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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.

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.

e20572 Background: ES-SCLC is an aggressive lung cancer with high rates of relapse following induction regimens. Immune checkpoint immunotherapy (ICI) seems promising in the refractory/relapsing setting based on a smaller number of studies with smaller sample sizes. Here we report a pooled estimate of clinical activity of ICI in above patients based on published phase II/III trials so far. Methods: PubMed, EMBASE, Cochrane review, and clinicaltrials.gov databases were searched for phase II/III randomized controlled trials studying immune checkpoint immunotherapy in second or third line setting for ES-SCLC treatment. Data were extracted based on Reviews and Meta- Analysis guidelines. DerSimonian-Laird (DL) random effects model was used to estimate the pooled proportion of patients achieving objective response rate (ORR), pooled proportion of patients experiencing therapy related adverse events (TRAEs grade ≥ 1), pooled median progression free survival (PFS) and pooled median overall survival (OS), and weights were estimated using inverse variance method. Statistical heterogeneity was calculated using the I2 and chi-squared test. Outcomes were calculated by using ‘Metafor’ and ‘Meta’ packages by R-Studio and “CRAN” project. Results: Five studies with a total of 698 patients who received immune checkpoint immunotherapy were analyzed. Median age of patients who received treatment was 63 yrs. The pooled proportion of patients who achieved ORR was 15% (95% CI 0.11 to 0.20). Pooled Median PFS was about 1.54 (95% CI, 1.34- 1.74) months and median OS was 6.46 (95% CI, 5.13- 7.73) months. The pooled proportion of patients who experienced adverse events during the treatment was 49% (95% CI 0.38 to 0.60). Conclusions: ICI as second or third line treatment choice offers modest improvement in progression free survival and overall survival in ES-SCLC patients who have not received ICI as first line in combination with etoposide and platinum based therapies.

In letzter Zeit ist das Instrumentarium zur Bekämpfung verschiedener maligner Erkrankungen maßgeblich um mehrere Immuntherapeutika erweitert worden - von PD-1-Inhibitoren (Nivolumab, Pembrolizumab) über PD-L1-Inhibitoren (Atezolizumab, Avelumab) bis hin zu CTLA4-Inhibitoren (Ipiliumumab). Sie alle sind in die Behandlungsprotokolle der ersten, zweiten oder dritten Therapielinie für diese metastatischen Krebserkrankungen aufgenommen worden. Der Immun-Checkpoint-Inhibitor Nivolumab ist derzeit von der FDA in folgenden Indikationen zugelassen: bei metastasiertem malignem Melanom (Redman JM, et al.: BMC Med 2016;14:20), bei metastasiertem nichtkleinzelligem Bronchialkarzinom (Guibert N, Mazières J: Expert Opin Biol Ther 2015;15:1789-1797), bei metastasiertem Nierenzellkarzinom (Farolfi A, et al.: Expert Opin Drug Metab Toxicol 2016;12:1089-1096) sowie bei rezidivierendem oder therapierefraktärem klassischem Hodgkin-Lymphom (Villasboas JC, Ansell SM: Expert Rev Anticancer Ther 2016;16:5-12). In Anbe- tracht der bereits bestehenden und hinzukommenden Anwendungsgebiete dieser Arzneimittel ist es für Ärzte unerlässlich, sich auch gut mit ihren typischen Nebenwirkungen vertraut zu machen und aufmerksam auf andere, weniger umfassend dokumentierte Gesundheitsstörungen zu achten, die durch Anwendung dieser Arzneimittel ermittelt werden könnten. Eine definitive Assoziation zwischen autoimmunhämolytischer Anämie und dem Immun-Checkpoint-Inhibitor Nivolumab ist nicht eindeutig belegt, jedoch wurde in jüngerer Zeit von mehreren Fällen berichtet (Kong BY, et al.: Melanoma Res 2016;26:202-204; Schwab KS, et al.: Case Rep Oncol 2016;9:373-378; Tardy MP, et al.: Hematol Oncol 2016;DOI:10.1002/hon.2338). Wir berichten hier über einen Fall von steroidrefraktärer, tödlich verlaufender autoimmunhämolytischer Anämie bei einem Patienten, der wegen metastasiertem Lungenkrebs mit Nivolumab behandelt wurde. Außerdem gehen wir auch auf die anderen in der Literatur vorliegenden Fälle von autoimmunhämolytischer Anämie nach Anwendung von Nivolumab ein. Übersetzung aus Case Rep Oncol 2016;9:691-697(DOI: 10.1159/000452296)

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.

