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COVID-19 outcomes in hospitalized patients with active cancer: Experiences from a major New York City health care system

Fu, Chen; Stoeckle, James H; Masri, Lena; Pandey, Abhishek; Cao, Meng; Littman, Dalia; Rybstein, Marissa; Saith, Sunil E; Yarta, Kinan; Rohatgi, Abhinav; Makarov, Danil V; Sherman, Scott E; Morrissey, Christy; Jordan, Alexander C; Razzo, Beatrice; Theprungsirikul, Poy; Tsai, Joseph; Becker, Daniel J
BACKGROUND:The authors sought to study the risk factors associated with severe outcomes in hospitalized coronavirus disease 2019 (COVID-19) patients with cancer. METHODS:The authors queried the New York University Langone Medical Center's records for hospitalized patients who were polymerase chain reaction-positive for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) and performed chart reviews on patients with cancer diagnoses to identify patients with active cancer and patients with a history of cancer. Descriptive statistics were calculated and multivariable logistic regression was used to determine associations between clinical, demographic, and laboratory characteristics with outcomes, including death and admission to the intensive care unit. RESULTS:A total of 4184 hospitalized SARS CoV-2+ patients, including 233 with active cancer, were identified. Patients with active cancer were more likely to die than those with a history of cancer and those without any cancer history (34.3% vs 27.6% vs 20%, respectively; P < .01). In multivariable regression among all patients, active cancer (odds ratio [OR], 1.89; CI, 1.34-2.67; P < .01), older age (OR, 1.06; CI, 1.05-1.06; P < .01), male sex (OR for female vs male, 0.70; CI, 0.58-0.84; P < .01), diabetes (OR, 1.26; CI, 1.04-1.53; P = .02), morbidly obese body mass index (OR, 1.87; CI, 1.24-2.81; P < .01), and elevated D-dimer (OR, 6.41 for value >2300; CI, 4.75-8.66; P < .01) were associated with increased mortality. Recent cancer-directed medical therapy was not associated with death in multivariable analysis. Among patients with active cancer, those with a hematologic malignancy had the highest mortality rate in comparison with other cancer types (47.83% vs 28.66%; P < .01). CONCLUSIONS:The authors found that patients with an active cancer diagnosis were more likely to die from COVID-19. Those with hematologic malignancies were at the highest risk of death. Patients receiving cancer-directed therapy within 3 months before hospitalization had no overall increased risk of death. LAY SUMMARY/UNASSIGNED:Our investigators found that hospitalized patients with active cancer were more likely to die from coronavirus disease 2019 (COVID-19) than those with a history of cancer and those without any cancer history. Patients with hematologic cancers were the most likely among patients with cancer to die from COVID-19. Patients who received cancer therapy within 3 months before hospitalization did not have an increased risk of death.
PMID: 34096048
ISSN: 1097-0142
CID: 4899602

Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy

Yamazaki, Takahiro; Kirchmair, Alexander; Sato, Ai; Buqué, Aitziber; Rybstein, Marissa; Petroni, Giulia; Bloy, Norma; Finotello, Francesca; Stafford, Lena; Navarro Manzano, Esther; Ayala de la Peña, Francisco; García-Martínez, Elena; Formenti, Silvia C; Trajanoski, Zlatko; Galluzzi, Lorenzo
Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.
PMID: 32747819
ISSN: 1529-2916
CID: 4583722

Exercise reduces immune suppression and breast cancer progression in a preclinical model

Wennerberg, Erik; Lhuillier, Claire; Rybstein, Marissa D; Dannenberg, Kyle; Rudqvist, Nils-Petter; Koelwyn, Graeme J; Jones, Lee W; Demaria, Sandra
Exercise is associated with favorable changes in circulating immune cells and improved survival in early-stage breast cancer patients, but the mechansims remain to be fully elucidated. Preclinical studies indicate that physical activity started before tumor injection reduces tumor incidence and progression. Here we tested whether exercise has anti-tumor effects in mice with established 4T1 mammary carcinoma, a mouse model of triple negative breast cancer. Exercise slowed tumor progression and reduced the tumor-induced accumulation of myeloid-derived suppressor cells (MDSCs). The reduction in MDSCs was accompanied by a relative increase in natural killer and CD8 T cell activation, suggesting that exercise restores a favorable immune environment. Consistently, exercise improved responses to a combination of programmed cell death protein 1 (PD-1) blockade and focal radiotherapy. These data support further investigations of exercise in breast cancer patients treated with combinations of immunotherapy and cytotoxic agents to improve cancer outcomes.
PMID: 32064049
ISSN: 1949-2553
CID: 4311972

