Immunotherapy in Bladder Cancer.

BACKGROUND: Bladder cancer is the fifth most common cancer in the United States. Cisplatin-based chemotherapy is the current standard of care in stage IV bladder cancer. It has increased overall survival but rarely results in complete remission, with an overall survival of 14-15 months. The most significant breakthrough in cancer therapy over the last decade was the development of immunotherapy. DATA SOURCES: KEYNOTE-045, IMvigor211, CheckMate275, Javelin Solid Tumor, MEDI4736, and KEYNOTE-0528 clinical trials. AREAS OF UNCERTAINTY: There are ongoing clinical trials using combination of immunotherapy and chemotherapy as first line of therapy in the setting of metastatic urothelial cancer and also to determine the duration of treatment. THERAPEUTIC ADVANCES: Immunotherapy is approved as a second-line treatment for metastatic urothelial cancer. Their use as a first-line agent is only limited to patients who are ineligible for cisplatin-based treatments. Five drugs are approved by Food and Drug Administration for metastatic urothelial cancer including 3 Programmed cell-death protein 1 (PD-1) inhibitors and 2 programmed cell-death ligand 1 (PD-L1) inhibitors in patients who have progressed during or after platinum-based therapy. Pembrolizumab, nivolumab, and atezolizumab are PD-1 inhibitors. Durvalumab and avelumab are PD-L1 inhibitors. However, only 2 drugs were approved based on phase III clinical trials-pembrolizumab and atezolizumab, of which only KEYNOTE study performed with pembrolizumab showed overall survival difference. Atezolizumab and pembrolizumab are the Food and Drug Administration-approved checkpoint inhibitors in cisplatin-ineligible patients. CONCLUSION: This review article summarizes the significance of immunotherapy in treatment of bladder cancer, its side effects, and limitations.

Use of Immunotherapy in Extensive-Stage Small Cell Lung Cancer.

Lung cancer is a leading cause of cancer death in the United States and around the world. Approximately 13% of lung cancers are small cell lung cancer (SCLC). SCLC is generally classified as a limited-stage and extensive-stage disease depending on the extent of involvement. For patients with the extensive-stage disease, until recently, chemotherapy alone has been the recommended treatment, although radiotherapy could be used in select patients for palliation of symptoms. The standard of care for extensive-stage SCLC is platinum doublet chemotherapy with either cisplatin or carboplatin in combination with etoposide. Even though first-line therapy has an initial response rate of 60-80%, the prognosis is poor, with overall survival of 10-12 months. The only FDA-approved second line of therapy is topotecan, approved both as an intravenous formulation as well as an oral formulation, with response rates of 6-12% in chemorefractory disease and 15-37% in chemosensitive disease. Immunotherapy has recently been approved as a first-line agent in metastatic SCLC in combination with chemotherapy. It is also approved as a third-line agent in metastatic SCLC after the failure of two chemotherapy regimens. The FDA approved four drugs, two of them being PD-1 inhibitors (pembrolizumab, nivolumab), and two of them being PD-L1 inhibitors (atezolizumab and durvalumab) in SCLC. This review article summarizes the significance of immunotherapy in the treatment of extensive-stage SCLC, its side effects, and limitations.

Immune Checkpoint Inhibitors-Related Cardiotoxicity.

BACKGROUND: Immunotherapy is a significant breakthrough in cancer therapy in the last decade. Immunotherapy is better tolerated compared with chemotherapy. However, it does have side effects, and one of the rare and serious side effects of immunotherapy is cardiotoxicity. Cardiotoxicity has been described with other cancer-related treatments such as chemotherapy and targeted therapy. A high index of suspicion is required, and prompt management with immunosuppression needs to be instituted as soon as possible to prevent fatal outcomes. AREAS OF UNCERTAINTY: Research is still ongoing to identify biomarkers that will help us to choose the patients, who will respond well to immunotherapy. Tumor-infiltrating lymphocytes, tumor PD-L1 expression, and tumor mutational burden explored as potential biomarkers. There are no predictive biomarkers to identify patients who are at higher risk of severe cardiotoxicity. Both cardiologists and oncologists should be aware of cardiac toxicity from immune checkpoint inhibitors. CONCLUSION: All patients who are starting immune checkpoint inhibitors should undergo baseline cardiac risk factor assessment with referral to a cardiologist in a patient with multiple risk factors or previous history of cardiovascular disease. Cardiac immune-related adverse events are higher in patients taking combination therapy with anti-CTLA-4/anti-PD-1 agents compared with monotherapy. Patients with known cardiac comorbidities require a higher level of vigilance to monitor for cardiac toxicity because nonspecific symptoms can lead to rapid clinical deterioration and a higher rate of mortality when treated with checkpoint inhibitors.

