bluuebunny/crossref_metadata_2025 huggingface dataset:
Futility and toxicity monitoring without halting for interim analyses.
Authors: Urbauer Diana L , Westin Shannon Neville , Yuan Ying
Published: June 2021

e13579

Background: Many trial designs with futility or toxicity monitoring require that accrual halt to wait for currently enrolled patients to complete their assessment window. However, logistics often prevent this. In these cases, the performance of those designs might be compromised. This study examines the performance of 2 popular designs when enrollment is not halted at interim. Methods: Simulations were run to examine the effect of continuous enrollment on the operating characteristics (OCs) of a Simon’s 2-stage design for futility monitoring and a design using Bayesian posterior probabilities for toxicity monitoring. Both sets of 10,000 simulations examined the OCs when accrual rate was 0.5, 1.5, 3 and 5 patients/month with an assessment window of 30, 60 and 180 days. Results: The first scenario examined the OCs of a Simon design with 12 patients in the first stage and 21 at the end of the second stage. Regardless of accrual rate, the expected number of patients (EN0) increased and probability of early termination (PET0) decreased under the null hypothesis. Rate of change increased as assessment window increased. EN0 was 16 and PET0 was 54% when halting enrollment between stages. With continuous enrollment, EN0 ranged from 16-19, 17-21, and 18-21 patients for the 30-, 90- and 180-day assessment windows. PET0 ranged from 54%-50% with a 30-day assessment window. It halved to 24% with 3 patients/month enrolled and a 90-day window. PET0 was essentially 0 with a 180-day window and an enrollment of 3 patients/month. OCs for toxicity monitoring were examined for the early stopping rule Pr(toxicity rate > 0.3 | data) > 0.85 with toxicity rate ̃ beta(1, 1) with a maximum sample size of 20 and cohort size of 5. Expected number of patients (EN) increased and probability of early termination (PET) decreased as accrual rate increased, with rate of change increasing as assessment window increased. When the true probability of toxicity was 50% and enrollment halted between cohorts, EN was 10 patients and PET was 78%. EN was 17 and PET 54% with an assessment window of 30 days and 5 patients were enrolled per month. With a 90-day assessment window and 3 patients/month enrolled, EN was 16 and PET 59%. EN was 20 and PET was 12% with a 180-day assessment window and 3 patients were enrolled per month. Similar results were noted for cohorts of size 10 and a maximum number of 40 patients. Conclusions: The performance of designs that require halting enrollment while waiting for results of an interim analysis can be compromised by continuous accrual when assessment windows are lengthy and the accrual is fast. In these circumstances, consideration should be given to designs, such as Bayesian multiple imputation for delayed outcomes (Cai et al Stat Med 2014) and TOP2 (Lin et al JNCI 2019), that do not require accrual halt to make real-time interim analysis in the presence of pending patients, which protects patients from excessive toxicity or a futile intervention.
Breast cancer and molecular testing in Brazil.
Authors: Aleixo Sabina B. , Pulido Jose Zago , Parmanhane Narelle
Published: June 2021

e13602

Background: Breast cancer is a common malignancy among women worldwide. Regardless of the economic status of a country, breast cancer poses a burden in prevention, diagnosis and treatment.Accurate pathologic and molecular diagnosis of high quality in breast cancer is a challenge in low- and middle-income countries (LMIC). The two most important aspects needed are the hormonal and epidermal growth factor receptor 2 (HER2) status as they are used as prognostic factor and as predictive biomarker for treatment. The most commonly used tests for assessing HER2 status are immunohistochemistry (IHC) assays for HER2 protein expression and fluorescence in situ hybridization (FISH) for HER2 gene amplification.In this study, we evaluated the hormonal and HER2 status of women with breast cancer and the need for FISH in HER2+++. Methods: We retrospectively reviewed the database of the Hospital Evangelico de Cachoeiro de Itapemirim, a regional cancer center from the south of Espirito Santo State – Brazil.The period covered in the study was from 01/08/2019 to 01/08/2020. We analyzed all new cases of invasive breast cancer diagnosed by IHC for the estrogen (ER), progesterone (PR) and HER2 receptors. All the HER 2++ and HER2 +++ were tested by FISH. We had during this period 152 newly diagnosed cases, 11 patients were excluded due to missing data. Results: The 141 cases were separated into four categories by hormonal status: 109 ER+PR+ (77,3%), 9 ER+PR− (6,4%), 2 ER−PR+ (1,4%) and 21 ER−PR− (14,9%). When these results were associated to HER 2 status we found 11 (7,8 %) triple negative breast cancer (TNBC) , 26 (18,43%) HER2 ++ and 23 (16,31%) HER 2+++. The HER2++ were tested by FISH and 8 (30,7%,) were found positive, 10 (38,6%) negative and 8(30,7%)indeterminate. Among the HER 2 +++ tested by FISH we found 15 (65,3 %) positive and 8 (34,7 %) indeterminate. Conclusions: Our study demonstrated a lower incidence of TNBC and higher incidence of hormone-receptor positive cases as compared with other institutions. Different from other countries, all HER 2++ and HER2+++ in Brazil need to go to molecular testing. Altough trastuzumab is available in the public Brazilian Health System (SUS) for HER 2 positive women, diagnosis with IHC alone is not permitted and there is a need for molecular testing confirmation. Therefore, the most troublesome data in this study was that 34,7% of HER 2+++ had indeterminate FISH results, in these cases SUS does not offer traztuzumab. Newer guidelines allow the use of IHC only in HER2 +++ . We consider important for SUS to review the recommendation for need of molecular testing for all HER2 +++ so this will avoid subtreating women in Brazil
Oncologists’ views on Expanded Access and Right-to-Try: The need for education and shared decision-making.
Authors: Master Zubin , Smith Cambray , Stout Jeremiah , Adjei Alex A. , Buckner Jan C. , Tilburt Jon Charles
Published: June 2021

