bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling analysis of COVID 19-related delays in colorectal cancer screening on simulated clinical outcomes.
Authors: Miller-Wilson Lesley-Ann , Vahdat Vahab , Brooks Durado , Limburg Paul J.
Published: June 2022

e13631

Background: Colorectal cancer (CRC) screening disruptions have been observed with the COVID-19 pandemic, putting patients at risk for more advanced-stage disease at the time of diagnosis. We estimated the impact of increased use of stool-based tests for screening during the COVID-19 pandemic on near-term clinical outcomes in a simulated United States (US) population. Methods: A previously developed budget impact model was adapted to assess the impact of increasing use of multi-target stool DNA [mt-sDNA] or fecal immunochemical [FIT] tests to offset the COVID-19 related disruption in colonoscopy screening. Adults, ages 50 – 75 years, at average risk for CRC were included over a 3-year time horizon (2020 – 2023) to explore the impact of increased screening for CRC using mt-sDNA or FIT, from the perspective of a US payer. Compared to the base case (S0; 85% colonoscopy and 15% non-invasive tests), the estimated number of missed CRCs and advanced adenomas (AAs) were determined for four COVID-19-affected screening scenarios: S1, 9 months of CRC screening at 50% capacity, followed by 21 months at 75% capacity; S2, S1 followed by increasing stool-based testing by an average of 10% over 3-years; S3, 18 months of CRC screening at 50% capacity, followed by 12 months of 75% capacity; and S4, S3 followed by increasing stool-based testing by an average of 13% over 3-years. Results: Increasing the proportional use of mt-sDNA, the detection of AAs improved by 6.0% (Scenario 2 versus 1) to 8.4% (Scenario 4 versus 3) and the number of missed CRCs decreased by 15.1% to 17.3% respectively. Increasing FIT utilization improved the detection of AAs by 3.3% (Scenario 2 versus 1) to 4.6% (Scenario 4 versus 3) and the number of missed CRCs decreased by 12.9% (Scenario 2 versus 1) to 14.9% (Scenario 4 versus 3). Across all scenarios, the number of AAs detected was higher for mt-sDNA than for FIT, and the number of missed CRCs was lower for mt-sDNA than for FIT. Conclusions: Using home-based stool tests for average-risk CRC screening can mitigate the consequences of reduced colonoscopy screening resulting from the COVID-19 pandemic. Use of mt-sDNA led to fewer missed CRCs and more AAs detected, compared to FIT.
Txagorrapid: Ultrarapid infusion in 30 minutes of the biosimilar of rituximab truxima—A cohort study.
Authors: Perez Persona Ernesto , Cuevas Palomares Laida , Unamunzaga Cilaurren Ariane , Gutierrez López de Gutierrez Xabier , Buendía Ureña Buenaventura , Molinillo Fernández Carmen Luisa , Benito Ibarrondo Begoña , Cordero Osua Ana Isabel , Benítez Delgado Beatriz , Andrés Moralejo Miguel Angel , García Albás Juan José , Guinea de Castro José María
Published: June 2022

e13638

Background: Rituximab (anti-CD20 Ab) is the cornerstone of the treatment of non-Hodgkin B lymphomas. Infusion-related reactions (IRR) are the most common adverse effects. To reduce them, intravenous premedication with antihistamine and acetaminophen is administered prior to rituximab. If no IRR after first infusion, subsequent infusions time takes 3-6 hours. Many centers use the rapid 90-minute infusion (off-label). Since 2017 subcutaneous rituximab formulation is available, that takes 5 minutes of administration. Nevertheless, in order to reduce cost, due to approval of biosimilars, some health providers continue using intravenous rituximab. On the other hand, with COVID pandemic, an effort to reduce visits and day-care hospitals stays has been made. In the current situation, it would be convenient to reduce day-care stay and the nursing care burden. We wanted to evaluate the safety of an ultrarapid infusion of biosimilar rituximab in a total time of 30 minutes by analyzing IRR and adverse events (AE). Methods: Since November 2021, 3 cohorts of ultrafast infusion have been studied as follows: One cohort (Cohort 1) with intravenous premedication with dexchlorpheniramine and acetaminophen, followed by rituximab infusion over 1 hour, and 2 cohorts with rituximab infusion over 30 minutes: Cohort 2: with intravenous premedication, and cohort 3 with oral premedication. IRR and adverse events have been independently reviewed and graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (November 27, 2017). Results: 34 patients have been included receiving 48 rituximab infusions (16 infusions in each cohort). Median age was 64 years old (range: 51-91). Diagnostic of NHL were as follows: large b cell: 10; follicular: 13; marginal: 7; mantle cell: 1, Waldeström: 1; Ritcher transformation: 2. Rituximab infusion was in monotherapy (21), and in combination (27) with: bendamustine: 9, CHOP: 17, GEMOX: 1. Considering safety, no IRR has been observed in cohort 1 (1 hour infusion), and 1 IRR grade II in cohort 3 (30 minutes, oral premedication). Other AE were: hypertension grade I and hypotension grade I, both in cohort 2. Conclusions: Ultrarapid rituximab infusion is safe. Oral premedication is feasibly allowing a total infusion time of 30 minutes. This infusion rate alleviates day-care burden saving between 75-90% of time in each rituximab infusion, reduce day-care stay and is comfortable for the patients. Clinical trial information: NCT05191225.
A feasibility study of remote patient monitoring among vulnerable patients with cancer.
Authors: Kessler Alaina J , Besculides Melanie , Kisswany Carol , Liu Mark , Berkalieva Asem , Mazumdar Madhu , Smith Cardinale B. , Gorbenko Ksenia O.
Published: June 2022

