Immune Checkpoint Inhibitor-Related Pulmonary Toxicity: A Comprehensive Review, Part II.

The development of immune checkpoint inhibitors (ICIs) has changed the treatment paradigm for cancer. The ICIs nivolumab, pembrolizumab, and cemiplimab target programmed cell death protein 1, and durvalumab, avelumab, and atezolizumab target programmed death ligand 1. Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4. Used as monotherapy or in combination, they have shown remarkable efficacy in melanoma, lung cancer, and many other solid tumors, and indications continue to evolve. These checkpoint inhibitors are typically well tolerated; however, they may cause immune-mediated adverse effects, resulting in inflammation of any organ system. Pulmonary toxicity is vital to recognize, and it can be more challenging to diagnose in patients with lung cancer, given the nature of the disease course and treatment.

Immune Checkpoint Inhibitor-Related Pulmonary Toxicity: Focus on Nivolumab.

The development of checkpoint inhibitors has changed the treatment paradigm for cancer. Checkpoint inhibitors nivolumab, pembrolizumab, and cemiplimab target programmed death-1 (PD-1), whereas durvalumab, avelumab, and atezolizumab target PD-ligand 1. Ipilimumab targets cytotoxic T lymphocyte-associated antigen 4. Used as monotherapy or in combination, these inhibitors have shown remarkable efficacy in melanoma, lung cancer, urothelial cancer, and many other solid tumors, and indications are continuing to evolve. Checkpoint inhibitors are well tolerated when compared with traditional chemotherapy. The major adverse effect profiles are idiosyncratic immune-mediated toxicities resulting from the abnormal activation of autoreactive T cells, which can lead to inflammation in any organ system. The most commonly affected organs are bowel, lung, skin, and endocrine. Pulmonary toxicity is important to recognize, and it can be more challenging to diagnose in lung cancer patients, given the nature of the disease course and treatment. This review article focuses on all of the pulmonary adverse effects of a single PD-1 inhibitor (nivolumab) that have been described in the literature. These complications include dyspnea, pneumonitis, pleural effusion, pulmonary sarcoidosis, pulmonary tuberculosis, acute fibrinous organizing pneumonia, organizing pneumonia, eosinophilic pneumonia, adult respiratory distress syndrome, and lung cavitation. Clinicians must be aware of these toxicities and mindful when prescribing these medications in patients with known lung dysfunction due to chronic lung diseases or lung cancer.

A Rare Case of Extensive Cerebral Venous Sinus Thrombosis Complicated by Heparin-Induced Thrombocytopenia.

Cerebral venous sinus thrombosis (CVST) is a rare but potentially life-threatening cause of stroke. Several risk factors have been identified including hypercoagulable state, malignancy, use of oral contraceptives, pregnancy, head injury, infection, and prothrombotic states such as heparin-induced thrombocytopenia (HIT). HIT is a prothrombotic state leading to thrombosis in several distinct locations including CVST requiring prompt discontinuation of heparin and initiation of nonheparin anticoagulation to prevent catastrophic consequences. Very rarely, HIT can complicate the ongoing CVST leading to worsening thrombosis and clinical deterioration. We here report an exceedingly rare case of CVST complicated by HIT in a 22-year-old female patient who showed remarkable clinical improvement after discontinuation of heparin and initiation of argatroban.

DNA Methyl Transferase 3A (DNMT3A) Mutation Presenting as Isolated Pure Red Cell Aplasia.

Pure red cell aplasia (PRCA) is a rare disorder mainly affecting the erythroid precursor cells. It presents with severe isolated reticulocytopenia with relatively normal counts in the myeloid and megakaryocytic lineages. It has been attributed to numerous congenital and acquired causes. DNA Methyl Transferase 3 Alpha (DNMT3A) mutation has been typically associated with myeloid and lymphoid malignancies. There is a scarcity of data regarding the association of DNMT3A mutation with PRCA. We report a case of a 73-year-old man who initially presented with anemia and reticulocytopenia. After a thorough evaluation and eventual bone marrow biopsy, he was diagnosed with PRCA. Further genetic testing identified a DNMT3A mutation. We are reporting this rare case to highlight the fact that DNMT3A mutation can also present as isolated PRCA in and of itself without the co-occurrence of leukemia, lymphoma, or myelodysplastic syndrome (MDS).

