bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of demographics and outcomes of surgical resection in the CNS of patients with melanoma.
Authors: Guddati Achuta Kumar , Komiya Takefumi , Hector Picon , Krutchik Allan N. , Kumar Gagan
Published: June 2021

e21534

Background: Patients with melanoma frequently develop central nervous system metastases. Oligometastatic disease is often treated either by surgical resection or by stereotactic radiotherapy. This study investigates the trends and clinical outcomes of patients with melanoma who have undergone surgical procedures on the central nervous system during their hospitalization. Methods: A retrospective cohort study was performed based on admissions of adult patients who underwent craniectomy/surgical resection for metastatic melanoma from 2002 -2014 using the Nationwide Inpatient Sample database. The primary outcome measure was all-cause in-hospital mortality. Secondary outcomes included length of hospital stay(LOS) and discharge disposition (home/home with health care and skilled nursing facilities/long term acute care (SNF/LTAC)). Factors associated with in-hospital mortality were examined by multivariable logistic regression. We adjusted for patient and hospital characteristics, payer, and comorbid conditions. We also examined trends of mortality for the study years. P was kept at 0.05. Results: There were an estimated 5972 discharges of patients with melanoma undergoing craniectomy/surgical resection during the study period. Patients undergoing surgical interventions were typically males (69%) and whites (79%). 98% of procedures were performed at teaching hospitals. Unadjusted all-cause in-hospital mortality was 3.1%. There was no significant difference in mortality over 13 years. Age, gender, and race were not associated with increased in-hospital mortality. Median LOS was 5 days (IQR 3-9 days). LOS was longer in elderly and those with higher Charlson co-morbid index. Of the survivors, 76% were discharged to home or with home healthcare while 24% were discharged to SNF/LTAC. Patients with age > 65 (OR 2.9; 95%CI 2.2-3.9, p < 0.001) and those with higher Charlson co-morbid index (OR 1.2; 95%CI 1.1-1.3) had higher odds for being discharged to SNF/LTAC. Conclusions: Patients who undergo craniectomy/surgical resection for melanoma have a low in-hospital mortality rate. One quarter of patients are discharged to SNF/LTAC.
Proteomics meets transcriptomics: Identification of tumor tissue signatures specific to anti-PD1 treatment in late-stage melanoma patients.
Authors: Sklodowski Kamil , Mallardo Domenico , Vowinckel Jakob , Capone Mariaelena , Soste Martin , Madonna Gabriele , Vanella Vito , Warren Sarah , Ascierto Paolo Antonio
Published: June 2021

e21543

Background: Despite advances of anti-PD1 treatment in melanoma, still large subset of patients does not respond or relapses due to primary or acquired resistance. One potential way to overcome the mechanisms of resistance is to identify molecular signatures associated with response to treatment. Here, we are presenting the results of an integrated deep transcriptomic and proteomic analysis of melanoma tissue samples coming from patients prior the treatment with anti-PD1. The combination of targeted transcriptomic approach with unbiased proteomic approach allowed for identification of a molecular response signature specific to anti-PD1 therapy. Methods: Unbiased quantification of proteins in tumor tissues was done using data-independent acquisition (DIA) LC-MS technology. Proteins from tissue samples were denatured, digested, and analyzed on a mass spectrometer. A deep spectral library was generated, and proteins were quantified using Spectronaut software (Biognosys). From the same tumor tissue RNA was extracted and subjected to transcriptomic analysis with NanoString nCounter using the PanCancer IO 360 panel. Integration analysis using latent components, a generalized PLS and sparse sGCCA method implemented in R mixOmics package was used for signature discovery. Results: Studied cohort was balanced for gender, BRAF mutations and stage. Treatment included Nivolumab or Pembrolizumab. Only among responding subjects, low grade (≤ 2) skin toxicity was identified at a significant level (p-value < 0.05). In total, 22 samples were measured (nine non-responders and 13 responders). Overall, the analysis of proteome across all samples resulted in 8548 proteins being identified and quantified. The IO 360 panel contained 770 targets. In combined analysis, 10 mRNA targets together with 64 protein targets were highly associated with response to treatment. Two top candidates identified for mRNA and proteins were SIGLEC5 and ACP6 respectively. The panel of 74 features was sufficient to separate all subjects using unsupervised hierarchical clustering into to two main clusters enriched for responders and non-responders (p-value < 0.05). String-DB analysis revealed numerous interactions and associations within identified panel. Functional analysis using GO enrichment showed major involvement of the selected mRNA and proteins in T-cell regulation as well as in neutrophil degranulation and antigen receptor mediated signaling. Conclusions: Combination of both omics assays provides a very comprehensive image of tumor tissue responses to anti-PD1 treatment in late-stage melanoma patients. Identified candidates show striking changes in responder and non-responder groups and should undergo further validation for use in precision medicine.
Impact of immunotherapy on survival differences in patients with melanoma and chronic lymphocytic leukemia.
Authors: Tripathi Raghav , Bordeaux Jeremy S. , Rothermel Luke , Mangla Ankit
Published: June 2021

