Erdheim-Chester Disease: A Case Report of BRAF V600E-Negative, MAP2K1-Positive ECD Diagnosed by Blood Next-Generation Sequencing Assay and a Brief Literature Review.

Erdheim-Chester disease (ECD) is a rare type of non-Langerhans cell histiocytosis. However, its prevalence has increased significantly the past few years due to increased awareness about the disorder, and 1500 cases have been reported worldwide. It is often a multisystemic disease with skeletal, cardiovascular, urologic, renal, retroperitoneal, pulmonary, endocrine, cutaneous, and neurologic involvement. MAPK pathway mutations, such as BRAF activating and MAP2K1 mutations, play a key role in its pathogenesis. In addition to the characteristic clinical, radiological, and histopathological findings, identifying underlying mutations helps diagnose and treat patients with highly effective targeted therapies such as BRAF and MEK inhibitors. We report a case of a man, aged 55 years, with an extensive and prolonged course of an unexplained multisystemic disease, later diagnosed with BRAF V600E-negative and MAP2K1-positive ECD on cell-free DNA testing. Additionally, we review common clinical manifestations, mutations, diagnoses, and targeted therapies for ECD.

Dipeptidylpeptidase 4 promotes survival and stemness of acute myeloid leukemia stem cells.

Leukemic-stem-cell-specific targeting may improve the survival of patients with acute myeloid leukemia (AML) by avoiding the ablative effects of standard regimens on normal hematopoiesis. Herein, we perform an unbiased screening of compounds targeting cell surface proteins and identify clinically used DPP4 inhibitors as strong suppressors of AML development in both murine AML models and primary human AML cells xenograft model. We find in retrovirus-induced AML mouse models that DPP4-deficient AML cell-transplanted mice exhibit delay and reversal of AML development, whereas deletion of DPP4 has no significant effect on normal hematopoiesis. DPP4 activates and sustains survival of AML stem cells that are critical for AML development in both human and animal models via binding with Src kinase and activation of nuclear factor κB (NF-κB) signaling. Thus, inhibition of DPP4 is a potential therapeutic strategy against AML development through suppression of survival and stemness of AML cells.

A Rare Case of Glioblastoma With Extensive Liver Metastases.

Glioblastoma (GBM), the most common primary brain tumor, is a highly aggressive malignancy for which the median survival is about 13 months, and 5-year survival is well under 5%. These tumors usually occur in the brain and enlarge and infiltrate through white matter, including crossing through the corpus callosum to the opposite cerebral hemisphere. They may spread to distant parts of the central nervous system (CNS) via cerebrospinal fluid pathways. Extraneural metastases from primary brain tumors are quite rare, for 2 probable reasons: because most patients survive less than 2 years, and because of the absence of true lymphatics in the CNS. Typical sites for distant extraneural metastasis of GBM are lungs and pleura, followed by lymph nodes and bones; spread to the liver is exceptional. Most of the reported cases with liver metastases had either single or only a few such metastatic lesions. We report a probably unique case of GBM with extensive liver metastases along with a review of previous cases of liver metastasis from GBM, and we discuss the possible mechanisms of metastasis.

Intracardiac metastasis from head and neck squamous cell carcinoma.

Cardiac metastasis from head and neck cancer is an extremely rare and devastating condition with an abysmal prognosis. Most of our knowledge about this condition is from case reports and series. We present a case of squamous cell carcinoma of the tonsils that was complicated by embolic stroke and critical limb ischemia that were found to be secondary to intracardiac metastasis. We believe that this condition is under-reported; hence, we conducted a thorough review of the literature to highlight the characteristics and previous therapeutic experiences with various presentations of cardiac metastasis from head and neck carcinoma. Clinicians are encouraged to report their experience with evaluating and managing this type of metastasis.

Bullous pemphigoid associated with the 480-mg nivolumab dose in a patient with metastatic renal cell carcinoma.

The US FDA has recently approved an updated nivolumab dosing schedule, a single 480 mg iv. dose every 4 weeks [1], across all its previously approved indications, including second-line therapy for metastatic renal cell carcinoma. As this regimen is still in its infancy, we have not yet observed significant differences in immune-related toxicities and have not yet identified clinical characteristics which would predict intolerance and increased risk for complications. Herein, we present a patient with metastatic renal cell carcinoma who developed bullous pemphigoid after a single 480 mg iv. dose of nivolumab after previously tolerating a 240 mg biweekly dose for 2 years.

Immunotherapy in Merkel cell carcinoma: role of Avelumab.

Merkel cell carcinoma (MCC), a rare skin cancer, is associated with high mortality, especially in a metastatic setting. Though conventional chemotherapy with platinum and etoposide has had high response rates, many of the patients have had early relapse without any effective therapy thereafter. Recently, immune check point inhibitors have shown very good durable responses, leading to the approval of a programmed death-ligand 1 inhibitor Avelumab for these patients. We briefly review the epidemiology and immune basis of the pathogenesis of MCC, which therefore explains the excellent response to check point inhibitors, and throw light on future directions of immunotherapy for this cancer.