e13652

Background: Patients with cancer have high rates of healthcare utilization due to complications of disease and treatment. Early identification of patient illness may help reduce acute care use and improve quality of care. Remote patient monitoring (RPM), a type of telemedicine involving collection and transmission of health data from a patient’s home to clinicians, has promise to alleviate disparities by providing timely access and early intervention, particularly during the COVID-19 pandemic. Studies of digital interventions in oncology have demonstrated reduction in symptom distress and unplanned hospitalizations but lack focus on minority patients whereas studies of telehealth aiming to address disparities have not focused on patients with cancer. In this pilot study, we aimed to evaluate the feasibility of RPM among patients with cancer at a large urban medical center serving a racially and socioeconomically diverse population. Methods: We partnered with a secure HIPAA-compliant platform and FDA-approved RPM device, Current Health, which monitored heart rate, temperature, respiration, oxygen saturation, and blood pressure. The kit included broadband access and a tablet to provide telehealth services. Oncology Clinicians determined clinical inclusion and exclusion criteria of RPM initiation for patients on the bone marrow transplant service and patients with myeloma and lung cancer. A centralized team of Nurse Practitioners (NPs) monitored alarms. Clinical alarms indicated abnormal vital signs; technical alarms indicated no data transmission for a 12-hour period. We measured feasibility by recruitment and retention, and used descriptive statistics to describe the study population, time enrolled on RPM, and alarms. Results: To date, we enrolled 30 patients on the RPM platform over a 10-month period with a weekly census of 9-10 patients undergoing RPM monitoring. Of the 30 patients, 17 (57%) were white, 7 (23%) Black, and 2 (7%) Asian; 2 patients (7%) identified as Hispanic. The average age was 57.4 years. The majority of patients (93%) had hematologic malignancies, all of whom were enrolled on hospital discharge. Of the 2 patients with lung cancer, 1 patient was enrolled from the outpatient setting and 1 following hospital discharge. The mean length of time per patient enrolled with the device was 21.7 days. Over 10 months, there were 393 technical and 62 clinical alarms with an average of 3 clinical alarms per week addressed by NPs by phone, indicating low clinician burden. Conclusions: This pilot study demonstrated the feasibility of RPM monitoring in patients with cancer. Future studies should evaluate patient-reported and healthcare utilization outcomes, as well as barriers to reimbursement. The identification of best practices in telemedicine implementation can accelerate adoption and increase high quality, timely, and equitable cancer care.
The effects of vascular endothelial cells on regulating post-irradiation microglia phenotype in irradiation-induced brain injury.
Authors: Wang Jiaojiao , Tong Fan , Lin Zhenyu , Dong Xiaorong
Published: June 2022

e14001

Background: The purpose was to elucidate the mechanism behind functional relevance between microglia and injured blood vessels after CRT and the role of fractalkine (FKN) for the dynamics in the microglia phenotype, hoping to provide a theoretical rationale for the therapeutic strategy of Radiation-induced brain injury (RIBI). Methods: The ultrastructural blood vessels in the hippocampus were examined by transmission electron microscopy. EMSA and dual-luciferase assays were used to confirm the activation of NF-κB induced by irradiation in. Migration and co-culture assays were used to investigate the the association between HUVEC and BV-2 cells after irradiation. We constructed CX3CR1-knockdown (receptor of FKN) lentiviral vector to produce CX3CR1-knockdown BV-2 cell lines. After cultured for 3h with/without FKN, BV-2 cells (Sh-NC/ Sh-CX3CR1) received 10-Gy irradiation. The CX3CR1wide-type/knockdownmice were used and subjected to lateral ventricular injection (ICV) of 5 μl FKN lentivirus or vector before CRT. The in vitro and in vivo phenotype transformation of microglia and its inflammatory factors release were detected by WB, real-time PCR, ELISA, and IF at different time-points after irradiation. Morris water maze test was used to test mice's cognitive function. Results: In the hippocampus of the CRT group, significant pathological changes were seen in ultrastructure of blood vessels.The NF-κB pathway was activated in vascular endothelial cells (ECs) after10-Gy irradiation. In vitro migration and Co-culture assays found that molecular signals, secreted by ECs via the NF-κB pathway, leading to the activation of microglia and their recruitment to blood vessels. ELISA and qRT-PCR revealed that 10-Gy irradiation promoted the secretion of FKN from the vascular ECs via activating the NF-κB pathway. Western blotting and Flow cytometry showed that pretreatment with exogenous FKN, before 10-Gy irradiation, promoted microglia M2 phenotype transformation, diminished radiation-induced pro-inflammatory factors, and enhanced phagocytosis capacity. In addition, in vivo experiments showed that up-regulation of FKN via FKN lentivirus promoted radiation-induced microglial M2 transformation in the hippocampus, and diminished the spatial memory injury of radiated mice. Lastly, while inhibiting the CX3CR1, which is exclusively expressed on microglia in the brain, the regulatory effect of FKN on microglia and cognitive ability of mice disappeared after radiation. Conclusions: FKN, mainly secreted by vascular ECs via the NF-κB pathway after radiation, may attenuate RIBI through microglia polarization toward M2 phenotype by binding to CX3CR1 on microglia. Our study has unveiled an important and novel role of FKN/CX3CR1 in RIBI, providing evidence to validate that promotion of the FKN/CX3CR1 axis could be a promising therapeutic strategy for the treatment of RIBI.
Outcomes and prognostic factors in patients with HER2-positive metastatic breast cancer with brain metastasis.
Authors: Dogan Izzet , Yirgin Inci Kizildag , Ozkurt Selnur , Ibıs Kamuran , Vatansever Sezai , Saip Pinar , Aydiner Adnan
Published: June 2022