Paraneoplastic Evans Syndrome in a Patient With Prostate Cancer With Small Cell Transformation.

Paraneoplastic syndromes are defined as tumor-associated indirect systemic effects. Prostate cancer-associated paraneoplastic syndromes typically have endocrine, neurologic, and dermatologic manifestations. Reports have suggested up to 70% of metastatic prostate cancers manifest as paraneoplastic entities. Although common in hematological malignancies, it is rare for prostate cancer and other solid tumors to be associated with immune-mediated cytopenias such as Evans syndrome. Based on our PubMed search for the keywords Evans syndrome and prostate cancer, only one other case has been reported in the literature with this association. We report the second such case in a 63-year-old male who initially presented with hemolytic anemia and thrombocytopenia. He was diagnosed with Evans syndrome with initial responses to both steroids and intravenous immunoglobulin. Extensive workup, including an eventual bone marrow biopsy, revealed metastatic prostate cancer with transformation to small cell neuroendocrine carcinoma.

Response of advanced cutaneous squamous cell carcinoma to immunotherapy: case report.

The most common cancer in the United States is non-melanoma skin cancer. Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer after basal cell carcinoma. It develops in the middle and outer layers of the skin. Its precursor is actinic keratosis, which can progress to squamous cell carcinoma in situ, invasive cSCC, and finally metastatic cSCC. About 20% of non-melanoma skin cancers are squamous cell and the remaining 80% are basal cell. Unlike basal cell, squamous cell carcinoma has the propensity to metastasize. This commonly occurs with squamous cell carcinoma (SCC) thicker than 2 millimeters. The risk of metastasis and local recurrence increases with 6 mm thickness and desmoplasia. The risk factors are excessive sun or ultraviolet light (tanning beds) exposure, immunosuppression (either having a weakened immune system or taking immunosuppressive therapy) and fair skin. Therefore, it most commonly affects skin in the head and neck area such as scalp, ears, lips, face, neck or the back of the hands. The treatment for local cutaneous squamous cell cancer is mainly surgery; excisional surgery, Moh's surgery, cryosurgery, curettage and electrodessication, laser surgery or radiation therapy, photodynamic therapy or topical agents such as fluorouracil or imiquimod. However, cSCC that is locally advanced, such as involvement of regional lymph nodes, or has metastasized to distant organs or tissue, is not amenable to surgery or radiation alone. Immunotherapy with cemiplimab, a programmed cell death 1 (PD-1) inhibitor, is a US Food and Drug Administration (FDA) approved therapeutic option for locally advanced and metastatic cSCC for patients who are not candidates for or whose disease is not susceptible to curative surgery or radiation therapy. Cemiplimab is a humanized recombinant immunoglobulin monoclonal antibody that binds to and blocks PD-1 receptor found on T cells inhibiting T-cell proliferation and cytokine production. We present a case of locally advanced cSCC with regional lymph nodes metastases, which achieved clinical remission, utilizing a unique approach of therapy combining a checkpoint inhibitor, Cemiplimab and radiotherapy.

COVID-19 induced immune thrombocytopenic purpura: case report.