PathEdEx - Uncovering High-explanatory Visual Diagnostics Heuristics Using Digital Pathology and Multiscale Gaze Data.

BACKGROUND: Visual heuristics of pathology diagnosis is a largely unexplored area where reported studies only provided a qualitative insight into the subject. Uncovering and quantifying pathology visual and nonvisual diagnostic patterns have great potential to improve clinical outcomes and avoid diagnostic pitfalls. METHODS: Here, we present PathEdEx, an informatics computational framework that incorporates whole-slide digital pathology imaging with multiscale gaze-tracking technology to create web-based interactive pathology educational atlases and to datamine visual and nonvisual diagnostic heuristics. RESULTS: We demonstrate the capabilities of PathEdEx for mining visual and nonvisual diagnostic heuristics using the first PathEdEx volume of a hematopathology atlas. We conducted a quantitative study on the time dynamics of zooming and panning operations utilized by experts and novices to come to the correct diagnosis. We then performed association rule mining to determine sets of diagnostic factors that consistently result in a correct diagnosis, and studied differences in diagnostic strategies across different levels of pathology expertise using Markov chain (MC) modeling and MC Monte Carlo simulations. To perform these studies, we translated raw gaze points to high-explanatory semantic labels that represent pathology diagnostic clues. Therefore, the outcome of these studies is readily transformed into narrative descriptors for direct use in pathology education and practice. CONCLUSION: PathEdEx framework can be used to capture best practices of pathology visual and nonvisual diagnostic heuristics that can be passed over to the next generation of pathologists and have potential to streamline implementation of precision diagnostics in precision medicine settings.

Hemoglobin Titusville: a rare low oxygen affinity hemoglobinopathy.

The relevance of this case lies in the extensive diagnostic workup that can be avoided with proper laboratory evaluation of relatively unsophisticated tests.

Autoimmune Hemolytic Anemia as a Complication of Nivolumab Therapy.

Recently, immunotherapeutic drugs, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, avelumab), and CTLA4 inhibitors (ipiliumumab), have emerged as important additions to the armamentarium against certain malignancies and have been incorporated into therapeutic protocols for first-, second-, or third-line agents for these metastatic cancers. Immune checkpoint inhibitor nivolumab is currently FDA approved for the treatment of patients with metastatic malignant melanoma [Redman et al.: BMC Med 2016;14: 20], metastatic non-small cell lung cancer [Guibert and Mazières: Expert Opin Biol Ther 2015;15: 1789-1797], metastatic renal cell cancer [Farolfi et al.: Expert Opin Drug Metab Toxicol 2016;12: 1089-1096], and relapsed or refractory classic Hodgkin's lymphoma [Villasboas and Ansell: Expert Rev Anticancer Ther 2016;16: 5-12]. Given the current and increasing indications for these drugs, it is essential for all physicians to become well versed with their common adverse effects and to be observant for other less documented clinical conditions that could be unmasked with the use of such medications. A definite association between autoimmune hemolytic anemia and the immune checkpoint inhibitor nivolumab has not been clearly documented, although a few cases have been reported recently [Kong et al.: Melanoma Res 2016;26: 202-204; Schwab et al.: Case Rep Oncol 2016;9: 373-378; Tardy et al.: Hematol Oncol 2016, DOI: 10.1002/hon.2338]. We report a case of fatal autoimmune hemolytic anemia refractory to steroids in a patient treated with nivolumab for metastatic lung cancer, and reflect on the other reported cases of autoimmune hemolytic anemia after the use of nivolumab.

Thromboprophylaxis and Incidence of Venous Thromboembolism in Patients With Hemophilia A or B Who Underwent High-Risk Orthopedic Surgeries.

Total hip replacement (THR) and total knee arthroplasty (TKA) carry a high risk of postoperative venous thromboembolism (VTE); therefore, anticoagulation prophylaxis is recommended in these patients. Unfortunately, there are no guidelines about VTE prophylaxis in patients with hemophilia who underwent these high-risk surgeries. To determine whether these patients have high risk of VTE, we conducted a retrospective study on patients with hemophilia who underwent elective THR/TKA at our institute from 2004 to 2012. Postoperatively, we collected information on duration and method of factor VIII/IX infusion, VTE-prophylaxis, and complications. There were 23 patients with hemophilia, 18 (78%) with hemophilia A and 5 (22%) with hemophilia B, who underwent high-risk surgeries (39% THR and 61% TKA). The VTE prophylaxis included sequential compression device, 12 (52%), and prophylactic enoxaparin, 1 (4%). Ten (43%) patients did not receive VTE prophylaxis. At 1-year follow-up, we did not find any evidence of clinical VTE in our patients. Better risk stratification is needed to identify patients who would benefit from pharmacological prophylaxis.

Tyrosine kinase inhibitors as a first-line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed-treatment comparison.

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.

Combined small-cell lung carcinoma: An institutional experience.

