United States

Background
Vitamin B12 (cobalamin) is a water-soluble vitamin required for normal DNA synthesis, myelination and function of central nervous system and development of hematopoietic cells. B12 isnaturally found in foods from animal but is also supplemented in many foods. However, even in high-income countries, 15-20% of individuals &gt;60 years of age are likely deficient. Risk factors for deficiency include inadequate dietary intake and conditions that limit absorption such as autoimmune disorders, prior gastric surgery and use of metformin. Although most cases of 
deficiency are asymptomatic or mild, ~2.5% of cases result in a hemolytic anemia with pancytopenia termed pseudothrombotic microangiopathy (pTMA). The syndrome is often mistaken for other forms of true hemolytic anemia and therefore accurate diagnosis is imperative,as pTMA can easily managed by supplemental B12.

Case Presentation
A 56-year-old woman presented to the emergency department complaining of two months of lethargy and anorexia. She had no significant medical history and took no medications other than intermittent acetaminophen. Laboratory evaluation revealed pancytopenia and serum markers (total bilirubin, LDH, and haptoglobin) consistent with hemolysis. Peripheral blood smear revealed schistocytes and dacrocytes. Following hospital admission, further work-up demonstrated undetectable serum B12, normal serum folate, a reticulocyte index of 0.43, and a serum methylmalonic acid of 20,701. The patient was transfused packed-RBCs and started on weekly intramuscular B12. Within two days of initial supplementation, the patient’s symptoms improved. Following discharge, direct and indirect antiglobulin and intrinsic factor auto-antibody testing confirmed the diagnosis of pTMA secondary to pernicious anemia.

Discussion
Although bibliometric analysis reveals an increasing proportion of publications over the past decade that discuss this clinical syndrome (n=93, 68%), pTMA continues to confound clinicians, leading to unnecessary diagnostic and therapeutic interventions. A systematic review of published cases found that of 321 patients with pTMA, 50 (16%) underwent bone marrow biopsy, 11 (3%) were treated with plasma exchange therapy, and 7 (2%) were treated with high dose glucocorticoid therapy prior to B12 supplementation. Such interventions are of limited benefit in pTMA and often confound the diagnosis, delaying therapy. Therefore, increased 
awareness is paramount for the practicing clinician in order to promptly recognize and reverse this illusive condition.

AMA Research Challenge 2022

B12 Deficiency: A Curious Cause of Pseudo-Thrombotic Microangiopathy

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Ricardo Correa, MD, EdD
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Jessica Li, MD/PhD Candidate
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Charles Lopresto, DO

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Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


Background
Vitamin B12 (cobalamin) is a water-soluble vitamin required for normal DNA synthesis, myelination and function of central nervous system and development of hematopoietic cells. B12 isnaturally found in foods from animal but is also supplemented in many foods. However, even in high-income countries, 15-20% of individuals >60 years of age are likely deficient. Risk factors for deficiency include inadequate dietary intake and conditions that limit absorption such as autoimmune disorders, prior gastric surgery and use of metformin. Although most cases of 
deficiency are asymptomatic or mild, ~2.5% of cases result in a hemolytic anemia with pancytopenia termed pseudothrombotic microangiopathy (pTMA). The syndrome is often mistaken for other forms of true hemolytic anemia and therefore accurate diagnosis is imperative,as pTMA can easily managed by supplemental B12.

Case Presentation
A 56-year-old woman presented to the emergency department complaining of two months of lethargy and anorexia. She had no significant medical history and took no medications other than intermittent acetaminophen. Laboratory evaluation revealed pancytopenia and serum markers (total bilirubin, LDH, and haptoglobin) consistent with hemolysis. Peripheral blood smear revealed schistocytes and dacrocytes. Following hospital admission, further work-up demonstrated undetectable serum B12, normal serum folate, a reticulocyte index of 0.43, and a serum methylmalonic acid of 20,701. The patient was transfused packed-RBCs and started on weekly intramuscular B12. Within two days of initial supplementation, the patient’s symptoms improved. Following discharge, direct and indirect antiglobulin and intrinsic factor auto-antibody testing confirmed the diagnosis of pTMA secondary to pernicious anemia.