Immune thrombocytopenic purpura (ITP) is an autoimmune state of decreased platelets caused by antibody or T-cell mediated destruction of platelets through the reticuloendothelial system and impairment of their production. Symptoms of ITP include bleeding usually from nose or gums, easy bruising, petechiae commonly of lower extremities, menorrhagia, hematuria, hematemesis, hematochezia and most dreadful, intra cranial hemorrhage. Molecular mimicry between viral antigens and host platelet antigens forming cross-reactive anti-platelet autoantibodies may lead to increased platelet clearance in ITP associated with viral infections. One of the many viruses associated with this is the Coronavirus disease 2019 (COVID-19). It has caused a devastating pandemic. It can activate innate and adaptive immune responses. It has numerous signs and symptoms including but not limited to dyspnea, fever, cough, fatigue, myalgias, loss of taste and smell. It leads to diseases such as pneumonia, acute respiratory distress syndrome, thrombosis and cardiomyopathy. Hematologic manifestations include thrombocytopenia and more commonly lymphopenia. Treatment includes steroids, immune globulin, romiplostim, eltrombopag, rituximab or splenectomy. Contact sports should be avoided due to risk of intra cranial bleeding with head impact. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin should be used with caution since they impair platelet function. We discuss a patient with COVID-19 who developed thrombocytopenia thought to be due to ITP. Not much is known about the association between the two. It is important to keep this differential in mind when taking care of patients with COVID-19 who develop thrombocytopenia.

Checkpoint inhibitors: literature review of new treatments for hepatocellular carcinoma.

OBJECTIVE: To systematically review the ongoing progress of effective treatment of advanced hepatocellular carcinoma (HCC), mainly focusing on immune checkpoint inhibitors (ICPI) as monotherapy and combination therapy. BACKGROUND: HCC in general has a poor prognosis; particularly in the advanced stage. For more than 10 years, the treatment with multikinase inhibitors was the first line treatment. Before the introduction of checkpoint inhibitors, very few treatments were available for patients with hepatocellular cancer in the advanced stage, especially in metastatic and unresectable disease. METHODS: We performed an extensive search of the ongoing and published clinical trials in the English written literature concerning of HCC with immune checkpoint inhibition when compared to first line chemotherapy. CONCLUSIONS: The treatment paradigm for advanced stage HCC has significantly changed recently with the introduction of immunotherapy; based on existing research, there is new era for HCC treatment which will positively affect the outcome in a malignancy that did not see therapy advancement for more than a decade. Monoclonal antibodies against programmed death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1), such as nivolumab and pembrolizumab appear to be a promising therapeutic option in HCC. This review outlines immunotherapy that has been approved, and what inhibitors are under investigation for patients with advanced stage HCC.

Testicular Plasmablastic Lymphoma in an HIV-Negative Patient: A Rare Case Presentation.

Plasmablastic lymphoma (PBL) is a very rare disease and it is usually considered a human immunodeficiency virus (HIV)-related B-cell lymphoma that carries a poor prognosis. It mostly involves the oral cavity, lungs, nasal cavity, gastrointestinal tract, lymph node, and skin. Therapeutic regimens like dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (DA-EPOCH) have shown better results in these aggressive lymphomas. We report a rare case of PBL in an HIV-negative patient who presented to the clinic with a complaint of left testicular swelling for 3 months. Ultrasound showed an enlarged left testicle. He underwent a left orchiectomy and the pathology showed PBL with involvement of the spermatic cord margin. Positron emission tomography scan showed hypermetabolic mediastinal and hilar lymph nodes. He was started on DA-EPOCH but showed no response. Accordingly, salvage therapy with bortezomib in addition to ifosfamide carboplatin and etoposide (B-ICE) chemotherapy was initiated with remarkable response. Several other regimens can be used in the refractory setting; however, the evidence is mostly based on retrospective analysis.

Cutaneous Disease as a Rare Presentation of Follicular Lymphoma Progression.

Follicular lymphoma, the third most common lymphoid malignancy, is considered indolent but incurable non-Hodgkin lymphoma. Isolated cutaneous relapse from follicular lymphoma is very uncommon, and very few cases have been reported in the literature. In this article, we present a case of an adult patient with a history of treated follicular lymphoma who presented with a skin lesion on his face and scalp. Further workup, including biopsy, led to the diagnosis of relapsed follicular lymphoma with no progression of disease elsewhere. We reviewed cases of follicular lymphoma, which relapsed with isolated cutaneous involvement. Treatment options for relapsed follicular lymphoma include observation, anti-CD 20 antibody alone, or in combination with chemotherapy, radio-immunotherapy, and stem cell transplantation in selected patients. Increased awareness of disease evolution and prompt diagnosis of this form of relapse from follicular lymphoma will improve the effectiveness and outcome of its management.

