Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma

INTRODUCTION: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. RESULTS: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35). CONCLUSIONS: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors

A Biological Global Positioning System: Considerations for Tracking Stem Cell Behaviors in the Whole Body

Many recent research studies have proposed stem cell therapy as a treatment for cancer, spinal cord injuries, brain damage, cardiovascular disease, and other conditions. Some of these experimental therapies have been tested in small animals and, in rare cases, in humans. Medical researchers anticipate extensive clinical applications of stem cell therapy in the future. The lack of basic knowledge concerning basic stem cell biology-survival, migration, differentiation, integration in a real time manner when transplanted into damaged CNS remains an absolute bottleneck for attempt to design stem cell therapies for CNS diseases. A major challenge to the development of clinical applied stem cell therapy in medical practice remains the lack of efficient stem cell tracking methods. As a result, the fate of the vast majority of stem cells transplanted in the human central nervous system (CNS), particularly in the detrimental effects, remains unknown. The paucity of knowledge concerning basic stem cell biology—survival, migration, differentiation, integration in real-time when transplanted into damaged CNS remains a bottleneck in the attempt to design stem cell therapies for CNS diseases. Even though excellent histological techniques remain as the gold standard, no good in vivo techniques are currently available to assess the transplanted graft for migration, differentiation, or survival. To address these issues, herein we propose strategies to investigate the lineage fate determination of derived human embryonic stem cells (hESC) transplanted in vivo into the CNS. Here, we describe a comprehensive biological Global Positioning System (bGPS) to track transplanted stem cells. But, first, we review, four currently used standard methods for tracking stem cells in vivo: magnetic resonance imaging (MRI), bioluminescence imaging (BLI), positron emission tomography (PET) imaging and fluorescence imaging (FLI) with quantum dots. We summarize these modalities and propose criteria that can be employed to rank the practical usefulness for specific applications. Based on the results of this review, we argue that additional qualities are still needed to advance these modalities toward clinical applications. We then discuss an ideal procedure for labeling and tracking stem cells in vivo, finally, we present a novel imaging system based on our experiments

COVID-19 Severity and Cardiovascular Outcomes in SARS-CoV-2-Infected Patients With Cancer and Cardiovascular Disease

BACKGROUND: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. OBJECTIVES: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. METHODS: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD RESULTS: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all CONCLUSIONS: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701)

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study

BACKGROUND: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. METHODS: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. RESULTS: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. CONCLUSIONS: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. FUNDING: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. CLINICAL TRIAL NUMBER: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701

A Biological Global Positioning System: Considerations for Tracking Stem Cell Behaviors in the Whole Body

Many recent research studies have proposed stem cell therapy as a treatment for cancer, spinal cord injuries, brain damage, cardiovascular disease, and other conditions. Some of these experimental therapies have been tested in small animals and, in rare cases, in humans. Medical researchers anticipate extensive clinical applications of stem cell therapy in the future. The lack of basic knowledge concerning basic stem cell biology-survival, migration, differentiation, integration in a real time manner when transplanted into damaged CNS remains an absolute bottleneck for attempt to design stem cell therapies for CNS diseases. A major challenge to the development of clinical applied stem cell therapy in medical practice remains the lack of efficient stem cell tracking methods. As a result, the fate of the vast majority of stem cells transplanted in the human central nervous system (CNS), particularly in the detrimental effects, remains unknown. The paucity of knowledge concerning basic stem cell biology—survival, migration, differentiation, integration in real-time when transplanted into damaged CNS remains a bottleneck in the attempt to design stem cell therapies for CNS diseases. Even though excellent histological techniques remain as the gold standard, no good in vivo techniques are currently available to assess the transplanted graft for migration, differentiation, or survival. To address these issues, herein we propose strategies to investigate the lineage fate determination of derived human embryonic stem cells (hESC) transplanted in vivo into the CNS. Here, we describe a comprehensive biological Global Positioning System (bGPS) to track transplanted stem cells. But, first, we review, four currently used standard methods for tracking stem cells in vivo: magnetic resonance imaging (MRI), bioluminescence imaging (BLI), positron emission tomography (PET) imaging and fluorescence imaging (FLI) with quantum dots. We summarize these modalities and propose criteria that can be employed to rank the practical usefulness for specific applications. Based on the results of this review, we argue that additional qualities are still needed to advance these modalities toward clinical applications. We then discuss an ideal procedure for labeling and tracking stem cells in vivo, finally, we present a novel imaging system based on our experiments