BACKGROUND: The purpose of this study is to determine prognostic factors and survival in patients who present with combined small-cell lung cancer (SCLC). METHODS: A retrospective review of combined SCLC histology in patients treated between1995-2010 was undertaken. Demographics, diagnostic information, disease characteristics, treatment modality, and survival were captured. Survival estimates were performed using Kaplan Meier analysis. Statistical significance was defined as P < 0.05. RESULTS: Forty-one patients were identified, and 35 records were available for analysis. Median age at diagnosis was 68 (range 50-85). The study included 20 (57%) women and 15 (43%) men; and 94% had a current or former history of smoking. Histology was SCLC/large cell carcinoma not otherwise specified in 28 (80%), and SCLC/adenocarcinoma or SCLC/squamous cell carcinoma in seven (20%). Cardiac or pulmonary comorbidities were present in 80% of patients, and 24 patients had metastatic disease at presentation. Twenty-eight patients received treatment of chemotherapy (n = 24), cranial radiotherapy (n = 5), or thoracic radiotherapy (n = 7). Staging was as follows: stage I-III (n = 11), stage IV (n = 24). Median survival was 15.4 months (range <1-53 months) and 3.4 months (range <1-21.9 months) for American Joint Committee on Cancer (AJCC) stage I-III and stage IV, respectively. Estimated overall six and 12 month survival was 82%, 55%, 37%, and 17% for stage I-III and stage IV, respectively. An improved overall survival rate was found for patients with an Eastern Cooperative Oncology Group performance status of <2, and no weight loss (P < 0.05). CONCLUSION: Akin to SCLC, advanced stage combined SCLC portends a poor prognosis. Perhaps novel chemotherapeutic drugs or targeted agents may improve outcomes for future patient populations.

Lung cancer screening: from imaging to biomarker.

Despite several decades of intensive effort to improve the imaging techniques for lung cancer diagnosis and treatment, primary lung cancer is still the number one cause of cancer death in the United States and worldwide. The major causes of this high mortality rate are distant metastasis evident at diagnosis and ineffective treatment for locally advanced disease. Indeed, approximately forty percent of newly diagnosed lung cancer patients have distant metastasis. Currently, the only potential curative therapy is surgical resection of early stage lung cancer. Therefore, early detection of lung cancer could potentially increase the chance of cure by surgery and underlines the importance of screening and detection of lung cancer. In the past fifty years, screening of lung cancer by chest X-Ray (CXR), sputum cytology, computed tomography (CT), fluorescence endoscopy and low-dose spiral CT (LDCT) has not improved survival except for the recent report in 2010 by the National Lung Screening Trial (NLST), which showed a 20 percent mortality reduction in high risk participants screened with LDCT compared to those screened with CXRs. Furthermore, serum biomarkers for detection of lung cancer using free circulating DNA and RNA, exosomal microRNA, circulating tumor cells and various lung cancer specific antigens have been studied extensively and novel screening methods are being developed with encouraging results. The history of lung cancer screening trials using CXR, sputum cytology and LDCT, as well as results of trials involving various serum biomarkers, are reviewed herein.

Systemic mastocytosis presenting as acute appendicitis: a case report and review of the literature.

Systemic mastocytosis is characterized by abnormal growth and accumulation of mast cells in various organs. Gastrointestinal (GI) symptoms are common disease manifestations in this disease and can significantly impair the quality of life. Signs of GI systemic mastocytosis include steatorrhea, malabsorption, hepatomegaly, splenomegaly, portal hypertension, and ascites. Acute appendicitis as a presenting feature in systemic mastocytosis has not been reported in the literature previously. In this report, we discuss the case of a female patient with systemic mastocytosis (c-KIT D816V (+)) who was admitted for right-sided acute abdominal pain. Laboratory study revealed an normal white blood cell count with eosinophilia and an elevated serum tryptase level of 23 µg/l. CT of the abdomen and pelvis showed an enlarged appendix of 12 mm in diameter, with minimal wall enhancement. Laparoscopic appendectomy was performed. The appendix was found to be hyperemic and firm, and it was densely adherent to the posterior cecum, the surrounding peritoneal wall, and the overlying mesenteric fat. Pathology revealed acute appendicitis with greater than 30 mast cells per high-power field by immunoperoxidase studies with mast cell tryptase and CD117. The patient subsequently improved and was discharged home. This case is the first reported case with a histological diagnosis of acute appendicitis resulting from mast cell infiltration. Physicians should be aware of acute appendicitis as a manifestation of systemic mastocytosis. Prompt diagnosis and management may prevent potentially fatal complications of appendiceal perforation and peritonitis.

A Novel del(20q) in Aggressive Nodal Marginal Zone Lymphoma.

This is a case report of a previously undescribed 20q chromosomal deletion (del(20q)) in marginal zone lymphoma (MZL). A 54-year-old Caucasian male presented with an enlarging neck mass and multiple violaceous skin nodules over his chest. Biopsy of the neck mass and cervical lymph nodes revealed MZL. Cytogenetic evaluation of both lymph node and bone marrow tissue revealed del(20q). This was an unexpected finding, as del(20q) is associated with myelodysplastic syndromes and myeloproliferative neoplasms and rarely seen in diffuse large B-cell lymphoma, follicular lymphoma, and T-cell lymphoma, but has not previously been described in MZL. We describe the case presentation and histologic findings and discuss the significance of this novel finding.