Using oral anticoagulants among chronic kidney disease patients to prevent recurrent venous thromboembolism: A systematic review and meta-analysis.

INTRODUCTION: Chronic kidney disease (CKD) increases the risk of venous thromboembolism (VTE) among affected patients. Vitamin K antagonists (VKA) and warfarin remains the main stay of its treatment. Due to novelty and unclear risk-to-benefit ratio of direct oral anti-coagulants (DOAC), they remain underutilized in preventing VTE among CKD patients. We aim to assess the efficacy and safety of DOACs and other oral anticoagulants in preventing recurrent VTE among high-risk population. MATERIAL METHODS: We conducted a literature search using PubMed, Embase, Cochrane, Web of Science and Clinicaltrials.gov for randomized controlled trials (RCTs) comparing anti-coagulants like DOAC, LMWH or VKA or any oral anti-coagulant (OAC) (This includes VKAs and DOACs) with either placebo or another anti-coagulant. Two independent reviewers screened the retrieved articles and extracted data using a piloted data extraction sheet. The primary outcome of interest was number of recurrent VTE and other side effects among CKD patients receiving respective treatment. Secondary outcomes were risk of major, non-major and intra-cranial bleed. RESULTS: We retrieved 7244 titles on initial search, reviewed full text of 818 articles, and selected 10 phase III RCTS for quantitative meta-analysis. Out of 36,326 patients in these trials, only 10,840 (29.8%) were evaluable. We stratified patients into four categories based on severity of renal impairment using serum creatinine clearance (SCr) as the marker e.g. mild (>50 - <80) moderate (>30 - ≤50) severe (<30) and any level (from <30 to <80). There was no difference between DOACs vs VKA in decreasing the risk of recurrent VTE among patients with mild (RR:0.86, 95% CI:0.61-1.22, I2 = 25%) moderate/severe (RR:0.72, 95% CI:0.44-1.17, I2 = 0%) or any level of renal impairment (RR:0.83, 95% CI:0.60-1.14, I2 = 34%). No difference in efficacy between LMWH vs VKA among patients with moderate (RR:2.40, 95% CI:0.44-12.96, I2 = 76%) and any level (RR:2.59, 95% CI:0.66-10.16, I2 = 71%) of renal impairment respectively. Similarly, no difference in efficacy between LMWH vs any OAC (This includes VKAs and edoxaban) among patients with (RR:2.16, 95% CI:0.66-7.-06, I2 = 51%) and any level (RR:1.48, 95% CI:0.79-2.78, I2 = 78%) of renal impairment. DOACs compared to VKAs had significantly lower risk of combined major and non-major bleeding (RR: 0.74, 95% CI:0.65-0.84, I2 = 26%), major bleeding (RR: 0.51, 95% CI:0.38-0.69, I2 = 7%) and non-major clinically relevant bleeding (RR: 0.73, 95% CI:0.57-0.94, I2 = 45%) respectively. Risk of intracranial bleeding was comparable (RR: 0.68, 95% CI:0.19-2.44, I2 = 0%). There was no difference in the risk of major bleeding between LMWH vs any OAC (RR: 0.83, 95% CI:0.46-1.51, I2 = 0%). CONCLUSION: DOACS and other anticoagulants (VKA and LMWH) showed no statistical difference in preventing recurrent VTEs among CKD patients but DOACs had significantly lower risk of major and non-major clinically relevant bleeding irrespective of the level of renal impairment compared to VKAs. There was no difference in risk of intra-cranial bleeding between DOACs and VKAs.

Bullous Skin Rash: A Rare Case of Palbociclib-Induced Dermatological Toxicity.