Cancer genomic research at the crossroads: realizing the changing genetic landscape as intratumoral spatial and temporal heterogeneity becomes a confounding factor

The US National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) created the Cancer Genome Atlas (TCGA) Project in 2006. The TCGA’s goal was to sequence the genomes of 10,000 tumors to identify common genetic changes among different types of tumors for developing genetic-based treatments. TCGA offered great potential for cancer patients, but in reality has little impact on clinical applications. Recent reports place the past TCGA approach of testing a small tumor mass at a single time-point at a crossroads. This crossroads presents us with the conundrum of whether we should sequence more tumors or obtain multiple biopsies from each individual tumor at different time points. Sequencing more tumors with the past TCGA approach of single time-point sampling can neither capture the heterogeneity between different parts of the same tumor nor catch the heterogeneity that occurs as a function of time, error rates, and random drift. Obtaining multiple biopsies from each individual tumor presents multiple logistical and financial challenges. Here, we review current literature and rethink the utility and application of the TCGA approach. We discuss that the TCGA-led catalogue may provide insights into studying the functional significance of oncogenic genes in reference to non-cancer genetic background. Different methods to enhance identifying cancer targets, such as single cell technology, real time imaging of cancer cells with a biological global positioning system, and cross-referencing big data sets, are offered as ways to address sampling discrepancies in the face of tumor heterogeneity. We predict that TCGA landmarks may prove far more useful for cancer prevention than for cancer diagnosis and treatment when considering the effect of non-cancer genes and the normal genetic background on tumor microenvironment. Cancer prevention can be better realized once we understand how therapy affects the genetic makeup of cancer over time in a clinical setting. This may help create novel therapies for gene mutations that arise during a tumor’s evolution from the selection pressure of treatment

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma

Basal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment. We conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0. A total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate. The clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease

Geriatric risk factors for serious COVID-19 outcomes among older adults with cancer: A cohort study from the COVID-19 and Cancer Consortium

Background: Older age is associated with poorer outcomes of SARS-CoV-2 infection, although the heterogeneity of ageing results in some older adults being at greater risk than others. The objective of this study was to quantify the association of a novel geriatric risk index, comprising age, modified Charlson comorbidity index, and Eastern Cooperative Oncology Group performance status, with COVID-19 severity and 30-day mortality among older adults with cancer. Methods: In this cohort study, we enrolled patients aged 60 years and older with a current or previous cancer diagnosis (excluding those with non-invasive cancers and premalignant or non-malignant conditions) and a current or previous laboratory-confirmed COVID-19 diagnosis who reported to the COVID-19 and Cancer Consortium (CCC19) multinational, multicentre, registry between March 17, 2020, and June 6, 2021. Patients were also excluded for unknown age, missing data resulting in unknown geriatric risk measure, inadequate data quality, or incomplete follow-up resulting in unknown COVID-19 severity. The exposure of interest was the CCC19 geriatric risk index. The primary outcome was COVID-19 severity and the secondary outcome was 30-day all-cause mortality; both were assessed in the full dataset. Adjusted odds ratios (ORs) and 95% CIs were estimated from ordinal and binary logistic regression models. Findings: 5671 patients with cancer and COVID-19 were included in the analysis. Median follow-up time was 56 days (IQR 22-120), and median age was 72 years (IQR 66-79). The CCC19 geriatric risk index identified 2365 (41·7%) patients as standard risk, 2217 (39·1%) patients as intermediate risk, and 1089 (19·2%) as high risk. 36 (0·6%) patients were excluded due to non-calculable geriatric risk index. Compared with standard-risk patients, high-risk patients had significantly higher COVID-19 severity (adjusted OR 7·24; 95% CI 6·20-8·45). 920 (16·2%) of 5671 patients died within 30 days of a COVID-19 diagnosis, including 161 (6·8%) of 2365 standard-risk patients, 409 (18·5%) of 2217 intermediate-risk patients, and 350 (32·1%) of 1089 high-risk patients. High-risk patients had higher adjusted odds of 30-day mortality (adjusted OR 10·7; 95% CI 8·54-13·5) than standard-risk patients. Interpretation: The CCC19 geriatric risk index was strongly associated with COVID-19 severity and 30-day mortality. Our CCC19 geriatric risk index, based on readily available clinical factors, might provide clinicians with an easy-to-use risk stratification method to identify older adults most at risk for severe COVID-19 as well as mortality. Funding: US National Institutes of Health National Cancer Institute Cancer Center