e21550

Background: Chronic lymphocytic leukemia (CLL) is well known to be associated with secondary malignancies like melanoma. Patients with melanoma and CLL are known to have poorer prognosis compared to patients without CLL. Checkpoint inhibitors (CPI) started gaining traction in 2011 after ipilimumab approval and are widely used in treatment of advanced melanoma. The objective of this study is to determine the survival of patients with melanoma and CLL in the era of CPI (2011 onwards) compared to previous years. Methods: We identified patients with melanoma and CLL reported to the Surveillance, Epidemiology, and End Results (SEER-18) program. We created cohorts of patients with melanoma and CLL vs. melanoma without CLL and split the cohorts into patients diagnosed from 2000-2010 and 2011-2017 to evaluate the impact of immunotherapy on overall all-cause survival. Kaplain-Meier survival curves were created for each of the four cohorts using the Ederer/direct-adjusted survival method. Standard Cox regression models adjusted for age and sex used to compare survival between subgroups. Two-sided p-values < 0.05 were considered significant. Results: From 2000-2017, 536,264 patients with melanoma were included in this study. 2,945 [0.55%] patients had coexisting CLL. Most patients were male (303,477 [56.6%]), age 60-79 (235,833 [44.0%]), non-Hispanic white (499,151 [93.08%]), and diagnosed from 2000-2010 (285,292 [53.2%]) with melanoma of the trunk (156,722 [29.2%]). From 2000-2010, patients with melanoma had an average survival of 91.4 months (95% CI 88.7-94.1) and those with coexisting CLL had an average survival of 59.3 months (95% CI 58.1-60.6). From 2011-2017, patients with melanoma had an average survival of 129.1 months (95% CI 127.7-130.5) and those with coexisting CLL had an average survival of 116.0 months (95% CI 113.5-118.5). The difference in survival in patients with melanoma vs. melanoma and CLL in 2000-2010 (32.1 months) is significantly greater than that of patients from 2011-2017 (13.1 months, p < 0.05). Conclusions: Although CLL continues to confer a survival disadvantage in patients with melanoma, the survival of patients with CLL and melanoma is better in the CPI-era. We also demonstrate that in the CPI era the gap between the survival of patients with melanoma and CLL and melanoma alone is also reducing significantly.
Modified operations to permit safe and timely delivery of essential surgical care for high-risk skin cancer during a pandemic.
Authors: Jackson Cullison Stephanie Renae , Celen Arda , Doudican Nicole Adell , Stevenson Mary , Carucci John A.
Published: June 2021

e21565

Background: Many surgical practices closed at the onset of the COVID-19 pandemic raising concerns that delayed cancer care might impact patient outcomes. We implemented operational changes to safely remain open and treat tumors with potential to threaten life or function. We studied the impact of these changes on safety, access, and treatment. Methods: A single-center retrospective study was conducted in an academic office-based dermatologic surgery practice. All patients consented to research. “Pre-pandemic” (Nov. 2019 – March 21, 2020) consultations served as controls. Consultations during the “pause” (March 22 - June 8, 2020) and “reopening” (June 9 – Sept. 30, 2020) were evaluated for time to treatment, tumor area, and upstaging. One-way ANOVA or Fisher Exact analyses were performed with P < 0.05 significant. Operational changes included (1) modified scheduling, staffing, and rooming; (2) COVID-19 symptom screening; (3) N95 masks and shields for patient contact; (4) triage by tumor acuity; (5) same day or video consultation; and (6) increased utilization of same day biopsy and surgery for suspicious lesions. Results: Data from 698 patients (23-103 yrs of age, avg 71 yrs) yielded 876 tumors treated by Mohs surgery (n = 776), standard excision (n = 73), staged excision (n = 14) or electrodessication and curettage (n = 13). The average time from biopsy or consultation to treatment was faster during the pause and reopening relative to pre-pandemic (Table). More frozen section diagnostic biopsies were performed in the pause (n = 6) and reopening (n = 4) compared to pre-pandemic (n = 0). Post-operative defects were similar to pre-pandemic sizes (3.2 cm2) during the pause (3.9 cm2) and reopening (3.2 cm2) (p = 0.72). A reduction in treatment of basal cell carcinoma (BCC, Χ2= 0.04) and shift toward treatment of higher risk tumors such as cutaneous squamous cell carcinoma (SCC, 49% of tumors during pause vs 37% pre-pandemic) and melanoma (11% pause vs 4.7% pre-pandemic) was noted. The percentage of SCC upstaged after treatment increased during the pause (42%, Χ2= 0.02) vs pre-pandemic (18.5%) or reopening (17.4%). Conclusions: Time to treatment, tumor size, and SCC upstaging pre-pandemic and during the reopening fail to identify any significant access interruptions. This likely reflects practice modifications of increased same day surgery, frozen section diagnostic biopsy, and tumor triage. Lack of COVID-19 transmission attributable to maintained operations suggests that essential surgical care can be delivered safely to patients with high-risk skin cancers during a pandemic.[Table: see text]
Aminergic status in the brain of urokinase gene-deficient mice with malignant tumors growing in presence of chronic neurogenic pain.
Authors: Pogorelova Yulia A. , Kaplieva Irina V. , Frantsiyants Elena M. , Surikova Ekaterina I. , Bandovkina Valeria A. , Neskubina Irina V. , Cheryarina Natalia D. , Shalashnaya Elena V. , Kachesova Polina S. , Nemashkalova Ludmila A. , Kit Oleg I. , Pozdnyakova Viktoria V.
Published: June 2021

