Eric Wiedower

Genomic alterations in neuroendocrine cancers of the ovary

BackgroundAs we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO.MethodsPatients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007–2015 were identified. Tumors were assessed with up to 21 IHC stains, in situ hybridization of cMET, EGFR, HER2 and PIK3CA, and next-generation sequencing (NGS) as well as Sanger sequencing of selected genes.ResultsForty-six patients with SCCO (10 SCCO, 18 SCCO-HT, 18 NET-O) were identified as well as 58 patients with SCLC for comparison. Patients with SCCO and SCCO-HT were younger (median 42 years [range 12–75] and 26 years [range 8–40], respectively) than patients with NET-O 62 [range 13–76] or SCLC 66 [range 36–86]. SCCO patients were more likely to be metastatic (70 %) than SCCO-HT (50 %) or NET-O (33 %) patients, but at a similar rate to SCLC patients (65 %). PD1 expression varied across tumor type with SCCO (100 %), SCCO-HT (60 %), NET-O (33 %) vs SCLC (42 %). PDL1 expression also varied with SCCO (50 %), SCCO-HT (20 %), NET-O (33 %) and SCLC (0 %). No amplifications were identified in cMET, EGFR, or HER2 and only 1 was found in PIK3CA (NET-O). Actionable mutations were rare with 1 patient with SCCO having a BRCA2 mutation and 1 patient with NET-O having a PIK3CA mutation. No other actionable mutations were identified.ConclusionsNo recurrent actionable mutations or rearrangements were identified using this platform in SCCO. IHC patterns may help guide the use of chemotherapy in these rare tumors.

Comorbidities Drive Outcomes for Both Malignancy-Associated and Non–Malignancy-Associated Hemophagocytic Syndrome

BACKGROUND Secondary hemophagocytic syndrome (SHPS) is a syndrome that develops as a result of infection, autoimmunity, or underlying malignancy. We studied novel predictors of mortality among adults with SHPS. PATIENTS AND METHODS SHPS were identified from the Nationwide Inpatient Sample for 2009 to 2011 using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), codes. Charlson comorbidity index (CCI) was used for comorbidity assessment, excluding malignancy. Patient- and hospital-related factors on mortality were assessed by chi-square test or analysis of variance. P values were 2 sided, and the level of significance was .05. RESULTS A total of 276 patient hospitalizations with SHPS were identified. Forty-four had an associated malignancy, 38 (86%) of which were hematologic. Median age was 42 years (range, 18-89 years). A total of 66% (n = 182) had a CCI of 0, 13% (n = 27) had a CCI of 1, and 21% (n = 57) had a CCI of 2 or more. On bivariate analysis, inpatient mortality rate was significantly higher in malignancy-associated hemophagocytic syndrome (HPS) (odds ratio [OR], 2.07; P = .04), age ≥ 50 years (OR, 3.46; P < .01), CCI ≥ 2 (OR, 3.04; P < .01), and Medicare patients (OR, 2.32; P < .01). In multivariate analysis, CCI ≥ 2 remained an independent predictor of survival in the overall study cohort (OR, 3.52; 95% confidence interval, 1.51-8.18; P < .01). CONCLUSION Malignancy-associated HPS, CCI ≥ 2, age > 50 years, and Medicare patients were associated with a worse in-hospital mortality. In multivariate analysis, greater comorbidity burden appeared to be the single most important predictor of mortality. This suggests that outcomes for adults with HPS are predicated by the extent of organ dysfunction at diagnosis.

Under-recognition of hemophagocytic syndrome in United States' rural, non-teaching hospitals.