Outcomes of Clostridioides difficile in Patients with Vitamin D Deficiency: A Propensity-Matched National Inpatient Sample Analysis.

OBJECTIVES: We aimed to determine in-hospital outcomes, length of hospital stay, and resource utilization in a contemporary cohort of Clostridioides difficile infection (CDI) and vitamin D deficiency (VDD). METHODS: The National Inpatient Sample database for 2016 and 2017 was used for data analysis using International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS) codes to identify the patients with the principal diagnosis of CDI and VDD. We assessed the all-cause in-hospital mortality, morbidity, length of hospital stay (LOS), and total costs between propensity-matched groups of CDI without VDD versus CDI with VDD. RESULTS: We identified 202,234 patients with CDI, 4515 of whom were patients with VDD and 197,719 of whom were without VDD. After propensity matching, there was no difference in the in-hospital mortality between the two groups (odds ratio [OR] 1.5, 95% confidence interval [CI] 0.58-4.3; P = 0.90). CDI with VDD has a higher odds of sepsis (OR 1.6, 95% CI 1.3-1.9; P = 0.0), and peritonitis (OR 1.6, 95% CI 1.4-3.8; P = 0.01). Mean LOS (5.9 ± 1.8 vs 5.4 ± 2, P < 0.01) and mean total charges ($11,500 vs $9971, P < 0.04) were higher in CDI with VDD. The factors affecting the LOS were acute coronary syndrome (P = 0.04), mechanical ventilation (P = 0.03), obesity (P = 0.004), acute kidney injury (P = 0.04), and sepsis (P = 0.05). CONCLUSIONS: In this large cohort in a propensity-matched analysis, VDD does not increase the in-hospital mortality in CDI. VDD increases the odds of complications with a higher LOS and resource utilization. These findings may be clinically relevant to guide clinicians to routinely monitor vitamin D status and supplement in patients at risk of CDI.

Acute Interstitial Nephritis Induced by Clozapine.

Acute interstitial nephritis (AIN) classically presents as acute kidney injury most often induced by offending drugs. Less frequently it is secondary to infections, autoimmune disorders, or idiopathic conditions. Development of drug-related AIN is not dose dependent and a recurrence can occur with re-exposure to the drug. We present a 50-year-old male with treatment resistant schizoaffective disorder who developed clozapine-induced AIN, confirmed with kidney biopsy within 2 months of taking this medication. His kidney function improved with removal of the drug and treatment with steroids. However, his kidney function was again significantly impaired when rechallenged with even a lower dose of clozapine a year later. Kidney function returned to baseline after stopping clozapine. Monitoring of kidney function during clozapine therapy is essential to therapy. Prompt diagnosis is imperative as discontinuation of offending agent can prevent acute kidney injury.

COVID-19 and Aortic Thrombosis: A Case Report.

Coronavirus disease 2019 (COVID-19) is an infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is known to cause a myriad of symptoms ranging from mild respiratory illness to severe pneumonia and acute respiratory distress. Since its discovery in late 2019 in Wuhan, China, the virus has caused a devastating worldwide pandemic. Although COVID-19 most commonly causes respiratory symptoms, complications such as hypercoagulability are now known to occur in some patients. In this case report, we present a COVID-19 patient that suffered a stroke and was found to have an aortic thrombus. In this case report, we discussed hypercoagulability, venous and arterial thrombosis in COVID-19 patients. We hope to highlight the importance of monitoring laboratory markers of hypercoagulability and thromboembolism symptoms in COVID-19 patients and encourage appropriate prophylaxis and treatment with anticoagulants when necessary. It is unclear whether or not a causal relationship exists given the nature of the syndrome. However, given the growing number of reported cases physicians should maintain awareness of this possible complication when evaluating COVID-19 patients.