e21582

Background: The fibrinolytic system of the brain is important for its normal functioning and participation in processes that are significant in various stressful influences, including tumor growth and chronic neurogenic pain (CNP). These pathological conditions change the activity of the brain neurotransmitter system. On the other hand, urokinase deficiency is associated with significant inhibition of tumor growth, while CNP – with its stimulation. The purpose of the study was to analyze the effect of CNP on the levels of biogenic amines in the brain of mice with urokinase deficiency (uPA-/-) with transplanted B16/F10 melanoma. Methods: The study included male and female mice: С57ВL/6 (uPA+/+, n = 48) and C57BL/6-Plautm1.1Bug-ThisPlauGFDhu/GFDhu (urokinase gene-knockout - uPA-/-, n = 48). Mouse strains were divided into subgroups (each n = 6): intact; with CNP (bilateral sciatic nerve ligation); 21 days after subcutaneous transplantation of B16/F10 melanoma; 21 days of B16/F10 melanoma growth in presence of CNP (B16/F10+CNP), with tumor transplantation 2 weeks after the sciatic nerve ligation. Levels of adrenaline (A), noradrenaline (NA), dopamine (DA), histamine, serotonin (5HT), and 5-hydroxyindoleacetic acid (5OHIA) were determined in the brain by ELISA (Cusabio, China). Statistical processing - Statistica 10.0. Results: Levels of NA, DA and 5HT in the brain of intact uPA-/- mice were 3.5, 2.1 and 1.9 times higher (p < 0.05), respectively, than in intact uPA+/+ animals, while histamine and 5OHIA were on average 2.0 times lower. The dynamics of cerebral levels of biogenic amines in uPA-/- mice with pathological factors, alone or combined, had practically no gender specificity, with rare exceptions. So, 5HT levels increased up to 4.5 times in uPA-/- mice of both sexes in response to CNP or B16/F10 growth. Melanoma growth in presence of CNP, on the contrary, decreased 5HT by 3-10 times and DA by 1.6 times (p < 0.05) both in males and females, and decreased NA by 1.6 times (p < 0.05) in females. Conclusions: CNP together with melanoma inhibits the initial activation of the HA-, DA- and 5HT-ergic systems in the brain of uPA-/- mice, which may be an important pathogenetic mechanism of the cancellation of genetically determined inhibition of subcutaneous B16/F10 melanoma growth in urokinase deficiency.
Suppression of tumor development by another tumor in primary immunodeficiency in experiment.
Authors: Surikova Ekaterina I. , Frantsiyants Elena M. , Kaplieva Irina V. , Bandovkina Valeria A. , Trepitaki Lidia K. , Neskubina Irina V. , Kotieva Inga Movlievna , Shumarin Konstantin A. , Zhukova Galina V.
Published: June 2021

e21583

Background: Multiple primary malignant tumors (MPMTs) are characterized by the presence of several primary neoplasms in one patient. The purpose of the study was to create an experimental model of MPMTs with one dominating tumor. Methods: The study included 21 female BALB/c Nude mice. The main group included mice with simultaneous subcutaneous inoculation of tumors: Guerin's carcinoma (0.5 million tumor cells in 0.5 ml of saline solution) under the right scapula and B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline solution) under the left scapula. Control groups included females with melanoma or carcinoma inoculated at the same dosage and volume as in the main group. Results: In a MPMT model, tumors appeared 3 times faster than in controls and demonstrated larger volumes: melanoma – by 7.5 times, carcinoma – by 2.2 times; the survival of mice with MPMTs decreased. Carcinoma in a MPMT model metastasized to melanoma and almost completely suppressed its growth. Melanoma was represented by a small “island” of tumor tissue 3-4 mm in diameter and was located just under the skin at the site of injection of melanoma cells. The light part of the same loose pasty consistency as the dark part, with a diameter of 6-7 mm, was located around the dark “center” of melanoma. The rest part of the tumor located under the left scapula looked like an elongated grayish-pink node of a dense elastic consistency - just like the tumor located under the right scapula, which was much larger in volume. The right and left tumors did not merge with each other; there was a small distance of about 2-3 mm between them. A small lesion of caseous necrosis, 6–7 mm in diameter, was recorded in the center of the right tumor node of Guerin's carcinoma; there was no necrosis in the left tumor. Smaller size, the absence of necrosis and visually more “young” carcinoma tissue on the left indicated its later appearance than that on the right, which, in combination with the remnants of melanoma fused to the left tumor and the absence of “contact” between the left tumor and the right one, indicated the metastatic nature of Guerin’s carcinoma on the left. B16/F10 melanoma did not metastasize. Conclusions: In simultaneous subcutaneous inoculation of murine B16/F10 melanoma and rat Guerin’s carcinoma to female BALB/c Nude mice, carcinoma cells metastasized to melanoma and suppressed its growth.
Long-term survival outcomes with immune checkpoint inhibitors (ICI) in metastatic uveal melanoma (MUM).
Authors: Lee Cha Len , Walsh Naomi , Keane Fergus , Lynch Emer , Reddan Tadhg , Craig Helen , O'Meara Aileen , Smith Deirdre , O'Neill Valerie , Horgan Noel , Kennedy Susan , Gullo Giuseppe , Crown John
Published: June 2021