e14002

Background: Breast cancer is the most common malignancy in females. Brain metastasis is a poor prognostic factor in breast cancer. Brain metastasis can develop in about half of the HER2- positive metastatic breast cancer patients. The study was aimed to determine outcomes and prognostic factors in HER2 positive metastatic breast cancer patients who had brain metastasis. Methods: We evaluated the HER2-positive metastatic breast cancer patients with brain metastasis between 2008 and 2018. Data of the patients were recorded retrospectively. Kaplan Meier and Cox regression analysis were used for survival analysis and prognostic factors. Results: Eighty-three patients were included in the study. The median age was 49 (range, 25-76). Thirty-two (38.6%) patients had de-novo metastatic disease at diagnosis. The most common histopathological type was invasive ductal carcinoma (88.4%). The estrogen receptor and progesterone receptor positivity ratios were 42.2% and 28.9%, respectively. At the beginning of brain metastasis, the median number of extra-cranial metastasis was 2 (range, 0-4). The most common extra-cranial metastasis sites were bone (63.9%), liver (41%), and lung (34.9%), respectively. Twenty-eight patients (41.8%) had solitary brain metastasis. The median size of brain metastasis was 16 mm (range, 5-63) at diagnosis. All patients had treated with trastuzumab-based chemotherapy, 29 patients (34.9%) TDM-1, and 73 patients (88%) lapatinib+capesitabine combination. Seventeen patients (20.5%) had undergone craniotomy, and 82 patients (98.8%) received brain radiotherapy. The patients also received hormonotherapy (41%) and bisphosphonates (56.6%). At a median follow-up of 36 months (range 5.9-177.7) from beginning metastasis, the median overall survival was 34.9 months (95% CI, range 24.6-45.2). In multivariate analysis, age at diagnosis (p = 0.005), presence of five and over brain metastasis (p = 0.016), the number of chemotherapy used with trastuzumab (p = 0.017), and receiving three different HER2-targetted therapy (p = 0.032) were statistically significant for overall survival. However, size of brain metastasis (p = 0.091), lung metastasis (p = 0.428), liver metastasis (p = 0.338), bone metastasis (p = 0.132), and hormone positivity of tumor (p = 0.238) were not. Conclusions: Real-life outcomes of HER2-positive breast cancer patients with brain metastases were presented in this study. We showed that age at diagnosis, number of brain metastasis, number of chemotherapy received with trastuzumab, and had received three different HER2 targetted therapy was prognostic factors for overall survival.
The epidemiology and current treatment of pediatric choroid plexus carcinoma: An analysis of the national cancer database.
Authors: Wu Xinxin , Swedek Michelle , Griffin Julia , Malouff Timothy Dean , Silberstein Peter T.
Published: June 2022

e14024

Background: Choroid Plexus Carcinoma (CPC), a subtype of choroid plexus tumors (CPT), is a rare central nervous system neoplasm mostly affecting the pediatric population. The epidemiology of CPC is poorly understood due to the rarity of the disease. By analyzing the National Cancer Database (NCDB), we describe the demographic and social factors that influence the risk and current treatment of the cancer. Methods: We conducted a retrospective cohort analysis utilizing the 2018 National Cancer Database (NCDB) and included patients with Choroid Plexus Carcinoma with a histology-confirmed WHO grade III tumor, between ages 0-99 years (N = 202). Analysis was completed for the frequency of cases, types of treatment received, and overall survival within the pediatric population (age < 18 years, N = 139) and the adult population. Demographic factors were analyzed using Pearson Chi-squared tests, and survival was estimated using Kaplan-Meier curves. Results: The majority of the cases analyzed were white (55.4%), male (54%), and pediatric patients (66.8%, mean age at diagnosis = 15.17 years) with an average Charlson-Deyo Score of 0.24. The mean age at diagnosis of the pediatric population was 2.34 years (min = less than 1 years old/diagnosed in utero, max = 16, std. deviation = 3.84) while the mean age at diagnosis of the adult population was 43.49 years (min = 18, max = 84, std. deviation = 18.23.) The most common primary site for CPC was malignant neoplasm of the cerebral ventricle (87.6%) followed by malignant neoplasm of the brain stem (5.9%). Surgical procedure of the primary site was performed in 92.6% of cases including local excision, subtotal resection, resection, radical resection, partial resection of a lobe of brain, lobectomy, and surgery NOS. Radiation was not used 71.3% of the time, but was more than three times as likely to be used in the adult population after surgery than in the pediatric population after surgery (44.4% vs 14.4%, p value < 0.001). Most patients received chemotherapy (53%) with the administration of chemotherapy higher in the cohort less than 18 years old (69.8% versus 15.9%, p value < 0.001). Multiagent chemotherapy was administered as the first course of therapy as the top chemotherapeutic choice (86%) especially among the pediatric population (88.6%) compared to the adult population (60%) Palliative care was not provided in any of the cases. There was no statistical significance difference between the general survival of CPC between the pediatric and adult population. Conclusions: Historically, CPC is known as a pediatric cancer, but this NCDB study suggests that the frequency of the adult population affected is not negligible (31.2%). There is a difference regarding the current treatment of CPC in the pediatric versus adult population. Further study is needed to determine the impact of treatment and the importance of socioeconomic factors on the survival of CPC.
A novel glioblastoma prognostic assay using droplet digital polymerase chain reaction.
Authors: Beck Patrick , Hutchings Kasen Reed , Grant Caroline , Sheng Kevin , Morales Joshua Aaron , Varghese Robin , Sheng Zhi
Published: June 2022