e13603

Background: Over half of Americans report favoring access to experimental treatments even if they have yet to be proven either safe or effective, yet only 3-5% are enrolled in clinical trials and a fraction of a percent in expanded access. The Expanded Access (EA) program (aka “compassionate use”) and Right-to-Try (RTT) are parallel federal mechanisms that offer qualifying patients access to off-trial experimental treatments. Our study aimed to capture the views and experiences of oncologists on obtaining eligible medicine using the FDA’s EA and is the first to report findings on physician attitudes toward RTT. Methods: We conducted 21 semi-structured interviews and qualitative analysis of oncologists at a major cancer center with 3 main sites across the U.S. Participants were purposely selected to have experience with EA. Results: Oncologists’ considerations for offering EA options to patients were based on a sound scientific rationale, reasonable risk-benefit ratio, functional status of the patient, and patient motivation. Although oncologists’ experience positively correlated with level of ease in navigating EA, most remained largely unfamiliar with RTT. Only 4 oncologists had experience discussing RTT with patients and none had obtained an experimental therapeutic under this pathway. When informed about RTT, oncologists articulated 3 sets of concerns including limited safety and oversight, unclear structure and lack of requirements to collect and report data, and the potential for inflating patient expectations. Published work by others have shown that patients desire experimental options to be offered and report that physicians do not always offer experimental medicine taking into account factors, such as, reimbursement. Given that oncologists may factor in variables such as patient motivation, and potentially affordability or health literacy, when considering whether experimental medicine is appropriate to offer their patient, there may be a need to develop a conversation aid so that clinically relevant options are presented to patients equitably and patient choice is enhanced. Conclusions: Further research to better understand patient perspectives and potential discordant views between patients and oncologists is needed in order to design shared decision-making tools to inform oncologists about off-trial preapproval pathways and help both oncologists and patients navigate the thorny issues of experimental oncology.
National survey on the effect of oncology drug shortages in clinical practice: A Hematology Oncology Pharmacy Association (HOPA) survey.
Authors: Hudson-Disalle Sarah , DeRemer David L. , Buie Larry W , Hamm Mark , Pilz Jeffrey , McBride Ali
Published: June 2021

e13609

Background: Drug shortages are a clear and growing challenge. Prominent shortages included oncology medications and supportive care products essential for the care of cancer patients. Oncology drug shortages often result in disruptions in the timing of chemotherapy treatments, alterations in the dose or regimen administered, or even missed doses when alternative agents are unavailable. The purpose of this survey was to characterize the impact of oncology drug shortages across the United States, including the experiences of health care organizations, resource implications, and the impact on patient safety, patient care, and clinical trials. Methods: A 34-item online survey was distributed to HOPA membership of the Hematology Oncology Pharmacy Association to gather information on shortages of oncology drugs (i.e., all drugs essential in the care of cancer patients, including supportive care agents. Results: Sixty-eight organizations completed the survey; almost all completed by pharmacists, and analysis completed. Sixty-three percent of institutions reported one or more drugs shortages a month, with a 34.33% increase in 2019 from 2018. Sixty four percent of responded had incurred increased costs from oncology drugs shortages, with 7% noting reimbursement issues when switched to brand name therapies due to shortages. Treatment delays, reduced doses or alternative regimens were reported by 74.63% of respondents. The most common disease states which causes a dose delay of treatment included Acute Lymphocytic Leukemia, Lymphoma and Multiple Myeloma with dose reductions noted in 36.36%, 36.36 and 15.91%. The top five oncology drugs on shortage included epirubicin, flutamide, decitabine, mechlorethamine, dactinomycin with the top 5 supportive care drugs on shortage being noted as hydrocortisone, bivalirudin, promethazine, mycophenolate sodium and scopolamine. Respondents noted medication errors related to oncology drug shortages at 4.48%, with noted errors including incorrect conversion from iv to oral etoposide and incorrect EMR drug builds. Oncology Drug shortages impacted clinical trials in 13.4% of respondents in which 54.55% of respondents noting patients not being enrolled in clinical trials. Conclusions: A survey of US oncology pharmacists and technicians indicated that oncology drug shortages occurred frequently in 2020. Shortages led to delays in chemotherapy and changes in treatment or omission, complicated clinical research and increased the risk of medication errors and adverse outcomes.
Evaluation of the effectiveness of telephone consultations and the level of satisfaction of patients attending the Unidad Docente Asistencial de Mastología [Mastology Care Teaching Unit] using this method during the COVID health emergency.
Authors: Camejo Natalia , Castillo Cecilia , Artagaveytia Nora , Amarillo Dahiana , Vitureira Florencia , Rodriguez Florencia , Delgado Lucia Beatriz
Published: June 2021

