Nodular Lymphocyte-Predominant Hodgkin Lymphoma: Review of Current Literature and Case Discussion.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subset of Hodgkin lymphoma (HL). It has a distinct clinical and pathological presentation. Unlike classic HL, where the predominant malignant cells are Reed Sternberg cells, the malignant cells in NLPHL are known as lymphocyte predominant (LP) cells, with their own unique immunohistochemistry antigen expression and staining pattern. Based on risk stratification and staging of the disease, treatment can range from active surveillance in asymptomatic patients with no organ compromise or bulky disease, to aggressive chemotherapeutic agents in advanced disease. Guidelines on which of these chemotherapy regimens would offer the most benefit to our patients are limited due to lack of randomized-controlled studies. Majority of the current prospective data on treatment were inclusive of both HL and NLPHL. Thus, the regimens employed in treatment of NLPHL are similar to the ones used in HL, though NLPHL is often viewed as its own distinct entity. This article aims to review the current literature and future advances on treatment of this rare disease.

First Case of Nodular Localized Primary Cutaneous Amyloidosis Treated With Bortezomib and Dexamethasone.

Nodular localized cutaneous amyloidosis is a rare form of cutaneous amyloidosis and is characterized by an extracellular deposition of insoluble amyloid fibrils which are either primarily cutaneous or a manifestation of an underlying systemic amyloidosis. Biopsy of the lesion is mandatory for the diagnosis, and histopathology shows diffuse amyloid deposits with plasmacytic infiltration. Apple-green birefringence characteristic of amyloidosis is observed when stained with Congo red and viewed under polarized light. Amyloid subtyping is done with laser microdissection followed by mass spectrometry. Majority of these lesions do not require any treatment but surgical excision, shave excision, laser therapy, and radiotherapy can be considered for symptomatic nodular localized primary cutaneous amyloidosis (NLPCA). We present a case of recurrent NLPCA in a 64-year-old woman who was treated with bortezomib and dexamethasone after failing several local therapies with excellent response.

Diagnostic Pearls and Clinical Implications of Prekallikrein Deficiency.

Prekallikrein (PK) deficiency is extremely rare, and manifestations are not well characterized due to a small number of cases reported and the lack of scientific clarity about its role in clot formation in vivo. Here, we report a case of a 64-year-old male, with no known history of abnormal bleeding, who scheduled to undergo deep brain stimulator placement for control of his Parkinson's disease. During pre-procedure testing, activated partial thromboplastin time (PTT) was found to be prolonged at 146 seconds. Mixing studies were suggestive of a coagulation factor deficiency. His PTT characteristically became shorter with prolonged incubation, providing a clue at testing for PK levels, which were found to be severely low. He, subsequently, underwent surgery without any complications. Our case further highlights the clinical pearls for diagnosis and further endorses that these patients can safely undergo surgical procedures without the need for plasma transfusions or factor concentrate usage.

MPL Y252H anMd PL F126fs mutations in essential thrombocythemia: Case series and review of literature.

Essential thrombocythemia (ET) is a clonal bone marrow disease, characterized by increased production of platelets along with other clinical and bone marrow findings. Most patients with ET will have a somatic mutation in one of the known gene locations of JAK2, CALR, or MPL that can upregulate the JAK-STAT pathway. MPL mutation is present in 5% of cases with the most common mutations being W515L and W515K. In this report we describe 2 cases of patients with clinical and laboratory picture of ET. One patient carried MPLY252H mutation which is previously unreported in the adult population but has been shown to be a gain-of-function mutation. The other patient carried MPL F126fs mutation which is not known to be of clinical importance and has not been previously reported.

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.

A Rare Instance of Simultaneous Infection with Disseminated Nocardia and Pulmonary Aspergillus in a Patient Receiving Treatment with Ibrutinib for Chronic Lymphocytic Leukemia.

Disseminated Nocardia infections are a rare occurrence that typically occur in immunocompromised hosts. Chronic lymphocytic leukemia (CLL) is a hematologic malignancy which makes patients susceptible to infections through various mechanisms. The treatments for CLL also target immunologic pathways which can contribute to infections. Ibrutinib is a commonly utilized tyrosine kinase inhibitor for CLL which targets the Bruton tyrosine kinase pathway. Although it is generally well tolerated, patients sometimes experience infections while on this medication, however, opportunistic infections are unusual. We present a rare, fatal case of a patient who developed simultaneous infections with bronchopulmonary Aspergillus and disseminated Nocardiosis to the subcutaneous tissues, lymph nodes and central nervous system while on treatment with ibrutinib for CLL.

Successful treatment of cytarabine-related neurotoxicity with corticosteroids, a case series.