Paget-Schroetter Syndrome in a Young Female.

Paget-Schroetter syndrome or effort thrombosis is a relatively rare primary spontaneous thrombosis of upper extremity deep veins secondary to entrapment of axillary subclavian veins from an abnormality of the thoracic outlet. It is commonly seen in young adults who lift heavy weights or strenuous use of the upper extremities during athletic activities. Repetitive microtrauma to the subclavian vein secondary to narrow costoclavicular space and strenuous activities leads to intimal layer inflammation, hypertrophy, fibrosis, and coagulation cascade activation. Management of Paget-Schroetter syndrome differs from the venous thrombosis of the lower extremity as treatment includes anticoagulation, thrombolysis, and surgical decompression. Early recognition and timely management are required to prevent significant disability from post-thrombotic syndrome and long-term morbidity from recurrent thromboembolism and pulmonary embolism. Internists and emergency physicians should be aware of the disease's presentation, treatment options, and early referral to vascular surgeons since prompt initiation of appropriate treatment will have better outcomes than delayed treatment. We discussed a case of a 31-year-old female who lifts heavyweight at work, presented with right arm swelling and pain for 2 weeks, and diagnosed with axillary subclavian vein thrombosis secondary to thoracic outlet obstruction. She received a high-dose heparin drip followed by catheter-directed thrombolysis and underwent surgical decompression of axillary subclavian vein via resection of the first rib, subclavius muscle resection, partial anterior scalenectomy, and venolysis. In our review of the literature, randomized controlled studies lack the efficacy and safety of surgical decompression. However, the results are promising based on accumulated experience from vascular surgery experts and small case series. Extensive studies are needed further to delineate the protocol for the management of Paget-Schroetter syndrome.

Fat Embolism Syndrome in Sickle Cell ß-Thalassemia Patient With Osteonecrosis: An Uncommon Presentation in a Young Adult.

Fat embolism syndrome is a relatively infrequent presentation in sickle cell thalassemia patients. It most commonly occurs in long bone fractures in the setting of trauma. However, nonorthopedic trauma and nontraumatic cases have been reported to contribute to fat embolism. The fat embolic syndrome is an underdiagnosed, life-threatening, and debilitating complication of sickle-ß-thalassemia-related hemoglobinopathies. It is primarily seen in milder versions of sickle cell disease, including HbSC and sickle cell ß-thalassemia, with the mild prior clinical course without complications; hence, diagnosis can be easily missed. Pathogenesis of fat embolic syndrome is a combination of mechanical obstruction from fat globules released into systemic circulation at the time of bone marrow necrosis and direct tissue toxicity from fatty acids and inflammatory cytokines released from fat globules. Prompt diagnosis and early initiation of treatment can reduce morbidity and mortality and result in better outcomes and prognosis. Red cell exchange transfusion is the mainstay of therapy with mortality benefits. Overall mortality and neurological sequelae continue to be high despite increased red cell exchange transfusion in the last few years. In this article, we discussed a case of a 34-year-old male patient with a history of sickle cell thalassemia and avascular necrosis of the hip, who presented with fever, hypoxia, encephalopathy, and generalized body aches, found to have thrombocytopenia and punctate lesions on magnetic resonance imaging brain, which led to the diagnosis of the fat embolism syndrome. Only a few sickle cell ß-thalassemia with fat embolic syndrome cases have been reported.

A case of neuromyelitis optica spectrum disorder with coexisting systemic lupus erythematosus.