e14026

Background: Glioblastoma (GBM) is an incurable brain tumor for which outcomes have seen little improvement in the past 30 years. Despite limited GBM therapies, accurate prognostic tools can be invaluable in informing best course of treatment. Recently, we have identified the GBM progression gene signature (GBM-PGS), a collection of 31 genes that shows superior accuracy at predicting GBM progression compared to existing biomarkers. From GBM-PGS expression, a GBM progression risk score can be calculated to provide clinicians with patient-tailored prognostic information. However, the question remains as to the best way to measure GBM-PGS to create a clinically applicable test. At our disposal are three approaches to quantify gene expression: quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), and RNA sequencing (RNA seq). We hypothesize that the combination of high accuracy and sensitivity, while also providing absolute quantification, will deliver ddPCR as the best option for creating a rapid clinical test that is scalable for measuring GBM-PGS. Methods: A ddPCR protocol was developed, and cDNA and primer concentrations were optimized using samples from two GBM cell lines (SF295, LN18). To confirm assay accuracy, GBM-PGS was quantified using ddPCR and compared to GBM-PGS expression by qPCR, a protocol that has previously been thoroughly validated. Finally, GBM-PGS expression was measured in patient tumors using ddPCR, and the GBM-PGS risk score algorithm was trained using an RNA seq data set from the Tissue Cancer Genome Atlas (TCGA). Following training, risk scores were calculated for the patient samples using ddPCR-measured GBM-PGS expression. Risk scores were compared with clinical patient survival to determine if GBM-PGS expression measured by ddPCR could predict patient outcomes. Results: Optimal primer concentration (200 nM) and cDNA concentration (1.2 ng/μl) were identified. GBM-PGS expression measured by ddPCR absolute quantification and qPCR Ct value demonstrated a strong correlation in the SF295 (R2 = 0.91) and LN18 (R2 = 0.88) cell lines. GBM-PGS was measured in two patient samples, and the resulting risk scores were calculated as 26.6 and 29.8 (score > 0 = high progression risk; score < 0 = low progression risk) compared to disease free survival times of 12.9 and 10.5 months, respectively, demonstrating an inverse relationship between patient risk score and survival time. Conclusions: Our results demonstrate that we have developed an accurate ddPCR-based assay capable of measuring GBM-PGS in multiple GBM cell lines, and preliminary results suggest that GBM-PGS quantified using ddPCR accurately predicts patient survival.
The landscape of EGFR mutation in Chinese patients with glioma.
Authors: Zhang Hui , Tao Rongjie , Zhu Xiaofeng , Luo Ningning , Qi Yingxue , Li Mengmeng , Sun Tingting , Qi Chuang
Published: June 2022

e14028

Background: Epidermal growth factor receptor (EGFR), a trans-membrane receptor tyrosine kinase, consists of an extracellular ligand-binding domain (ECD), a single transmembrane domain (STMD) and an intracellular kinase domain (ICD). Glioma is the most common primary brain tumor, and variations of EGFR are frequently reported in glioma patients. This study aimed to analysis the landscape of EGFR mutation subtype in Chinese patients with glioma. Methods: We retrospectively collected 1779 patients with glioma. In all patients enrolled, the comprehensive genomic profiling containing EGFR gene was detected using tumor tissue, including WES, 539 tumor related-gene panel or 131+4 gene panel (Simceredx). And the somatic mutations including SNV, INDEL, CNV, fusion were analyzed correspondingly. Results: Among 1779 patients with glioma, EGFR mutations were identified in 392 (22.03%) patients. The age was significantly higher in patients with EGFR-mutant group than in patients without EGFR-mutant group, with median age 54 vs. 45 (p = 4.81e-19). The sex didn’t reach statistical significance in two group. The incidence rate of different EGFR mutation types among all patients with EGFR-mutant were amplification (314,80.10%), SNV(198,50.51%), Indel(24,6.12%) and fusion(44,11.22%) respectively. 162 (46.69%) had two or more mutation types simultaneously. The main partner gene of EGFR fusion was LOC100996654, followed by ELDR and SEC61G, and the main EGFR breakpoints were in intron24, intron7, exon7. Within 347 SNV and Indel mutations, exon7, 15, 20, 6 and 8 were detected in 103(29.68%), 50(14.41%), 28 (8.07%), 25(7.20%) and 18 (5.19%) respectively. The top three mutaton subtypes within exon7 were account for 19.31%, which included p.A289V,p.A289T,p.T263P. Meanwhile, the mutation frequency within ICD encoded by exons 18-24 was 17.00%, in which exon20 mostly distributed (8%). In exon20, the most common mutation subtypes were p.V774M,p.H773dup,p.T790M, while in the second proportion exon18 (3.46%), the main subtype were p.G719A/D. Conclusions: EGFR amplification was the most common mutation type. There were 122 SNV and Indel subtypes altogether and occurred throughout almost the entire exon region, in which exon7 contained maximum 21 different subtypes and the p.A289V was the main type. The distribution of subtypes in ECD were much more than in ICD. The relationship between subtypes occurrence and cancer will be further studied in the future.
Retrospective review of glioma patients with confirmed MET amplification or fusion.
Authors: Tadipatri Ramya , Miller Adela , Ekhator Chukwuyem , Ahluwalia Manmeet Singh , Grewal Jai , Fonkem Ekokobe
Published: June 2022