Background The distinction of diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subgroups (germinal center B-cell-like [GCB] or activated B-cell-like [ABC]) based on gene expression profiling is associated with prognosis and has potential therapeutic implications to mitigate the worse outcome for patients with DLBCL. Other phenotypic and molecular/cytogenetic features such as concurrent translocations of oncogene MYC and BCL2 and/or BCL6 (so-called double-/triple-hit lymphoma, DHL/THL) and coexpression of MYC and BCL2 proteins (so-called double-expressor lymphoma, DEL) are also recognized to have great prognostic impact (Swerdlow SH et al. Blood 2016;127(20):2375-2390). This study investigated the prevalence of COO, DHL/THL and DEL in a real-world cohort of patients with DLBCL who had documented results of diagnostic testing. Methods This study used the Flatiron Health electronic health record-derived de-identified database to abstract information on patients diagnosed with DLBCL between 2011-2019. Information on diagnostic testing from immunohistochemistry (IHC) for expression of MYC, BCL2, BCL6, CD10 or MUM1, and from fluorescence in situ hybridization (FISH) or karyotype analysis for rearrangement of MYC, BCL2 or BCL6 was abstracted from pathology reports or clinical visit notes, where available. We calculated the proportions of COO subgroups (GCB vs. ABC) that were derived from IHC testing results according to Hans algorithm (Hans C et al., Blood 2004;103(1):275-282), DHL/THL, and DEL. We also examined concordance of COO classification derived from IHC testing results with that directly reported by the healthcare providers. Differences in patient characteristics between IHC testing results-derived COO subgroups (GCB vs. ABC) were assessed using chi-square tests. Results 4400 patients had documented results of IHC and 73% (n=3194) can be classified into either GCB or ABC DLBCL (GCB/ABC ratio of 1.38). 3205 patients had documented results of FISH or karyotype analysis and 8% (n=245) were DHL/THL; only 33 patients were DEL. Within the GCB DLBCL patients derived from IHC testing results (n=1854), 163 patients were DHL/THL and 11 were DEL, whereas 24 DHL/THL and 18 DEL were identified within the ABC type (n=1340). When comparing COO classification derived from IHC testing results (n=3194) with that directly reported by the healthcare providers (n=2765), additional 695 and 439 patients can be classified as GCB and ABC DLBCL by IHC, respectively (Table). Univariate analysis showed that patients who were non-White ethnic group, diagnosed in academic centers, with lower body mass index but elevated serum lactate dehydrogenase levels and worse ECOG performance status, and without transformation from a prior indolent lymphoid malignancy, were more likely to be associated with ABC DLBCL (for all variables, p Discussion In this large real-world DLBCL cohort, a lower-than-expected proportion of DEL patients were identified vs. the 20-35% reported in the literature (Karube K and Campo E. Hematology 2015;52(2):97-106). This is likely due to our cohort of patients requiring clear evidence of coexpression for MYC and BCL2 (≥40% and >50%, respectively) that are not related to underlying chromosomal rearrangements, and few pathologists reported levels of percent staining for IHC testing among those with documented positive results of MYC/BCL2 protein coexpression. In addition, results from this study showed that only half of cases had COO classification documented by healthcare providers, despite available IHC results. Although this study indicated lack of details in the reporting of diagnostic testing (e.g. COO identification, levels of percent staining, methods for DLBCL subgroup identification), findings should be interpreted with caution, as patients with DLBCL might have been tested but not documented in the electronic health record system or might have biomarker testing performed at sites outside of the Flatiron Health network. Disclosures Yang: F. Hoffmann-La Roche: Current Employment. Zhang:F. Hoffmann-La Roche: Current Employment. Xiao:F. Hoffmann-La Roche: Current Employment. Hammer:Roche: Consultancy, Honoraria, Research Funding; Caris Lifesciences: Honoraria; PER Med education: Honoraria; PathEdEx: Current equity holder in private company. Prime:F. Hoffmann-La Roche: Current Employment.