Neuromyelitis Optica or Devic disease is changed to Neuromyelitis Optica spectrum disorder to include more diverse neurological and autoimmune manifestations. This is a severe relapsing autoimmune demyelinating disorder commonly affecting the optic nerve and spinal cord. It has been reported as either the first manifestation of SLE or as a coexisting condition with other autoimmune disorders commonly included but not limited to SLE and SS. We discussed a case of a 49-year-old female patient who was initially presented with a left-sided weakness that rapidly progressed to quadriparesis and bladder dysfunction within a few days. She had positive autoimmune serology tests for SLE posing a diagnostic challenge as SLE is associated with neurological manifestations. Due to a lack of definitive diagnostic criteria for SLE, presence of AQP-4 antibodies in CSF, and evidence of longitudinal extensive transverse myelitis in MRI cervical spine, we conclude that she has Neuromyelitis Optica spectrum disorder with probable SLE. It is possible that she may develop more signs and symptoms of SLE with time and will need close follow up. Timely diagnosis and prompt treatment are vital to decrease morbidity and mortality, as done in our case. The patient was started on high-dose steroids with significant improvement in her symptoms. These patients may need early treatment with plasmapheresis and long-term follow-up with immunotherapy to prevent relapse. There are few case reports in the literature, and more information is needed to understand and better diagnose NMO with coexisting SLE.

Pembrolizumab related Guillain barre syndrome, a rare presentation in a patient with a history of lupus and bladder cancer.

Immune checkpoint inhibitor-related neurotoxicity causing Guillain Barre Syndrome is relatively uncommon. We discussed an 80-year-old patient with known systemic lupus erythematosus who presented with lower extremity weakness, areflexia and then progressed to respiratory muscle and upper extremity weakness after receiving immunotherapy with checkpoint inhibitors for metastatic bladder cancer. With the increasing use of immunotherapy for the management of cancer, awareness of neurological autoimmune side effects is essential. Immune checkpoint inhibitor-mediated GBS can be severe and fatal if not diagnosed promptly. The hospitalists, neurologists, and oncologists should be aware of neurotoxicity related to immune checkpoint inhibitor therapy requiring a multidisciplinary approach to patient care. Prompt initiation of immunosuppressive therapy is required for the management of immune checkpoint inhibitor-related neurotoxicity.

COVID-19 and APOL-1 High-Risk Genotype-Associated Collapsing Glomerulonephritis.

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the lungs and can lead to acute respiratory distress syndrome (ARDS). The ongoing global pandemic has created healthcare and economic crisis for almost every nation of the world. Though primarily affecting the lungs, it has also affected the kidney in various ways including acute kidney injury (AKI), proteinuria, and hematuria. It has been increasingly shown that African American (AA) individuals affected with COVID-19 and presenting with AKI and nephrotic-range proteinuria are very susceptible to focal segmental glomerulosclerosis (FSGS). The APOL-1 gene, associated with the African American population, has been increasingly recognized as a risk factor for FSGS affected with COVID-19. Our case highlights a similar case of COVID-19 in a 65-year-old AA descendant with biopsy-proven FSGS and genetically confirmed APOL-1 alleles.

Multiple morphological phenotypes of monoclonal immunoglobulin disease on renal biopsy: Significance of treatment.

Plasma cell dyscrasias frequently involve the kidney causing renal dysfunction. Multiple morphologic manifestations of κ light chain disease occurring simultaneously in the same kidney biopsy are uncommon and suggest local microenvironment effects in addition to structural properties of the light chain. A 61-year-old female presented with new onset renal failure and proteinuria. Serological workup revealed monoclonal gammopathy with elevated κ : λ ratio of 1,371. Renal biopsy revealed several paraprotein manifestations including κ light chain deposition disease, monoclonal fibrillary glomerulonephritis, cryocrystalglobulenemia and fibrillar/microtubular cast nephropathy. There was also incidental leukocyte chemotactic factor 2 amyloidosis (ALECT 2), negative for κ light chain and confirmed by immunohistochemistry (IHC). Bone marrow biopsy revealed 10 - 20% κ restricted plasma cells. The patient received 10 cycles of CyBorD (cyclophosphamide, bortezomib, and dexamethasone) chemotherapy. Renal function improved with decreased κ : λ ratio. Repeat bone marrow biopsy showed no evidence of abnormal plasma cells by IHC. The renal recovery demonstrates there may be response to chemotherapy irrespective of the morphologic manifestations of light chain-related injury. Additionally, if amyloid is not demonstrated to be of light chain origin, other amyloid types should be considered.

Association of Autoimmune Hashimoto's Thyroiditis with Systemic Lupus Erythematosis.

