Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and ...strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, ...myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Patients with lung cancer are particularly vulnerable to complications from coronavirus disease-2019 (COVID-19). Recurrent hospital visits and hospital admission are potential risk factors for ...acquiring infection with its causative pathogen, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As immune checkpoint inhibitors (ICIs) constitute the therapeutic backbone for the vast majority of patients with advanced lung cancer in the absence of actionable driver oncogenes, there have been intense discussions within the oncology community regarding risk-benefit of delaying these treatments or use of alternative extended-interval treatment strategies to minimize the risk of viral transmission secondary to unintended nosocomial exposures. In the midst of the COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) granted accelerated approval for extended-interval strategy of pembrolizumab at a dose of 400 mg every 6 weeks for all already approved oncologic indications. Herein, we summarize the evidence from the
pharmacokinetic modeling/simulation studies supporting extended-interval dosing strategies for the ICIs used in lung cancer. We further review the evolving clinical evidence behind these approaches and predict that they will continue to be used in routine practice even long after the pandemic, particularly for patients with durable disease control.
In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in ...antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events. Both cohorts experienced similar event-free and overall survival. Both regimens led to a distinct pattern but similar degree of mid-cycle immune activation, manifested as increased expression of cytokines and lytic genes in T and natural killer (NK) cells. Pomalidomide induced poly-functional T-cell activation, with increased proportion of coinhibitory receptor BTLA+ T cells and Tim-3+ NK cells. Baseline levels of ikaros and aiolos protein in tumor cells did not correlate with response or survival. Pomalidomide led to rapid decline in Ikaros in T and NK cells in vivo, and therapy-induced activation of CD8+ T cells correlated with clinical response. These data demonstrate that pomalidomide leads to strong and rapid immunomodulatory effects involving both innate and adaptive immunity, even in heavily pretreated multiple myeloma, which correlates with clinical antitumor effects. This trial was registered at www.clinicaltrials.gov as #NCT01319422.
•Pomalidomide leads to rapid immune activation in vivo correlating with clinical outcome in relapsed myeloma.•Baseline expression of ikaros/aiolos protein in tumor cells is not predictive of outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•GDC-0994 inhibits the growth of BRAF mutant cancer cells in vitro and in vivo.•GDC-0994 induces cell cycle arrest in BRAF mutation positive cancer cells.•GDC-0994 treatment affects the expressions ...of cell cycle-related genes.•BRAF mutation confers sensitivity to multiple ERK1/2 inhibitors.
BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ObjectiveTransposition of great arteries is a common cyanotic heart defect. Balloon atrial septostomy aims to improve circulatory mixing and oxygenation. Previous studies have combined infants with ...intact ventricular septum and those with ventricular septal defect. Additionally, the septostomy was performed much later after birth. The objectives were to ascertain any correlation between the atrial septal defect size and oxygenation, before and after septostomy, as well the change in parameters pre-post procedure.MethodsWe performed an audit of the last 10 years of clinical and echocardiographic data (2010–2020) for infants with transposition of great arteries with intact ventricular septum. A pediatric cardiologist, masked to clinical data, reviewed the images.ResultsOur study of 25 infants with transposition of great arteries with intact ventricular septum noted that the procedure was performed at a median interquartile range (IQR) of 3 (2, 4) hours after birth. Prostaglandin was administered to the majority of infants 20/25 (80%). While significant increases in partial pressure of oxygen (24±5 vs 40±6 mmHg, p<0.001) and preductal oxygen saturations (67%±18% vs 81%±11%, p=0.003) were noted, and while the atrial septal defect increased in size from 1.8±0.6 vs 4.8±0.7 mm (p<0.001), no correlation was noted between atrial septal defect size and oxygen saturations.ConclusionsIn our study of infants with transposition of great arteries and intact ventricular septum managed with balloon atrial septostomy, no correlation was noted between the atrial septal defect size and oxygen saturations. Pulmonary vascular resistance and pulmonary blood flow may be important physiological variables determining oxygenation.