e21585

Background: The treatment of MUM remains highly unsatisfactory. Single agent ICI produce low response rates. Two recent phase II trials of combination Ipilimumab and Nivolumab yielded response rates of 12% and 18%. We report the long-term survival results of MUM patients (pts) treated with ICI in our institution. Methods: We conducted a retrospective analysis of all pts with a diagnosis of MUM in St Vincent’s University Hospital. Overall survival (OS) was calculated from time of first systemic relapse to death or latest follow-up. One-way ANOVA is used with p < 0.05 considered statistically significant. Results: Out of 244 pts with UM registered in our clinics between April 2008 to October 2020, 52 developed MUM. Median age at initial diagnosis 63 years. 26(50%) are females. Median duration of follow-up of the MUM pts is 35.1 months [2.71-123.2]. Median duration of follow-up from initiation of ICI therapy is 9.1 months [1.6-84.2]. First sites of metastases: liver only 71%, liver plus extrahepatic 17%, and extrahepatic only 12%. Fifteen pts (29%) underwent radical metastasectomy as initial treatment. Thirty-seven (71%) had non-resectable MUM and received systemic treatment (23 total: ICI = 18, chemotherapy = 4, BRAF inhibitors = 1), non-surgical locoregional therapies (5 total: chemosaturation = 3, radiofrequency ablation = 2) or supportive/palliative care (9) as first-line. An additional 22 pts received ICI as second or subsequent treatment, for a total of 40 treated with ICI. Of these, 17 received single agents ICI (Ipilimumab = 11, Pembrolizumab = 6), 13 received sequential Ipilimumab and anti-PD1, and 10 received combination Ipilimumab /Nivolumab. At the time of analysis on 31st October 2020, 9 out of 52 pts (17%) are alive at 2.6, 5.0,5.4,8.9,17.3, 54.7, 77.5, 83.1 and 121.7 months (the 6 longest all had ICI). The median OS is 14.3 months [0.6-121.7]. Pts treated with ICI demonstrated longer OS than pts who did not receive ICI [15.0 months, 5.0-121.7 vs 7.2 months, 0.6-34.6; p = 0.089]. The median OS is 24.9 months (sequential Ipilimumab and anti-PD1) vs 15.0 months (combination Ipilimumab/Nivolumab) vs 13.4 months (single agents). Of the three pts remain alive > 5 years, one is currently disease-free. Conclusions: Prolonged survival beyond five years is achieved by a minority of pts with MUM who receive ICI during their treatment history, although durable initial ICI-induced remission is very rare. Our data suggest that pts who receive two ICI drugs during their illness may have longer survival compared to those who receive only a single ICI.
The importance of variants of unknown significance (VUS) in BRCA mutation.
Authors: Mullai N
Published: June 2021

e22507

Background: Genetic testing of patients for BRCA mutation may report variants of unknown significance (VUS). The use of multi-gene panels in clinical care has been increasing. Consequently, the reporting of variants of unknown significance has also increased. More than two decades of research and testing have elevated the status of BRCA1 and BRCA2 genes as the most well characterized genes. However, VUS are found even in BRCA1/2 testing. This raises many ethical and policy issues including communicating the significance of the results and possible clinical management options to patients. The practicing physicians would face the ethical and potential legal burden of contacting and explaining to patients, when any role of VUS changes and gets reclassified as potentially harmful. Methods: Data were collected retrospectively from medical records of patients tested for BRCA mutations. The results of fifty-two patients were analyzed. Eight patients had BRCA1 and BRCA2 mutations and twelve patients had variants of unknown significance. Results: When the results of thirteen patients with BRCA mutations with VUS were analyzed further, the variants included POLE, CHEK2, PALB2, MUTHYH, BR1P1, MSH3, ATM, RAD51C, GALNT12, etc. The age of these patients ranged from 39 years to 69 years. Four patients had ovarian cancer and eight patients had breast cancer, and one patient had both breast and ovarian cancers. The number of patients with stage IV, III, II, and I diseases were six, one, two, and two respectively. One patient had bilateral breast cancer and one patient had carcinoma in-situ. Eight patients had family histories of various cancers, including cancers of the breast, uterine, and prostate cancer. All patients were treated appropriately and three patients died due to their disease. Conclusions: Based on patients’ age, family histories, and disease characteristics BRCA mutation analyses were done. All patients tested positive for BRCA mutations and VUS were informed about their results. Variants of BRCA1 and BRCA2 occur in 2%-4% of tests depending on the laboratories, where the tests were performed. There is no concordance as to how VUS results were reported. There is conflicting evidence regarding the pathogenicity of VUS. These make clinical recommendations very complex. Based on existing guidelines, physicians can explain the details of the significance of BRCA! And BRCA2 mutations to patients with clarity. However, it is difficult and unclear to give recommendations regarding prophylactic measures, specific treatment options for BRCA mutation positive breast and ovarian cancer, follow-ups, and family testing in patients with VUS. Therefore, during BRCA testing, when VUS are reported routinely along with mutations of known significance, the treating physicians would need a better guidance to advise their patients without unduly increasing their anxiety, fear, and potential for misunderstanding.
Oncologist management of NTRK fusion-positive NSCLC improves after virtual patient simulation participation.
Authors: Worst Michelle Arielle , Cain Brittany , Nelson Tipp , Cohen Jacob , Drilon Alexander E.
Published: June 2021

