Detecting Multiple Driver Mutations in a Patient with Essential Thrombocythemia.

BACKGROUND Three driver mutations have been identified in patients with essential thrombocythemia - JAK2 V617F, CALR, and MPL. Out of these, JAK2 V617F is mostly common. These mutations are thought to be mutually exclusive; therefore, the initial workup may not include the identification of all mutations separately. CASE REPORT We present a case of a 55-year-old woman who was referred to the hematology clinic for an elevated platelet count noted when she was hospitalized for a renal stone. The patient was asymptomatic. A workup was initiated for essential thrombocythemia, and she was tested for JAK2 V617F mutation using an allele-specific polymerase chain reaction (AS-PCR) test in peripheral blood, which came back positive. The variant allele frequency was 2%. She underwent a bone marrow biopsy, and next-generation sequencing (NGS) showed a CALR mutation. A 52 bp deletion-type mutation was detected in the CALR gene on exon 9, with a variant allele frequency of 7%. The NGS did not detect JAK2 mutation due to its low sensitivity. She was started on aspirin alone as she was less than 60 years old and had no history of thrombotic events. The patient has been following up with the hematology clinic for the last 2 years and has not had any thrombotic events. CONCLUSIONS We propose that in patients with a low JAK2 V617 allele variant, testing for other driver mutations should be performed. In our patient, JAK2 mutation could be clonal hematopoiesis of indeterminate potential; therefore, the dominant mutation (CALR) would determine the disease phenotype.

Adult-onset Still's disease with concurrent thrombotic microangiopathy: Observations from pooled analysis for an uncommon finding.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder that is characterized by quotidian fevers, arthritis, and an evanescent rash. Occurrence of concurrent thrombotic microangiopathy (TMA) in AOSD is rare. The treatment aspects of TMA in AOSD are actively being debated. METHODS: Medline search using MeSH terms and snowballing yielded a total of 29 articles with co-occurrence of AOSD and thrombotic thrombocytopenic purpura (TTP) including our own. Pooled data were synthesized for descriptive analysis. RESULTS: Median age was 35 years with a majority of females (68.96%). A majority of these studies/patients were either Asian (34.48%) or Caucasian (31.03%). Concurrent TMA at the time of AOSD diagnosis was seen in 65.51% patients. Only 3/29 patients had ADAMTS13 level less than 10%, consistent with TTP and 3/29 were diagnosed with hemolytic uremic syndrome (HUS). The remainder were diagnosed clinically. Complication rate was high, and 15/29 (51.72%) patients died or had permanent neurological/renal/vision/gangrenous complications. Median and mean ferritin peak was observed to be higher (7458 and 12 349, respectively) in patients who either died/had partial remission, compared to those who had complete response (3257 and 10 899, respectively), p = .829. CONCLUSIONS: A majority of patients with AOSD-associated TMA either died or had permanent complications. TMA was diagnosed alongside AOSD in 65% patients, while the rest developed TMA during the course of their disease. Blurred vision may precede TMA and could help risk-stratify high-risk AOSD patients clinically. Glycosylated ferritin remains low several weeks to months after disease remission and may be used to monitor severity of disease process. Further studies are necessary to confirm the existing vascular endothelial growth factor hypothesis in AOSD-associated TMA.

Co­existence of triple­negative essential thrombocythemia and double transcript chronic myeloid leukemia: A case report.

Chronic myeloproliferative neoplasms (MPN) include polycythemia vera (PV), primary myelofibrosis, essential thrombocythemia (ET) and chronic myeloid leukemia (CML). Overlapping MPNs are rare; however, they can occur in the same individual. The present case report describes a patient with both triple-negative ET and CML. A 64-year-old woman was followed-up at our hematology clinic at Feist Weiller Cancer Center, Louisiana State University Health Shreveport (Shreveport, LA, USA) since 2000 after she was diagnosed with JAK2V617F-negative ET. The patient remained stable on hydroxyurea until 2012, when they underwent a bone marrow biopsy for progressively increasing white blood cell counts, and the pathology was consistent with CML; PCR for BCR-ABL was positive for both P210 and P190 transcripts. The patient was then initiated on dasatinib. After dasatinib, they were given a trial of imatinib, and were later transitioned to nilotinib and finally to bosutinib (2019) due to unchanged thrombocytosis. Next-generation sequencing from a bone marrow biopsy in 2019 demonstrated an EZH2 mutation that may be associated with triple-negative ET. CML was in major molecular response at that time. The patient was continued on bosutinib with hydroxyurea, after which hydroxyurea was changed to anagrelide due to worsening anemia and persistent thrombocytosis. However, bosutinib and anagrelide were discontinued due to worsening pulmonary hypertension. The patient was noted to have peripheral blasts of 14% by flow cytometry, after which they underwent a repeat bone marrow biopsy in 2022, which showed extensive myelofibrosis. BCR-ABL transcripts were undetectable. Given their accelerated myelofibrosis, the patient was started on a hypomethylating agent, decitabine/cedazuridine, along with darbepoetin for anemia in June 2022. Given their persistent thrombocytosis, the patient was also started on peginterferon α. Most studies reporting two clonal processes in the same patient have been for PV and CML. To the best of our knowledge, this is the first reported case of triple-negative ET with double transcript CML in the same individual.