e14029

Background: The MET pathway is a key oncogenic pathway in gliomas and is involved in tumor survival, angiogenesis, and invasion. MET alterations have been increasingly identified as a potential therapeutic target. Methods: Our objective was to further characterize the natural history of gliomas which harbor MET alterations and study outcomes as determined by progression free survival (PFS) and overall survival (OS). Results: We identified 22 glioma patients seen at our institution between 2015 and 2021 who had a MET alteration confirmed through comprehensive molecular profiling. There were 18 grade 4 astrocytomas/glioblastomas, 3 grade 3 gliomas (2 astrocytomas, 1 oligodendroglioma), and 1 grade 2 glioma (oligodendroglioma). MET amplification was observed in 13 patients and fusion in 16 patients, with 7 patients carrying both amplification and fusion alterations. MET fusion partners included PTPRZ1 (8 patients), CAPZA2 (6 patients), and ST7 (3 patients). Median OS was 12.8 months, and median PFS was 8.47 months. IDH1/2 mutation was associated with significantly improved survival, with an estimated OS of 146 months for IDH1/2 mutant tumors and 17.9 months for IDH1/2 wildtype tumors (F2,2 = 38.907, p < 0.001), MGMT methylation status had no significant survival impact. No significant survival differences were observed between the fusion only, amplification only, and combined fusion and amplification groups. No therapy was predictive of improved outcomes. Conclusions: MET amplification and fusion alterations were observed in both low and high grade gliomas, suggesting that they may be involved in early tumorigenesis. Survival outcomes were poor compared with historical data, with no differences observed between treatment groups, suggesting that current therapeutic modalities may be inadequate. This study indicates that MET may be an appropriate therapeutic target, laying the groundwork for clinical trials investigating MET-targeted agents.
Genomic features of IDH-mutant adult diffuse astrocytoma.
Authors: Zhang Hongjun , Duan Qianqian , Zhang Qin , Tan Yuan , Sun Tingting , Qi Chuang
Published: June 2022

e14032

Background: The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, which indicated that all IDH mutant diffuse astrocytic tumors are considered a single type (Astrocytoma, IDH-mutant) and are then graded as CNS WHO grade 2, 3, or 4. Besides, the guideline eliminates the term “Glioblastoma (GBM), IDH-mutant”. Moreover, grading is no longer entirely histological, since the presence of CDKN2A/B homozygous deletion results in a CNS WHO grade of 4, even in the absence of microvascular proliferation or necrosis. Therefore, more clinical and genomic characteristics of IDH-mutant astrocytoma under molecular typing need to be further studied. Methods: Adults pathological diagnosed with diffuse astrocytoma and glioblastoma in our Chinese dataset were identified retrospectively. All patients included in the analysis were tested for 131 CNS tumor-related genes (including IDH1/2), chromosomes 1p/19q and chromosomes 7/10. Results: 63 initial diagnosed IDH-mutant diffuse astrocytomas including 46 patients with grade 2-3 and 17 patients with uncertain grade. While, 5.2% of GBM (9/174) harbored IDH1/2 mutation which should be redefined as diffuse astrocytoma, IDH-mutant, WHO 4 grade. And these patients had a high frequency of CDKN2A/B homozygous deletion (88.9%, 8/9). In patients with 2-3 grade and unclear grade, CDKN2A/B homozygous deletion accounted for 18.7% (9/48) and 27.8% (5/18), respectively, which meant the grade of these diffuse astrocytomas should be revised to WHO 4 grade according to guideline. While mutation frequency of crucial prognosis factors in glioma, including chromosomes 7 loss, chromosomes 10 gain, EGFR amplification, PIK3CA/R1, PDGFRA amplification, CDK4 amplification, were 9.7%, 2.8%, 5.6%, 13.9%, 6.9% and 8.3% in all 72 astrocytomas, respectively. In addition, we found 83.3% (5/6) KDR copy number variant were occurred in which initially pathological diagnosed as IDH-mutant GBM. Conclusions: we conducted comprehensive analysis of IDH mutant diffuse astrocytoma. CDKN2A/B homozygous deletion as a specific grade-classified molecular marker could better re-distinguish about 20%-30% 2-3 grade and uncertain grade astrocytoma. KDR copy number variant may be a marker in IDH-mutant astrocytoma to identify the tumor which pathology is closer to GBM.
Toxicity of concurrent and adjuvant temozolomide in patients with glioblastoma multiforme (GBM).
Authors: Mcmahon David , Hussein Awab , Mangleburg Hunter , Nichianain Aine , Fitzpatrick Orla , McLaughlin Ronan Andrew , Conroy Michael R. , Marks Sam Jonathan , Naidoo Jarushka , Grogan William , Murphy Adrian Gerard , Breathnach Oscar S. , Hennessy Bryan T. , Morris Patrick G.
Published: June 2022