Demographics, outcomes, and risk factors for patients (Pts) with sarcoma and COVID-19: A multi-institutional cohort analysis

11523 Background: Sarcoma pts often receive aggressive, highly immunosuppressive therapy and may be at high risk for severe COVID-19. Demographics, outcomes and risk factors for pts with sarcoma and COVID-19 are unknown. We aimed to describe the course of COVID-19 in sarcoma pts and to identify factors associated with adverse outcomes. Methods: The COVID-19 and Cancer Consortium (NCT04354701) is an international registry of pts with cancer and COVID-19. Adult pts (≥18 years old) with a diagnosis of sarcoma and laboratory confirmed SARS-CoV-2 were included from 50 participating institutions. Data including demographics, sarcoma diagnosis and treatment, and course of COVID-19 infection were analyzed. Primary outcome was the composite rate of hospitalization or death at 30 days from COVID-19 diagnosis. Secondary outcomes were 30 day all-cause mortality, rate of hospitalization, O2 need, and ICU admission. Descriptive statistics and univariate Fisher tests are reported. Results: From March 17, 2020 to February 6, 2021, N=204 pts were included. Median follow up was 42 days. Median age was 58 years (IQR 43-67). 97 (48%) were male. 30 (15%) had ECOG performance status ≥2. 104 (51%) received cancer treatment, including surgery or radiation, within 3 months of COVID-19 diagnosis. 153 (75%) had active cancer, of whom 34 (22%) had lung metastases. 100 (49%) pts met the composite primary endpoint; 96 (47%) were hospitalized and 18 (9%) died within 30 days from COVID-19 diagnosis. 64 (31%) required oxygen, and 16 (8%) required ICU admission. Primary endpoint rates were similar for pts who received cytotoxic chemotherapy (38/58, 66%) or targeted therapy (16/28, 57%). Pts with higher rates of the primary endpoint included patients ≥60 years old (59% vs 40%, OR 2.04, 95% CI 1.12-3.74, p=0.016), pts with ECOG PS ≥2 vs 0-1 (90% vs 41%, OR 12.2, 95% CI 3.44-66.8, p<0.001), pts receiving any systemic therapy within 3 months of COVID-19 diagnosis (62% vs 39%, OR 2.65, 95% CI 1.43-4.97, p=0.001), and pts with lung metastases (68% vs 42%, OR 2.77, 95% CI 1.19-6.79, p=0.013). Primary endpoint rates were similar across sarcoma subtypes (Table). Conclusions: This is the largest cohort study of pts with sarcoma and COVID-19 to date. Sarcoma pts have high rates of complications from COVID-19. Older patients, those with poor performance status, those recently receiving systemic cancer therapy, and those with lung metastases appear to have worse outcomes.[Table: see text