Hemophagocytic syndrome (HPS) is a rare clinical syndrome characterized by hyper-inflammation due to an excessive immune response with an aggressive disease course and life-threatening consequences. Familial HPS is an autosomal recessive disorder caused by various gene defects that usually presents in infants and children.[1–4] Acquired or secondary HPS (SHPS) can occur at any age but primarily arises in adults due to extreme immunologic activation, which can be triggered, by infections, autoimmune disorders, and malignancies, with leukemia and lymphoma being the most common.[5,6] This syndrome is highly fatal without prompt diagnosis and treatment, but its rarity and complex clinical picture often leads to a delayed or missed diagnosis. Epidemiologic data on SHPS in the adult population is sparse. We sought to define the characteristics of SHPS in different hospital settings as well as the mortality when associated with hematologic malignancies, solid tumors, and in patients without a reported malignancy. We obtained IRB approval to search the United States Nationwide Inpatient Sample (NIS) database for adult patients diagnosed with HPS.[7] Utilizing search parameters established by Johnson et al. [8], we identified all adult hospitalizations from 2009 to 2011 with the diagnosis of HPS based on International Classification of Diseases-9th revision, Clinical Modification (ICD-9-CM) code 288.4 combined with ICD-9-CM procedure code 41.31 for bone marrow biopsy to improve diagnostic accuracy. Patient characteristics included age at diagnosis, race, and gender. We identified the underlying conditions associated with each case (malignant vs non-malignant) as well as the inpatient mortality. Lastly, we assessed the distribution of cases by hospital teaching status (teaching versus non-teaching) and location (rural versus urban). Statistical analysis was done using STATA 13.0 (StataCorp LP, College Station, TX). All p values were two sided and the level of significance was 0.05. A total of 896 HPS cases were identified and 276 of those cases also had bone marrow biopsies. Of the 276 cases identified for analysis, 44 (16%) had a concomitant diagnosis of a malignancy. The median age at diagnosis was 42 years (range 18–89 years), and 43% (n1⁄4 114) of the cases were females. Of the 232 non-malignant HPS cases, related causes could only be identified for 37 patients: 1 HIV (1%), 3 histoplasmosis (1%), 12 systemic lupus erythematosus (4%), and 21 rheumatoid arthritis (7%). There were a total of 23,634,793 hospitalizations in the NIS from 2009 to 2011; 12,532,948 (53%) belonged to non-teaching hospitals and 11,101,845 (47%) belonged to teaching hospitals. Similarly, 2,867,148 (12%) belonged to rural hospitals and 20,767,645 (88%) belonged to urban hospitals. Among HPS cases, 90% (n1⁄4 248) belonged to teaching hospitals and 99% (n1⁄4 273) belonged to urban hospitals. Chi-squared test showed that cases of HPS were more likely to be diagnosed in a teaching hospital (p < 0.01) and urban hospitals (p< 0.01). Of the 44 cases with an underlying malignancy, 38 (86%) were associated with a hematological malignancy and 5 (11.3%) with a solid tumor. The tumor type was not specified for one patient. The in-hospital mortality for HPS with and without underlying malignancy was 29.6% (n1⁄4 13) and 14.2% (n1⁄4 33), respectively (p value 0.01) [Table 1]. Inpatient mortality was 29% (n1⁄4 11) for patients with an associated hematological malignancy and 40% (n1⁄4 2) for those with associated solid tumor. Comparison of outcomes between rural and urban hospitals and teaching and non-teaching hospitals was not feasible due to the skewing of case distributions. To better understand reasons for the concentration of HPS cases in urban centers, we explored referral patterns using the NIS ‘‘transfer out’’ variable, which was only available in 2010 and 2011. Data was available for two of the three cases diagnosed in rural hospitals, and neither case

Unusual, spontaneous aneurysm formation in a patient being treated with ibrutinib for chronic lymphocytic leukemia.