Neurotoxicity from high-dose cytarabine, a pyrimidine metabolite used in treatment for acute myeloid leukemia, is a known but dose-limiting toxicity which has incidences in up to 14% in patients receiving high doses of the drug. Neurologic symptoms vary but range from somnolence and ataxia to more severe complications such as seizures and even death. There are no validated treatments other than discontinuation of the drug and supportive measures. We present two cases of cytarabine-related neurotoxicity treated with corticosteroids with complete resolution of symptoms.

Chronic lymphocytic leukaemia with necrotic herpetic adenitis: an elusive clinical condition.

Herpes simplex virus (HSV) adenitis is a rare but important cause of morbidity in immunocompromised patients. Chronic lymphocytic leukaemia (CLL)/Small lymphocytic lymphoma (SLL) is an indolent disease which impairs the cellular and humoral immunity, predisposing patients to a myriad of infections. Clinically, herpetic adenitis can mimic large cell (Richter's) transformation in patients with CLL. To date, less than 30 cases of HSV adenitis have been reported in the literature. We report a case of a patient with CLL with no prior history of HSV infection, who presented with rapidly enlarging lymph nodes after initial response to idelalisib raising the suspicion of Richter's transformation. However, excisional biopsy of a lymph node revealed HSV adenitis along with CLL, which was confirmed by immunohistochemical staining.

Treatment-Free Remission: a New Therapeutic Goal in Chronic Myelogenous Leukemia.

PURPOSE OF REVIEW: Chronic myelogenous leukemia (CML) is a chronic myeloproliferative neoplasm characterized by the presence of Philadelphia chromosome [t(9:22)] leading to the presence of pathognomonic fusion gene product, BCR-ABL1. This leads to constitutive activation of ABL1 kinase. CML was a difficult-to-treat illness until the advent of small molecule tyrosine kinase inhibitor (TKI), imatinib which revolutionized therapy of CML. Since then, multiple second- and third-generation TKIs have been formulated which have proven effective and has led to marked improvement in survival. In this article, we review currently available data on possibility of holding TKI therapy in patients in deep remission [treatment-free remission (TFR)] and safety of this approach. RECENT FINDINGS: As CML treatment has become more effective, new questions have emerged, most important being whether the treatment with TKIs can ever be stopped. This is especially relevant in patient experiencing side effects from therapy or who may be subject to increased health risks due to treatment. There is now evidence that some CML patients who have achieved stable deep molecular response can safely stop TKI. Furthermore, patients can safely re-establish remission after restarting their TKI therapy in the situation of relapse. CML is highly treatable disease, but the treatment has untoward physical and socioeconomic consequences. The idea of TFR is hence attractive. There is a growing body of evidence that some CML patients who have achieved stable deep molecular response can safely stop TKI.

Double-Hit Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for approximately 25% of NHL cases. It is a heterogeneous group of diseases. BCL2, BCL6, and MYC are the most frequent mutated genes in DLBCL. Double-hit lymphoma (DHL) is an aggressive form of DLBCL with an unmet treatment need, in which MYC rearrangement is present with either BCL2 or BCL6 rearrangement. Patients typically present with a rapidly growing mass with B symptoms. DHL has been linked to very poor outcomes when treated with RCHOP chemotherapy. Dual-expressor lymphoma is a form of DLBCL with overexpression of MYC and BCL2/BCL6. There is a paucity of prospective trials evaluating the treatment of DHL. Retrospective series suggest that more aggressive treatment regimens such as DA-EPOCH and hyper CVAD may be more efficacious. However, there remains a lack of consensus regarding optimal treatment for DHL. Further clinical trials, including novel agents, are needed for improvement in outcomes.

Agranulocytosis - Sequelae of Chronic Cocaine Use: Case Series and Literature Review.

Agranulocytosis is a rare condition with a reported incidence ranging from one to five cases per million population per year. Most commonly, agranulocytosis is secondary to chemotherapeutic agents, however, other medications have also been associated with it. An immune mediated destruction of circulating granulocytes and/or granulocyte precursors secondary to drug-dependent or drug-induced antibodies is the postulated mechanism. Agranulocytosis has also been reported secondary to recreational drug use. Cocaine is one of the most commonly used recreational drugs and is often laced with Levamisole to enhance its psychostimulatory properties. Levamisole is an immune modulator and can cause bone marrow suppression. It can be detected in urine by gas chromatography-mass spectrometry. We report two cases of recurrent agranulocytosis in non-oncology patients secondary to chronic cocaine abuse, who were treated with granulocyte colony-stimulating factor (GCSF) and broad spectrum antibiotics without sustained response. The high prevalence of cocaine use continues to be a serious public health concern. This case series discusses the association of adulterated cocaine as an etiology of unexplained neutropenia and highlights the diverse clinical complications of chronic cocaine abuse. Currently, the available literature is reviewed.