e14037

Background: (MGMT) promotor is prognostic and predictive of temozolomide (TMZ) benefit in newly diagnosed GBM. It has been suggested that MGMT methylation is associated with TMZ toxicity in some cancers such as melanoma but is not clearly defined in GBM. Methods: To investigate this, a retrospective electronic chart review of patients (pts) with resected GBM in a tertiary neurosurgical referral center from 1 July 2017 – 31 Dec 2020 was conducted. Hematological toxicities during TMZ with RT (concurrent) and subsequent TMZ (adjuvant) were assessed and graded by CTCAE V5.0. Toxicity was compared by MGMT methylation status. Results: In a 3.5 year period, 417 GBM resections were performed. Of these, 186 (45%) patients received at least 1 dose of TMZ in our institution: 180 pts received concurrent TMZ, 6 pts received adjuvant only. MGMT was methylated, unmethylated and unknown in 72, 97 and 17 pts respectively. In the concurrent and adjuvant phases respectively, thrombocytopenia incidence was 20%(N=14) and 52%(N=25) in the methylated group and 15%(N=15) and 51%(N=37) in the unmethylated group. In the adjuvant phase, incidence of ≥ grade 3 thrombocytopenia was 8%(N=4), in the methylated patients and 9%(N=7) for those unmethylated. Neutropenia incidence was low in the concurrent phase, however in the adjuvant phase was 29%(N=14) in the methylated group and 23%(N=17) in the unmethylated group. ≥G3 incidence was 10%(N=5) and 3%(N=2) respectively. Conclusions: In this retrospective study, a higher incidence of hematological toxicity was not seen in pts with MGMT methylated tumors. Methylation of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase.[Table: see text]
A prognostic model for overall survival in primary central nervous system lymphoma using post-steroid neutrophil-lymphocyte ratio.
Authors: Lo Yu Tung , Lim Vivian Yujing , Ng Melissa , Tan Ya Hwee , Chiang Jianbang , Chang Esther Wei Yin , Chan Jason , Poon Eileen Yi Ling , Somasundaram Nagavalli , Harunal Rashid Mohamad Farid Rin , Tao Miriam , Thye Lim Soon , Yang Valerie Shiwen
Published: June 2022

e14049

Background: Ratios of differential blood counts (hematological indices, HI) had been identified as prognostic variables in various cancers. In primary central nervous system lymphomas (PCNSL), higher baseline neutrophil-lymphocyte ratio (NLR) in particular was found to portend a worse overall survival. However, it was often observed that differential counts shift drastically following steroid administration. Moreover, steroids are an important part of the arsenal against PCNSL due to its potent lymphotoxic effects. We showed that the effect of steroids on differential blood cell counts and HI could be an early biomarker for subsequent progression-free (PFS) and overall survival (OS). Methods: This study retrospectively identified all adult patients who received a brain biopsy from 2008 to 2019 and had histologically confirmed PCNSL, and included only those who received chemoimmunotherapy, with documented use of corticosteroids prior to treatment induction. Different blood cell counts and HI were calculated at three time-points: baseline (pre-steroid), pre-chemoimmunotherapy (post-steroid) and post-chemoimmunotherapy. Tumor progression and survival data were collected and analyzed through Kaplan-Meier estimates and Cox regression. We then utilized selected variables found to be significant on Kaplan-Meier analysis to generate a decision-tree prognostic model, the NNI-NCCS score. Results: A total of 75 patients who received chemoimmunotherapy were included in the final analysis. For NLR, OS was longer with higher pre-chemoimmunotherapy (post-steroid) NLR (dichotomized at NLR≥4.0, HR 0.42, 95% CI: 0.21-0.83, p = 0.01) only. For platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), OS was better for lower post-chemoimmunotherapy PLR (dichotomized at PLR≥241, HR 2.27, 95% CI: 1.00 to 5.18, p = 0.05) and lower pre-chemoimmunotherapy (post-steroid) LMR (dichotomized at LMR ≥25.7, HR 2.17, 95% CI: 1.10 to 4.31, p = 0.03) respectively only. Decision-tree model using age ≤70, post-steroid NLR > 4.0, and pre-steroid (baseline) NLR < 2.5 divided patients into three risk categories – low, medium, high – and achieved good accuracy (area-under-curve of 0.78), with good calibration (Brier score: 0.16) for predicting 2-year overall survival. Conclusions: We found that post-steroid NLR, when considered together with baseline NLR, has prognostic value, and incorporation into a prognostic model allowed accurate and well-calibrated stratification into three risk groups.
Clinical trial and translational research for cancer immunology in Asian countries: Understanding the new frontier.
Authors: Ordinario Mel Valerie Cruz , Kojima Yuki , Sudo Kazuki , Iida Namiko , Okamoto Shinichiro , Nakamura Kenichi , Yonemori Kan , Watanabe Keisuke , Imasa Marcelo Severino Bulauitan
Published: June 2022