Sickle cell disease and coronavirus disease-2019 (COVID-19) infection: a single-center experience.

PURPOSE: Sickle cell disease (SCD) has been found to be associated with an increased risk of hospitalization and death from coronavirus disease-2019 (COVID-19). We sought to study clinical outcomes in patients with SCD and a diagnosis of COVID-19 infection. METHODS: We conducted a retrospective analysis of adult patients (>18 years) with SCD who were diagnosed with COVID-19 infection between 1 March 2020 and 31 March 2021. Data on baseline characteristics and overall outcomes were collected and analyzed using SAS 9.4 for Windows. RESULTS: A total of 51 patients with SCD were diagnosed with COVID-19 infection in the study period, out of which 39.3% were diagnosed and managed in the outpatient setting/emergency room (ER) and 60.3% in the inpatient setting. Disease-modifying therapy such as hydroxyurea did not impact inpatient vs outpatient/ER management (P > 0.05). Only 5.71% (n = 2) required intensive care unit admission and were mechanically ventilated and 3.9% (2 patients) died of complications of COVID-19 infection. CONCLUSION: We identified a lower mortality (3.9%) rate among patients in our cohort in comparison to previous studies and a higher burden of inpatient hospitalizations as compared to outpatient/ER management. Further prospective data are needed to validate these findings. Key messages What is already known on this topic COVID-19 has been shown to have a disproportionately unfavorable impact on African Americans, including longer hospital stays, higher rates of ventilator dependence, and a higher overall mortality rate. Limited data also suggest that sickle cell disease (SCD) is associated with an increased risk of hospitalization and death from COVID-19. What this study adds Our analysis did not show a higher mortality due to COVID-19 in patients with SCD. However, we identified a high burden of inpatient hospitalizations in this population. COVID-19-related outcomes did not improve with the use of disease-modifying therapies. How this study might affect research, practice, or policy These results will aid in decision making for triage of patients with COVID-19 and SCD and ensure the most appropriate use of healthcare resources. Our analysis underscores the need for more robust data to identify patients at higher risk of severe disease and/or mortality, necessitating inpatient hospitalization and aggressive management.

Sickle Cell Trait: Is It Always Benign?

Sickle cell disease is a well-known homozygous inherited hemoglobinopathy that causes vaso-occlusive phenomena and chronic hemolysis. Vaso-occlusion results in sickle cell crisis and can eventually lead to complications involving multiple organ systems. However, the heterozygous counterpart, sickle cell trait (SCT) has less clinical significance as these patients are generally asymptomatic. This case series examines three unrelated patients with SCT ranging from the age of 27 to 61 years, who presented with pain in multiple long bones. Hemoglobin electrophoresis confirmed a diagnosis of SCT. Radiographic images of the affected sites showed osteonecrosis (ON). Interventions included pain management and bilateral hip replacement in two of the patients. Historically, vaso-occlusive disease in patients with SCT with no evidence of hemolysis or other hallmark findings of sickle cell disease is rare. There are limited reported cases of ON in SCT patients. Clinicians should explore other hemoglobinopathies not tested on routine hemoglobin electrophoresis and alternative risk factors for ON in these patients.

Unusual case of pernicious anaemia masquerading as thrombotic thrombocytopenic purpura in the setting of multiple normal vitamin B12 deficiency parameters: preventing anchoring and overdiagnosis.