Background A better understanding of diffuse large B-cell lymphoma (DLBCL) subtypes characterized by cell of origin (COO), molecular and immunophenotypic features is associated with more accurate prognosis and may guide treatment selection to achieve better outcomes. Current World Health Organization (WHO) and National Comprehensive Cancer Network (NCCN) guidelines recommend for all patients with DLBCL, immunohistochemistry (IHC, such as Hans algorithm) as a surrogate of gene expression profiling to identify COO, and molecular testing by fluorescence in situ hybridization (FISH) or karyotype to identify molecular/cytogenetic features. Despite advances in treatment and increasing knowledge of clinical importance of DLBCL subtype classification, socioeconomic disparities persist in the treatment of DLBCL in the US (Shenoy PJ, et al. Cancer 2011;117(11):2530-2540) and the use of guideline-recommended diagnostic testing in clinical practice remains unclear. Understanding whether test utilization varies by socioeconomic determinants is important to enable all patients to achieve better/equal access to health care and optimal outcomes. Methods To understand guideline-recommended diagnostic testing utilization in real-world settings and to assess socioeconomic disparities in relation to test utilization among patients with DLBCL in the US, this retrospective cohort study leveraged data from the Flatiron Health electronic health record (EHR)-derived de-identified database. Patients above 18 years old with a diagnosis of DLBCL between Jan-2011 and Dec-2019 were included in the study. Information on IHC, FISH and karyotype analysis was abstracted from pathology reports or clinical visit notes, where available. Utilization of guideline-recommended diagnostic testing was defined as patients with documentation of a confirmed known result on: 1) expression of MYC, BCL2, BCL6, CD10 or MUM1 protein for IHC; and 2) rearrangement of oncogene MYC, BCL2 or BCL6 by FISH or karyotype analysis for molecular testing. 'Not tested' was defined as patients with no evidence/documentation of diagnostic testing for all of the aforementioned markers. Socioeconomic determinants included age, gender, type of insurance plan, race/ethnicity group and geographic location of residency. We assessed changes in rates of IHC and molecular testing during the study follow-up period using Cochran-Armitage trend tests. To assess the impact of socioeconomic determinants on test utilization, multivariable logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI) for IHC and molecular testing separately, while adjusting for several demographic and clinical characteristics. Results In total 5387 patients with DLBCL were included in the study. Guideline-recommended diagnostic testing rates increased between 2011 and 2019 (66.9 to 85.6% for IHC and 49.5 to 67.0% for molecular testing, both P-values Discussion Although the results of this study showed a significant increase in the adoption of guideline-recommended diagnostic testing for patients with DLBCL in the US between 2011-2019, socioeconomic disparities appeared to still exist in the access to molecular testing. Providing equitable access to diagnostic testing would be a critical parameter for patients' clinical benefit. It should be noted that findings about test utilization need cautious interpretation, as patients with DLBCL might have been tested but not documented in the EHR or might have the test performed at sites outside of the Flatiron Health network. Disclosures Yang: F. Hoffmann-La Roche: Current Employment. Zhang:F. Hoffmann-La Roche: Current Employment. Xiao:F. Hoffmann-La Roche: Current Employment. Hammer:PER Med education: Honoraria; PathEdEx: Current equity holder in private company; Caris Lifesciences: Honoraria; Roche: Consultancy, Honoraria, Research Funding. Prime:F. Hoffmann-La Roche: Current Employment.

Cardiac tumors are divided into primary tumors and secondary metastasis from a distant malignancy. Cardiac metastases from head and neck SCCs are extremely rare and pose a diagnostic and therapeutic challenge to clinicians. In this case, we aim to highlight the importance of prompt cardiac testing

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.

We read with interest the recent article by He et al1 comparing conventional karyotyping and fluorescence in situ hybridization (FISH) in acute myeloid leukemia (AML). While the authors clearly show no advantage to FISH when karyotyping is adequate and propose an algorithmic approach to testing, there is no discussion regarding practical matters, such as turnaround time, potential delay in diagnosis, and actual cost vs benefit. Cytogenetics and FISH are often send-out tests at many institutions, and as noted, this is often done concurrently rather than sequentially. Chromosome analysis has long been the gold standard for identification of the common, recurrent chromosome abnormalities in AML. However, this analysis requires dividing cells, takes 5 to 7 days to process, and can miss subtle or cryptic rearrangements (eg, inv[16] and MLL anomalies). We, like others, are also looking at best practices to provide value and quality care in the new health care environment. We find the algorithmic strategy is beneficial in many situations and can prevent unnecessary testing. Being curious of the implications in this scenario, we asked for a turnaround time report for conventional cytogenetics and multiprobe AML FISH panel from our reference laboratory (a large national reference laboratory) for the past 6 months. The average turnaround time for cytogenetics was 7 days vs 2.5 days for FISH. This could potentially result in a significant delay of definitive treatment regimens or increased length of stay. In this regard, time from diagnosis to treatment (TDT) has been reported to predict survival in younger but not older patients with AML.2 In that study, response rate and survival were decreased after a 5-day treatment delay in patients younger than 60 years. On the other hand, Bertoli et al3 recently reported that TDT did not adversely affect outcome of patients with AML. Nonetheless, …

72 Background: Checkpoint inhibitors have demonstrated efficacy in many cancer types. Neurological side effects are not well studied with check point inhibitors therapy. We conducted systematic review and meta analysis to evaluate the incidence of neurological side effects among various check point inhibitors. Methods: Eligible studies were searched for in PubMed and Google scholar. We searched for randomized controlled trials with cancer patients treated with check point inhibitors with neurological adverse effects. A total of 26 randomized controlled trials involving 6110 patients met eligibility criteria for the study. Results: Incidence rate of all grade neurological side effects include 5.6%(95% confidence interval [CI], 5.4-6.7%). Most common side effects include Headache (4.6%) (95% confidence interval [CI] 3.7-4.7%) followed by peripheral neuropathy (0.3%) (95% confidence interval [CI] 0.1-0.5%). Ipilimumab plus Nivolumab is associated with higher risk of headache and serious neurological side effects including myasthenia gravis, encephalitis, toxic encephalopathy and seizures. Conclusions: The incidence of neurological side effects associated with immune checkpoint inhibitors is low but not negligable. Patients on combination immunotherapy need more close monitoring for serious neurological side effects.