Discussion
Although bibliometric analysis reveals an increasing proportion of publications over the past decade that discuss this clinical syndrome (n=93, 68%), pTMA continues to confound clinicians, leading to unnecessary diagnostic and therapeutic interventions. A systematic review of published cases found that of 321 patients with pTMA, 50 (16%) underwent bone marrow biopsy, 11 (3%) were treated with plasma exchange therapy, and 7 (2%) were treated with high dose glucocorticoid therapy prior to B12 supplementation. Such interventions are of limited benefit in pTMA and often confound the diagnosis, delaying therapy. Therefore, increased 
awareness is paramount for the practicing clinician in order to promptly recognize and reverse this illusive condition.

poster

Introduction: Renal oncocytoma (RO) is a highly differentiated tumor that accounts for 4.3% of solid renal masses and 16% of all renal masses. ROs have a benign clinical course with excellent long-term outcomes and 100% disease specific survival. Up to 30% of the small renal masses detected on routine imaging are benign, but most are still treated without a tissue diagnosis. Partial nephrectomy (PN) is suggested for patients with a renal tumor <4 cm, while radical nephrectomy is recommended for tumors 4 cm and larger. The patient is subsequently followed post-partial nephrectomy with active surveillance (AS), which includes routine imaging tailored to the patient’s profile and risk factors to monitor tumor growth after initial complete staging. Biopsy followed by AS can be considered as an alternative in cases of benign tumors as it avoids overtreatment. 
Case Presentation: A 66-year-old man presented with flank pain was diagnosed with bilateral ROs. Patient underwent left partial nephrectomy and received a histological diagnosis of RO. Subsequently, the patient elected to undergo partial nephrectomy to remove the contralateral right renal mass.
Discussion: In patients who have undergone partial nephrectomy with diagnosis of RO, there is an increased likelihood of benign neoplasm and decreased risk of RCC, similar to that of the general population. After our patient’s left partial nephrectomy, given the diagnosis of RO and the absence of constitutional symptoms or gross hematuria, the chance of RCC or hybrid tumor with RO was decreased. Because the left renal mass was 3.3 cm in size and undiagnosed prior to intervention, the mass was more concerning for RCC; however, with the diagnosis of RO in the left kidney and the decreased size of the right renal mass at 2 cm, there was a negligible risk of metastasis, which warranted AS rather than intervention. The patient could have undergone a confirmatory biopsy of the contralateral right renal mass with AS imaging protocols instead of undergoing a right partial nephrectomy. Given advancements in technology, AS with core renal biopsy is a promising approach to accurately diagnose and manage ROs conservatively.

Bilateral Renal Oncocytoma: Active Surveillance vs. Partial Nephrectomy

Introduction
Heart failure is the most common initial manifestation of infiltrative cardiomyopathies, which in many instances can remain underdiagnosed. In patients with oncological history, it can be due to cancer or its treatment complications. The incidence of metastatic disease to the heart is rare at less than <10% (most common with lung, breast, melanoma, and hematological malignancies). We present a rare case of recurrent breast cancer that presented as new-onset heart failure. 
Case description
81 y/o female with a past medical history of hypertension and breast cancer treated with lumpectomy and radiation without adjuvant chemotherapy in remission since 2004, presented with dyspnea on exertion and orthopnea. Noted to have elevated BNP, bilateral pleural effusions, and ejection fraction (EF) of 30 %, was treated for CHF exacerbation. During outpatient follow-up, a new echocardiogram showed an EF 40-45% with an apical thrombus, which resolved with apixaban. On cardiac catheterization, she was noted to have mild nonobstructive coronary disease. Her EF eventually improved to 55%, however, she continued with symptoms despite diuresis and heart failure treatment. She was readmitted 2 months later and found to be in CHF exacerbation, right pleural effusion, for which she had a thoracentesis and was discharged when stable. Cardiac MRI was done and showed normal EF with diffuse late gadolinium enhancement consistent with infiltrative disease. A Technetium pyrophosphate scan was performed and was negative for amyloidosis. The patient presented recurrent symptoms and pleural effusion a month later. She was referred to the hospital for a myocardial biopsy. The procedure was complicated with right ventricle perforation and pericardial effusion with tamponade and cardiogenic shock that warranted an emergent pericardial window. She was in the ICU until improved. Pleural fluid from prior thoracentesis, and myocardial biopsy revealed malignant cells consistent with breast cancer ER+. She was started on letrozole and would continue further oncologic workup with PET/CT as an outpatient. 
Discussion
Detection of Infiltrative cardiomyopathies has led to improved to better outcomes via disease-specific therapy. Heart failure in oncologic patients can be caused by different mechanisms including radiation, chemotherapy, and cancer metastases. Breast cancer gets to the heart by lymphatic spread most commonly in pericardium; myocardium metastases are rare. Treatment is symptomatic. In our case, the recurrent malignant pleural effusions, nonobstructive CAD, MRI suggestive of infiltrative disease, and negative PYP led to the suspicion of cardiac metastasis. Pathology is the gold standard for the diagnosis of cardiac metastasis.
Conclusion
Cardiac metastases should be considered in any individual with new cardiac symptoms and known malignancy. The prognosis of patients with breast cancer with cardiac metastases is poor.

