targeted therapy vs. without targeted therapy, respectively. The 1-year, 2-year, 3-year and 5-year OS were 85.7% vs. 261%, 42.9% vs. 13%, 28.6% vs. 0% and 14.3% vs. 0% for patients with primary lesion vs. without primary lesion, respectively. 20 patients were interrogated genes using NGS of ctDNA. 80% of patients exhibited ctDNA alterations; TP53-associated genes were most commonly altered (13/20,65%) followed by genes involved in the MAPK pathway (20%), PI3K signaling (10%) and the cell cycle machinery (5%). The genomic profiles help guide treatment in 4 cases. Conclusions: CUPS has a poor prognosis. The pathological type is mostly adenocarcinoma, and lymph node metastasis is the first diagnosis. Chemotherapy is still the main treatment method. Molecular detection is helpful for individualized treatment.
Dihydropyrimidine dehydrogenase deficiency in patients treated with 5FU or capecitabine based regimens: A single center experience from South India.
Authors: Pavithran Keechilat , Ariyannur Prasanth , Jayamohanan Hridya , Philip Arun , Jose Wesley Mannirathil , Soman Sumi
Published: June 2021

e15517

Background: DPYD deficiency is present in 3-5% of patients. The risk of treatment-related death in DPYD mutation carriers who receive fluoropyrimidine chemotherapy has been estimated at 3-10%. There is growing data in support of widespread screening for DPYD deficiency prior to fluoropyrimidine chemotherapy. The purpose of our study was to identify the prevalence of DPYD deficiency among patients receiving 5-fluorouracil (5FU) or capecitabine based combination chemotherapy, and to analyse the toxicity profile among the DPYD deficient group. Methods: The study involved patients who have received 5FU and capecitabine based chemotherapy for the treatment for gastrointestinal, breast and head and neck cancers between 2019-2020. Four DPYD variants were checked using real-time PCR based Genotyping assay. Three common DPYD variants recommended by the CPIC guidelines (IVS14+1 G>A (*2A), c.1679T>G (*13), c.2846A>T) and a common variant in Asian population (c.496A>G), based on previous studies, was included in our analysis. These variants were assessed prior to the initiation of the chemotherapy and dose was modified based on the activity score and the toxicity profile was assessed. Descriptive statistics was performed using SPSS version 20. Results: 375 patients were included in this analysis. The median age of the cohort was 61years (21-84 years). 51.3% were males and 49.7% females. Among the 375 patients, 47 patients had DPYD mutation (12.5%). The median age of the DPYD mutated patients were 68 years; 29 (61.7%) males and 18 (38.2%) females. 32 (68.8%) had deleterious mutation in DPYD variant c.496A>G (rs2297595) and 15 (31.9%) showed mutation IVS14+1 G>A (rs3918290). 35 out 47 patients had grade II-III toxicity even after dose reduction during the first cycle of chemotherapy. The commonly seen adverse events were hand and foot syndrome in 18 (38.3%), mucositis in 7 (14.9%), diarrrhoea in 15 (31.9%) and neutropenia in 25 (31.9%) patients. Four patients had febrile neutropenia. One patient experience myocardial infarction. There was no mortality. Chi square analysis showed DPYD mutation had significant association with presence of severe adverse reaction (74.5%, p-value. 0.002). Conclusions: Prevalence of DPYD mutation in our patients was 12.5%. They experienced more toxicities while receiving 5-FU/Capecitabine even after dose modification. c.496A>G (rs2297595) was the most common variant seen in our patients. Screening of patients for DPYD mutations prior to administration of 5-FU/capecitabine using pharmacogenetic methods may help identify those patients who are at risk for adverse effects, allowing a more individualized approach to their chemotherapy management. c.496A>G (rs2297595) variant should also be in included routinely in DPYD screening among South Asian population.