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.

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

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.

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

Because cancer is a leading cause of mortality in the United States, the number of therapeutic modalities available for the treatment of neoplastic processes has increased. This has resulted in a large number of patients being exposed to a wide variety of cancer therapy. Historically, it has been well recognized that antineoplastic agents may have adverse effects on multiple organs and normal tissues. The most commonly associated toxicities occur in tissues composed of rapidly dividing cells and may spontaneously reverse with minimal long-term toxicity. However, the myocardium consists of cells that have limited regenerative capability, which may render the heart susceptible to permanent or transient adverse effects from chemotherapeutic agents. Such toxicity encompasses a heterogeneous group of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. In some instances, the pathogenesis of these toxic effects has been elucidated, whereas in others the precise etiology remains unknown. We review herein the various syndromes of cardiac toxicity that are reported to be associated with antineoplastic agents and discuss their putative mechanisms and treatment.

[Figure][1] A 26-year-old male was evaluated for chest pain and was found to have a white cell count of 63 000 per cubic millimeter, hemoglobin 10.5 g/dL, platelets 102 000 per μL, with 18% blasts and promyelocytes (panel A). Bone marrow was hypercellular, with promyelocytes and myeloblasts

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.

Vascular complications associated with chemotherapy and hormonotherapy are being reported with increasing frequency. Such vascular toxicity is clinically heterogenous, ranging from asymptomatic venous lesions to fatal hepatic venoocclusive disease of the liver. Putative mechanisms for such toxicity include drug-induced endothelial cell damage, perturbation of the clotting cascade, platelet activation and aggregation, alteration of thromboxane-prostacyclin homeostasis, and dysregulation of cytokines. Better documentation of the incidence and types of vascular toxicity and studies to help elucidate the pathogenesis and management of such toxicity are needed.

Skin metastasis associated with lung cancer is an uncommon manifestation and usually portends an aggressive clinical course. It can be either synchronous with the underlying malignancy or be the sign of recurrence. Solitary metastases can be treated with surgical resection or radiation therapy, but multiple lesions are usually treated with palliative chemotherapy. With standard platinum-based doublet regimens, treatment results are usually poor. With the advent of newer agents like pemetrexed, bevacizumab and erlotinib, perhaps results may improve with ongoing clinical trials.