SLE (systemic lupus erythematosus) can be associated with other autoimmune disorders with overlapping clinical symptoms. We present a case of a 22-year-old male with recurring exertional dyspnea, chest pain, dry cough and chills, which on further testing revealed large pericardial effusion and bilateral pleural effusions along with laboratory abnormalities consistent with a diagnosis of overlap of SLE with serositis and Hashimoto's thyroiditis. SLE patients with underlying hypothyroidism are slow to respond to standard therapy unless the underlying hypothyroidism is adequately treated.

Cocaine and Alcohol Co-Ingestion-Induced Severe Rhabdomyolysis With Acute Kidney Injury Culminating in Hemodialysis-Dependent End-Stage Renal Disease: A Case Report and Literature Review.

Cocaine toxicity is associated with several organ dysfunctions, including acute kidney injury (AKI). Rhabdomyolysis is the most likely mechanism that mediates AKI, and associated alcohol co-ingestion can amplify the situation. AKI, if severe, can result in end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). All patients with cocaine intoxication should be screened for rhabdomyolysis and AKI along with testing for other drug toxicity, including alcohol. Aggressive measures should be taken to treat the underlying cause that contributes to AKI, and the patients need to be educated about this severe condition. Our patient is a unique case where cocaine and alcohol co-ingestion led to severe rhabdomyolysis, AKI, and subsequently developed ESRD requiring ongoing hemodialysis (HD). He was on daily cocaine and alcohol co-ingestion for seven days and subsequently developed AKI with oliguria from rhabdomyolysis. His creatine kinase (CK) was significantly elevated to 141974 IU/L, and his serum creatinine was 11 mg/dl. Despite aggressive intravenous hydration, his kidney function did not improve, and he ended up needing HD for more than one year despite abstaining from cocaine.

Bacteremia Secondary to Uncommon Gram-Negative Bacilli Transmitted From the Canine in a Patient With Multiple Myeloma.

Sphingobacterium multivorum is a gram-negative rod found in the environment and rarely associated with human infections. Sphingobacterium is the causative agent of infections in an immunocompromised host in most cases. We report a rare case of cellulitis in an immunocompromised host by Sphingobacterium multivorum.

Coronavirus Disease 2019 (COVID-19) in a Renal Transplant Patient.

Coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality worldwide. Transplant patients are particularly at a higher risk of contracting COVID-19 because of their immunosuppressed state, and they have the propensity to develop opportunistic infections. The pre-immunosuppressed state, along with other existing comorbidities, can influence the outcomes of COVID-19 in transplant patients. We describe a case of a renal transplant patient who developed COVID-19. Real-time nucleic acid testing (NAT) should be done in deceased and living donors. The most common management strategy is the modification of immunosuppression along with current experimental strategies for COVID-19.

Potential Zoonotic Origins of SARS-CoV-2 and Insights for Preventing Future Pandemics Through One Health Approach.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that has resulted in a global pandemic and is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Zoonotic diseases are infections that are transmitted from animals to humans. COVID-19 caused by SARS-CoV-2 most likely originated in bats and transmitted to humans through a possible intermediate host. Based on published research so far, pangolins are considered the most likely intermediate hosts. Further studies are needed on different wild animal species, including pangolins that are sold at the same wet market or similar wet markets before concluding pangolins as definitive intermediate hosts. SARS-CoV-2 is capable of reverse zoonosis as well. Additional research is needed to understand the pathogenicity of the virus, especially in companion animals, modes of transmission, incubation period, contagious period, and zoonotic potential. Interdisciplinary one health approach handles these mosaic issues of emerging threats by integrating professionals from multiple disciplines like human medicine, veterinary medicine, environmental health, and social sciences. Given that the future outbreak of zoonotic diseases is inevitable, importance must be given for swift identification of the pathogen, source, and transmission methods. Countries should invest in identifying the hot spots for the origin of zoonotic diseases, enhance diagnostic capabilities, and rapid containment measures at local, regional, and national levels. The threat posed by emerging infectious diseases in modern-days also needs combined efforts internationally where a single discipline or nation cannot handle the burden alone.