e13610

Background: In March 2020, a health emergency was decreed due to COVID-19 and this produced changes in the organization of health services. One of the objectives of the reorganization that took place was a reduction in face-to-face consultations (FTFC), and the promotion of telephone consultations (TC). Objective: Evaluate the effectiveness of TC and the level of satisfaction of patients attending the Mastology Unit using this method during the COVID health emergency. Methods: A prospective, cross-sectional study. A survey was used to assess the effectiveness of TC and the level of satisfaction with the method. Results: : Forty-two patients were surveyed, of which 69% were receiving adjuvant treatment and 14.2% palliative treatment. With regard to the effectiveness of TC, 76.1% of those surveyed had their appointment resolved by telephone; 78.6% of patients preferred to do the consultation by telephone; 97.6% believed that sufficient time was spent and that the timing of the appointment was appropriate. The responses showed a high degree of satisfaction with the care received. The medical care met the expectations of all patients, and 83.3% believed that once normalcy was restored, TC would be an option for their situation Conclusions: The TC method was evaluated with a high degree of satisfaction and allowed care to be maintained during the emergency. Although it is early to assess the healthcare impact of TC and the method's capacity to resolve issues, preliminary results show that it is a useful and valuable tool in clinical practice during periods of healthcare emergency.
Telemedicine visits result in a significantly lower rate of cancellations compared to in-person visits for interventional oncology clinic patients.
Authors: Shah Suken , Solomon Stephen Barnett
Published: June 2021

e13624

Background: Telemedicine allows increased access to specialists, less time in a waiting room and on-demand options with little to no transportation costs. These changes have been accelerated by the COIVD-19 pandemic. The purpose of the study was to test the hypothesis that a virtual telemedicine clinic would significantly decrease no-show rates and cancellations compared to in-person visits for interventional oncology (IO) clinic patients. Methods: Telemedicine visits were performed by a physician or advanced practice provider (PA or NP) at a single institution, academic medical center including 5 regional sites to patients at home in multiple states. Total patients encounters and data from January 2020 to December 2020 were analyzed. Visit types included new visits and follow up visits. Phone only visits were excluded. Primary outcome measures were an analysis of total cancelled visits (both same day and rescheduled visits), completed visits, and total scheduled visits with calculation of the telemedicine and in-person cancellation rates. Results: There was a total of 9,044 IR clinic visits in 2020 from 6,348 unique patients across the MSK Main Campus and Regional Network. Of these clinic visits, 5586 were telemedicine visits and 3458 were in-person visits. There was a significant decrease in no show and cancellation rates for telemedicine patients (6.3%) compared to in-person visits (8.1%) (p-value <0.00001). Conclusions: Telemedicine visits resulted in a significantly lower rate of visit cancellation compared to in-person visits. This reduction in no-show and cancellation rates may yield significant cost savings by eliminating gaps in the interventional oncology clinic schedule to allow for more efficient use of physician time and resources.
Treatment pattern and outcomes of leptomeningeal carcinomatosis in India: CRSF201901 study.
Authors: Goyal Gautam , Singh Ashish , Prasad Manu , Raut Nirmal Vivek , Talreja Vikas , Chandrasekharan Arun , Gupta Kushal , Bhosale Bharat , Kothari Rushabh Kiran , Poladia Bhavesh Pradip , Ghosh Joydeep , Talele Avinash , Shrirangwar Sameer , Karpe Ashay
Published: June 2021

e14012

Background: Leptomeningeal carcinomatosis (LCM) is a rare event and has a dismal prognosis. Limited data is available from India on LCM. Hence we did this country wise audit of LCM. Methods: This was a retrospective, multicentric audit of adult (age ≥ 18 years) patients with diagnosis of LCM, conducted across India in 2020 for patients treated from 2010 to 2020. Baseline characteristics, previous treatments, cancer sites, LCM diagnosis details, treatment pattern and overall survival (OS) were collected. Descriptive statistics were performed and Kaplan Meier analysis was performed for estimation of OS. Results: We had 84 patients diagnosed with LCM. The diagnosis of LCM was confirmed in 52 (61.9%) and probable 32 (38.1%) patients. The mean age was 51.8 years (SD-10.8) and we had 46 (54.8%) females. The three most common site of malignancy were lung, breast and gastrointestinal with 45 (53.6%), 22 (26.1%) and 9 (10.7%) patients. The ECOG PS at the presentation of LCM was 1, 2 in and 3-4 in 41 (48.8%), 28 (33.3%) and 15 (17.9%) respectively. LCM was seen at diagnosis in 2 patients (2.4%) and at progression in rest. The status of the extracranial disease at the occurrence of LCM was progressive disease in 39 patients (46.1%). The treatment offered was best supportive care in 24 patients (28.6%), systemic therapy only in 27(32.1%), systemic therapy and intrathecal therapy in 22 (26.2%) and only intrathecal therapy in 11(13.1%). Among 33(39.3%) patients receiving IT methotrexate was used in 23 (27.4%) and the combination of methotrexate, AraC and hydrocortisone was used in 10 (11.9%). The CSF clearance rate was assessed in 24 (28.6%) patients and the clearance rate was 13.1% (n=11). The median duration of therapy was 4 weeks (IQR 1-14). The median os was 90 days (95% CI 46.2-133.8). Conclusions: LCM has a grave prognosis and nearly 1/3rd patients are treated with best supportive care. Intrathecal therapy though part of all guidelines is administered in 39% of patients. This data can serve as a benchmark for further improvement to facilitate studies for further improving the outcomes.
Anlotinib alone or in combination with temozolomide in recurrent high-grade glioma: A retrospective study.
Authors: Yang Qun-ying , Guo Cheng-Cheng , He Zhenqiang , Lin Fuhua , Zhang Ji , Guo Xiaoyu , Chen Yinsheng , Jiang Xiaobing , Ke Chao , Chen Zhongping , Mou Yonggao
Published: June 2021

