The Evolving Landscape of Neoadjuvant Immunotherapy in Gastroesophageal Cancer.

Despite advances in treatment strategies and surgical approaches in recent years, improving survival outcomes in esophagogastric cancer (EGC) patients treated with curative intent remains a significant area of unmet need. The recent emergence of adjuvant immunotherapy as the standard of care for resected EGC demonstrates the impact of immunotherapy in improving recurrence-free survival. Neoadjuvant and perioperative immunotherapies represent another promising approach with potential advantages over adjuvant therapy. Despite the promising results of early neoadjuvant immunotherapy studies, there are several challenges and future research needs. The optimal timing, duration and number of doses in relation to surgery and the optimal combination of immunotherapies are still unclear. In addition, rigorous correlative studies need to be performed to identify biomarkers for patient selection and treatment response prediction to maximize the benefits of neoadjuvant immunotherapy. In this review, we provide a concise summary of the current standard of care for resectable EGC and discuss the rationale for the use of immune checkpoint inhibitors in this setting and the pre-clinical and early clinical data of these novel therapies. Finally, we will examine the potential role and future direction of immunotherapy in the treatment paradigm and the perceived challenges and opportunities that lay ahead.

Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development.

Heart Failure as the Initial Presentation of Anomalous Left Coronary Artery From the Pulmonary Artery.

Coronary arteries arising from the pulmonary artery have an incidence of 0.002% in the general population. We present a 29-year-old woman who presented to our hospital with acute decompensated heart failure and atrial fibrillation with a rapid ventricular rate. She underwent a cardiac catheterization to rule out ischemic disease, which revealed retrograde contrast flow through the left coronary artery from the right coronary artery. A coronary computed tomography (CT) angiogram was pursued which showed the presence of an anomalous left coronary artery arising from the pulmonary artery (ALCAPA). For the management of her atrial fibrillation, she was electrically cardioverted. She was discharged on guideline-directed medical therapy for her heart failure, with a cardiac surgery referral for the surgical fixation of her ALCAPA.

Routine Use of Prescription Adderall Leading to Non-cardiogenic Pulmonary Edema and Respiratory Failure.

A 47-year-old female with attention-deficit/hyperactivity disorder on prescription Adderall presented to the hospital with worsening dyspnea for the one-month duration. She was admitted to the medical intensive care unit with respiratory failure requiring non-invasive positive pressure ventilation. Cardiac catheterization confirmed the diagnosis of non-cardiogenic pulmonary edema. With the discontinuation of Adderall, use of BiPAP, and aggressive diuresis with loop diuretics, there was evidence of symptomatic, laboratory, and radiological improvement. Her symptoms were attributed to Adderall use as a diagnosis of exclusion. To our knowledge, this paper reports the first case of Adderall-induced non-cardiogenic pulmonary edema leading to respiratory failure. Although case reports of abuse or overdose of other stimulants such as amphetamine and cocaine leading to a plethora of cardiac and pulmonary complications such as acute respiratory distress syndrome (ARDS), cardiogenic pulmonary edema, and non-cardiogenic pulmonary edema exist, there are no reports that using Adderall at routine prescription doses can lead to these problems.

An Uncommon Incidence of Pulmonary Hypertension Associated With Neurofibromatosis Type 1: A Case Report.

Pulmonary hypertension (PH) is often a difficult condition to diagnose, since it occurs insidiously and is a diagnosis of exclusion. Patients with neurofibromatosis type 1 (NFT1) have been associated with severe exacerbations of PH. To our knowledge, less than 20 cases of PH in NFT1 patients have been reported. However, the severity of presenting symptoms requires physicians to be aware of this association and pursue the appropriate diagnostic workup. In our report, we present a 54-year-old NFT1 patient who presented with worsening dyspnea secondary to PH, which was being treated with trepostanil and macitetan. She required a right heart catheterization to assess her pulmonary artery pressures (which remained elevated). She was placed on tadalafil in addition to trepostanil and macitetan and noted significant resolution of her symptoms. Further studies are required to explore the association between PH and NFT1 and examine the efficacy of triple therapy with endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and parenteral prostanoids in the initial treatment of PH in the aforementioned patient population.