Palbociclib is an FDA-approved cyclin-dependent kinase inhibitor to treat hormone-positive, HER2-negative metastatic breast cancer. Severe skin toxicities are rare but important adverse events associated with these agents. Early detection of severe forms of skin lesions is crucial to permit the immediate discontinuation of palbociclib in order to avoid unacceptable risk level in the form of severe cutaneous toxicities like Steven-Johnson Syndrome. In such cases, palbociclib should be abruptly discontinued and an early aggressive support should be initiated. We here present a case of 50-year-old Caucasian female, who developed acute onset blistering skin lesions one to two weeks after she was started on palbociclib. We sought to report this case given the unusual toxicity and to emphasize the importance of identifying the acute onset of blistering skin lesions, regardless of their extension, should prompt awareness of their potential severity.

Atypical Takotsubo Cardiomyopathy Secondary to Combination of Chemo-Immunotherapy in a Patient With Non-Small Cell Lung Cancer.

Takotsubo cardiomyopathy (TC) also known as broken heart syndrome or stress-induced cardiomyopathy is a relatively rare and transient form of cardiomyopathy. It usually mimics myocardial infarction in terms of clinical and electrocardiographic presentation, but coronary angiography usually does not reveal any evidence of coronary artery occlusion. Even though many underlying causes including emotional, physical or physiological stress have been identified, the exact pathogenesis remains uncertain. Few of anticancer therapies have been reported as an emerging cause of TC; however, no strong evidence of immunotherapy causing cardiomyopathy. We here present a very rare case of atypical TC in a 57-year-old female with advanced stage non-small cell lung cancer who underwent combined cytotoxic chemotherapy and immunotherapy with carboplatin, pemetrexed and pembrolizumab.

Immune Checkpoint Inhibitors in Locally Advanced, Unresectable, and Metastatic Upper Gastrointestinal Malignancies.

BACKGROUND: Upper gastrointestinal (UGI) malignancies including esophageal, gastroesophageal junction (GEJ), and gastric cancers have a poor prognosis in the metastatic setting. Treatment with cytotoxic chemotherapy remains the treatment of choice in the first-line setting with the addition of trastuzumab, a monoclonal antibody against HER-2, if the tumor is HER2-positive. Before the era of checkpoint inhibitors, there were only few treatment options after failure of the first-line systemic therapy. METHODS: We extensively searched the English written literature for peer-reviewed manuscripts regarding the use of checkpoint inhibitors in advanced stage and metastatic UGI cancer. We also searched and reviewed ongoing clinical trials from Clinicaltrials.gov. RESULTS: Checkpoint inhibition is a promising therapeutic option in UGI cancers, which have overexpression of PD-L1, high mutation burden, or microsatellite instability. Checkpoint inhibitors that are being investigated or are approved in advanced UGI malignancies include PD-1 antibodies, nivolumab and pembrolizumab, PD-L1 antibody, avelumab, and CTLA-4 inhibitors, ipilimumab and tremelimumab. CONCLUSIONS: Based on recent and ongoing studies, eligible patients who have progressed beyond the first-line cytotoxic chemotherapy may benefit from immunotherapy. This review outlines the checkpoint inhibitors that are currently or previously being investigated for patients with metastatic UGI cancers.

Long-term direct oral anticoagulation in primary osteonecrosis with elevated plasminogen activation inhibitor.

Osteonecrosis is a pathological condition that could lead to a debilitating physical disease and impede daily activities. It is generally categorised into aetiology - primary (idiopathic) or secondary. When direct damage to the bone vasculature or direct injury of the bone marrow is related to an identifiable cause such as traumatic injuries, steroid or bisphosphonate use, increased alcohol intake, sickle cell disease, autoimmune diseases, chemotherapy or malignancy, it is categorised as secondary osteonecrosis. On the other hand, osteonecrosis wherein the mechanisms of development are not fully understood is categorised as primary or idiopathic osteonecrosis. This category includes inherited thrombophilia and hypofibrinolysis as potential causes. There are no clear guidelines or general agreements about anticoagulation treatment and duration in primary osteonecrosis due to thrombophilia or hypofibrinolysis. We report a case of primary osteonecrosis associated with hypofibrinolysis and successful control with lifelong direct oral anticoagulation therapy.

Neutropenic enterocolitis in patients with FLT3 mutated acute myeloid leukemia undergoing induction chemotherapy with midostaurin.