e23008

Background: Although relatively rare, neurotrophic receptor tyrosine kinase (NTRK) fusions, represent a clinically relevant subgroup of NSCLC that can derive benefit from targeted therapies. Relatively quick and durable responses have been achieved with these targeted therapies in advanced NSCLC and intracranial activity has also been observed. The objective of this study was to determine if an online, virtual patient simulation (VPS)-based continuing medical education (CME) intervention improved performance of oncologists in using appropriate strategies to diagnose and manage patients with NTRK fusion-positive advanced NSCLC. Methods: The CME intervention consisted of two patient cases presented in a VPS platform that allowed learners to order lab tests, diagnoses and treatments in a manner matching the scope and depth of actual practice. Clinical decisions made by the learners using open field entries within an EHR interface were analyzed and, after each decision, tailored clinical guidance (CG) was provided based on current evidence and expert recommendation. Learner decisions were collected post-CG and compared with each user’s baseline (pre-CG) data using a McNemar’s test to determine P values. Results were then aggregated for the two cases based on clinical decisions and stratified by practice setting. The activity posted July 31, 2020; data were collected through December 1, 2020. Results: Overall significant improvements were seen after CG in clinical decisions made by oncologists in both the community and academic settings [reported as % absolute improvement (% correct pre-CG vs % correct post-CG); P value]. Conclusions: This analysis demonstrated that VPS that immerses and engages oncologists in an authentic and practical learning experience can significantly improve evidence-based clinical decisions related to the diagnosis and management of patients with NTRK fusion-positive advanced NSCLC. Despite the improvements, additional educational activities are needed to address any residual gaps and further increase oncologists’ ability in this clinical setting.[Table: see text]
Refining the approach to patients with primary soft tissue sarcoma of the extremities and trunk wall (ESTSTS): Outcome improvement over 30 years at a single institution.
Authors: Danieli Maria , Barretta Francesco , Fiore Marco , Radaelli Stefano , Sangalli Claudia , Barisella Marta , Stacchiotti Silvia , Palassini Elena , Miceli Rosalba , Callegaro Dario , Casali Paolo Giovanni , Gronchi Alessandro
Published: June 2021

e23548

Background: In 2011 we reported the improved outcome of ESTS pts treated between 1987 and 2007 at Istituto Nazionale Tumori (INT), Milan (Italy). We updated the analysis at a later follow-up (FU) to assess possible changes in survival of ESTSTS. Outcomes according to histology were also explored. Methods: Pts with primary localized adult-type ESTSTS surgically treated at INT between 1987 and 2017 were retrospectively reviewed and divided into 6 groups according to the date of primary surgery. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local relapse (LR), distant metastases (DMs) were calculated for each group in a competing risks framework. DM free survival (DMFS) was calculated for each group taking into account all DMs (occurred as first or later). PostDM survival and all outcomes according to histology were calculated before and after 2002. Results: 2384 pts were included. At a 104-mo m-FU, median post-DM FU was 76 mos. Clinicopathologic characteristics were comparable among groups. The use of preoperative chemo (ChT) and radiotherapy (RT) increased from 18% (1987-92) to 29% (2013-17) and from 1.6% to 26%. The rate of preoperative combined ChT-RT also increased from 0.8% to 14.3%. 1st event before SSM was LR in 17.9% pts, DM in 72.2% pts and synchronous LR-DM in 9.3% pts. Table shows 7-yrs outcomes incidence estimates for each period. CCI-SSM (p < 0.001), CCI-LR (p < 0.001) and DMFS (p = 0.040) improved significantly since 2003. 7-yrs postDM survival before vs. after 2003 increased from 15% to 23.6% (p = 0.012). Outcomes by histology were comparable to overall results. Conclusions: In the time frame analyzed, SSM improved by over 15%. An equal improvement in DMFS, the 50% decrease in CCI-LR (1 pts out of 5 had LR as 1st event before death), and the significant postDM increase might explain SSM improvement. Maximum change was seen since 2003 and was paralleled by an increase in the use of preoperative ChT and RT, that might have contributed to a better local and distant control. Of note, the increase in DMFS was not accompanied by a decrease in CCI-DM. The increase in DMFS might be attributable to combined modalities’ ability to offset the negative prognostic impact of positive surgical margins, while no effect was observed on DMs occurred as first event.[Table: see text]
Oncologists' perception of frailty.
Authors: Alam Zuhair , Singeltary Brian Patrick
Published: June 2021