Risk factors for and clinical management of venous thromboembolism during pregnancy

Rybstein, Marissa D; DeSancho, Maria T
Venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism, is one of the leading causes of non-obstetric maternal death in the United States. Physiologic and anatomic changes associated with pregnancy set the stage for a hypercoagulable state. In addition, other risk factors-including those associated with certain fetal characteristics such as low birth weight or stillbirth-have been correlated with an increased risk for VTE. Women with a personal or strong family history of VTE, as well as documented thrombophilia, represent a unique group in whom antepartum and/or postpartum prophylaxis can be considered. The choice of anticoagulant therapy for either treatment or prophylaxis in most cases is heparin, most commonly low-molecular-weight heparin. This is owing to the fact that vitamin K antagonists and the direct oral anticoagulants are contraindicated in pregnancy because of potential teratogenicity. With careful management and vigilant monitoring, appropriate anticoagulation can be used safely and effectively to improve patient outcomes.
PMID: 31449506
ISSN: 1543-0790
CID: 4065202

Hypercoagulable States and Thrombophilias: Risks Relating to Recurrent Venous Thromboembolism

Rybstein, Marissa D; DeSancho, Maria T
Inherited and acquired thrombophilias and hypercoagulable states, such as active cancer, estrogen-induced, autoimmune disorders, major surgery, hospitalization, and trauma, are well-known risk factors for venous thromboembolism (VTE). The effect of these on recurrent VTE is different for each specific risk factor. The major risk factors affecting VTE recurrence include the presence of active cancer and an unprovoked first VTE. In addition, the use of combined female hormones in a woman with a previous history of estrogen-related VTE is a major risk factor for VTE recurrence. The extent of influence of inherited thrombophilia on the risk of recurrence is controversial. Conversely, the presence of antiphospholipid antibodies, specifically triple positive carriers, appears to increase the risk of VTE recurrence. Understanding the rates of recurrent VTE in a patient and the individual risk of bleeding is important in determining the duration of anticoagulation therapy.
PMID: 29872244
ISSN: 0739-9529
CID: 4065192

The autophagic network and cancer

Rybstein, Marissa D; Bravo-San Pedro, José Manuel; Kroemer, Guido; Galluzzi, Lorenzo
Mammalian cells harness autophagy to eliminate physiological byproducts of metabolism and cope with microenvironmental perturbations. Moreover, autophagy connects cellular adaptation with extracellular circuitries that impinge on immunity and metabolism. As it links transformed and non-transformed components of the tumour microenvironment, such an autophagic network is important for cancer initiation, progression and response to therapy. Here, we discuss the mechanisms whereby the autophagic network interfaces with multiple aspects of malignant disease.
PMID: 29476153
ISSN: 1476-4679
CID: 4065182

Dermatologic Adverse Events Associated With Use of Adjuvant Lapatinib in Combination With Paclitaxel and Trastuzumab for HER2-Positive Breast Cancer: A Case Series Analysis [Case Report]

Friedman, Marissa D; Lacouture, Mario; Dang, Chau
PMID: 26707653
ISSN: 1938-0666
CID: 4068192

Glioblastoma: molecular pathways, stem cells and therapeutic targets

Jhanwar-Uniyal, Meena; Labagnara, Michael; Friedman, Marissa; Kwasnicki, Amanda; Murali, Raj
Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM.
PMID: 25815458
ISSN: 2072-6694
CID: 1519012

Targeting cancer stem cells in glioblastoma multiforme using mTOR inhibitors and the differentiating agent all-trans retinoic acid