BACKGROUND: Pseudo-thrombotic microangiopathy (pseudo- thrombotic microangiopathy (TMA)) is a rare presentation of B12 deficiency. Overlapping features like elevated LDH/total bilirubin with low haemoglobin/haptoglobin/platelets could deceivingly suggest thrombotic thrombocytopenic purpura (TTP) resulting in avoidable procedures/treatments. CASE PRESENTATION: A 36-year-old female with hypothyroidism initially presented to clinic with fatigue, palpitations, lightheadedness, and dyspnoea over a 3-month duration and was found to have a haemoglobin of 5.7 g/dL. She received two packed red blood cell units in the emergency room and subsequently discharged with outpatient follow-up and empiric oral iron. During her follow-up visit, she was found to have easy bruisability, gum bleeding, and generalized weakness from hemolytic anaemia (mean corpuscular volume (MCV) 90 fL, haptoglobin <8 mg/dL, LDH >4,000 U/L and schistocytosis on CBC) and thrombocytopenia of 52 K/uL. Due to PLASMIC score of 6 and suspicion for TTP, she was transferred to our facility and tr eated with three cycles of plasma exchange and prednisone but were discontinued when ADAMTS13 levels returned normal. While the patient had normal B12 levels, further testing revealed positive intrinsic factor antibodies (IF-Ab) and an elevated MMA level of 1.56 umol/L. Replacement with cobalamin led to normalization of labs and symptoms. CONCLUSIONS: Timely diagnosis of pseudo-TMA was exceptionally challenging due to several overlapping features with TTP including normal B12 and normal MCV. B12 levels may falsely appear normal in pernicious anemia due to IF-Ab interference with chemiluminescent immunoassay. Schistocytes lower the MCV in automated cell counters. Lower reticulocyte index (<2%), presence of immature/large platelets and teardrop cells, elevated MMA and a higher LDH (>2500) are indicative of B12 deficiency.

A rare synchrony of adenocarcinoma of the ampulla with an ileal gastrointestinal stromal tumor: A case report.

BACKGROUND: This is a unique case of a patient who was found to have two extremely rare primary malignancies synchronously, i.e., an ampullary adenocarcinoma arising from a high-grade dysplastic tubulovillous adenoma of the ampulla of Vater (TVAoA) with a high-grade ileal gastrointestinal stromal tumor (GIST). Based on a literature review and to the best of our knowledge, this is the first report of this synchronicity. Primary ampullary tumors are extremely rare, with an incidence of four cases per million population, which is approximately 0.0004%. Distal duodenal polyps are uncommon and have a preponderance of occurring around the ampulla of Vater. An adenoma of the ampulla ( AoA) may occur sporadically or with a familial inheritance pattern, as in hereditary genetic polyposis syndrome such as familial adenomatous polyposis syndrome (FAPS). We report a case of a 77-year-old male who was admitted for painless obstructive jaundice with a 40-pound weight loss over a two-month period and who was subsequently diagnosed with two extremely rare primary malignancies, i.e., an adenocarcinoma of the ampulla arising from a high-grade TVAoA and a high-grade ileal GIST found synchronously. CASE SUMMARY: A 77-year-old male was admitted for generalized weakness with an associated weight loss of 40 pounds in the previous two months and was noted to have painless obstructive jaundice. The physical examination was benign except for bilateral scleral and palmar icterus. Lab results were significant for an obstructive pattern on liver enzymes. Serum lipase and carbohydrate antigen-19-9 levels were elevated. Computed tomography (CT) of the abdomen and pelvis and magnetic resonance cholangiopancreatography were consistent with a polypoid mass at the level of the common bile duct (CBD) and the ampulla of Vater with CBD dilatation. The same lesions were visualized with endoscopic retrograde cholangiopancreatography. Histopathology of endoscopic forceps biopsy showed TVAoA. Histopathology of the surgical specimen of the resected ampulla showed an adenocarcinoma arising from the TVAoA. Abdominal and pelvic CT also showed a coexisting heterogeneously enhancing, lobulated mass in the posterior pelvis originating from the ileum. The patient underwent ampullectomy and resection of the mass and ileo-ileal side-to-side anastomosis followed by chemoradiation. Histopathology of the resected mass confirmed it as a high-grade, spindle cell GIST. The patient is currently on imatinib, and a recent follow-up positron emission tomography (PET) scan showed a complete metabolic response. CONCLUSION: This case is distinctive because the patient was diagnosed with two synchronous and extremely rare high-grade primary malignancies, i.e., an ampullary adenocarcinoma arising from a high-grade dysplastic TVAoA with a high-grade ileal GIST. An AoA can occur sporadically and in a familial inheritance pattern in the setting of FAPS. We emphasize screening and surveillance colonoscopy when one encounters an AoA in upper endoscopy to check for FAPS. An AoA is a premalignant lesion, particularly in the setting of FAPS that carries a high risk of metamorphism to an ampullary adenocarcinoma. Final diagnosis should be based on a histopathologic study of the surgically resected ampullary specimen and not on endoscopic forceps biopsy. The diagnosis of AoA is usually incidental on upper endoscopy. However, patients can present with constitutional symptoms such as significant weight loss and obstructive symptoms such as painless jaundice, both of which occurred in our patient. Patient underwent ampullectomy with clear margins and ileal GIST resection. Patient is currently on imatinib adjuvant therapy and showed complete metabolic response on follow up PET scan.

Isolated ovarian vein thrombosis in COVID-19 infection.

