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CD62Ldim Neutrophils Specifically Migrate to the Lung and Participate in the Formation of the Pre-Metastatic Niche of Breast Cancer

Lung metastasis is one of the leading causes of death in patients with breast cancer. The mechanism of tumor metastasis remains controversial. Recently, the formation of a pre-metastatic niche has ..... see more

Source : https://doi.org/10.3389/fonc.2020.540484

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Natural killer cells in the human lung tumor microenvironment display immune inhibitory functions

Background Natural killer (NK) cells play a crucial role in tumor immunosurveillance through their cytotoxic effector functions and their capacity to interact with other immune cells to build a coordinated ..... see more

Source : https://jitc.bmj.com/content/8/2/e001054

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A Seven Immune-Related lncRNAs Model to Increase the Predicted Value of Lung Adenocarcinoma

BackgroundRecent research has shown that immune-related lncRNA plays a crucial part in the tumor immune microenvironment. This study tried to identify immune-related lncRNAs and construct a robust prediction model to ..... see more

Source : https://doi.org/10.3389/fonc.2020.560779

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OPDIVO® (nivolumaub) + YERVOY® (ipilimumab)

View dosing details for 2 approved indications in 1L NSCLC

View dosing information for a 1L treatment option for certain NSCLC patients.
 ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ ‌ 
 
OPDIVO(R)(nivolumab) + YERVOY(R) (ipilimumab) logo
APPROVED DOSING FOR TWO
1L mNSCLC INDICATIONS1
See detailed dosing information for OPDIVO® + YERVOY® and OPDIVO + YERVOY with limited chemo* below.
 
recurrent/metastatic non-small cell lung cancer icon Indications
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first‑line treatment of adult patients with metastatic non‑small cell lung cancer (NSCLC) whose tumors express PD‑L1 (≥1%) as determined by an FDA‑approved test, with no EGFR or ALK genomic tumor aberrations.1
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab) and 2 cycles of platinum‑doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.1
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for
intravenous (IV) use.1,2
OPDIVO® + low‑dose YERVOY® (1 mg/kg) dosing for Checkmate 227 and Checkmate 9LA1
Checkmate 227 Dosing: For patients with mNSCLC (PD‑L1 ≥1%)1
Checkmate 227 dosing schedule
OPDIVO is administered as an IV infusion over 30 minutes1
YERVOY is administered as an IV infusion over 30 minutes1
Checkmate 9LA Dosing: For patients with r/m NSCLC, regardless of PD‑L1 expression1
Checkmate 9LA dosing schedule
OPDIVO is administered as an IV infusion over 30 minutes1
YERVOY is administered as an IV infusion over 30 minutes1
 
SELECT IMPORTANT SAFETY INFORMATION
Summary of Warnings and Precautions
OPDIVO is associated with the following Warnings and Precautions including immune‑mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion‑related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo‑fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials. YERVOY is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplant after YERVOY, embryo-fetal toxicity and risks associated when administered in combination with OPDIVO.
Please see additional Important Safety Information for OPDIVO and YERVOY below and U.S. Full Prescribing Information for OPDIVO and YERVOY.
Serious Adverse Reactions
In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi‑system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.
Common Adverse Reactions
In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%).
Please see additional Important Safety Information for OPDIVO and YERVOY below and U.S. Full Prescribing Information for OPDIVO and YERVOY.
For patients with mNSCLC (PD-L1 ≥1%)
OPDIVO® + YERVOY® was assessed in a landmark phase 3 study that included patients regardless of histology1
Checkmate 227 Part 1a Study Design1,3
Checkmate 227 study design
Patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded1
Tumor specimens were evaluated prospectively using the PD‑L1 IHC 28‑8 pharmDx assay at a central laboratory1
In an extended OS analysis for Checkmate 227, median follow‑up was 43.1 months: Longest median follow‑up of any I‑O–based combination in a phase 3 trial4
§
 
For patients with r/m NSCLC, regardless of PD-L1 expression
The first approved combination therapy of its kind—OPDIVO® + YERVOY® with limited chemo*—was evaluated in a randomized phase 3 trial1
Checkmate 9LA Study Design
Checkmate 9LA study design
Patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded1
Trial evaluated patients regardless of PD‑L1
expression and histology1
Please see additional Important Safety Information for OPDIVO and YERVOY below and U.S. Full Prescribing Information for OPDIVO and YERVOY.
For more information about treatment options
for 1L mNSCLC, please visit
OPDIVOYERVOYmNSCLC.com

Expand +

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions
 
Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur at any time after starting or discontinuing YERVOY. Early identification and management are essential to ensure safe use of YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue YERVOY depending on severity. In general, if YERVOY requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less followed by corticosteroid taper for at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroid therapy. Institute hormone replacement therapy for endocrinopathies as warranted.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In NSCLC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. The incidence and severity of immune-mediated pneumonitis in patients with NSCLC treated with OPDIVO 360 mg every 3 weeks in combination with YERVOY 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy were comparable to treatment with OPDIVO in combination with YERVOY only.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for
Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. 

Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Withhold for Grades 2, 3, or 4 endocrinopathies if not clinically stable. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. 

Immune-Mediated Skin and Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. 

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous exfoliative rashes. Withhold YERVOY until specialist assessment for Grade 2 and permanently discontinue for Grade 3 or 4 exfoliative or bullous dermatologic conditions.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. 

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Dose modifications for YERVOY for adverse reactions that require management different from these general guidelines are summarized as follows. Withhold for Grade 2 and permanently discontinue YERVOY for Grade 3 or 4 neurological toxicities. Withhold for Grade 2 and permanently discontinue YERVOY for Grade 3 or 4 myocarditis. Permanently discontinue YERVOY for Grade 2, 3, or 4 ophthalmologic  adverse reactions that do not improve to Grade 1 within 2 weeks while receiving topical therapy OR that require systemic therapy. Across clinical trials of OPDIVO in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome. In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: autoimmune neuropathy (2%), meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, nerve paresis, angiopathy, temporal arteritis, pancreatitis (1.3%), arthritis, polymyositis, conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis, blepharitis, episcleritis, orbital myositis, scleritis, and solid organ transplant rejection. Some cases of ocular IMARs have been associated with retinal detachment.
 
If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and YERVOY and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion-related reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. Severe infusion-related reactions can also occur with YERVOY. Discontinue YERVOY in patients with severe or life-threatening infusion reactions and interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. In patients receiving OPDIVO monotherapy as a 60-minute 
infusion,  infusion-related  reactions occurred in 6.4%  (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 or CTLA-4 receptor blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody or YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on mechanism of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO or YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO or YERVOY, advise women not to breastfeed during treatment and for at least 5 months after the last dose. 

Serious Adverse Reactions

In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Common Adverse Reactions

In Checkmate 227, the most common (≥ 20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). 

Please see U.S. Full Prescribing Information for 
OPDIVO and YERVOY

INDICATIONS

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

References:
1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2020.
2. YERVOY [package insert]. Princeton, NJ: Bristol‑Myers Squibb Company; 2020.
3. Hellmann MD, Paz‑Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non‑small‑cell lung cancer. N Engl J Med. 2019;381(21):2020‑2031.
4. Ramalingam SS, Ciuleanu TE, Pluzanski A et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. Oral presentation at ASCO 2020. Abstract 9500.
5. Hellmann MD, Paz‑Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non‑small‑cell lung cancer (suppl). N Engl J Med. 2019;381(21):2020‑2031.

© 2020 Bristol-Myers Squibb Company. All rights reserved.

7356US2002411-01-01 09/20

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59-Year-Old Male with Dizziness and Headaches

Thomas is a 59-year-old male who presents at his primary care physician’s office, complaining of headaches, dizziness, and fatigue for several days. His ..... see more

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Coagulation factor V is a marker of tumor-infiltrating immune cells in breast cancer

ABSTRACT ABSTRACT Factor (F) V is an essential cofactor in blood coagulation, however, F5 expression in breast tumors has also been linked to tumor aggressiveness and overall survival. The specific ..... see more

Source : https://doi.org/10.1080/2162402X.2020.1824644

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Tumor-Infiltrating Lymphocyte-Based Risk Score for Predicting Prognosis in Gastric Cancer

Tumor-infiltrating lymphocytes (TILs) in gastric cancer are closely related to clinical prognosis; however, little is known regarding the immune microenvironment in this disease. Thus, RNA-sequencing data from gastric cancer patients ..... see more

Source : https://doi.org/10.3389/fonc.2020.522015

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Immunogenicity and antitumor efficacy of a novel human PD-1 B-cell vaccine (PD1-Vaxx) and combination immunotherapy with dual trastuzumab/pertuzumab-like HER-2 B-cell epitope vaccines (B-Vaxx) in a syngeneic mouse model

ABSTRACT Therapeutic blockade of PD-1/PD-L1 signaling with monoclonal antibodies (mAbs) has shown clinical success and activity across a broad set of cancer subtypes. However, monotherapy with PD-1/PD-L1 inhibitors are only ..... see more

Source : https://doi.org/10.1080/2162402X.2020.1818437

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CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy

Background Combination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of ..... see more

Source : https://jitc.bmj.com/content/8/2/e000847

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A Molecular Subtype Model for Liver HBV-Related Hepatocellular Carcinoma Patients Based on Immune-Related Genes

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world with a very poor prognosis. Immunotyping is of great significance for predicting ..... see more

Source : https://doi.org/10.3389/fonc.2020.560229