A pilot study of zoledronic acid in the treatment of patients with advanced malignant pleural mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal median survival of <12 months with current therapy. Single and combination chemotherapy regimens have shown only modest clinical benefit. In preclinical studies, nitrogen-containing bisphosphonates (zoledronic acid) inhibit growth of mesothelioma cells by different mechanisms: inhibition of mevalonate pathway, inhibition of angiogenesis, activation of apoptosis through caspase activation, and alteration in activity of matrix metalloproteinases, thereby affecting invasiveness of cancer cells. PATIENTS AND METHODS: We investigated the role of zoledronic acid in a pilot, single-arm trial of MPM patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 who had progressed on prior treatments or had not received systemic therapy due to poor PS. Primary end point was composite response rate by modified response evaluation criteria in solid tumors and/or metabolic response by 2-deoxy-2-[fluorine-18]fluoro-d-glucose (18F-FDG) positron emission tomography criteria. Secondary end points were progression-free survival (PFS) and overall survival (OS). Exploratory end points include the effect of zoledronic acid therapy on vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 8, transforming growth factor beta, mesothelin, and osteopontin levels. RESULTS: Eight male patients (median age of 62 years) with the following clinical characteristics were treated; ECOG PS was 0-2, 75% with epithelioid type, and 62% had prior chemotherapy Overall composite response rate was 12.5% and the clinical benefit rate (response + stable disease) was 37.5%. Median PFS was 2 months (0.5-21 months) and median OS was 7 months (0.8-28 months). No treatment-related toxicities were observed. Lower VEGF levels were predictive of favorable response and mesothelin levels correlated with disease course. CONCLUSION: Zoledronic acid shows modest clinical activity without significant toxicity in patients with advanced MPM.

State-of-the-art acute and chronic GVHD treatment.

Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

Tivozanib: status of development.

Tivozanib is a potent and highly specific orally available, tyrosine kinase inhibitor that targets vascular endothelial growth factor (VEGF) receptor-1, VEGF receptor-2, and VEGF receptor-3 at very low concentrations with a long half-life (4 days). After its promising activity in xenograft and preclinical models, tivozanib was evaluated in early phase clinical trials in various solid tumors. The phase III trial (TIVO-1) compared tivozanib with sorafenib in metastatic clear cell renal cell carcinoma (RCC). Because of detrimental overall survival (OS), Oncology Drug Advisory Committee (ODAC) voted against its approval in RCC. Tivozanib is also being evaluated in various other solid tumors like breast, gastrointestinal cancers, hepatocellular cancer, sarcomas, and gynecological cancer. In BATON-CRC trial, low-serum neuropilin-1 (NRP-1) levels were associated with better progression-free survival (PFS) in patients treated with tivozanib. The NRP-1 will be evaluated as a biomarker for tivozanib response in future clinical trials. Ongoing clinical trial will further characterize activity of tivozanib in hepatocellular carcinoma, sarcomas, and gynecologic cancers.

Syncope: experience at a tertiary care hospital in Karachi, Pakistan.

INTRODUCTION: Our aim was to determine the characteristics of patients presenting with syncope at a tertiary care hospital in Karachi, Pakistan. METHODS: A review of medical records was conducted retrospectively at the Department of Medicine, Aga Khan University Hospital, Karachi. Patients aged 16 and above, admitted from January 2000 to December 2005 with the diagnosis of syncope made by the attending physician were included. RESULTS: A total of 269 patients were included (75% males, mean age: 57.4 years). Neurogenic (vasovagal) syncope was the most common cause (47%), followed by cardiogenic syncope (18%) and orthostatic syncope (9%). A total of 24% were discharged undiagnosed. Twenty patients (7.4%) did not have any prodrome. Common prodromal symptoms included dizziness (61%), sweating (25%), palpitations (19%), nausea/vomiting (19%) and visual symptoms (17%). The distribution of symptoms according to cause of syncope revealed only breathlessness to be significantly associated with cardiogenic syncope (p = 0.002). Most patients with cardiogenic syncope were aged above 40 (98%, p < 0.001), had coronary artery disease (72%, p < 0.001) and abnormal electrocardiogram at presentation (92%, p < 0.001). CONCLUSION: Despite differences in burden of diseases, our findings were similar to those of published syncope literature. Further studies are needed to develop a protocol to expedite the evaluation and limit the work-up and admission in low-risk patients.