Introduction: Brown recluse spider bites are encountered commonly in endemic areas of North and South America. Loxosceles reclusa is the species of Loxosceles most commonly seen in the states of MO, KS, OK, TX, AK, LA, KY, TN, MS, AL and parts of IL, IA, IN and GA. The incidence of hemolytic anemia with systemic loxoscelism in the USA seems to be significantly higher and more severe than the incidence and severity reported in studies from South America (13%-15% incidence). In our 6 cases of loxoscelism associated with severe hemolysis, we noticed that there are signs and symptoms that could be helpful to guide the follow up and facilitate early diagnosis. Method: We reviewed 6 cases of hemolytic anemia from Loxoscelism treated at the University of Missouri Hospitals. Of these 6 cases 4 were treated within 1 year. All of the cases presented with systemic and cutaneous manifestations. Each patient was initially treated symptomatically and discharged without a close follow up. This resulted in delayed presentations with symptoms of severe hemolytic anemia associated with significant morbidity [Syncope (1), Syncope with fracture (1), Hypotension needing ICU care (1), Necrotizing fasciitis (1), and severe hepatosplenomegaly with hyperbilirubinemia (1)]. We have summarized the systemic symptoms, peripheral blood smear and laboratory findings that correlate with hemolytic anemia. Results:Patients presented with Nausea (6/6), Vomiting (5/6), Fever (5/6), and Target lesion (6/6) within 48 hours after spider bite [Table 1]. Severe hemolysis developed at a median of 6.5 days after the spider bite. DAT was positive for IgG and C3 in all of the cases. Peripheral smear findings included leukocytosis with toxic granulations, Dohle bodies and left shift, Nucleated RBC, anisopoikilocytosis with some schistocytes, hemophagocytosis and normal to decreased platelets [[Figure 1][1]] [[Figure 3][2]]. When not recognized patients presented with sudden and severe hemolysis (median drop in Hb =7.5 g/dL) [Table2] resulting in hospitalization with severe morbidity ([Figure 2][3]). | | Initial Presentation | Significant Morbidity | | --------- | ------------------------------------------------------------------------------------------------ | --------------------------------------------------------- | | Patient 1 | Nausea and vomiting. Fever. Diffuse rash, RUQ pain Target lesion on back | Severe Jaundice Hepatomegaly Splenomegaly | | Patient 2 | Nausea, vomiting and diarrhea. Fever Target lesion on left arm | Syncope Ankle fracture | | Patient 3 | Nausea, fatigue and malaise. Target lesion on right back | Recurrent syncope | | Patient 4 | Nausea, Vomiting Fever Target lesion right arm. | Severe Hypotension ICU care | | Patient 5 | Nausea, dry heaves Fever. Thigh pain Target lesion right thigh. | Necrotizing fasciitis Fasciotomy | | Patient 6 | Nausea, vomiting and fatigue. Fever. Target lesion right shoulder. | | Table 1 ![Figure 1:][4] Figure 1: Peripheral Smear Findings of Systemic Loxoscelism ![Figure 2:][4] Figure 2: Significant Morbidity from Systemic Loxoscelism ![Figure 3:][4] Figure 3: Peripheral smear findings | | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Median | | ------------------------------------ | --------- | --------- | --------- | --------- | --------- | --------- | ------ | | Age | 34 | 31 | 21 | 25 | 21 | 22 | 23.5 | | Days after bite to lowest Hemoglobin | 8 | 5 | 6 | 6 | 7 | 9 | 6.5 | | Baseline Hb (g/dL) | 11 | 12 | 15 | 13 | 13.8 | 15.7 | 13.4 | | Lowest Hb (g/dL) | 5.7 | 4 | 5 | 6 | 6.6 | 8.4 | 5.85 | | MCV with lowest Hb (fL) | 70 | 107 | 100 | 90 | 96.6 | 101 | 98.3 | | WBC (103/µL) | 12.6 | 42 | 32.3 | 14.5 | 33.4 | 26.6 | 29.45 | | Platelets (103/µL) | 160 | 141 | 234 | 64 | 261 | 576 | 197 | | LDH (unit/L) | hemolysed | 2080 | 951 | 1348 | 744 | 346 | 951 | | T. Bili (mg/dL) | 35.4 | 13.2 | 5 | 1.8 | 3.7 | 7.4 | | | D. Bili (mg/dL) | >10 | 9.2 | .3 | .5 | 0.3 | 1.4 | | | Ind. Bili (mg/dL) | | 3.9 | 4.7 | | | | | | AST (unit/L) | 100 | 52 | 25 | 201 | 120 | 156 | | | ALT (unit/L) | 86 | 95 | 19 | 91 | 104 | 294 | | | Alk phos (unit/L) | 94 | 88 | 67 | 36 | 160 | 159 | | | Blood group | A Pos | A Pos | O Pos | B Pos | O Pos | | | Table 2 Discussion: Systemic loxoscelism from Loxosceles reclusa in USA is associated with a high incidence of severe hemolytic anemia. Increased awareness of the delayed presentation with hemolysis after initial signs of systemic loxoscelism could avoid life threatening events. Initial symptoms developed within 48 hours of the spider bite and led to medical attention in all of the reported cases. With appropriate follow up, peripheral smear review and labs at 5-7 days after the spider bite most of the cases would have been recognized early and could have potentially avoided life threatening complications. The different species of Loxosceles prevalent in South America could explain the difference in the incidence of hemolytic anemia. Studies from Brazil have reported the use of antivenom in about 50% of loxoscelism cases. Effectiveness of antivenom is not established and is seldom used in the USA but, could account for some differences in the incidence of hemolysis. Disclosures No relevant conflicts of interest to declare. [1]: #F1 [2]: #F3 [3]: #F2 [4]: pending:yes