Cardiac Metastases Mimicking Amyloidosis In New- Onset Heart Failure: A Rare Presentation Of Recurrent Breast Cancer 

Carotid sinus syncope in the setting of metastatic disease 

Background
Carotid sinus syncope, also referred to as carotid sinus hypersensitivity is a condition in which the stimulation of the carotid artery baroreceptors results in a greater than expected fall in heart rate and drop in blood pressure. In such cases, activities that stimulate the carotid baroreceptors such as turning the neck or looking upward stimulate the vagus nerve which results in significant reduction of heart rate. 

Case Presentation 
Our case involved a 65-year-old female with an enlarged right cervical lymph node. The lymph node was previously biopsied and found to be SCC with suspected SCC esophageal primary. Patient was admitted to our service for syncope. The patient had unresponsive with some body rigidity while in the car with her daughter who drove her to the ED. A similar event occurred in the ED on arrival and an RRT was called. She had received her second of fifteen fractions of 45 Gy to the lymph node three days prior to this event and after treatment, the swelling of the node had increased. Patient was admitted for syncope workup and continuous video EEG monitoring was negative for seizure activity. She had severe sinus bradycardia down to 43 upon the admission. Vascular imaging was obtained due to concern for carotid artery occlusion secondary to the mass. The lymph node was observed to be necrotic and encasing the carotid sinus. She was started on steroids considering her recent radiotherapy and concern for increased inflammation compressing the carotid sinus triggering a vagal induced syncope. The patient’s heart rate improved to the 70s initially with steroids before settling to between 51-61 prior to discharge. She was started on midodrine to increase blood pressure and maintain brain perfusion during syncopal events under the advisement of cardiology. Diagnosis was determined to be sinus syncope due to metastatic right cervical lymph node enlargement and right carotid sinus encasement.

Discussion
The case illustrates the diagnosis and management of carotid sinus syncope secondary to non-resectable metastatic disease. It further elucidates the importance of educating patients on symptom recognition and modification of daily life activities. 


Carotid sinus syncope in the setting of metastatic disease

Background  

Despite showing remarkable remission rates in patients with refractory hematological malignancy, Chimeric Antigen Receptor T cell (CAR-T) therapy has raised increased concern over its side effects, such as Cytokine release syndrome (CRS) and neurotoxicity. It should be used carefully, especially in hemodynamically unstable patients. This vignette describes a patient with relapsing B Cell-Acute Lymphocytic Leukemia(B-ALL) who was in hemorrhagic shock prior to CAR-T infusion but showed significant improvement after being infused with CAR-T.  