e24012

Background: Frailty is an under recognized yet clinically important consideration in treatment decision making for older adults with cancer. The Comprehensive Geriatric Assessment (CGA) is considered gold standard for recognition of frailty and is endorsed by the International Society of Geriatric Oncology. Additionally, multiple screening tools have been validated to reliably detect frailty. Nevertheless, studies suggest that formal screening for frailty is not prevalent in community oncology practices and that oncologists’ clinical judgement is not as sensitive in identifying frailty as CGA. This survey was designed to assess the perceptions of frailty amongst oncology providers, as well as the prevalence and method of frailty screening in these practices. Methods: After approval by an independent research ethics board, a secure online survey was circulated amongst community oncology providers within the TriHealth Cancer Institute, including MD’s, DO’s, and NP’s, via email. Survey was live from January 24th to February 12th. Data was analyzed using descriptive statistics. Results: There were 20 total respondents from medical, surgical, gynecologic, and radiation oncology, 70% MD/DO. 70% of total respondents reported having > 50% of their patients over the age of 65. All respondents reported being familiar with the concept of frailty and the ECOG performance status, while only 45% had heard of CGA. 40% respondents reported that they screen for frailty and all used ECOG alone or along with Karnofsky, none used CGA or other validated screening tools. 60% respondents did not formally assess frailty, however all but one felt frailty assessment to be beneficial. Most commonly cited barriers to screening were time restraints and lack of availability of follow up services. Conclusions: Despite proven clinical benefit of CGA and various validated screening tools, few oncology providers screen for frailty. Furthermore, only 45% report having heard of CGA while none incorporate it in their practice. This shows that professional education amongst oncology providers is needed to promote the use of CGA or alternative frailty screening measures to improve outcomes in older adults with cancer. Additionally, strategies must be implemented that would mitigate time restraints and lack of access to follow up services so that these providers may be more inclined to conduct such frailty assessments. Limitations of this study include potential for reporting bias and indeterminate generalizability. Next steps include quality improvement initiative of implementing a frailty screening tool in these practices.
Vaccination coverage in cancer outpatients: An interventional multicenter before/after study.
Authors: Rivière Pierre , Penel Nicolas , Faure Karine , Marie Guillaume , Panaget Sophie
Published: June 2021

e24026

Background: Despite largely diffused guidelines, Pneumococcal and Influenza vaccination coverage (VC) remains insufficient in cancer patients receiving chemotherapy. We evaluated VC and carried out an interventional study to improve VC in cancer patients treated in 3 medical oncology departments in 3 hospitals of North-of-France. Methods: Using a standardized questionnaire, we assessed the VC in adult cancer patients receiving anticancer treatment in day hospital between 02 and 07 Dec. 2019. Then, in each hospital, we organized trainings with physicians to discuss the current vaccination guidelines (January 2020). Finally, to assess the impact of this intervention on Pneumococcal and Influenza VC, we have conducted a similar survey using the same questionnaire in March 2020. Since there were no specific guidelines on Diphtheria-Tetanus-Pertussis (DTP) VC and we did not expect an improvement, we have monitored DTP VC as internal control. Results: 272 patients have been enrolled in the “before study” in the 3 hospitals, whereas 156 patients have been enrolled in the “after study” in only 2 hospitals (the after-study was not feasible in 3rd hospital because of COVID-19 pandemic national containment). Predictors associated with DTP VC was age, with Pneumococcal VC was center and with Influenza VC were age, gender and tumor histology (adenocarcinoma vs others). Influenza VC was significantly improved after intervention (42.6 vs 55.1% with p = 0.016) especially in fragile patients, but Pneumococcal VC was not (11.8 vs 15.4% with p = 0.357). Conclusions: As expected, VC was very low in cancer patients, our figures are consistent with literature data. The impact of intervention (training of physicians) is limited without improvement of Pneumococcal VC. We presume that this increase in Influenza VC mainly reflects the overall result of national Influenza vaccination campaign.
Does prior treatment with anti-PD 1 immune check point inhibitors (ICIs) mitigate infection with herpes and SARS-CoV-2 viruses: Clinical evidence supporting basic hypotheses.
Authors: Jayarangaiah Apoorva , Gralla Richard J. , McLellan Beth
Published: June 2021