Neutropenic enterocolitis mostly affects patients with acute myeloid leukemia (AML) who get treated with intensive chemotherapy which is associated with prolonged neutropenia; its pathogenesis is not well understood and the main factors in this life-threatening condition appear to be neutropenia, mucosal injury and a weakened immune system as a consequence of intensive chemotherapeutic agents. Midostaurin in combination with chemotherapy became the standard of care for FLT3 mutant AML since its approval by the United States Food and Drug Administration (FDA) in April 2017. Anecdotally in our institution, we noticed the common occurrence of neutropenic colitis in three out of three patients who were treated with midostaurin as part of induction chemotherapy for AML.

Check point inhibitors a new era in renal cell carcinoma treatment.

In the United States, the estimated number of new cases of renal cell carcinoma (RCC) is approximately 65,000 case with about 15,000 deaths in the year of 2018 (Siegel et al. in CA Cancer J Clin 68(1):7, 2018). RCC as an immunogenic malignancy is supported by many theories and facts which include tumor richness of lymphocytes infiltrate, the occurrence of spontaneous tumor regression, and the proved effect of traditional immunotherapy (Finke et al. in J Immunother 11(1):1-11, 1992), all these factors support the potential therapeutic effect of the novel immunotherapeutic agents in RCC. Historically, complete tumor regression in metastatic RCC is achievable in a minority of patients through traditional immunotherapies such as high-dose interleukin-2 (IL-2) (Fyfe et al. in J Clin Oncol 13(3):688, 1995) and interferon-alfa (IFNa) (Negrier et al. in N Engl J Med 338(18):1272, 1998); however due to the significant rate of toxicities and low efficacy; accordingly the targeted therapy with tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor-antibodies (VEGF) became the standard and prevalent treatment approach for advanced RCC both in front and subsequent lines of therapy (Escudier et al. in Ann Oncol. 25(Suppl 3):iii49-iii56, 2014). A new avenue of immunotherapy utilizing novel strategy to block immune checkpoints has emerged in a new era for RCC treatment (Ascierto et al. in J Transl Med 12:291, 2014). Results from clinical trials are encouraging in both front-line and second-line settings, in a phase III trial (CheckMate 025) nivolumab compared to everolimus improved overall survival in previously treated metastatic RCC who had progressed on prior treatment with targeting agents (Motzer et al. in N Engl J Med 373:1803, 2015). CheckMate 214, a phase III trial, demonstrated superior overall survival and objective response with combined checkpoint inhibitors compared to sunitinib in Treatment-Naïve Advanced RCC among intermediate- and poor-risk group (Motzer et al. in N Engl J Med. 378(14):1277-1290, 2018). In this review, we discuss the systemic Immunotherapy with checkpoint inhibitors that have been approved or are currently being investigated in RCC, clinical experience with these agents, and its future development.

Solitary Lytic Bone Metastasis: A Rare Presentation of Small Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a hematologic malignancy characterized by an over accumulation of incompetent neoplastic lymphocytes. Bone metastasis in CLL/SLL is very rare. We report a case of a 76-year-old Caucasian female presented with an unresolving pulmonary infiltrate with mediastinal lymphadenopathy concerning for malignancy. Positron emission tomography (PET)/computed tomography (CT) showed an infiltrative mass in the mediastinum with diffuse uptake and a hypermetabolic mass within the left iliac bone. Transbronchial biopsy revealed morphology and features of SLL. However, with concern for another primary cancer, a CT-guided biopsy of the PET avid left iliac bone was performed and revealed bone and marrow with involvement of CLL/SLL similar to the chest lymphadenopathy. To our knowledge and after extensive review of medical literature, this is first reported case of SLL with solitary bone metastasis to the hip.

Immunotherapy in triple-negative breast cancer.

