Kleinstern, Geffen

AbstractIntroductionPrevious reports have shown that suboptimal antenatal corticosteroids administration occurs in most cases. However, as multifetal gestations were either excluded or constituted a small proportion of the participants in these studies, little is known about the patterns of use of antenatal corticosteroids in twin pregnancies.Material and methodsWe reviewed the records of women who received antenatal corticosteroids and delivered between 240/7 and 346/7 weeks of gestation during 2015‐2017 at 2 university hospitals. Optimal antenatal corticosteroids timing was defined as delivery ≥24 hours ≤7 days from the previous antenatal corticosteroids course.ResultsOf 424 pregnancies, 307 (72.4%) were singleton and 117 were (27.6%) twin. For twin compared with singleton pregnancies, gestational age at initial antenatal corticosteroids administration was lower (P = 0.02), the proportion of deliveries within the optimal window of the initial antenatal corticosteroids course was lower (19.7% vs 33.2%, P = 0.001), and the proportion of women eligible for a rescue antenatal corticosteroids course was higher (58.1% vs 32.9%, P < 0.0001). However, despite similar rates of rescue antenatal corticosteroids administration (P = 0.64), the overall rate of delivery within any optimal window (either initial or rescue course) was lower in twin than singleton pregnancies (26.5% vs 42.3%, P = 0.004), and the antenatal corticosteroids‐to‐delivery interval was longer (median 6.9 vs 4.2 days, P = 0.0009). In multivariate analysis, optimal antenatal corticosteroids administration was negatively associated with twin pregnancy (P = 0.04) and preterm labor (P = 0.05), and positively associated with the presence of gestational hypertensive disorders (P = 0.03).ConclusionsTwin pregnancy is an independent risk factor for suboptimal antenatal corticosteroids administration. Directed efforts should be made to improve the utilization of antenatal corticosteroids in this vulnerable group of women.

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

AbstractAlthough autoimmune diseases (AIDs) are known to predispose to non‐Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B‐cell NHL onset by comparing AID history (determined by self‐report and medication review and supplemented by chart review where possible) among 435 adult B‐NHL patients in Hadassah‐Hebrew University Medical Center, diagnosed 2009‐2014, and 414 age‐and‐sex frequency‐matched controls. We examined AIDs as a whole, B‐ and T‐cell–mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan‐Meier and Cox regression models to assess the association of AID with overall survival and relapse‐free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup.Autoimmune diseases were associated with B‐NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31‐2.92), especially AIDs mediated by B‐cell activation (OR = 5.20; CI, 1.90‐14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59‐80.9). We found that time to relapse for all B‐NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HRadj] = 1.69 (CI, 1.03‐2.79). Specifically, in patients with diffuse large B‐cell lymphoma, of whom 91.8% had received rituximab, a history of B‐cell–mediated AIDs was associated with shorter relapse‐free survival and overall survival, HRadj = 8.34 (CI, 3.01‐23.1) and HRadj = 3.83 (CI, 1.20‐12.3), respectively.Beyond confirming the well‐known association between AIDs and B‐NHL, we found that AID is an adverse prognostic factor in B‐cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID‐associated B‐NHL. In the era of immunotherapy, these findings have particular relevance.

AbstractObjectiveWe aimed to determine hemostatic changes and characterize the procoagulant potential among patients with reactive thrombocytosis (RT).MethodsSixty patients with RT (median platelet count 718 × 109/L) and 20 healthy persons were tested for complete blood count, C‐reactive protein, von Willebrand factor (VWF), factor VIII and fibrinogen, and thrombin generation. Platelet studies, including light transmission aggregometry and Cone and Plate(let) Analyzer, were also conducted. Reticulated platelets and platelet P‐selectin expression were measured using flow cytometry.ResultsCompared to patients with mild thrombocytosis (platelet count 500‐700 × 109/L; n = 27), those with moderate‐to‐severe thrombocytosis (platelet count >700 × 109/L; n = 33) had significantly higher fibrinogen, factor VIII, and VWF antigen and activity levels; higher endogenous thrombin potential, peak thrombin generation and velocity index levels, and shorter time‐to‐peak thrombin level. VWF antigen and activity, fibrinogen, and factor VIII were positively associated with platelet count, whereas VWF activity/antigen ratio was inversely correlated. In a multivariate analysis of RT and control participants, only platelet count predicted endogenous thrombin potential with a positive‐linear correlation. No patients developed acquired von Willebrand syndrome.ConclusionsAs determined by thrombin generation, RT was associated with in vitro prothrombotic tendency, which correlated with platelet count. This may explain the increased thromboembolic risk previously reported in patients with RT.