Background: Tyrosine kinase inhibitors (TKI) are associated with marked improvements in molecular response and survival compared with previous therapies for patients with chronic myelogenous leukemia (CML) in chronic phase (CP). We previously reported efficacy and safety of TKI at 12-month follow-up (Firwana et. al.JCO. 2014; 32(15_suppl): 7054). Here, we summarize the evidence of TKI efficacy and safety of TKI, comparing them directly and in-directly, in the mature follow-up for patients with newly diagnosed CP-CML. Methods: We included randomized controlled trials (RCTs) evaluating TKI in adults with newly diagnosed CP-CML. TKI (imatinib, dasatinib and nilotinib) were included if used as an initial treatment. Studies on bosutinib were excluded as it is only approved in the US for the treatment of CP-CML after failure of initial therapy. Studies that included patients with accelerated- or blast-phase CML, intolerant or resistant patients to first-line treatment, those on IFN-α, older agents or stem cell transplantation were excluded. Main outcomes are efficacy, represented by major molecular response (MMR, ≤ 0.1% BCR-ABLIS) and deeper molecular responses (MR4.5, ≤ 0.0032%IS), survival, represented by overall survival (OS) and progression free survival (PFS), and safety represented by medication discontinuation rate due to adverse events. Latest period of reporting outcome data were considered. As available trials provides direct comparison with imatinib, with no head-to-head trials to compare other TKI, we conducted a mixed treatment comparison (MTC) analysis which pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments. Bayesian mixed-treatment comparison method was used to rank TKI in terms of effectiveness. Results: Four landmark trials reported in 15 published articles and conference abstracts were identified involving 1647 patients with CP-CML. Follow-up times ranged from 3 months to 6 years. Table-1 depicts the results of MTC for imatinib, dasatinib and nilotinib. MTC analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy and safety. Nilotinib ranked first in efficacy with better improvement in MMR and MR4.5 at 48-month follow-up despite its different regimens, followed by dasatinib. Dasatinib has the highest medication discontinuation rate due to adverse events or drug-related toxicity. Among TKI, nilotinib was found to have the best survival profile; however, it was statistically nonsignificant. Conclusion: Both nilotinib and dasatinib are associated with significantly better efficacy and safety profiles compared to imatinib. At 48-month follow-up period, nilotinib ranked first to achieve MMR and MR4.5, with lower discontinuation rate due to adverse events. This analysis shows that new generation TKI 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. Table-1: Results of mixed treatment comparison for imatinib, dasatinib and nilotinib using fixed-effect Bayesian method. Comparison Mean risk difference (95% CrI) compared to from reference standard (Imatinib) Rank* MMR MR 4.5 PFS OS Discontinuation due to adverse events 48 months 48 months 36 months 48 months 48 months Imatinib Reference Reference Reference Reference Reference 4 Dasatinib 0.62 (0.26 to 1.01) 0.32 (-0.05 to 0.69) 0.21 (-0.43 to 0.85) 0.17 (-0.49 to 0.83) 0.59 (-0.05 to 1.25) 3 Nilotinib 300 0.92 (0.56 to 1.28) 0.81 (0.45 to 1.18) 1.02 (0.24 to 1.86) 0.19 (-0.51 to 0.89) -0.11 (-0.66 to 0.43) 1 Nilotinib 400 0.76 (0.41 to 1.12) 0.68 (0.31 to 1.05) 0.05 (-0.57 to 0.65) 0.81 (0.01 to 1.67) 0.30 (-0.20 to 0.81) 2 *Reported rank is valid for all outcomes, except for PFS and OS, where Nilotinib 400 ranks #1 and Nilotinib 300 ranks #2. Also, for rate of medication discontinuation due to adverse events, Dasatinib has the highest rate for discontinuation, followed by Nilotinib, both doses. Abbreviations: CrI, credible intervals; MMR, major molecular response, BCR-ABLIS ≤ 0.1%; MR4, deeper molecular responses, BCR-ABLIS ≤ 0.0032%; PFS, progression free survival; OS, overall survival. Disclosures No relevant conflicts of interest to declare.