e14019

Background: High-grade glioma (HGG) is the most common malignant brain tumor and lacks effective treatment regimen. Anlotinib is a multikinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. This study was performed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide (TMZ) in the treatment of recurrent HGG. Methods: This is a single-center, retrospective study. Eligible patients (pts) were diagnosed with pathologically confirmed high grades (WHO III/IV) glioma and had recurrent or progressive disease on or after prior treatment. Other key eligibility criteria included Karnofsky Performance Status (KPS) ≥ 40, aged 16 ̃75 years and having at least one measurable lesion (RANO criteria). Pts were administrated with anlotinib once daily for 14 days every 3 weeks till disease progression, intolerable toxicities or death. The initial dose was 12mg for younger pts ( < 40 years old) with KPS ≥ 60 and 10 mg for others. Combination treatment was allowed if previous TMZ was effective and tolerable. TMZ was administered on dose-dense schedule (150mg/m2, QD, d1-d7 and d15-d21 every 28 days) or metronomic schedule (25-50mg/m2 QD). The primary endpoint was progression-free survival at 6 months (PFS6m) accessed according to RANO criteria. The second endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Between August 2019 and June 2020, 23 pts with HGG (15 grade IV; 8 grade III; 12 males, 11 females) were enrolled. The median age and median KPS was 42 years and 60. 16 pts have multifocal or disseminated disease. 18 pts received ≥2 lines previous treatment. At the data cutoff date on September 2020, the median duration of treatment was 9 weeks (range: 3-33). The PFS6m was 39.1% and the median PFS was 4.2 months (95% CI: 2.8, 5.6). The median OS was not reached (95% CI: NE, NE) and the OS at 12 months (OS12m) was 54.8%. 8 pts observed tumor response and 9 pts had stable disease. The ORR and DCR were 34.8% and 73.9% respectively. The results of survival analysis for subgroups were summarized in table below. Grade 1 or 2 treatment-related adverse events (TRAEs) occurred in 65.2% pts. No ≥ grade 3 TRAE was found. All hematological TRAEs occurred in patients received combination regimen. No TRAE-induced treatment termination occurred. The lower incidence of TRAE may partly attributed to that most pts (18/23) received lower initial dose (10mg) of anlotinib and the relatively shorter treatment duration. Conclusions: This study showed treatment with anlotinib alone or in combination with TMZ had promising efficacy and favorable tolerability in patients with recurrent HGG.[Table: see text]
Integrated genomic and transcriptomic analysis identified KRT18 mutation and MTAP loss as key genetic alterations related to the prognosis of astrocytoma and glioblastoma.
Authors: Li Zhiyong , Jin Yinghui , Zou Qingping , Shi Xiaofeng , Li Kaishu , He Qun , Lin Zhiying , Wang Xiran , Xie Sidi , Gao Lei , Ni Bowen , Zhang Yunxiao , Wang Ziyu , Liu Rui , Liu Yawei , Huang Guanglong , Qi Songtao
Published: June 2021

e14039

Background: Astrocytoma and glioblastoma (GBM) are two main subtypes of glioma classified by WHO guide of center nervous system (CNS) tumors to different grades. GBM is the most malignant among all CNS tumors with a 5-year survival rate of less than 5%. Although the prognosis of patients with astrocytoma is better than that of GBM in general, astrocytoma patients with IDH wild-type have a similar prognosis as GBM. Exploring the molecular driving force behind the malignant phenotype of astrocytoma and GBM will help explain the diversity of glioma and discover new drug targets. Methods: We enrolled 12 patients with astrocytoma and 12 patients with GBM and performed whole-exome sequencing (WES) and RNA-seq analysis on tumor samples from the patients. Comparative analysis of somatic mutation, copy number variation, cytoband alteration and differently expressed genes were performed between astrocytoma and GBM. Immune cells infiltration was analyzed by CIBERSORT Algorithm with LM22 immune subsets. Results: This study includes 14 male patients and 10 female patients, and the median age was 45.5 (range, 18-68) years old. Seven patients had IDH1 mutation, including 6 patients with astrocytoma and 1 patient with GBM. Somatic mutation of KRT18, which is associated with cell apoptosis and adhesion by interacting with TRADD and Pinin , was significantly enriched in astrocytoma, but rare in GBM. Copy number loss of MTAP, which is a potential drug target and closely related to a poor prognosis of glioma, was found significantly enriched in GBM. Pathway enrichment analysis found that GBM was mainly enriched in tumor-related pathways, such as cell adhesion, cell division, and angiogenesis, but astrocytoma was mainly enriched in pathways with ion transport, cell-cell signaling and neurogenesis. Immune cells infiltration analysis showed that macrophages M0 was significantly enriched in GBM, and activated mast cells, monocytes and plasma cells were significantly enriched in astrocytoma. Conclusions: This study revealed the distinct characteristics of astrocytoma and GBM at the DNA and RNA levels. Somatic mutation of KRT18, which was first reported in glioma, may be closely related to the malignant phenotype of astrocytoma. Copy number loss of MTAP, which was associated with the susceptibility to purine starvation and specific chemotherapy, was a key genetic alterative gene in GBM and had the potential to become the therapeutic target of GBM.
Cutaneous adverse events associated with immune checkpoint blockade: A meta-analysis.
Authors: Han Yiqun , Wang Jiayu , Xu Binghe
Published: June 2021