Ibrutinib has been shown to be beneficial for B-cell malignancies with overall response rates of 71% in initial clinical trials for chronic lymphocytic leukemia (CLL), irrespective of high-risk characteristics [Byrd et al. 2013; Parmar et al. 2014]. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment of selected leukemias and lymphomas, has been associated with bleeding events [Byrd et al. 2013, 2014; Wang et al. 2013]. Kamel and colleagues illustrated that BTK inhibitors, such as ibrutinib, cause an interruption in collagen-mediated platelet aggregation, and thus increase bleeding risk [Kamel et al. 2015]. Levade and colleagues demonstrated ibrutinib’s effects on adhesion of platelets to von Willebrand factor by the disruption of collagen receptors. It was also shown that removal of the drug, and the generation of new, unaffected platelets provided a decrease in the risk of bleeding [Levade et al. 2014]. While as many as 50% (or half) of patients may experience grade 1 or 2 bleeding on ibrutinib, other studies have revealed more serious bleeding events [Jones et al. 2014]. Wang and colleagues evaluated patients with mantle cell lymphoma being treated with ibrutinib. Approximately 5% of patients were shown to have grade 3 or higher bleeding events; however, the majority of these patients had sustained some sort of trauma [Wang et al. 2013]. Burger and colleagues compared ibrutinib with chlorambucil as initial therapy for patients with CLL. The median treatment duration with ibrutinib was 17.4 months, and major hemorrhage was reported in 4% of these patients [Burger et al. 2015]. Despite a noted disruption in platelet function, ibrutinib has been shown to improve overall platelet counts with the control of the underlying CLL [Farooqui et al. 2012]. Jones and colleagues evaluated the concomitant use of antiplatelet agents and anticoagulants in patients treated with ibrutinib, and the majority of the patients having major bleeding were treated with one of these agents, in addition to the BTK inhibitor [Jones et al. 2014]. Though major bleeding events have been present in patients treated with ibrutinib, the role of vascular remodeling has not previously been described. We present the case of a patient with an unusual bleeding event secondary to a vascular anomaly on ibrutinib for the treatment of CLL. The patient is a 46-year-old man treated for CLL with ibrutinib with no other medical history. He had no prior lines of therapy for his disease. At presentation he had diffuse lymphadenopathy, lymphocytosis with a white blood count of 35,000 mm3, splenomegaly and platelet count of 65,000 mm3. The patient had Rai stage IV CLL at diagnosis which was his indication for treatment. Three months after starting therapy, he experienced a dramatic positive response both in lymph node size and peripheral blood counts. WBC did increase to 55,700 mm3 within a month of treatment but had normalized to 5600 mm3 within 3 months. However, he was admitted to the hospital 3 months after initiating therapy with a severe headache and found to have a subarachnoid hemorrhage on CT and magnetic resonance imaging. Ibrutinib was discontinued upon hospitalization. He was not on any home medications including antiplatelet agents or anticoagulants at the time of this event, nor was any trauma experienced prior to admission. He had no prior history of bleeding diathesis. His prothrombin time (PT), partial thromboplastin time (PTT) and fibrinogen were within normal limits and his platelet count was 99,000 mm3, which was a significant improvement from his pretreatment platelet count of 65,000 mm3. His pretreatment hemoglobin (Hb) was 12.6 g/dl and had normalized to 15.3 g/dl within 3 months of treatment. Hb was stable throughout hospitalization averaging 15 g/dl, as well as platelet count, with no evidence of autoimmune hemolysis. Initial angiography was normal, but 5 days later repeat angiography demonstrated slow filling of an unusual aneurysm arising from the basilar artery demonstrated by the blue arrow in panels A and B of Figure 1. Three days later, a third angiogram was performed which showed spontaneous resolution of the aneurysm. Ibrutinib was held during the patient’s hospitalization and he ultimately recovered. He had no further bleeding episodes. We hypothesize that ibrutinib may interact with the collagen component of vasculature, leading to abnormal remodeling which may be associated with the increased risk of bleeding described with this agent. Figure 1. Angiogram performed on day 8 of hospitalization demonstrating unusual aneurysm. The blue arrow in panels A and B indicates location of this abnormal aneurysm from different views. This aneurysm was not present on initial angiography and was absent during ... Some researchers have used this known disruption in collagen structure and function as a beneficial side effect of ibrutinib. Dubovsky and colleagues described using the drug to deliberately interrupt collagen’s role in forming the fibrotic tissue changes that contribute to chronic graft-versus-host disease [Dubovsky et al. 2014]. The aforementioned patient likely did not have bleeding that was secondary to disrupted platelet aggregation, but rather, we hypothesize that ibrutinib may have caused some intermittent disruption or remodeling of the collagen fibers comprising his vasculature. This intermittent nature of disruption could explain his lack of initial aneurysm at presentation, spontaneous aneurysm formation, and its subsequent resolution with removal of the drug. The package insert for ibrutinib quotes a 6% grade 3 or higher bleeding risk in patients treated with ibrutinib, with this risk increased in patients on other anticoagulants or antiplatelet therapy (ibrutinib package insert, Pharmacyclics, Sunnyvale, CA, 2013). As the mechanism for bleeding events secondary to ibrutinib is not completely understood, this case illustrates that abnormal vascular remodeling leading to aberrations in normal vasculature could be a component of these hemorrhagic events in addition to disruption in platelet aggregation.

Sweet’s syndrome associated with clonal hematopoiesis of indeterminate potential responsive to 5-azacitidine

Sweet’s syndrome (SS) is a rare condition characterized by the abrupt appearance of painful skin lesions due to neutrophilic dermal infiltration. Hematologic neoplasms, particularly acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs), have been commonly reported in association with SS. Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging entity that is a precursor state to myeloid neoplasms. CHIP has not been previously associated with SS. We report the case of a 71-year-old man who presented with recurrent, painful edematous and erythematous papules and nodules for 18 months despite treatment with corticosteroids. He had normal blood counts, but a macrocytosis was noted (110 fl). Alternative causes of macrocytosis were ruled out. A skin biopsy confirmed a diagnosis of SS. Bone marrow biopsy specimen yielded a normal karyotype except for loss of the Y chromosome and equivocal morphologic findings. Polymerase chain reaction (PCR) and reverse transcription polymerase chain reaction (RT-PCR) of selected genes from the peripheral blood demonstrated a mixed lineage leukemia (MLL) partial tandem duplication (PTD) and sequence variant in CCAAT/enhancer binding protein alpha (CEBPA). These findings were consistent with a diagnosis of CHIP. The patient was treated with 5-azacitidine and achieved a complete remission of his skin lesions and was able to discontinue corticosteroids. To our knowledge, this is the first report of a patient with recurrent SS associated with CHIP. In addition to other myeloid neoplasms like AML and MDS, CHIP should be considered as a potential etiology in cases of recurrent SS. Treatment with a hypomethylating agents such as azacitidine could also serve as an alternative to systemic corticosteroid therapy.