Myocardial Infarction in a Patient With Hereditary Hemorrhagic Telangiectasia: A Case Report and Review of Literature.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that results in vascular defects and arteriovenous malformations. We present a 25-year-old male with a past medical history of HHT who came in with chest pain and was found to have an ST-elevation myocardial infarction (STEMI) and subsequently received a bare-metal stent to the mid-left anterior descending artery (LAD). Although there is a predisposition for bleeding, HHT can lead to thrombotic manifestations such as myocardial infarction (MI), as seen in our patient. Healthcare providers should be aware of this association to be able to efficiently diagnose acute coronary syndrome in HHT patients. Further studies are required to assess the efficacy of bare-metal stents in HHT patients who present with an MI.

Metastatic Cancer Masquerading as Acute Coronary Syndrome.

Patients with heart metastases could present insidiously, with symptoms that mimic those of congestive heart failure or acute coronary syndrome. Our patient initially presented with vague lower sternal and abdominal pain and had a past medical history of coronary artery disease. Her first two troponin levels were elevated, and her EKG was significant for ischemic changes. Echocardiography showed a large mass in the right ventricle and the presence of pericardial effusion. CT scan of the thorax, abdomen, and pelvis showed multiple pulmonary nodules as well as liver metastases. Our patient opted not to pursue further imaging such as cardiac MRI or a liver biopsy. It is imperative that medical professionals are aware of the presentational overlap between acute coronary syndrome and metastatic heart disease, in order to ensure proper diagnosis and management of the latter with echocardiography, cardiac MRI, and possibly surgery.

Systemic Embolization as the Initial Presentation of a Rare Cause of Infective Endocarditis.

Infective endocarditis is a rare disease and is associated with a high mortality rate. The following case describes a 56-year-old gentleman who presented to our hospital with a pulseless left leg concerning for acute limb ischemia, which was managed with emergent revascularization. His subsequent workup revealed IE due to a rare organism known as Streptococcus dysgalactiae. Through this case, we want to showcase this rare cause of IE and also highlight systemic embolization as its possible initial presentation.

A Unique Interplay of Multiple Predisposing Factors Culminating in a Catastrophic QT Prolongation.

Implantable cardioverter-defibrillators (ICDs) are used in patients without a reversible cause for long QT syndrome (LQTS) and secondary prevention in patients with LQTS-associated sudden cardiac arrest. We present a female patient with multiple reversible factors for QT prolongation, including the use of antidepressants, antidiarrheals, antiemetics, and antihistamines; chronic malabsorption from bariatric surgery; probable Gitelman syndrome and urinary losses of electrolytes, causing QT prolongation which leads to polymorphic ventricular tachycardia and a successfully resuscitated cardiac arrest. Our patient also had history suggestive of probable congenital LQTS with multiple childhood syncopal episodes and a history of seizures in first-degree relatives, further justifying the placement of an ICD. Also, this case gives us an opportunity to delve into the risks of catastrophic QT prolongation in the morbidly obese population undergoing bariatric surgery.

Manganese Neurotoxicity as a Complication of Chronic Total Parenteral Nutrition.

Manganese accumulation in the central nervous system creates clinical symptoms of cognitive dysfunction, behavioral changes, and movement disorders resembling Parkinson's disease. Radiographic features of this rare clinical entity include symmetric T1 hyperintensities in the bilateral globus pallidi, with corresponding hypointensities on T2-weighted images. Total parenteral nutrition (TPN) is an increasingly used potentially lifesaving therapy for patients who cannot tolerate enteral nutrition. However, when used over a period of several weeks to months, its associated risks and complications carry significant morbidity and mortality. One of the more rare complications of TPN use is manganese toxicity. We provided care for a 38-year-old female on chronic TPN who presented to the hospital with Parkinsonian features, confusion, falls, and lethargy. MRI brain showed T1 hyperintensities in the bilateral globus pallidi, which were attributed to manganese toxicity from chronic TPN use. Supporting evidence for this rare entity included decreased signal intensity in the bilateral globus pallidi on T2-weighted images and T1 hyperintensities in the substantia nigra. With antifungal treatment and permanent cessation of TPN, her mentation and neurological symptoms began to improve within a week. Repeat MRI brain performed one month after discontinuation of TPN revealed improvement of the T1 hyperintensities in the bilateral globus pallidi. Our objective in presenting this case is to highlight manganese neurotoxicity as a rare complication of TPN in a patient without known hepatic dysfunction and to emphasize the importance of routinely monitoring patients for the possible adverse effects of chronic TPN. Our case is among the handful of published cases in which a patient without known liver dysfunction, which is the primary organ responsible for manganese elimination from the body, developed manganese neurotoxicity.