e14500

Background: Dermatological toxicity is the most common immune-related adverse events (irAEs) following immune checkpoint inhibitors (ICIs). A better understanding of this side effect enables early recognition, diagnosis, and management in clinical practice. Methods: We did a meta-analysis of literature published on ClinialTrials.gov, Pubmed, Embase, and Cochrane Library up to April 30, 2020. Randomized controlled trials (RCTs) which reported the cases of cutaneous irAEs following ICIs (anti-PD-1, anti-PD-L1, anti-CTLA-4) were included. We comprehensively assessed the differences in cutaneous irAEs among ICIs, the effect from dosage and combined treatment on the incidence, the correlations of cutaneous irAE with other organ-specific irAEs, and the predictive values for prognosis. This study was prospectively registered in the PROSPERO platform (ID: CRD42020182247). Results: A total of 687 publications were initially identified and 46 eligible RCTs involving 28569 patients were included. Compared with that in patients receiving anti-CLTA-4 antibody, the overall risk of dermatological irAEs tended to be lower in patients receiving anti-PD-1 antibody (RRrash, 0.60; 95%CrI, 0.36-0.99; RRpruritus, 0.51; 95%CrI, 0.22-1.10) and was lower in those receiving anti-PD-L1 antibody (RRrash, 0.63; 95%CrI, 0.43-0.90; RRpruritus, 0.37; 95%CrI, 0.20-0.67). In general, neither treatment in combination nor dosage were estimated to add additional risk to the incidence of cutaneous irAEs. Dermatological toxicity was positively associated with immune-related hepatitis (P = 0.006), neuropathy (P = 0.040) and gastrointestinal dysfunctions (P = 0.038). The cutaneous irAEs was not confirmed as a surrogate predictor for survival with ICIs monotherapy. Conclusions: This study indicates that cutaneous irAEs are dose-independent and agent-specific immune reactions with the highest risk observed in CTLA-4 blockade, and the occurrence is associated with hepatic, neurological, and gastrointestinal disorders. The exploration in the predictive value of cutaneous irAEs for response and survival outcomes will be warranted in the future.
A phase I study to evaluate the safety and effectiveness of neoantigen-based personalized dendritic cell vaccine in patients with advanced solid tumors.
Authors: WU Jianhui , LIU Daoning , Yan Liang , Lv Ang , Tian Xiuyun , CHENG Xudong , Fu Meng , Qiu Hui , Liu Bonan , Liu Qiao , Li Chengpeng , Wang Zhen , Wang Xiaopeng , Hao Chunyi
Published: June 2021

e14512

Background: Patients with solid tumor may get benefits from neoantigen-based cancer vaccines, which has showed some clinical efficacy data in clinical trials. This study was designed to evaluate the safety and efficacy of a neoantigen-based dendritic cell vaccine in patients with advanced solid tumors Methods: In this single arm study, patient-specific mutation-containing epitopes were detected from patient's tumor tissue. Tumor specimens were processed for whole transcriptome RNA sequencing, whole exome sequencing and HLA typing analysis. Total 10-20 immunogenic neoantigens for each patient were formulated and loaded into patient’s dendritic cells to manufacture the patient-specific anti-cancer vaccines. The patient was administered vaccine injections (Days 0, 14, 35, 56 and 98) into inguinal lymph nodes and intra-cutaneous. Peripheral blood was collected during the treatment (Days 14,15, 35, 36, 56, 57,77, 99 and 120) for safety evaluation and for assessment of the expansion of antigen-specific T cells in vivo. Patients were followed up until confirmed disease progression, withdrawal consent or adverse event intolerance. Results: Between 2019 and 2020, six patients received the neoantigen-based DC vaccine. The tumor types were laryngeal carcinoma, leiomyosarcoma, biliary tract carcinoma and hepatocellular carcinoma. All six enrolled patients had stage III or IV disease and had failed at least one line of systematic therapy at baseline. Preliminary data revealed that 6 pts (5 female and 1 male) with mean age of 44 (41-50) yrs. received ≥3 dose of DC vaccine. Doses ranged from 2×106 cells/ml to 10×106 cells/ml. All observed treatment related Adverse Events were Grade 1 or Grade 2. The most common (≥10%) drug-related adverse events were fatigue (15%), fever (15%), and elevated AST (20%). Five patients received at least one disease assessment post baseline visit. There were no tumor response. The patient with biliary tract carcinoma, laryngeal ca, leiomyosarcoma had SD status for 11 weeks, 30 weeks and 16 weeks respectively. Patients were assessed with the ELISPOT, which showed a CD8 + neoantigen-specific T-cells expansion was detected from each of the six patients’ peripheral blood after the fifth vaccine injection, which demonstrate the preliminary proof of concept for this personalized neoantigen-based dendritic cell vaccine. Conclusions: In this study, neoantigen-based dendritic cell vaccine has showed preliminary activity in advanced solid tumor patients with well-tolerated safety profile, which indicated the neoantigen-targeting DC vaccine has potential to be an effective treatment (with alteration of the immune cell milieu) in solid tumor patients.
Modification of intrinsic ovarian cancer tumor factors by Wnt-pathway agents influences macrophage recruitment and activity.
Authors: Dholakia Jhalak , Scalise Carly Bess , Katre Ashwini A. , Arend Rebecca Christian
Published: June 2021