AbstractBackgroundThromboembolic events following splenectomy are not uncommon. However, the role of thromboprophylaxis and risk factors for thrombosis, as well as the clinical course and outcomes, are not well characterized.MethodsA retrospective review of individuals who underwent splenectomy between January 2006 and December 2015 in two university hospitals.ResultsOverall, 297 patients underwent splenectomy [open splenectomy (n = 199), laparoscopic splenectomy (n = 98)]. Mechanical (thigh‐length pneumatic compression stockings) and pharmacologic thromboprophylaxis (40 mg enoxaparin daily, starting 12 h after surgery until discharge) was provided for all patients. One hundred and sixteen patients (39%) also received an extended thromboprophylaxis course of enoxaparin for 2–4 weeks after discharge. Twenty‐three patients (7.7%) experienced thrombotic complications following splenectomy, including 16 cases (5.4%) of portal‐splenic mesenteric venous thrombosis (PSMVT), 5 (1.7%) pulmonary embolism and 2 (0.7%) deep vein thrombosis. Longer operative time (mean operative time of 405 vs. 273 min, P = 0.03) was independently associated with PSMVT. Post‐splenectomy thrombocytosis was not associated with thrombosis (P = 0.41). The overall thrombosis rate was significantly lower in patients who received an extended thromboprophylaxis course following splenectomy (3.4 vs. 10.5%, P = 0.02). Complete resolution of thrombosis was observed in most cases (n = 20, 87.0%), with no recurrent thrombosis during a mean follow‐up of 38 ± 25 months.ConclusionsThromboembolic complications, mainly PSMVT, are common following splenectomy. Longer operative time was associated with thrombosis. Significantly lower rates of thrombosis were found in patients who received an extended thromboprophylaxis course.

Abstract Background Thirty-four single nucleotide polymorphisms (SNPs) are associated with CLL risk to-date. Moreover, family history (FH) of hematological malignancy has been consistently found to be associated with CLL, with an 8.5-fold increased risk of CLL among first-degree relatives. However, there has not been an evaluation of the interactive effects among genetic factors and FH with CLL risk. Methods We pooled data from 8 CLL case-control studies within the InterLymph Consortium (1499 CLL cases and 2601 controls). We computed a polygenic risk score (PRS), a weighted average of the number of risk alleles across the 34 SNPs, with the weights being the log of the previously reported odds ratio (OR) for each SNP. We categorized the PRS by quintiles using the cutoff points based on the distribution of all InterLymph controls (N=8228). Self-reported FH data was available for 60% of cases and 73% of controls. FH was defined as any hematological malignancy in one or more first-degree relative. Logistic regression was used to estimate ORs and 95% confidence intervals (CIs) adjusted for age, sex, socioeconomic status and study. Results The median age at diagnosis of CLL was 63 years and median age of consent was 60 years in the controls. 67% were male in CLL cases and 57% in controls. As expected, FH was associated with CLL risk (OR= 2.14, CI= 1.60-2.86). The median PRS in the cases was 0.40 and in the controls was -0.36 with the frequency of CLL cases in the upper PRS quintile as 48% while in the lowest quintile only 6%. The PRS was strongly associated with CLL risk (OR= 2.90, CI= 2.35-3.56 for upper versus middle quintile). When jointly modeling FH with PRS, a significant interaction was observed (P=0.03). When stratifying by FH, the upper quintile of the PRS had an 11.8-fold (CI= 3.97-34.8) increased risk relative to those in the middle quintile in the FH+ strata, while a 3.11-fold (CI= 2.35-4.10) increased risk was observed in the FH- strata. Conclusions Our data suggest that the PRS has a strong association with CLL risk and this association varies with FH status. Among those with FH-, the risk of CLL was 3-fold for those with many inherited variants while the CLL risk was much higher than that in those with a FH+. Studies are needed to see whether this PRS stratifies risk among those with monoclonal B-cell lymphocytosis, the CLL precursor condition that affects 5-7% of the general population. Citation Format: Geffen Kleinstern, Silvia de Sanjosé, Nicola Camp, Claire M. Vajdic, Timothy G. Call, Mark Liebow, Dennis Robinson, Neil E. Kay, Julie Cunningham, Yolanda Benavente, Alain Monnereau, John Spinelli, James R. Cerhan, Susan L. Slager. Association of polygenic risk scores and family history with the risk of chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4267. doi:10.1158/1538-7445.AM2017-4267

