Fondaparinux cross-reactivity in heparin-induced thrombocytopenia successfully treated with high-dose intravenous immunoglobulin and rivaroxaban.

HIT, a prothrombotic disorder caused by heparin-dependent antibodies, is often treated with fondaparinux, usually with good outcomes. A 70-year-old female developed severe HIT (platelet count, 25 × 109/L) post-glioblastoma resection during heparin thromboprophylaxis, complicated by disseminated intravascular coagulation (DIC) and symptomatic lower-limb deep-vein thrombosis (DVT). Despite therapeutic-dose fondaparinux, thrombocytopenia/hypofibrinogenemia persisted, with new symptomatic catheter-associated upper-extremity DVT. This clinical picture could be explained by autoimmune HIT (aHIT) refractory to fondaparinux or by fondaparinux cross-reactivity, so high-dose intravenous immunoglobulin (IVIG) was given (to treat possible aHIT) and fondaparinux switched to rivaroxaban, with subsequent clinical recovery. In vitro studies revealed strong fondaparinux cross-reactivity, without aHIT antibodies. Moreover, the patient's serotonin-release assay became negative post-IVIG, suggesting in-vivo inhibition of HIT antibody-induced platelet activation. Our case illustrates fondaparinux cross-reactivity in HIT manifesting as persisting thrombocytopenia, new thrombosis, and DIC, with successful rivaroxaban treatment, adding to emerging data that oral factor Xa inhibitors are efficacious for treating HIT.

Severe facial necrosis in a type 1 diabetic patient secondary to mucormycosis masquerading as an internal maxillary artery occlusion: a case report.

BACKGROUND: Mucormycosis is a group of rare but life threatening angioinvasive infections caused by fungi of the order Mucorales that often occurs in immunocompromised patients and individuals with poorly controlled diabetes. Rhinocerebral mucormycosis can mimic sinusitis but can rapidly progress to deeper disease and cause facial necrosis. Facial vascular thrombosis is a rare complication of mucormycosis and can confound diagnosis of the disease. CASE PRESENTATION: We report the case of a 25-year-old female with poorly controlled type 1 diabetes mellitus who initially presented with symptoms of sinusitis but rapidly progressed with signs of left-sided facial necrosis due to occlusion of the left internal maxillary artery. Early surgical debridement did not yield a microbiological diagnosis. Deeper surgical debridements ultimately revealed angioinvasive fungal disease consistent with mucormycosis. The patient recovered after repeated surgical intervention and aggressive parenteral antifungal therapy. CONCLUSION: This case illustrates an atypical complication of mucormycosis, and emphasizes that a high index of suspicion in vulnerable patient populations aids in the diagnosis of this life-threatening infection.

Acute HIV infection presenting as hemophagocytic lymphohistiocytosis: case report and review of the literature.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory condition that can result from infections, autoimmune diseases and malignancies. It is a rarely reported life threatening complication of an acute HIV infection, with only ten documented case reports per our literature search. We present a case of HLH secondary to acute HIV infection with a negative HIV antibody-based assay and high plasma viral load. CASE PRESENTATION: A 45 year old male with a past medical history of well controlled hypertension presented with fever, dizziness and non-bloody diarrhea. Initial lab work revealed a new thrombocytopenia, marked renal failure and an elevated creatine kinase, ferritin, lactate dehydrogenase and D-dimer. A bone marrow biopsy revealed HLH. As part of the work up for thrombocytopenia, a rapid HIV antibody based assay was done and was negative. The sample was later routinely tested with a fourth generation antigen/antibody assay as per local protocol and was strongly positive. The plasma RNA viral load was >10,000,000 copies /mL confirming the diagnosis of an acute HIV infection. The patient was urgently started on antiretroviral therapy and recovered. CONCLUSION: This case illustrates a diagnostic approach to HLH which is an uncommon but life threatening multisystem disease, requiring the involvement of a multidisciplinary team of experts. Following any diagnosis of HLH, rapid identification and treatment of the underlying condition is critical. A negative rapid HIV antibody test can be misleading in the context of early HIV infection and the additional use of fourth generation antigen/antibody test or plasma RNA viral load may be required within the right clinical context for diagnosis.

Nuclear Export in Non-Hodgkin Lymphoma and Implications for Targeted XPO1 Inhibitors.

Exportin-1 (XPO1) is a key player in the nuclear export pathway and is overexpressed in almost all cancers. This is especially relevant for non-Hodgkin lymphoma (NHL), where high XPO1 expression is associated with poor prognosis due to its oncogenic role in exporting proteins and RNA that are involved in cancer progression and treatment resistance. Here, we discuss the proteins and RNA transcripts that have been identified as XPO1 cargo in NHL lymphoma including tumour suppressors, immune modulators, and transcription factors, and their implications for oncogenesis. We then highlight the research to date on XPO1 inhibitors such as selinexor and other selective inhibitors of nuclear export (SINEs), which are used to treat some cases of non-Hodgkin lymphoma. In vitro, in vivo, and clinical studies investigating the anti-cancer effects of SINEs from bench to bedside, both as a single agent and in combination, are also reported. Finally, we discuss the limitations of the current research landscape and future directions to better understand and improve the clinical utility of SINE compounds in NHL.