Case Presentation  

A 40-year-old male with an 18-month history of B-ALL was admitted to our hospital due to leukemia relapse, infectious mastoiditis, and pneumonia. Workup suggested extensive liver leukemic infiltration and fungal pneumonia. The following seven hospital days were complicated by severe anemia, thrombocytopenia, neutropenia requiring frequent blood transfusion, and acute hypoxic respiratory failure requiring mechanical ventilatory support. Further, he suffered an episode of hematemesis leading to hemorrhagic shock, which was treated with IV norepinephrine. The CAR-T therapy was planned for refractory leukemia, but the impaired hemodynamic status posed a therapeutic dilemma for us. However, given his poor prognosis and no other option for leukemia, we proceeded with its infusion despite his hemodynamic instability. He continued to require blood product replacements with extensive volume support and norepinephrine infusion to maintain adequate blood pressure. His vitals, inflammatory markers, hemoglobin, and blast cell count started improving six days post-CAR-T. He was extubated to a high-flow nasal cannula and transitioned to hemodialysis from the continuous renal replacement therapy. He maintained adequate BP without any vasopressor and was transferred to the floor. His hospital stay was further complicated by resistant thrombocytopenia, anemia, GI bleeding, and acute renal failure, and increasing circulating blasts limiting treatment options. As such, after a stay in the hospital of more than 30 days, at his family’s request, he was transferred to hospice care, where he died the next day. 

Conclusion 

The case demonstrates the use of CAR-T therapy in a hemodynamically unstable and clinically deteriorating patient. Despite hypotension on therapy initiation, this patient tolerated the infusion well and did not develop severe CRS. In contrast, the patient showed improved hemodynamic stability, decreasing signs of inflammation, and improvements in resistant anemia. The patient was able to be extubated while on the therapy. This case suggests CAR-T therapy may be an option for rapidly progressing patients or when alternative therapies are not an option. 

Case Report: Chimeric Antigen Receptor T Cell Therapy in Patient with B Cell Acute Lymphocytic Lymphoma Shortly after Developing Shock

There is a known relationship between Clostridium septicum bacteremia and colorectal malignancies. C. septicum is a gram-positive, anaerobic, spore-forming bacterium that can survive the acidic colorectal tumor microenvironment, where it is thought to enter the blood by tumor-mediated epithelial tissue damage. While in circulation, C. septicum can release exotoxins which may lead to life-threatening sepsis. The patient in this case presented with a mild fever, abdominal pain, and left handed weakness. Imaging of the head and abdomen revealed a right frontal lucency and wall thickening of the ascending colon. Two colonic adenocarcinomas were found and removed via an exploratory laparotomy and right hemicolectomy. The blood culture was positive for C. septicum. Brain MRI confirmed a right frontal mass concerning for metastasis. Here, we discuss the relationship between colonic cancers and Clostridium septicum bacteremia.


Concurrent Clostridium Septicum Bacteremia and Colorectal Adenocarcinoma with Metastasis to the Brain

Abstract Title:
Diffuse Bone Disease as Primary Clinical Manifestation of Adult T-Cell Leukemia/Lymphoma: Time for a Classification Update?

Background
ATLL is an aggressive mature T-cell leukemia/lymphoma caused by the human T-lymphotropic virus type 1. (HTLV-1). Shimoyama published the first diagnostic criteria and classification of ATLL in 1991, and since then, efforts have been made to keep clinical subclassifications up to date. In this context, we believe it is worthwhile to propose an extranodal primary-bone presentation of ATLL. We describe a novel presentation of ATLL with solely bone lesions.

Case Presentation
A 33-year-old woman presents with 1-year of diffuse bone pain and tumor-like chest wall lesions. Laboratory and radiological examinations were remarkable for hypercalcemia and diffuse osteolytic lesions. Initial concern was for multiple myeloma. Workup was negative for the presence of monoclonal gammopathy. Bone marrow examination of the iliac crest did not show any abnormal B-, T-, or plasma cell population. A repeated sternal bone marrow aspirate and biopsy of one of the chest wall lesions demonstrated a CD3+ T-cell neoplasm. Western blot analysis was positive for HTLV-1. A diagnosis of HTLV-1-associated ATLL was concluded. Patient was managed with multiagent chemotherapy, however, patient died from rapid disease progression after completing 2 cycles of treatment. This case highlights bone disease as primary ATLL presentation.