e14514

Background: The Wnt/B-catenin pathway is associated with a “cold” phenotype in the gynecologic malignancy tumor microenvironment (TME), resulting in immunosuppression. Research is limited regarding this pathway’s effects on TME myeloid cell populations. We aimed to characterize the impact of Wnt pathway modulation on macrophage activity in ovarian cancer. Methods: Syngeneic murine models harboring ID8 parental (ID8par) tumors were treated with DKN-01 and CGX-1321 as single agents or in sequence (DKN-01 followed by CGX-1321.) Flow cytometry analyses were performed on harvested omenta and blood. Ascites from 10 high grade serous epithelial ovarian cancer patients were treated with DKN-01 (Wnt activator) or CGX-1321 (Wnt inhibitor) for 48 hours; multiplex cytokine array was performed to determine changes in cytokine/chemokine expression. Lastly, we performed co-culture analyses on the effects of ID8par and ID8p53-/- isolated cell media on murine macrophage (RAW264.7) activity. Results: In the ID8par model, sequential DKN-01/CGX-1321 resulted in the greatest macrophage influx into the TME. CGX-1321 monotherapy increased the M2:M1 macrophage ratio (pro-tumor) while DKN-01 monotherapy resulted in decreased M2:M1 ratio (anti-tumor.) In human ascites, DKN-01 increased macrophage colony stimulating factor (M-CSF) expression. Of note, ascites from a patient harboring a p53 mutation demonstrated an increase in M1 polarization cytokines IFNy and TNFa in response to DKN-01; CGX-1321 treatment resulted in increased M2 polarization cytokines IL-4 and IL-13. In co-culture analysis, ID8par isolated media increased RAW264.7 migration and polarization towards an M2 phenotype; ID8p53-/- isolated media polarized towards an M1 phenotype. Conclusions: Macrophage activity influences immune responses and tumor behavior. For example, M2 macrophages are pro-tumor and can enhance tumor growth and immune evasion. In our studies, we demonstrated that macrophage recruitment and polarization (M1 vs M2) are influenced by genetic alterations that can be modified by treatment. The ID8par model positively influenced M2 macrophage activity; ID8p53-/- cells positively influenced M1 macrophage activity. Importantly, DKN-01 treatment reverses the M2-dominant phenotype in ID8par model towards M1. These results suggest that p53 mutation and/or DKN-01 treatment in ovarian cancer influences M1 anti-tumor macrophage activity, and posits a novel targetable pathway. Further studies should investigate Wnt/B-catenin modulation on macrophage activity for immunotherapy in gynecologic malignancies.
Immune effector cell therapies in oncology: A systematic analysis and forecast from ClinicalTrials.gov.
Authors: Forero-Forero Jose Vicente , Garcia-Robledo Juan Esteban , Castro-Martinez Daniela A. , Moreno Eider Felipe , Diaz Paula Andrea Lengerke , Booth Natalie , Castro Januario E.
Published: June 2021

e14516

Background: IEC are arguably the most promising therapy in oncology, and FDA approvals for CAR T cells are a testament to their real potential. This has led to a great growth of clinical trials (CT), making the evaluation of their associated data increasingly challenging. To facilitate this process, we performed a systematic review of ClinicalTrials.gov focused on IEC therapies in oncology. We performed an analysis of the CT data and forecast trends for 2025. Methods: CT registries were retrieved from ClinicalTrials.gov with a systematic search query. We included CT registered between 1993-2020, which used IEC-based therapies in oncology. Statistical analysis using descriptive and inferential methods allowed us to identify trends and establish forecasts. Results: We identified 938 registrations of IEC-CTs in oncology, and 51% of those were active. The most common IEC type was CAR T (51%), followed by NK (15%), TCR T (8%), TIL (8%), and CIK (3%). 69% of IEC-CTs were aimed at a specific target vs. 31% that lack that specificity. The number of annual CAR T-CTs continue to increase, and we forecast 320 registrations during 2025. Since 2018, the number of CTs using unmodified T cells and TIL has increased (largely due to metastatic melanoma studies). NK cells CTs represent 8% of all registrations, and by 2025 we anticipate that >150 NK-based CTs will be registered per year, a number similar to CAR T-CTs registered during 2020. IEC-CTs based on allogeneic sources represent 18% of all registrations and are expected to grow 2.5 fold in the next 5 years. In solid tumors, the most common IEC-CTs are based on Non-CAR studies, while in hem-malignancies 76% of CTs are CAR T. Only one solid tumor, CAR T-CT, has reached phase 2/3, while 7 CIK-CTs were used to target various organ tumors. Conclusions: IEC-CTs continue to grow exponentially and represent an active field of clinical research in oncology. Allogeneic and NK-CTs increase rapidly and are among the most promising IEC-CTs. A rising proportion of CTs in solid tumors are using CIK and TIL rather than CAR T-cells, which are more popular for treating hem-malignancies. This is a direct reflection of the challenges associated with CAR T infiltration and persistence in solid tumors. Our analyses indicate that annual IEC-CTs registrations will double by 2025. We anticipate the increase in cellular therapy options will demand an organized response, including adequate logistical planning and policy implementation in response to the landscape changes in clinical oncology during the upcoming years.[Table: see text]
Systemic and local inflammation characteristics in patients with cancer after lung transplantation.
Authors: Steindl Ariane , Nackenhorst Maja , Puhr Hannah Christina , Marhold Maximilian , Sinn Katharina , Hoetzenecker Konrad , Hoda Mir Alireza , Preusser Matthias , Berghoff Anna Sophie
Published: June 2021