An evaluation of pembrolizumab for classical Hodgkin lymphoma.

INTRODUCTION: Pembrolizumab is an immune checkpoint inhibitor (ICI) targeted against the programmed death 1 (PD-1) pathway, a key pathway in the biology of Classical Hodgkin lymphoma (cHL). Anti-PD-1 antibodies are approved for use in relapsed/refractory cHL but ongoing studies continue to optimize the use of this treatment. AREAS COVERED: This review highlights recent and established data regarding pembrolizumab in the management of relapsed/refractory cHL and emerging areas of study including translational biology, combinations with chemotherapy and trials earlier in the disease course. EXPERT OPINION: Pembrolizumab provides superior progression-free survival for patients with cHL who relapse post-autologous stem cell transplant or who have chemotherapy refractory disease and should be used in these high-risk populations. A key challenge remains the development of predictive biomarkers for anti-PD1 antibodies. There is promising evidence of the improved efficacy of salvage chemotherapy regimens and frontline regimens incorporating pembrolizumab but larger randomized studies are needed to demonstrate clear patient benefit.

Clinical utility of interim CT scans in patients receiving chemoimmuntherapy for first line treatment of follicular lymphoma.

Interim imaging with computed tomography (iCT) to assess response is common during frontline chemoimmunotherapy for follicular lymphoma (FL), but there is little evidence of its utility. We retrospectively reviewed outcomes of iCT in 190 patients with biopsy-proven FL who received first-line chemoimmunotherapy from 2003-2018. Most iCTs showed partial response (PR, 83%), with a minority showing complete response (CR, 8%) or stable disease (5%). Seven patients (4%) had radiographic disease progression (PD) on iCT; on repeat biopsy, four had another malignancy identified and three had transformation to DLBCL. Only one had asymptomatic PD. The 3-year PFS of all patients was 74% (median follow up 75 months). Patients with PR on iCT had similar 3-year PFS and OS as those with CR. In conclusion, iCT has limited utility in identifying patients with asymptomatic early progression during first-line treatment. Patients with PD mid-treatment warrant biopsy to identify histologic transformation or other malignancies.

Novel synthetic drugs for the treatment of non-Hodgkin lymphoma.

Introduction: Over the past two decades, deeper understanding of B-cell signaling pathways and other mechanisms of lymphomagenesis have yielded promising targets for novel drugs in the treatment of non-Hodgkin lymphoma.Areas covered: This article provides a comprehensive review of approved synthetic drugs targeting the BTK, PI3K, immunomodulation, proteasome, HDAC, EZH2, and nuclear export pathways in non-Hodgkin lymphoma. The review includes coverage of the pharmacology, efficacy, toxicity, and active areas of research for each drug. The authors also provide their expert perspectives on the field and their opinions for the future.Expert opinion: Although novel synthetic drugs have generally not impacted clinical practice to the same extent as immune and cellular therapies, there remains an important role for targeted drugs in the treatment of non-Hodgkin lymphoma, particularly in the relapsed setting and for patients ineligible for more intensive therapies. Clinical outcomes and tolerability may improve further with the development of newer generations of synthetic drugs and emerging combination regimens with other targeted and immune therapies.

Severe Undifferentiated Vasoplegic Shock Refractory to Vasoactive Agents Treated with Methylene Blue.

Methylene blue is a phenothiazine-related heterocyclic aromatic molecule presently used in the treatment of methemoglobinemia. Recently, it has been implicated in the treatment of severe refractory vasoplegic shock caused by anaphylaxis, sepsis, or postcardiopulmonary bypass. We present a case of a 27-year-old male with profound vasoplegic shock of unknown etiology which was refractory to vasopressors who responded within hours to a single dose of methylene blue. Additionally, we review the evidence of methylene blue's role in the treatment of shock. This case illustrates a diagnostic approach and treatment options in the setting of undifferentiated vasodilatory shock and outlines a new and emerging role for methylene blue in this clinical setting.

Comparison of dual energy subtraction chest radiography and traditional chest X-rays in the detection of pulmonary nodules.

BACKGROUND: Dual energy subtraction (DES) radiography is a powerful but underutilized technique which aims to improve the diagnostic value of an X-ray by separating soft tissue from bones, producing two different images. Compared to traditional chest X-rays, DES requires exposure to higher doses of radiation but may achieve higher accuracy. The objective of this study was to assess the clinical benefits of DES radiography by comparing the speed and accuracy of diagnosis of pulmonary nodules with DES versus traditional chest X-rays. METHODS: Five radiologists and five radiology residents read the DES and traditional chest X-rays of 51 patients, 34 with pulmonary nodules and 17 without. Their accuracy and speed in the detection of nodules were measured using specialized image display software. RESULTS: DES radiography reduced reading time from 13 to 10 sec (P<0.0001) in staff and from 21 to 15 sec in residents (P<0.0001). There was also a small increase in sensitivity 0.58 to 0.67 overall (P<0.10) with no change in specificity (0.85 overall). CONCLUSIONS: By eliminating rib shadows in soft tissue images, DES improved the speed and accuracy of radiologists in the diagnosis of pulmonary nodules.