Intractable Left Internal Mammary Artery Spasm After Coronary Artery Bypass Grafting.

Graft spasm is a rare but well-recognized complication of coronary artery bypass grafting (CABG). The occurrence of graft spam is multifactorial and can be fatal if not diagnosed and treated promptly. There are no well-defined guidelines for the management of a severe spasm. We report the case of a 29-year-old man with left internal mammary artery (LIMA) spasm in the immediate post-operative period following CABG. The intracoronary infusion of nitroglycerin relieved the spasm temporarily, confirming the diagnosis. The patient eventually underwent redo bypass grafting.

Pembrolizumab-Induced Mobitz Type 2 Second-Degree Atrioventricular Block.

Pembrolizumab is a monoclonal antibody directed towards programmed cell death protein 1 (PD-1) and is an antineoplastic drug which has a growing variety of oncologic uses. Pembrolizumab is commonly associated with immune-related adverse events (IRAEs) but is infrequently noted to cause cardiotoxicities such as myocarditis, arrhythmias, and heart failure. The following case report illustrates the clinical course of a 67-year-old female patient with stage IV non-small-cell lung cancer who developed Mobitz type 2 second-degree atrioventricular block three weeks after receiving her first infusion of pembrolizumab. Within a few hours of presentation, she progressed to symptomatic complete heart block requiring emergent placement of a temporary transvenous pacemaker. The article further discusses proposed mechanisms to explain IRAEs and management of IRAEs. We conclude by recommending a higher degree of caution and awareness among all physicians when treating patients on immunotherapy and a multidisciplinary approach when considering resumption of immune checkpoint inhibitor therapy.

The First Case of Native Mitral Valve Endocarditis due to Micrococcus luteus and Review of the Literature.

Gram-positive cocci species, notably Staphylococcus, Streptococcus, and Enterococcus account for 80 to 90% of infective endocarditis cases. HACEK microorganisms (Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) account for approximately 3% of cases and Candida species account for 1-2% of cases. Micrococcus luteus is a rare cause of endocarditis. To our knowledge, only 17 cases of prosthetic valve endocarditis have been described due to M. luteus and a single case of native aortic valve endocarditis has been described. The following case is the only documented case of native mitral valve endocarditis. A review of the literature pertaining to Micrococcus endocarditis was performed to further characterize the entity.

Hepatobiliary strongyloidiasis presenting as an ampullary lesion on esophagogastroduodenoscopy/endoscopic ultrasound.

Strongyloidiasis is an intestinal infection caused by the parasitic nematodes of the Strongyloides species, most commonly Strongyloides stercoralis. We report a case of a 66-year-old immigrant male from Haiti who presented with complaints of diarrhea and an unintentional 80-lb weight loss over the past 5 years. Stool examination was positive for strongyloidiasis. Following albendazole therapy, esophagogastroduodenoscopy (EGD) showed a unique ampullary lesion. Histopathology of the ampullary lesion showed reactive epithelium with Strongyloides larva. In addition, endoscopic ultrasound (EUS) detected a large pancreatic cyst. Both these findings were absent on EGD 5 years previously, prior to the onset of his symptoms. This paper documents a rare case of an ampullary lesion and pancreatic cyst secondary to hepatobiliary strongyloidiasis in a non-Human Immunodeficiency Virus (HIV) patient. We review the epidemiology, life cycle, clinical presentation and treatment of strongyloidiasis.