e24045

Background: We present the initial clinical evidence of likely mitigation of viral infections in patients with non-small cell lung cancer (NSCLC) who previously responded to pembrolizumab. This may constitute a late beneficial effect of ICI treatment, and may identify patients with decreased risk for poor outcomes from major viral infections.While prior clinical reports are lacking, there is abundant laboratory evidence that: 1) immune checkpoint inhibition of the PD-1-mediated signaling pathway augments the response of antigen-specific T cells which likely leads to enhanced viral clearance (Dyke, Eur J Clin Immunol 2017); and 2) high levels of PD-1 positive CD-8 T cells have been demonstrated in HIV, Hepatitis B & C infections, akin to the PD-1 positive tumor-reactive tumor infiltrating cells described in host directed mechanisms against cancer (Rao, Int J Inf Dis 2017). Methods: We report the limited pattern and shortened course of three instances of herpetic infection, and one occurrence of SARS-CoV-2, which suggest enhanced mitigation of viral infection in patients previously treated with ICIs. We have seen no other cases of such limited and rapidly clearing herpes in our thoracic oncology practice. Results: Patient characteristics: ages 38 – 78; 1 female; all stage IV extent; 1 with squamous cell carcinoma and the others had adenocarcinoma/sarcomatoid carcinoma NSCLC; PDL-1 tumor proportion scores > 90% except for the 1 patient with squamous cell carcinoma who had a PDL-1 score < 1%. One patient received only pembrolizumab; the others also received cisplatin-based combination chemotherapy. All responded well to anticancer treatment, were off all treatment for > 1 year, and continue to do well 2 – 5 years after diagnosis. Three infections diagnosed as Herpes zoster presented in each case with only one or two vesicles within a single dermatome. Each infection was diagnosed 48 – 72 hours after eruption, was only minimally symptomatic, and cleared within one or two days. The case of documented SARS-CoV-2 occurred in a 60 year old woman with NSCLC and COPD who was off ICI therapy for 3 years with a complete response. She had minimal COVID-19 symptoms which cleared within 3 days. Conclusions: We conclude that: 1) these cases suggest mitigation of viral infections in patients with NSCLC who had prior anticancer benefit with pembrolizumab, and constitute a long term positive effect of ICIs; 2) these results support the pre-clinical findings and hypotheses of enhanced antiviral immune response with ICI agents; and 3) prospective evaluation of large populations of patients with cancer receiving ICIs is warranted to determine if this benefit is reproducible, what proportion of patients benefit, the magnitude of benefit, and to guide in prospective antiviral treatment in the highly vulnerable NSCLC population.
Feasibility of digital life coaching during stem cell transplantation for multiple myeloma.
Authors: Banerjee Rahul , Huang Chiung-Yu , Dunn Lisa , Knoche Jennifer , Brassil Kelly Jean , Jackson Lindsey , Patel Dhiren , Lo Mimi , Arora Shagun , Wong Sandy Wai Kuan , Wolf Jeffrey Lee , Martin Thomas G. , Dhruva Anand A. , Shah Nina
Published: June 2021

e24103

Background: Patients with multiple myeloma (MM) experience acute quality of life (QOL) exacerbations following autologous stem cell transplantation (ASCT) that can lead to long-term complications. Life coaching can improve QOL in a structured & personalized manner. We investigated the feasibility of a digital life coaching (DLC) platform, where coaching is accomplished through phone calls and text messages, for patients with MM during ASCT. Methods: Our pilot study (clinicaltrials.gov ID: NCT04432818) enrolled adult patients with MM, English proficiency, and cellphone ownership (smartphone not required). The 16-week DLC program, beginning at Day -5 before ASCT, included unlimited digital access to a certified life coach to help with identifying and accomplishing wellness-related goals. Our primary outcome was ongoing DLC engagement (≥ 1 bidirectional conversation every 4 weeks). Secondary outcomes were ePRO assessments of QOL (PROMIS Global Health), insomnia (PROMIS Sleep Disturbances), and distress (NCCN DT). Electronic patient-reported outcome (ePRO) assessments were delivered via automated REDCap emails every 1-2 weeks. Results: Of 18 screened patients, 15 (83%) enrolled in our study; 2 patients dropped out before initiating DLC (including 1 who was unable to connect with her coach between Day -5 and 0). Of 13 remaining patients, median age was 65 (range 50-81) and 23% had an ECOG performance status of 1 (remainder 0). DLC conversations occurred a mean of every 7.6 days (range 3-28) overall and every 6.5 days (range 2.8-14) during the initial 28-day period including high-dose melphalan and hospitalization. 80% of patients maintained ≥ 1 conversation every 4 weeks. Selected ePRO results (mean ± standard error) are shown in the table. Conclusions: Certain MM patients are able to engage digitally with a life coach and complete email-based ePRO assessments during and after ASCT. Limitations of our study include selection bias and the Day -5 start date, which may be too late logistically and symptom-wise (given our ePRO findings suggestive of peak distress pre-ASCT). DLC may play an innovative and scalable role given the emphasis on remotely delivered care during the COVID-19 pandemic. A Phase II randomized study of DLC versus usual care is under way (clinicaltrials.gov ID: NCT04589286). Clinical trial information: NCT04432818. [Table: see text]
Awareness, perceptions, and usage of whole person integrative oncology practices: Similarities and differences between breast cancer patients and oncologists.
Authors: Crudup Terri , Li Linna , Lawson Elizabeth , Dorr Jennifer Wright , Stout Rachel , Niknam Pedram Vazifeh , Jones Judi , Steen Robert , Lu Lynn L , Casner Susan , Wang Yi , Scott James , Zanine Shelby , Robertshaw Stacey , Broderick Gabriella , Palommella Vaishali , Harris Tye , Hanamirian Michael , Reddy Mula Shivani , Jonas Wayne
Published: June 2021