Breast cancer can be classified based on the expression or lack of expression of protein receptors including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (Her2). The basal molecular subtype is mostly made up of breast cancers that do not express ER/PR or Her2, triple-negative breast cancers (TNBC) (Bertucci et al. in Int J Cancer 123(1):236, 2008). TNBC tends to be more aggressive as there are no approved targeted treatments and the only treatment option currently is cytotoxic chemotherapy. Recent data show that some chemotherapies, specifically anthracyclines, not only have cytotoxic effects but also use the immune system by activating CD8+ T cell responses to kill cancer cells (Stagg et al. in Ther Adv Med Oncol 5(3):169-181, 2013), and thus, tumor-infiltrating lymphocytes respond well to chemotherapy. Currently, systemic immunotherapy which utilizes the patient's own immune system directly to eradicate and target neoplastic cells is being explored as treatment for TNBC as this type of breast cancer has been shown to be immunogenic (Yu et al. in Int J Environ Res Public Health 14:68, 2017). According to the Cancer Genome Atlas, TNBC has higher PD-L1 mRNA expression (Mittendorf et al. Cancer Immunol Res 2(4):361-370, 2014). Higher rates of CD8+ T cell infiltration were also found in TNBC according to a study by Liu et al. (Breast Cancer Res 14:R48, 2012). In TNBC patients, Pembrolizumab, a monoclonal antibody that targets programmed cell death protein 1 (PD-1), and Atezolizumab, a monoclonal antibody that targets its ligand, have been investigated to assess dose tolerability and side effects. Further studies involving vaccines, immunotherapy that targets cytotoxic T lymphocyte-associated protein-4 and PD-L1, are currently being investigated for treatment of TNBC. This review outlines the systemic immunotherapies that are currently being investigated for patients with TNBC.

Checkpoint inhibitors: the new treatment paradigm for urothelial bladder cancer.

Bladder cancer is the most common malignancy involving the genitourinary system (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). In the USA, it is the fifth most common cancer and approximately 79,000 new cases will be diagnosed in 2017 (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). The mortality from bladder cancer is approximately 17,000 deaths each year (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). The incidence rate for bladder cancer is higher in men compared to women. Risk factors are predominantly related to tobacco smoking, although infection with Schistosoma haematobium is another risk factor in selected populations (Antoni et al. in Eur Urol, 71:96-108, 2017). Cisplatin-based systemic chemotherapy regimens remain the standard of care in both the neoadjuvant and metastatic setting for muscle-invasive bladder cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602-4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012; Bellmunt et al. in J Clin Oncol, 27: 4454-4461, 2009). There is an estimated overall survival of 9-15 months in metastatic bladder cancer in those who receive the standard of care platinum-based chemotherapy (Von der Maase et al. in J Clin Oncol, 23:4602-4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012). The median survival, however, is significantly reduced after relapse in patient treated with platinum chemotherapy to less than 7 months (Bellmunt et al. in J Clin Oncol, 27: 4454-4461, 2009). Thus, this approach is preferred for patients who can tolerate this treatment as first-line chemotherapy (Gupta et al. in Cancer, 9(15):1-14, 2017). Until recently, there were few treatment options for those patients with poor performance status who are ineligible to receive cisplatin including renal insufficiency and multiple comorbidities or had disease progression after receiving platinum-based chemotherapy (Gupta et al. in Cancer, 9(15):1-14, 2017). With further understanding of tumor immune evasion, systemic immunotherapy which utilizes the patient's own immune system directly to eradicate and target neoplastic cells, has now been approved for urothelial bladder cancer. Monoclonal antibodies that target programmed cell death protein 1 (PD-1), including Nivolumab and Pembrolizumab, and its ligand, PD-L1, including Atezolizumab, Durvalumab, Avelumab, have all been investigated and approved in the setting of metastatic refractory urothelial cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602-4608, 2005; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). Atezolizumab and Pembrolizumab have also been approved as first-line therapy in the setting of cisplatin-ineligible metastatic bladder cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). Those that target cytotoxic T-lymphocyte-associated protein 4, including Ipilimumab and Tremelimumab, have also been investigated and further studies are being performed (Gupta et al. in Cancer, 9(15):1-14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). This review outlines the systemic immunotherapies that have been approved or are currently being investigated.