Discussion
Although the above case represents the first case of extranodal primary bone ATLL-variant ever described in Peru, similar cases have also been encountered in our cohort in Miami where 56% had diffuse bone disease and 44% localized bone disease but that progressed to diffuse bone disease upon relapse. High calcium and LDH levels were found in 25% and 38% of patients, respectively. Three patients had HIV co-infection. The median OS time were 16.8 months.

ATLL cells have the HTLV-1 genome clonally incorporated. Tax-induced NF-kb pathway activation by the HTLV-1 genome promotes cell growth and the progression of ATLL. Deregulation of the NF-B has been linked to the development of lytic bone lesions and hypercalcemia in multiple myeloma. We hypothesized that our patient's distinct clinical presentation was influenced by physiopathology similar to that of multiple myeloma.


Diffuse Bone Disease as Primary Clinical Manifestation of Adult T-Cell Leukemia/Lymphoma: Time for a Classification Update?

Squamous Cell Carcinoma of Breast: a Rare Case

Background
Yolk sac tumors are non-seminomatous germ cell tumors found most often in children and rarely in adults. Even in adult populations, a testicular mass is typically the first presenting sign of a primary testicular malignancy, and seldom is there a testicular cancer diagnosis with no mass palpated on physical exam. 
Case Presentation
We present a 44-year-old man with family history of testicular cancer who presented initially with gastrointestinal symptoms and no testicular mass who was ultimately found to have pure yolk sac tumor pathology per liver metastasis biopsy.
Discussion
We compare our case to the other reports of post-pubertal yolk sac tumors currently reported in the literature. Though not only rare for an adult male to have a pure yolk sac tumor, but also an entirely gastrointestinal presentation, it is important for clinicians to weigh the importance of family oncological history combined with classic metastatic patterns when determining a primary tumor location. Furthermore, despite signs and symptoms pointing toward a likely gastrointestinal pathology, testicular cancer should remain on the differential for patients with any risk factors for malignancy. We present a rare case of yolk sac tumor, and testicular cancer in general, demonstrating the diversity of possible pathologic presentations of this cancer.


Unusual Presentation of a Pure Yolk Sac Tumor in an Adult Male: A Case Report

Case Presentation:

A 50-year-old male patient with a past medical history of well-controlled diabetes mellitus type 2 presented with non-productive cough and worsening dyspnea of 7-day duration. He was diagnosed with COVID-19 infection before presentation in urgent care and was prescribed oral methylprednisolone. He was noted to be febrile with a temp of 101.3 F, tachypneic at 24 CPM. BP was 110/60 mm Hg and HR was 110 bpm. Chest X-ray reported bilateral diffuse groundglass opacities. CRP, Ferritin, LDH were all elevated at 7.4 mg/L, 756 ng/mL, 455 U/L respectively. D-Dimer was also high at 7 mcg/mL. He was diagnosed with ARDS due to COVID-19 pneumonia, admitted to ICU, and was subsequently intubated. He was started on dexamethasone 6 mg iv twice daily, enoxaparin 50 mg bid. He was not a candidate for remdesivir as per institutional protocol. 36 hours into admission, he was noted to have a cold right lower extremity with loss of popliteal and dorsals pedis pulsations. CT angiography Aorta (CTA) revealed a near-occlusive thrombus involving the right common iliac artery and occlusive thrombus of the right popliteal artery. He
underwent urgent thrombectomy with the continuation of anticoagulation, now changed to heparin drip infusion. There was no evidence of intracardiac thrombus on a 2D transthoracic echocardiography. CTA was repeated 4 days later which showed persistent occlusion of the right common iliac artery with now thrombus extending into right external iliac and internal iliac arteries. Thrombectomy and angioplasty were repeated. Unfortunately right lower extremity remained
ischemic and pulseless necessitating above-knee amputation. Hypercoagulable work-up was sought. Blood pressure and platelet counts remained stable throughout. Serology for IgM Anticardiolipin (aCL) antibodies was weakly positive at 38 MPL. Anti-beta2-GP I antibodies (GP) and lupus anti-coagulant were not found. Prothrombin Gene mutation and Factor V Leiden were also not detected.