e14527

Background: Immune suppressive treatment is associated with an increased cancer risk due to its negative impact on immunosurveillance. We analyzed the association of immune suppressive treatment with the inflammatory tumor microenvironment and systemic inflammation parameters in patients with solid cancers after lung transplantation. Methods: Systemic inflammation was measured by neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) and analyzed at time of lung transplantation and time of tumor diagnosis. In tumor samples, the expression of tumor infiltrating lymphocytes (TIL) including CD3, CD8, CD45RO and PD-L1 using the Ventana Benchmark Ultra system for immunohistochemistry were investigated. Automated tissue analyses were performed for CD3, CD8 and CD45RO TIL (Definiens software). PD-L1 expression was determined by using the combined positive score (CPS). Results: 28 patients with cancer (10 lung cancer, 4 colorectal cancer, 2 renal cell carcinoma, 2 gastric cancer, 2 pancreatic cancer, 2 head&neck tumor, and others) were included in the study. Median time from transplantation to cancer diagnosis was 45 months (range 29-61). 57% (16/28) experienced a period of transplant rejection between transplantation and tumor diagnosis. Therefore, 25% (7/28) of the patients received intensified immunosuppression up to 8 weeks before tumor diagnosis. Median density of CD3+TIL was 5742 cells/ mm2 (range 3,203-8,429), median density of CD8+TIL was 6,363 cells/ mm2 (range 3,643-8,190), median density of CD45RO TIL was 72 cells/ mm2 (range 4-635) and median expression of PD-L1 was 60 (range 5-100) in tumor samples. No statistically significant changes in systemic inflammation were observed from time of transplantation to time of tumor diagnosis (p>0.05; Wilcoxon Signed-Rank Test). Furthermore, a history of transplant rejection before tumor diagnosis was not statistically significant associated with changes in TIL densities or systemic inflammation parameters (p>0.05; Mann Whitney U test). Conclusions: An activated local inflammatory tumor microenvironment as well as stable systemic inflammation characteristics were observed in our cohort. These results support the further development of immunotherapy as treatment approach also in cancer patients under immunosuppression after lung transplantation.[Table: see text]
Personalized DNA neoantigen vaccine in combination with plasmid IL-12 for the treatment of a patient with anaplastic astrocytoma.
Authors: Johanns Tanner Michael , Perales-Puchalt Alfredo , Stupp Roger , Berger Mitchel , Gillanders William E. , Miller Chris , Hundal Jasreet , McLellan Michael D. , Goedegebuure S. Peter , Rochestie Sarah , Cooch Neil , Peters Joann , Dunn Gavin P. , Sardesai Niranjan
Published: June 2021

e14561

Background: Tumor neoantigens are epitopes derived from tumor-specific mutations that may be incorporated in personalized vaccines to prime T cell responses. DNA vaccines delivered with electroporation have recently shown strong CD8 and CD4 T cell responses in clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth. Methods: Two resection samples from a patient with IDH+ MGMT-methylated anaplastic astrocytoma were subject to whole exome and transcriptome sequencing. Epitopes derived from 27 neoantigens and 3 shared tumor-associated antigens were prioritized and included in a personalized vaccine. The patient was treated with surgery, radiotherapy and temozolomide starting June 2018 and received the first dose of the personalized vaccine in June 2019 under a compassionate use single patient IND application with the FDA. Results: As of February 10, 2021, the patient has received 10 doses of the DNA personalized vaccine. No serious adverse events have been reported. Related adverse events are limited to grade 1 injection site reactions. The patient remains progression-free 32 months after surgery and 20 months after starting vaccination. Three weeks following the third dose, a hyperintense image on the tumor bed was identified, which disappeared on the following MRI, 2 weeks following dose 5, being catalogued as pseudo progression. Ex vivo ELISpot have identified T cell responses to 21/30 epitopes (70%), including 18/27 (67%) neoantigens and 3/3 (100%) shared antigens. Flow cytometry analysis has determined that T cell responses are 92.3% CD8 and 69.2% CD4 (30.8% CD8 only; 61.5% both CD8 and CD4; and 7.7% CD4 only). Conclusions: This compassionate use treatment in an adjuvant setting demonstrates manufacturing feasibility, safety, tolerability, immunogenicity, and suggests potential for persistent clinical response of DNA encoded personalized vaccines. The data supports further investigation of DNA-encoded personalized vaccines into newly diagnosed high-grade gliomas.
Immune-related adverse events associated with immune-checkpoint inhibitors therapy in Mexican patients: Experience at a single center.
Authors: Gonzalez Espinoza Iván Romarico Romarico , Cortés Escobar Neil , Chiquillo-Domínguez Mariana , Juárez Salazar Gabriela , Garibay Diaz Julio Cesar , Gozalishvili Boncheva Anna , Acosta Ponce De León Eric , Sánchez Sosa Sergio , Ibarra Fernández Rebeca , Miguel Cruz Enrique , Sabaté Fernández Mónica , García Reyna Juan Carlos , Aguilar Priego José Manuel , Domínguez Peregrina Alfredo , Tobón Helú Giovanni , Cordero Vargas Carlos , Gonzalez Blanco María de Jesús , Aguilar Carmen , Arroyo Kuribreña José Carlos , Vizcarra Ramos Feliciano de Jesús
Published: June 2021

e14580

Background: The use of immune-checkpoint inhibitors (ICIs) for solid malignancies is rapidly rising, and many new agents and treatment combinations are in development. However, ICIs have a unique side-effect profile of immune-related adverse events (irAEs) compared with chemotherapeutic agents or targeted therapies. The aim of this work was to describe the irAEs in diverse types of malignant tumors using real-world data. Methods: This is a retrospective and descriptive study of patients with diverse types of advanced malignancies treated with immunotherapy at Centro Oncológico Integral of the Hospital Ángeles in Puebla, México; during the period 2016-2020. Data about the primary neoplasm, ICIs, irAEs, organ system affected, grade and treatment was collected. Clinical and laboratory parameters were obtained by reviewing medical records. Results: A total of 117 patients were included, median age of 65 years, of which 63.2% were male and 36.8% were female. The most frequent neoplasms treated with ICIs were: lung (27.4%), kidney (16.2%), melanoma (12.8%), hepatocellular (9.4%), breast (8.5%), non-melanoma skin cancer (6.0%), mesothelioma (4.3%) and other tumors (15.3%). 39.3% of the patients had no metastases, 41.9% had metastases to at least 1 or 2 sites, and 18.8% to 3 or more sites. The types of ICIs were: nivolumab (35.0%), pembrolizumab (28.2%), atezolizumab (23.9%), ipilimumab + nivolumab (12.0%) and durvalumab (0.9%). The most frequent irAEs were: gastrointestinal (61.5%), neurologic (46.2%), pulmonary (38.5%), metabolic (32.5%) and hematologic (29.1%). 39.3% of the irAEs were reported as grade 1, 31.6% as grade 2, 14.5% as grade 3 and 2.6% as grade 4. Conclusions: Our work shows the incidence of irAEs in a poorly studied population and provides new data that complement that reported by other works, however, further prospective studies are necessary.[Table: see text]
Venous thromboembolism in patients on check point inhibitors.
Authors: Giri Upama , Yu Xiao , Resnick Karen , Larsen Travis , In Gino Kim
Published: June 2021