Abstract Waldenström macroglobulinemia (WM) is a unique subset of lymphoplasmacytic lymphoma (LPL) that is defined by the presence of an LPL infiltrate in the bone marrow together with a monoclonal IgM protein in the serum. A somatic activating mutation, MYD88 L265P, occurs in 85+% of WM and in 25%-50% of patients with the precursor condition, IgM monoclonal gammopathy of undetermined significance (MGUS); however, germline MYD88 mutations have not been observed in WM patients, and the genetic basis for WM predisposition remains undefined. To identify novel WM susceptibility loci we conducted a two-stage genome-wide association study (GWAS) in over 450 WM cases and 4300 controls of European ancestry. Discovery (stage 1) included 217 WM cases (40% familial) and 3798 controls genotyped on the Illumina Omni Express or Illumina Omni2.5 platforms following standard quality control procedures. The genotyped data were imputed using the Haplotype Reference Consortium panel as a reference and analyzed using logistic regression. In stage 1, we identified three loci on chromosomes 6, 14 and 3 significantly associated (P&lt;5.0x10-8) with risk of WM. Eleven promising SNPs in these and other suggestive loci (P&lt;5.0x10-7) were selected for replication (stage 2) in 269 WM or LPL cases (4% familial) and 571 controls, and genotyping was conducted using standard methods on Taqman and Sequenom platforms or Sanger sequencing (1 SNP). Preliminary results confirm replication of the chromosome 6 locus. Stratification on familial status will illuminate the contribution of familial disease. These results will provide insight into the underlying genetic basis of WM susceptibility. Citation Format: Mary L. McMaster, Sonja I. Berndt, Shengchao A. Li, Susan Slager, Joseph Vijai, Charles C. Chung, Bin Zhu, Laurie Burdette, Brenda Birmann, Elizabeth E. Brown, James R. Cerhan, Karin Ekstrom-Smedby, Henrik Hjalgrim, Geffen Kleinstern, Brian K. Link, James McKay, Alain Monnereau, Lindsay M. Morton, Alexandra Nieters, Nathaniel Rothman, Christine F. Skibola, Alex Smith, Lauren R. Teras, Claire M. Vajdic, Roel Vermeulen, Belynda Hicks, Lynn R. Goldin, Neil E. Caporaso. A genome-wide association study of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma demonstrates association with chromosome 6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1318. doi:10.1158/1538-7445.AM2017-1318

Background and ObjectivesWe investigated the risk factors, incidence, and role of thromboprophylaxis in the development of thrombosis following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).MethodsWe reviewed data of patients with CRS/HIPEC in three hospitals.ResultsOverall, 192 patients underwent CRS/HIPEC during 2007‐2016. Mechanical (thigh‐length pneumatic compression stockings) and pharmacologic thromboprophylaxis (40 mg enoxaparin daily, starting 12 h before surgery until discharge) was provided for all patients; and 116 (60.4%) also received an extended course of enoxaparin for 2‐4 weeks after discharge. Twenty‐six patients experienced thrombotic complications (13.5%) including portal‐splenic‐mesenteric venous thrombosis (n = 11, 5.7%), pulmonary embolism (n = 10, 5.2%), and deep vein thrombosis (n = 5, 2.6%); most (n = 21, 80.8%) occurred after hospital discharge. Univariate analysis identified Peritoneal Cancer Index, intraoperative transfusion requirement, operative blood loss, operative time, lengths of hospital, and intensive care unit stay, and lack of administration of anticoagulation at discharge as significantly associated with thrombosis. With multivariate analysis, only the lack of anticoagulation therapy at discharge remained significantly associated with thrombosis (P = 0.0001).ConclusionsThromboembolic complications are common following CRS/HIPEC. As significantly lower rates of thrombosis were found in patients who received an extended course of anticoagulation, we support its use for at least 2 weeks after discharge.

Background: Multiple enchodromatosis of bone, termed Ollier’s disease, or Maffucci syndrome when associated with hemangiomas, is a rare disease that can affect the pediatric hand. This condition often causes a finger mass, deformity, pain and possible pathologic fractures, and has been associated with malignant transformation to chondrosarcoma. The aim of our study is to describe the long-term sequela of multiple enchondromatosis of the hand in the pediatric population, specifically the rates of malignant transformation, tumor recurrence, rates of pathologic fracture, and phalangeal growth arrest. Methods: We examined 15 pediatric patients who were treated in our institute with a total of 127 phalanges and metacarpals lesions. Only patients with follow-up of at least 4 years were included. We retrospectively reviewed patients’ chart and hand radiograph for symptoms including pathologic fractures, indications for surgery, and postoperative complications including tumor recurrence, and malignant transformation. We assessed phalangeal growth arrest with radiographs and normalized phalangeal growth charts. Results: Mean age of diagnosis was 5.8 years and mean follow-up time was 15.4 years. Pathologic fractures were common at 46% of pediatric patients, but ceased to occur once reaching adulthood. Outcomes of pathologic fractures were excellent, regardless of treatment. Malignant transformation occurred in 1 patient and did not occur during childhood. A total of 80% of patients and 29% of lesions underwent surgical treatment of curettage and bone graft for the lesion, yet recurrence was common and affected 33% of treated patients. Phalangeal growth arrest was the most common long-term sequela and affected 11% of phalanxes and metacarpals. This sequela was significantly more prevalent in patients who had surgical excision of the tumor. Conclusions: Our findings reassure that malignant transformation of enchodromatosis of the hand is unlikely in the pediatric population. Pathologic fracture is common, but has excellent outcomes. When considering surgery, parents should be counseled about the possibility of phalangeal growth arrest and recurrence of the lesion. Type of Study/Level of Evidence: Level IV—therapeutic.