Discussion:
COVID-19, an acute viral infection caused by SARS-CoV-2, continues to challenge the healthcare system worldwide despite availability of vaccines against it. Some of the complications that are associated with COVID-19 are ARDS, myocardial injury, myocarditis, arrhythmia, strokes, and even opportunistic infections such as aspergillum, mucormycosis. [1, 2] These complications overall increase mortality among COVID-19 patients. Coagulopathy is another complication that is associated with organ dysfunction and mortality, particularly in critically ill COVID-19 patients. [3] The index patient did not have any prior history or evidence of venous or arterial thrombosis. No similar history in his family was found. His anti-cardiolipin antibody was minimally elevated. Although this may indicate anti-phospholipid syndrome, confirmation of this abnormal test requires repeating the test 12 weeks later. We believe that COVID-19 infection is, at least, responsible for decreasing the threshold of developing refractory arterial thrombosis requiring limb amputation in this patient with the probable anti-phospholipid syndrome. Endothelial dysfunction, platelet activation, stasis, and enhanced inflammatory response are some of the
mechanisms that can increase the risk of thrombosis in COVID-19 patients.

Conclusions:
Prothrombotic states are not uncommon in critically ill COVID-19 patients. Early initiation of therapeutic anticoagulation in high-risk COVID-19 patients is necessary to prevent limb or lifethreatening complications.


A Case of Limb-threatening Refractory Arterial Thrombosis in a Patient With Covid-19

Background: Primary infection with varicella zoster virus (VZV) causes varicella (chickenpox), while herpes zoster (shingles) is a secondary infection that occurs when latent VZV is reactivated. Both primary and secondary VZV infections can cause central nervous system manifestations, including encephalitis, which is rare and often fatal.

Case Presentation: A 66-year-old woman with history of rheumatoid arthritis, psoriasis, and coronary artery disease presented to our hospital with sudden-onset altered mental status. She was found naked, confused, and covered in feces and urine at home. At presentation, she was afebrile, tachycardiac (106 bpm), tachypneic (24 breaths/min), saturating 97% breathing ambient air. Labs were unremarkable. Non-contrast head CT revealed disproportionately enlarged ventricles and temporal lobe volume loss. Brain MRI confirmed ventriculomegaly. Blood cultures were drawn, and IV vancomycin, ceftriaxone, and ampicillin were started empirically. Initial blood cultures were negative. On Day 3, lumbar puncture with cerebrospinal fluid (CSF) analysis showed elevated WBC (1,077 cells/mcL) with 97% lymphocytes, low glucose (21 mg/dL) and elevated protein (298 mg/dL). CSF viral PCR panel was positive for VZV, necessitating initiation of IV acyclovir. Given no significant improvement despite treatment, lumbar puncture was repeated on Day 8, with similar findings as the initial CSF analysis. Ampicillin was discontinued because repeated blood cultures and CSF analysis were negative for Listeria. By Day 17, she had completed a 14-day course of IV acyclovir but remained febrile and confused. The patient’s family decided to transition her to comfort care measures, and she expired on Day 23.

Discussion: Nervous system manifestations of VZV include meningitis, encephalitis, cerebellar ataxia, vasculopathy, and myelopathy. Unlike encephalitis caused by herpes simplex virus type-1 and enteroviruses, VZV encephalitis is uncommon, occurring in one out of every 33,000 to 50,000 cases of VZV infection. VZV encephalitis is associated with intense inflammation, and often has an acute presentation. Studies report higher median CSF protein levels and higher CSF lymphocytosis in VZV encephalitis compared to enterovirus encephalitis. Even with appropriate treatment, VZV encephalitis is almost 100% fatal in immunocompromised hosts. A high index of suspicion and early initiation of appropriate treatment for VZV encephalitis is essential, especially in immunocompromised hosts.

Next from AMA Research Challenge 2022

Bilateral Renal Oncocytoma: Active Surveillance vs. Partial Nephrectomy

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