e14582

Background: Checkpoint inhibition (CPI) therapy, including PD-1/PD-L1 and CTLA-4 inhibition strategies, has significantly improved the prognosis for patients with advanced malignancies. Anticancer treatments like chemotherapy and antiangiogenic agents are associated with higher rate of cancer associated thrombosis. However, the association of CPI with venous thromboembolism (VTE) is not well established. Methods: We conducted a retrospective cohort study of patients with advanced malignancy who were started on CPI between 2016 and 2019 at a tertiary care medical center in Southern California. We used descriptive statistics to describe the occurrence of VTE. Logistic regression was used to identify factors that had a significant impact on occurrence of VTE. Results: The cohort comprised 240 patients with median age of 60 years (range 27-96) at initiation of CPI and majority of the patients were males (57%). 45% were Hispanic, followed by Asian (19%), Caucasian (18%) and African American (8%). 80% had metastatic disease and the most common indication for use of CPI was lung cancer (20%), followed by gynecological malignancies (19%) including ovarian, endometrial and cervical cancer, melanoma (15%) and genitourinary malignancies (15%) including renal and urothelial cancer. The most used agent was nivolumab (68%) followed by pembrolizumab (25%), with most patients receiving single agent CPI (94%). Combination CPI and CPI with other agents including chemotherapy or targeted therapy was given to 3% and 4% respectively. The incidence of VTE was 10% (24/240) – pulmonary embolism (5), upper extremity deep vein thrombosis (5), lower extremity deep vein thrombosis (10) and visceral vein thrombosis (4). Patients were also stratified by Khorana score (KS) based on laboratory values and body mass indices at initiation of CPI (median score 1, range 0-4). VTEs occurred in patients on nivolumab in 8.02% of cases and in 18.2% of cases for pembrolizumab. VTEs occurred in 7.04% of patients with initial KS 0; 8.33%, KS 1; 17.5%, KS 2; and 15.4%, KS 3. Logistic regression analysis using a significance level of p < 0.05 showed no significant association between occurrence of VTE and age, sex, race, type of cancer or Khorana score. Conclusions: In our study, VTE risk in patients receiving CPI was similar to that with other systemic therapy. Further larger studies are needed to assess clinical significance of these findings, stratify for risk factors, and account for dose-dependence.
Corticosteroid use and its impact on the efficacy of immunotherapy in multiple tumor types.
Authors: Nelson Blessie Elizabeth , Greiner Benjamin , Hong Angelina , Tipton Shelby , Lee Marissa , Dixon Andre , Venkatesan Rohit
Published: June 2021

e14583

Background: Studies have suggested that concurrent corticosteroid use may decrease the efficacy of immunotherapy for cancer treatment, however, the data remains limited. The purpose of this study is to expand upon the previous literature to analyze the outcomes of patients with the following cancer sites: renal cell, lung, melanoma, urothelial, head and neck, hepatocellular, or breast cancer who received immunotherapy and steroids concurrently. Our primary objective was to analyze the overall survival (OS) and objective response rate (ORR) of patients receiving immunotherapy with corticosteroids compared to immunotherapy alone. Methods: A retrospective cohort study was conducted of patients receiving immunotherapy plus corticosteroids compared to immunotherapy alone using University of Texas Medical Branch patients. Patients receiving nivolumab, pembrolizumab, atezolizumab, ipilimumab, durvalumab, or avelumab between January 1, 2012-August 2020 with one of the following cancers were included in the analysis: Renal cell carcinoma, lung carcinoma, melanoma, urothelial carcinoma, head and neck carcinoma, hepatocellular carcinoma, and breast cancer carcinoma. The resulting sample was then separated into two arms. The experimental sample received any of the following steroids either as part of their therapeutic regimen or for symptom management and within 30 days of immunotherapy initiation or at any time during the immunotherapy regimen: dexamethasone, prednisone, methylprednisolone, or hydrocortisone. The control did not receive steroids within 30 days of initiation or during the course of their immunotherapy regimen. Weibull regression models were then constructed to compute hazard ratios for OS at 6 months, 12 months, and 3 years. ORR - complete and partial response, stable disease, and disease progression - between the two arms was assessed using a chi-squared test. Results: Two hundred and sixty patients met inclusion criteria. Of this, 164 received corticosteroids. Our sample was primarily male (70.38%), white (66.54%), and had 0-1 comorbidities (83.08%), lung cancer (45%), and metastases (81.92%). There was no significant difference between the two arms regarding sex, age, number of comorbidities, ECOG score, cancer type, or race. There was no statistically significant difference in OS between the experimental and control arm at 6 months (HR: 1.01; 95%CI 0.63-1.62), 12 months (1.02; 95% CI 0.69-1.51), or 3 years (1.06; 95% CI 0.79-1.42). There was no significant difference in ORR at 6 months between the two arms (2 = 6.3, p=0.178). Conclusions: There was no statistically significant difference in OS or PFS between the two study arms. This study suggests that corticosteroid use does not affect immunotherapy efficacy as previous literature suggests. Larger studies are needed to assess the impact of corticosteroids on immunotherapy efficacy in patients with cancer.