Friedman, Marissa D; Jeevan, Dhruve S; Tobias, Michael; Murali, Raj; Jhanwar-Uniyal, Meena
Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, portends a poor prognosis despite current treatment modalities. Recurrence of tumor growth is attributed to the presence of treatment-resistant cancer stem cells (CSCs). The targeting of these CSCs is therefore essential in the treatment of this disease. Mechanistic target of rapamycin (mTOR) forms two multiprotein complexes, mTORC1 and mTORC2, which regulate proliferation and migration, respectively. Aberrant function of mTOR has been shown to be present in GBM CSCs. All-trans retinoic acid (ATRA), a derivative of retinol, causes differentiation of CSCs as well as normal neural progenitor cells. The purpose of this investigation was to delineate the role of mTOR in CSC maintenance, and to establish the mechanism of targeting GBM CSCs using differentiating agents along with inhibitors of the mTOR pathways. The results demonstrated that ATRA caused differentiation of CSCs, as demonstrated by the loss of the stem cell marker Nestin. These observations were confirmed by western blotting, which demonstrated a time-dependent decrease in Nestin expression following ATRA treatment. This effect occurred despite combination with mTOR (rapamycin), PI3K (LY294002) and MEK1/2 (U0126) inhibitors. Expression of activated extracellular signal-regulated kinase 1/2 (pERK1/2) was enhanced following treatment with ATRA, independent of mTOR pathway inhibitors. Proliferation of CSCs, determined by neurosphere diameter, was decreased following treatment with ATRA alone and in combination with rapamycin. The motility of GBM cells was mitigated by treatment with ATRA, rapamycin and LY29002 alone. However, combination treatment augmented the inhibitory effect on migration suggesting synergism. These findings indicate that ATRA-induced differentiation is mediated via the ERK1/2 pathway, and underscores the significance of including differentiating agents along with inhibitors of mTOR pathways in the treatment of GBM.
PMID: 23877261
ISSN: 1021-335x
CID: 964022

PI3K/mTOR signaling pathways in medulloblastoma

Mohan, Avinash L; Friedman, Marissa D; Ormond, D Ryan; Tobias, Michael; Murali, Raj; Jhanwar-Uniyal, Meena
Medulloblastoma is the most common malignant brain tumor in children. Recent studies have implicated sonic hedgehog (SHH) and insulin growth factor (IGF) as important mediators in deregulated pathways, which directly inactivate tuberous sclerosis complex, leading to activation of the serine/threonine kinase, mammalian target of rapamycin (mTOR). mTOR consists of two catalytic subunits of biochemically distinct complexes called mTORC1 and mTORC2. This study aims to further elucidate the role of the mTOR pathway, in the development of medulloblastoma, and assess the use of mTOR inhibitors as novel therapeutic agents. Medulloblastoma cells treated with mTORC1 inhibitor, rapamycin, down-regulated pERK expression initially; however ERK activation was evident upon prolonged treatment. Phosphorylation of mTORC1 substrate, p70S6K at thr389 was reduced by rapamycin and pretreatment with rapamycin abrogated platelet-derived growth factor (PDGF)-induced activation of S6K, as well as that of mTORC2 substrate pAKT(Ser473). Activation of AKT was decreased at 1, 3, and 6 h of treatment, but extended treatment with rapamycin increased expression of pAKT(Ser473). Expression of cyclic dependent kinase inhibitor, P27, decreased following PDGF and increased following rapamycin treatment, suggesting their respective impact on cell proliferation via cell cycle control. Cell proliferation was increased by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of medulloblastoma cells, while it was suppressed following treatment with rapamycin or U0126 (MEK1/2 inhibitor). pp242, a novel combined mTORC1/2 inhibitor, and rapamycin limited proliferation by reducing the S-Phase entry as assessed by EdU incorporation, while PDGF increased EdU incorporation. pp242 reduced the number of cells entering the S-phase to a greater extent than did rapamycin. Migration of medulloblastoma cells towards fibronectin was suppressed in a time-dependent manner after rapamycin treatment. These results indicate that the mTOR pathway is involved in the pathogenesis of medulloblastoma, and that targeting this pathway may provide a strategy for therapy of medulloblastoma.
PMID: 22843885
ISSN: 0250-7005
CID: 963992