Introduction: Incidence of secondary malignant neoplasm in patients with chronic lymphocytic leukemia (CLL) is already established. Genetic predisposition has been considered to be a possible contributory factor for the preponderance of second cancers in this population. In the present study, we examined the frequency, characteristics, and clinical outcomes of secondary malignancies in patients with CLL based on their Interphase fluorescence in situ hybridization (FISH) panel. Methods: We reviewed the medical records of consecutive patients with CLL observed or treated at Ellis Fischel Cancer Center during the period from 2007-2014. We collected demographic data, CLL Rai stage, treatment history, Interphase fluorescence in situ hybridization (FISH) panel results and the presence of a secondary malignancy (skin cancers, solid tumors and hematologic malignancy excluding CLL transformation).Our aim was to investigate the association between secondary malignancy and chromosomal abnormalities and other risk factors using Chi2test for categorical variables and Wilcoxon rank-sum test for continuous variables. Cox proportional hazard models and logistic regression models were used to evaluate risk factors of developing secondary malignancy and overall survival. Results: We identified 142 CLL patients who were either observed (n=62) or had a history of treatment (n=80) for CLL. 67% were male and 33% were female. 85% of patients were Caucasians, 10% African Americans, and 5% other. Familial CLL was present in 6% of cases. 51% of patients were non-smokers. 5% of patients had cancers preceding the diagnosis of CLL (non-melanoma skin cancers=3, melanoma=1, Hodgkin's lymphoma=1, Prostate=2). 28% of patients developed secondary malignancies after the diagnosis of CLL; among them non-melanoma skin cancers were the most common (78%), followed by cutaneous melanoma (9.5%) and papillary thyroid cancer (4.7%). Other malignancies included lung (2.3%), kidney (2.3%), prostate (2.3%) and ocular melanoma (2.3%). 12% patients had aggressive non-melanoma recurrent skin cancers that require multiple treatments along-with systemic therapy for progressive CLL. CLL-FISH panel at diagnosis was available in 98 patients. Among these patients,13q deletion was present in 45%. Within the 13q deletion group, secondary malignancy was noted in 50% during a median follow up of 7 years. All cases of papillary thyroid cancers were also present in 13q deletion. In contrast, 11q deletion was detected in 15% and trisomy 12 in 18% of patients with incidence of secondary malignancy 40% and 10%, respectively. No solid malignancy other than skin was identified in the 11q deletion and trisomy 12 groups. 17p deletion was present in 5% of cases and 60% of 17p deletion cases had secondary cancers (skin 80%). Normal FISH panel was present in 17% cases and 20% of normal FISH had secondary malignancy (solid 10%, skin 10%). The median overall survival time is 6 years for the entire cohort (IRQ: 3-9 years). Secondary malignancy was associated with worse overall survival (OS) (HR=0.57, 95% CI:0.33-0.98, p=0.04) compare to patients who did not have secondary malignancy. The risk of secondary malignancy is increased in patients with advanced age (OR=1.05, 95% CI:1.00-1.10, p=0.04) and in those who were treated with alkylating agent for CLL OR=6.62, 95% CI:2.08-21.03, p=0.001. However, there were no significant difference on risk of developing secondary malignancy based on specific chromosomal FISH result, Rai stage, smoking, family history and gender. Conclusion: Secondary malignancies are frequent in patients with detectable chromosome abnormality on FISH panel. However, the increased risk of secondary malignancy does not correlate with specific cytogenetic abnormality. Non melanoma skin cancers are exceedingly common in CLL patients and carries aggressive couse in progressive CLL patients. Larger studies are required to identify subtype of CLL based on integrated mutational and cytogenetic subgroup that are at increased risk of specific secondary malignancies. Disclosures No relevant conflicts of interest to declare.

[Figure][1] A 56-year-old male presented to the emergency department with acute abdominal pain. Computed tomography scan showed multiple cervical, supraclavicular, periaortic, and mesenteric lymphadenopathy; a ruptured spleen measuring 19 cm; and free intraperitoneal hemorrhage. He underwent

e19088 Background: Fluoro-deoxyglucose positron emission tomography-computed tomography 18F FDG PET-CT (PET) is a useful tool for diagnosis, staging, and confer prognostic information based on trea...

7054 Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder of blood stem cells. After the introduction of tyrosine kinase inhibitors (TKi), patients with CML have had substant...

A 43-yr-old man presented to the clinic with abdominal pain, jaundice, nausea, and vomiting and weight loss over a 6-month period. Physical exam was unrevealing other than mild epigastric tenderness. A computed tomographic scan of the abdomen revealed a mass in the head of the pancreas, which was resected at laparotomy by a Whipple's procedure. The histology showed a biliary tract carcinoid tumor. The patient had normal hydroxy-indole-acetic acid (HIAA) levels throughout. There has been no evidence of disease or tumor recurrence at 3.5 yr of follow up.

Three cases of peripheral T-cell lymphocytosis associated with thymoma are described. Each patient had a malignant, predominantly lymphocytic thymoma with resolution of lymphocytosis upon treatment of the epithelial neoplasm. These findings suggest that lymphocytosis complicating thymoma is a paraneoplastic phenomenon and is not part of the neoplastic process.

Forty-three patients with myelodysplastic syndromes (MDS) received treatment with oral etoposide 50 mg/day for 21 consecutive days every 4 weeks. Eighteen patients (42%) experienced hematological responses, including 12 of 17 (70%) patients with chronic myelomonocytic leukemia (CMML). Three of five CMML patients who failed treatment with hydroxyurea experienced major hematological responses with oral etoposide. Median response duration exceeded 9 months (range: 4-49 + months), and one patient remains in an unmaintained complete remission for 4 years. Toxicity included nausea/vomiting in five patients, fever (four patients), infection (three patients), mucositis (two patients), and anorexia (two patients). Two patients had grade 4 neutropenia with sepsis necessitating treatment withdrawal. We conclude that low-dose oral etoposide has remitting activity in MDS and is an effective treatment alternative for patients with CMML.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, accounting for about 1/3rd cases of NHL. At diagnosis, DLBCL involves the bone marrow in approximately 15-25% of cases. However, the bone marrow may reveal discordant morphology from the lymph node, usually an indolent lymphoma. Bone marrow biopsy is routinely used in the staging evaluation of patients with DLBCL. The aim of this study was to determine if clinical variables could predict bone marrow involvement by DLBCL. Methods Retrospective chart review of all patients with a diagnosis of DLBCL at University of Missouri-Columbia/Ellis Fischel Cancer Center from 1993-2013. The following parameters were reviewed: bone marrow biopsy reports, anemia (Hb Results 80 charts were available for review and 7 patients had bone marrow involvement by DLBCL. Univariate analysis for cytopenias (p=0.459), elevated LDH (p=0.442), anemia (p=0.436), leukopenia (p=1.0) and thrombocytopenia (p=0.434) and bone marrow involvement by DLBCL showed no statistical significance (Fischer Exact test). Multivariate analysis comparing anemia, leukopenia, thrombocytopenia, elevated LDH and clinical stage with respect to bone marrow involvement revealed p=0.789, p=0.134, p=0.062, p=0.827 and p=0.521 respectively, and disclosed no statistical significance (logistic regression analysis). Univariate (Fisher exact tests and Cochran-Mantel-Haenszel statistics) and multivariate (logistic regression) analyses were used to test for the relationship of these parameters with bone marrow involvement. Disclosures: No relevant conflicts of interest to declare.