BackgroundHistological transformation of oncogene-driven lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with tyrosine kinase inhibitors (TKIs) is a well-described ...phenomenon. Whether a similar transformation may drive acquired resistance to immune checkpoint inhibitors (ICPIs) in non-SCLC (NSCLC) is uncertain. Hence, tissue biopsies are not universally recommended at progression of NSCLC on ICPIs, unlike TKIs.Case presentationWe report a case of a woman in her mid-60s with a 35 pack-years tobacco history and stage IV squamous cell lung carcinoma with no targetable genomic alterations, whose disease progressed within 4 months of first line carboplatin/gemcitabine therapy. Her treatment was switched to second line nivolumab monotherapy which resulted in sustained partial response lasting 21 months. She subsequently developed rapid, bulky progression of mediastinal disease. Biopsy showed transformation to SCLC. Comparison of genomic profiling results from the initial NSCLC diagnosis and SCLC transformation revealed near-identical tumor profiles. Her disease responded to next line carboplatin/etoposide, though lasting for only 10 months. She died 14 months after detection of neuroendocrine transformation of her NSCLC.Systematic reviewWe performed a systematic review of the literature to identify similar cases of NSCLC-to-small cell transformation on ICPIs. Nine patients, including our index case, were identified, with seven (77.8%) on nivolumab and two (22.2%) on pembrolizumab monotherapy. Median survival time since small cell transformation was 13.0 months (95% CI 2.0 to 16.0). Using our patient case as a framework, we further discuss the lack of consensus criteria to distinguish small cell transformation from de novo metachronous SCLC.ConclusionsHistological transformation to SCLC is a potential mechanism of acquired resistance to ICPIs in NSCLC. Repeat tissue biopsies should be considered at the time of progression, similar to oncogene-directed therapies. Prospective larger studies are warranted to further characterize NSCLC-to-small cell transformation on ICPIs using molecular fingerprinting with paired tumor genomic profiles, evaluation of neuroendocrine features at baseline and consideration of initial response.
BackgroundImmune checkpoint inhibitors (ICIs) are approved to treat patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, currently approved biomarkers are ...limited due to the heterogeneity and availability of tumor samples. The development of peripheral biomarkers offers an alternative noninvasive approach to assess immunotherapy response. DNA methylation-based immune cell deconvolution provides opportunities for developing blood-based biomarkers to predict immunotherapy response outcomes in HNSCC.MethodsOur study is an ongoing prospective multi-center study aimed at identifying blood DNA methylation biomarkers of therapy response in patients with HNSCC undergoing standard-of-care, FDA-approved ICIs. Blood was drawn prior to immunotherapy initiation. DNA isolated from these samples underwent methylation profiling using the Illumina EPIC microarray. Peripheral blood immune profiles were generated using cellular deconvolution.1 69 HNSCC patients with anti-PD-1 monotherapy were included (figure 1). 47 patients’ tumor samples were sequenced to evaluate tumor mutational burden (TMB) (figure 2). We investigated 48 immune variables and TMB for relation with progression-free survival (PFS) and overall survival (OS) using Cox proportional-hazard models adjusted for age, sex, and a marker for corticosteroid exposure.2 12 primary immune cell proportions and TMB were investigated for interaction. A p-value < 0.05 was used as the cut-off for statistical significance.ResultsIn 69 patients with HNSCC who received anti-PD-1 therapy, neutrophil proportion, monocyte count, and total B cell count were associated with worse PFS outcomes while CD4T memory cell count and total T cell count were associated with better PFS outcomes (figure 3). Regarding OS, NLR, neutrophil proportion, total naïve lymphocyte proportion, monocyte count, CD4T naïve percentage, CD4T naïve to memory ratio, and T regulatory cell percentage were found to be associated with poorer survival while total CD4 T cell count, total CD4 T cell proportion, CD4 T memory cell proportion, total T cell count, lymphocyte to monocyte ratio, and total lymphocyte proportion were found to be associated with better outcomes (figure 4). Higher TMB was found to be associated with better survival outcomes. TMB exhibits significant interaction with peripheral monocyte proportion. TMB is a better predictor of survival in individuals with a lower level of monocyte proportion (figure 5).ConclusionsDNA methylation-based immune profiling in peripheral blood at baseline identifies clinically relevant biomarkers of benefit from ICIs. Our results demonstrate the potential of new blood DNA methylation-based biomarkers to predict immunotherapy response prior to the initial treatment, and connected peripheral immune profile with TMB through their interactive impact on survival outcomes.ReferencesSalas LA, Zhang Z, Koestler DC, Butler RA, Hansen HM, Molinaro AM, Wiencke JK, Kelsey KT, Christensen BC. Enhanced cell deconvolution of peripheral blood using DNA methylation for high-resolution immune profiling. Nat Commun 2022;13:761.Wiencke JK, Molinaro AM, Warrier G, Rice T, Clarke J, Taylor JW, Wrensch M, Hansen H, McCoy L, Tang E, et al. DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival. Nat Commun 2022;13:5505.Ethics ApprovalThe study is approved by Dartmouth Cancer Center IRB (STUDY02001227), Brown University IRB (1901002321), and Dana-Farber Cancer Institute IRB (18–548).Abstract 47 Figure 1Abstract 47 Figure 2Abstract 47 Figure 3Abstract 47 Figure 4Abstract 47 Figure 5
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