e14510

Background: Among the major advances in cancer treatment is the progress in cancer immunotherapy; however, despite the strides, there is few information specific to the Asian population. It is unclear to what extent clinical trial and translational research in cancer immunology are conducted in Asian institutions. Methods: This questionnaire-based survey was conducted among researchers and healthcare professionals who are involved in cancer immunology research and therapeutics in Asia-Pacific countries. The study identified the involvement of respondents in various phases of clinical trials, and immunotherapy research. In addition, the current capabilities of the institutions to conduct translational research were surveyed. Results: We received a total of 122 responses from 20 Asia-Pacific countries. More than half (58%) of the responders are currently conducting clinical trials on cancer immunology with 25% having performed more than 10 Phase 3 trials in the last 3 years. In clinical trials and clinical practice, immune checkpoint inhibitors were performed in most countries (81.8% and 88.6%, respectively). Clinical trials and clinical practice of CAR-T and TCR-T were performed only in some countries (CAR-T; 22.7% and 15.9%, TCR-T; 2.3% and 0%, respectively). In the absence of novel therapeutics in their institution, 18% of the responders refer their patient to facilities that have ongoing clinical trials. Among the institutions that perform Hematopoietic stem cell transplant (55.1%), the most common type offered include autologous (81.3%) and allogenic (70.8%) peripheral blood stem-cell transplantation. About 51.7% of the respondents have institutions that can conduct early drug phase development studies with only 11.2% capable of utilizing their own immunotherapeutic agents. Less than half of the respondents (40.7%) belong to institutions that have conducted translational researches using patient-derived samples for the last three years. Furthermore, more than half of the respondent institutions have no personnel that is experienced to handle and/or run patient-derived fresh peripheral blood or fresh tumors. Collaboration among neighboring countries can allow send out of specimens to other institutions that have such capability, however, 56.9% of countries have regulations or restrictions in transporting lymphocytes or tumor tissues. Conclusions: Oncologists and researchers in Asia recognize the importance of cancer immunology researches for patients. There were institutional and inter-country differences particularly in the conduct of early phase clinical drug development and translational research.
Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, Galectine-3 and NLRP3-MyD88-chemokine pathways.
Authors: Quagliariello Vincenzo , Passariello Margherita , Di Mauro Annabella , Cipullo Ciro , Paccone Andrea , Inno Alessandro , De Lorenzo Claudia , Maurea Nicola
Published: June 2022

e14516

Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy for improving cancer therapy outcomes. However, several ICIs-induced side effects emerged in a fraction of these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models. Methods: C57/Bl6 mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injections for 10 days. Before (T0) and after treatments (T10), analysis of fractional shortening, ejection fraction, radial and longitudinal strain were performed through 2D-echocardiography (Vevo 2100, Visual Sonics Fujfilm). Fibrosis, necrosis, hypertrophy and vascular/myocardial NF-kB expression were analyzed through Immunohistochemistry (IHC) of treated cardiac tissues. Systemic levels of SDF-1, myocardial expression of DAMPs (Fibronectin-EDA, S100/Calgranulin, Galectine-3), NLRP3, MyD88 and twelve cytokines/growth factors have been analyzed. In parallel, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines/growth factors were analyzed in the supernatant through colorimetric and enzymatic assays. Results: Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Systemic SDF-1 was drastically increased after treatment with ICIs. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88. Conclusions: This study demonstrates that therapy with anti-CTLA-4 and anti-PD-1 antibodies increases systemic SDF-1 and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A significant secretion of pro-inflammatory cytokines in myocardial tissue was also induced after ICIs therapy. Significant histological changes were seen and strong vascular NF-kB expression was observed in all groups.
Tracking of tumor-derived exosomal PD-L1 for cancer diagnosis and surveilance of immunotherapy response by dual-aptamer-encoded nanocatalyst assembly.
Authors: Zeng Tianyu , Shi Hai , Sun Chunxiao , Yang Fan , Li Wei , Liang Yan , Fu Ziyi , Yin Yongmei
Published: June 2022

e14528

Background: Immunohistochemistry is still the gold standard for identifying suitable populations for ICB therapy by staining PD-L1 in tumor tissue. However, IHC may be frustrated by intratumoral heterogeneity, subject to sampling error, and risk damaging tissue. Application of tumor-derived exosomal PD-L1 (Exo-PD-L1) for searching suitable populations for immunotherapy and monitoring immunotherapy response in breast cancer is often hindered by normal cells-derived Exo-PD-L1and the limitation of existed tools. Methods: We have developed a dual-target-specific aptamer recognition activated in situ hybridization chain reaction (HCR)-weaved nanocatalyst assembly (TRACE) on exosome for visualized tracking of Exo-PD-L1. Leveraging theexcellent selectivity of dual-aptamer recognition, high sensitivity of HCR-encoded nanocatalyst assembly, and high accessibility of color changes-based analysis. The clinical significance of tumor-derived Exo-PD-L1 were evaluated in a small cohort of clinical samples (4 healthy donors (HDs), 20 PD-L1-negative (PD-L1-N) breast cancer patients, and 10 PD-L1-positive (PD-L1-P) breast cancer patients) by using this TRACE system. All serum is collected and CT is scanned at approximately every 2 cycles. Results: The TRACE system can accurately distinguish PD-L1-positive breast cancer patients from healthy donors and PD-L1-negative patients by selectively and sensitively detecting tumor-derived Exo-PD-L1, with the most appropriate cutoff value of 0.6168 and 0.3603, respectively. The receiver operating characteristic (ROC) curve demonstrates the excellent accuracy (AUC: 1) of this TRACE system due to the high sensitivity and specificity. Moreover, the TRACE system provide a quantified and visualized tool for dynamically revealing immunotherapy response based on the levels of tumor-derived Exo-PD-L1, including stable, progressive, and partial response. Conclusions: The TRACE system may have a great potential for supplementing the existing standards and assisting to screen appropriate patients for ICB therapy and explore situable patients from different therapeutic regimenin-depth. As a companion diagnostics tool, the TRACE system may also rise great hope for improving the management of dosage, therapeutic regimen, and efficacy evaluation by providing timely feedback of immunotherapy response.
The mobilization of endogenous bi-specific natural killer T-like cells and independent of glucocorticoid receptor activation related to acute supra-pharmacologic weight-based dexamethasone (AVM0703) and 18 mgs/kg body weight.
Authors: Deisher Theresa , Jarzyna Peter , Poulin Kendra , Zahid Yumna , Ashok Arya , Sawas Spencer , Pathak Manisha , Rylatt Colleen , Parthasarathy Vaishnavi
Published: June 2022