4967 Background: Multiple myeloma (MM) is a common hematological malignancy affecting all races and the incidence is increasing. The rise in incidence is partly due to an increase in average life span in the patient population above the age of 65. It is estimated that 21, 700 individuals will be diagnosed with and 10, 710 patients will die of myeloma in 2012. The comparative epidemiological and survival data on different ethnic groups has not been analyzed on a large population scale. The aim of this study is to analyze and compare the epidemiologic and survival parameters of MM in major US ethnic groups which may provide new insights into disease pathophysiology. Methods: The SEER (Surveillance Epidemiology and End Results) database has been reporting cancer incidence since 1973. Using SEER 18 registries database 1973–2009, appropriate frequency and survival analyses (Kaplan-Meier survival method age adjusted) were performed and compared. Results: US whites (USW) accounted for the highest reported cases (77%) while the next highest reported cases were AA population (17%) ([Table 1][1]). On the contrary, the incidence of MM was highest in AA (11. 7%) and lowest in the US-Hispanic group (3. 4%). Male to female distribution was similar among groups. The median age at diagnosis was 63yrs in AA and 62yrs in US-Asians compared to ∼70yrs in the other ethnic groups. The cancer at presentation was more advanced in the AA and US-Asian groups. However, as shown in both [Tables 1][1] & [2][2], the mortality rates were significantly lower in the US-Asian population when compared to other ethnic groups (2. 4%). | Variables | All | USW | AA | Hispanic | US-Asian | |:-----------------------:| ------------- | ------------ | ------------ | ---------- | ---------- | | Reported cases (%) | 79,186 (100%) | 61,083 (77%) | 13,611 (17%) | 2,393 (3%) | 1,872 (3%) | | Incidence rate | 5.8 | 5.3 | 11.7[*][3] | 3.4 | 4.1 | | Male | 7.4 | 6.9 | 14.3 | 6.3 | 4.7 | | Female | 4.7 | 4.1 | 10.1 | 4.7 | 3.9 | | M% - F% | 53%–47% | 54%–46% | 49%–51% | 53%–47% | 49%–51% | | Median age of diagnosis | 69 | 71 | 63[*][3] | 70 | 62[*][3] | | Age

e17525 Background: In 1999, we reported demographics, staging, and treatment outcomes of patients with mixed histology small cell lung cancer (MHSCLC). The purpose of this abstract is to report pattern of presentation and survival in patients during 2000-2009. Methods: Records from 24 patients diagnosed with MHSCLC were reviewed under an institutional review board outcomes study. One patient was excluded as records were missing. Patient and disease characteristics, treatment, and outcomes were analyzed. Results: Twenty-three patients were analyzed, with median age at diagnosis of 63 (range 50 to 84). Twenty (86%) patients were Caucasian. Fourteen (61%) patients were female, 9 (39%) were male. Twenty-one (91%) patients were current or former smokers. Staging was as follows: 1-2: 3, 3: 6, 4: 11, extensive-stage: 1, limited-stage: 2. Sites of diagnosis were lung in 18 (78%), and metastatic sites in 5 (22%). Presenting symptoms were cough or shortness of breath in 12 (52%), CNS in 4 (17%), chest pain in 2 (9%), various others in 5 patients. Paraneoplastic syndrome was seen in 2 patients, and 6 patients reported weight loss of 10-15 lbs within 3-6 months of diagnosis. Metastatic presentation was as follows: 4 brain, 1 bone, and 1 soft tissue. Histology included 15 large cell, 6 adenocarcinoma, and 1 squamous cell. Seventeen patients were treated as follows: chemotherapy (14), 5 thoracic radiotherapy (RT), 3 cranial RT, with treatment status unknown in 1 patient with 3 year survival. Twenty-one (91%) patients had expired, with median survival of 4.6 months (range