e24123

Background: The use of Complementary and Lifestyle (C&L) approaches in conjunction with medical treatments is known as Integrative Oncology. While Integrative Oncology practices have been steadily rising in the past few decades, there are still awareness and education gaps that medical professionals can help address for their patients. Methods: Survey-based data collection and analysis was used to assess awareness, perceptions, and usage of Integrative Oncology. Patients were randomly sampled among breast cancer patients diagnosed within 2 years and included all stages (0-IV) and all US regions (NE, South, Midwest, West). Physicians were sampled from a panel of community and academic practices across the US, with the requirement they treat at least 10 breast cancer patients in a typical 3-month period and have been in practice for at least 6 years since residency or fellowship. Results: Survey invitations were sent to 1,901 patients and 2,758 Oncologists; 164 breast cancer patients and 115 Oncologists completed the surveys. Approximately two-thirds of Oncologists and patients agree that C&L approaches contribute to improved quality of life and well-being for patients (table row 1, 2). However, significantly more patients than Oncologists believe that Integrative Oncology also leads to better treatment outcome and survival (row 3). In addition, Oncologists are significantly more aware of C&L practices than are patients (row 4). When asked what percent of breast cancer patients they discuss C&L methods with, Oncologists report 55% average (CI: 50-60%). However, when asked how they became aware of C&L, only 28% of patients (CI: 21-35%) mention their Oncologist/cancer care team or the institution where they were treated (not in table). Ideally, patients desire information about C&L to come directly from Oncologists, but that is not the predominant model (row 5). Conclusions: Many breast cancer patients believe an Integrative approach will improve their treatment outcomes and prefer their providers to discuss this with them.[Table: see text]
ENVASARC: A pivotal trial of envafolimab, and envafolimab in combination with ipilimumab, in patients with advanced or metastatic undifferentiated pleomorphic sarcoma or myxofibrosarcoma who have progressed on prior chemotherapy.
Authors: D'Angelo Sandra P. , Robinson Steven Ian , Lam Joelle , Adams Bonne J. , Freddo James L. , Theuer Charles P. , Maki Robert G
Published: June 2021

TPS11581

Background: Metastatic undifferentiated Pleomorphic Sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, efficacy remains limited in the 2nd line setting and beyond. Pazopanib, the only approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: microsatellite instability-high (MSI-H) cancer and biliary tract cancer. The activity of envafolimab appears to be similar to other PD-1 antibodies administered i.v. Envafolimab demonstrated a 32% objective response rate (ORR) in MSI-H colorectal cancer patients who failed three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patient populations, respectively. The rationale for the ENVASARC trial is based on the previously reported activity of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ̃25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n = 80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (cohort B; n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT 04480502.
A phase 1 study to evaluate chimeric antigen receptor (CAR) T cells incorporating a chlorotoxin tumor-targeting domain for patients with MMP2+ Recurrent or progressive glioblastoma (NCT04214392).
Authors: Badie Behnam , Barish Michael E , Chaudhry Ammar , D'Apuzzo Massimo , Forman Stephen J. , Portnow Jana , Wang Shirong (Sean) , Ressler Julie A , Simpson Jennifer , Kilpatrick Julie , McNamara Paige , Wagner Jamie , Blanchard Suzette , Wang Dongrui , Brown Christine
Published: June 2021

TPS2662

Background: Glioblastoma (GBM) is the most common and most aggressive primary brain tumor. Around 294,900 new cases are diagnosed globally with 241,000 deaths each year. The 5-year survival is only 5%. Median overall survival from first recurrence is only 5-8 months. There is no established standard of care for recurrent GBM. City of Hope (COH) has developed and optimized a CAR T cell therapy utilizing the chlorotoxin peptide (CLTX) as the CAR’s tumor recognition domain against GBM. CLTX-CAR T cells specifically and broadly target GBM through recognition of a receptor complex including membrane-bound matrix metalloprotease 2 (MMP-2). CLTX-CAR T cells do not exhibit off-tumor recognition of normal human or murine cells and tissues in preclinical models. In in vitro studies, COH evaluated patient-derived brain tumor (PBT) cell lines for CLTX binding and expression of IL13Rα2, HER2 and EGFR, three targets of CAR T cell trials for GBMs. Strong CLTX binding to tumor cells was observed in of the majority of primary GBM lines, independent of these other antigens. In preclinical studies using in vivo mouse models, a single intratumoral (ICT) injection of CLTX-CAR T cells (1×106 CAR+ T cells) exhibited robust anti-tumor activity against ffLuc+ PBT106 tumors orthotopically-engrafted in NSG mice. Overall, when compared to mice treated with mock-transduced Tn/mem (no CAR) T cells, the CLTX(EQ)28ζ/CD19t+ T cells reduced tumor burden and significantly increased survival. Taken together, these preclinical findings support the potential safety and efficacy of CLTX-CAR T cells, and provide the rationale for clinical testing of this therapy. As cellular heterogeneity intrinsic to GBM likely contributes to resistance to therapy and limited response rates, CLTX-CAR T cells may provide greater tumor eradication in a higher proportion of patients with GBM. Methods: This study is a phase 1, single center, safety and maximum tolerated dose (MTD) finding study of CLTX-CAR T cells for subjects with MMP2+ recurrent or progressive GBM. A safety lead-in of 3−6 participants receiving CLTX-CAR T cells by ICT delivery will be completed first. Subsequently, subjects would receive cells administered through both ICT and intraventricular (ICV catheters) (i.e. dual delivery) in two dose schedules. Subjects will be evaluated for safety and tolerability, and may continue to receive treatment until disease progression. Time to progression, overall survival, and disease response by Response Assessment in Neuro-Oncology (RANO) criteria, will be evaluated and descriptively compared to historical data. The study is actively enrolling patients. Clinical trial information: NCT04214392.