e14545

Background: Glucocorticoids (GC) are a common component of blood cancer regimens, at doses 40 mg or lower due to concerns of pancreatitis and hepatotoxicity (Walasik-Szemplińska et al. Thyroid Research (2019) 12:13; Ataallah et al. Cureus. 2020 Jul; 12(7)) and neuropsychiatric effects. AVM Biotechnology has developed a high concentration, high volume, preservative-free, patent pending formulation of dexamethasone (Dex) (AVM0703), allowing administration up to 21 mg/kg (1470 mg for 70 kg) in one-hour IV infusion. Prophylactic use of physiologic hydrocortisone reduces the risk of GC neuropsychiatric side-effects (Warris, L. T. et al. J. Clin. Oncol. (2016) 34:2287; Meijer & de Kloet Endocrinology (2017) 158:448). At supra-pharmacologic doses (>6 mg/kg) AVM0703 mobilizes endogenous bispecific gamma delta invariant TCR+ Natural Killer T-like cells (AVM-NKT) (PCT/US21/19773), via a non-GC receptor, that rapidly home to cancer in tumor models and are directly related to tumor killing. GCs have been reported to induce biological responses independent of GCRs: corticosterone has been shown to bind a G-protein coupled receptor that does not bind either Dex or aldosterone (Mitre-Aguilar, et. Al International Journal of Clinical and Experimental Pathology (2015) 8:1; Powell, C. E., et. Al. Endocrine (1999) 10: 271) and the non-GCR mineralocorticoid receptor has high affinity for prednisone but not Dex. Methods: a) Mouse splenocytes or human whole blood were incubated with Dex from 1nM to 1mM. Apoptosis was measured for human whole blood by CBCs and for mouse splenocytes by flow cytometry 4 to 6 hours later. RU486 was used to block expected transmembrane (tm)GCR activity. b) Naïve, tumor bearing and humanized mice were dosed with AVM0703 at human equivalent doses (HED) >18 mg/kg. Depending on the disease state of the mice, novel AVM-NKT were observed in the blood between 3 and 96 hours later, determined by flow cytometry. Results: a) Apoptosis via the tmGCR was observed at expected concentrations between 10nM and 100uM and was blocked by the GCR antagonist RU486. At concentrations above 250uM, which correspond to in vivo peak blood levels from acute 7mg/kg and greater, no Dex-induced apoptosis was observed. b) Acute supra-pharmacologic AVM0703 induced the appearance of CD3+, CD56+, gdTCR+, invariant TCR+ bi-specific Natural Killer T-like cells, that in a cancer setting also expressed activation markers like CD16 and NKp44. Intriguingly, the AVM-NKT also express B220 in certain settings, and CD3+ B220+ DP has been indicative of IL-2 or IL-12 lymphoma killing (Masztalerz, A, et. Al. Anticancer Res (2004) 24(5A):2633). Conclusions: CBC’s and clinical chemistries from enrolling clinical trial confirmed the in vitro non-GCR findings.
Efficacy of the novel treatments of BCC with bone metastasis.
Authors: Esmaeil Pour Mohammad Ali , Mohebtash Mahsa , Amin Ali , Khayyat Azadeh , Khalili-Toosi Amir-Reza , Mousavi Seyedreza , Guo Mengni , Liu Jieying
Published: June 2022

e14547

Background: Eighty percent of nonmelanoma skin malignancies are basal cell carcinomas (BCC). Metastasis in BCC is about 0.0028 to 0.55. Diagnosis and treatment of metastatic BCC is challenging due to its rarity. In approximately 85% of metastatic BCC, the most common metastatic organs are lymph nodes. Methods: We reviewed 31 skin BCCs with bone metastasis in the past 60 years and 10 observation studies on the efficacy of Sonic hedgehog inhibitors (SHHis). We focused on treatment and outcome of 31 metastatic BCC. Results: The main treatment option was surgery and radiotherapy is a palliative option. Among chemotherapeutic and immunotherapeutic agents, SHHis (e.g. vismodegib and sonidegib) appear to be effective, with reported ORR of 43-100%, and CRR range of 3%-54%. In locally advanced BCCs, vismodegib shows 10 times higher CRRs compared to sonidegib, although ORRs were similar. In metastatic BCC, overall response to vismodegib was three times higher. The common adverse effects of SHHis limit their administration. Conclusions: BCC is a common skin neoplasm that rarely demonstrates metastasis. Among the chemotherapy agents administered, vismodegib appears promising.[Table: see text]