COVID-19 (coronavirus disease-19) is associated with an increased risk for thrombosis due to endothelial dysfunction and hyperactivation of the immune system induced by the virus. Most cases of venous thromboembolism associated with COVID-19 are either pulmonary emboli or deep vein thromboses. Ovarian vein thrombosis is a rare condition most commonly seen in the postpartum period. This report describes a case of COVID-19-associated ovarian vein thrombosis in a nonpregnant woman with no evidence of underlying inherited coagulopathy.

Plasmablastic Lymphoma or Plasmablastic Myeloma: A Case of Post-Transplant Lymphoproliferative Disorder.

Plasmablastic lymphomas and plasmablastic myelomas are malignancies with overlapping clinical and pathological features which pose a diagnostic dilemma and are known to be aggressive with a poor outcome. CD38 is a common immunophenotypic maker for both these malignancies and provides a rationale for using daratumumab-based regimes. We describe a 57-year-old male with a history of end-stage renal disease who underwent a deceased-donor renal transplant maintained on chronic immunosuppression who presented with ascites and was found to have abdominal adenopathy and a lytic lesion in the humerus and diagnosed with a post-transplant lymphoproliferative disorder with features intermediate between plasmablastic lymphoma and plasmablastic myeloma. The patient was subsequently treated with a daratumumab-based regime with an excellent response. This case highlights a rare scenario that poses a diagnostic and therapeutic challenge. As there is no standard of care for the treatment of both these malignancies, this case report also describes the use of daratumumab with a good long-term outcome, especially when the pathological distinction between the two entities is difficult.

Pulmonary sarcomatoid carcinoma presenting as subcutaneous nodules.

Subcutaneous nodules secondary to metastasis can be a presenting symptom of lung cancer. Underlying cancer must be ruled out in patients presenting with multiple subcutaneous nodules with suspicious history, physical, and radiological findings. Prognosis is extremely poor with limited treatment options.

Melanoma and mantle cell lymphoma in a single collision tumor.

The simultaneous occurrence of two different neoplasms is uncommon, and collision tumors are even rarer. We describe a cutaneous collision tumor of melanoma and mantle cell lymphoma presenting synchronously in a previously healthy individual.

Bariatric Surgery Causing Hyperammonemia.

Bariatric surgery is recognized as a highly effective therapy for obesity but it does carry a risk of short term and long term complications since it results in a permanent alteration of the patient's anatomy. We present a case of 45-year-old female presented with a macular rash on extremities and facial rash from a rehabilitation center after having been discharged a month earlier from a revision surgery on her gastric bypass for anastomotic bleeding. She progressively became lethargic with Magnetic Resonance Imaging (MRI) of the brain showed symmetrically restricted diffusion concerning for hypoxic injury. Her ammonia levels were at 142 micromoles per liter (mmol/L) at the initial check which worsened to 432 mmol/L over a few days, despite treatment. Laboratory investigation later revealed her to be deficient in zinc along with many essential and nonessential amino acids. Supplemental nutrition was initiated, specifically fortifying her parenteral feeds with the essential amino acid combinations that were found deficient on testing. This lead to a slow but progressive improvement in encephalopathy. This case highlights the importance of understanding the short and long term complications of bariatric surgery. Although neurological complications are rare with peripheral neuropathy being the most common one, hyperammonemic encephalopathy is a very severe complication, with incompletely understood mechanisms and predispositions, frequently resulting in failure of recognition and subsequent delays in intervention.

Differential expression of miRNAs in acute myeloid leukemia quantified by Nextgen sequencing of whole blood samples.

New approaches are needed for understanding and treating acute myeloid leukemia (AML). MicroRNAs (miRs) are important regulators of gene expression in all cells and disruption of their normal expression can lead to changes in phenotype of a cell, in particular the emergence of a leukemic clone. We collected peripheral blood samples from 10 adult patients with newly diagnosed AML, prior to induction chemotherapy, and 9 controls. Two and a half ml of whole blood was collected in Paxgene RNA tubes. MiRNA was purified using RNeasy mini column (Qiagen). We sequenced approximately 1000 miRs from each of 10 AML patients and 9 controls. In subset analysis, patients with NPM1 and FLT3 mutations showed the greatest number of miRNAs (63) with expression levels that differed from control with adjusted p-value of 0.05 or less. Some of these miRs have been described previously in association with leukemia, but many are new. Our approach of global sequencing of miRs as opposed to microarray analysis removes the bias regarding which miRs to assay and has demonstrated discovery of new associations of miRs with AML. Another strength of our approach is that sequencing miRs is specific for the 5p or 3p strand of the gene, greatly narrowing the proposed target genes to study further. Our study provides new information about the molecular changes that lead to evolution of the leukemic clone and offers new possibilities for monitoring relapse and developing new treatment strategies.