Citations

Abstract Abstract 440 Background: Complement plays a central role in innate immunity, and also functions as a regulator of the overall immune response, including T-cell responses. We recently reported that germline genetic variation in C2, C5, C7 and C9 was associated with risk of developing non-Hodgkin lymphoma (Br J Haematol 2009;145:614). Here we evaluate whether complement genes are associated with event-free survival (EFS) in follicular lymphoma. Methods: We genotyped 166 single nucleotide polymorphisms (SNPs) from 32 complement pathway genes in a prospective cohort study of 115 newly diagnosed follicular lymphoma patients enrolled at the Mayo Clinic from 2002-2005 as part of the Lymphoma SPORE. All patients were systematically followed through 2008 for EFS (defined as disease progression, retreatment, or death due to any cause). Tagging and nsSNPs were selected from HapMap for the genes encoding complement proteins and their key regulators (C1QB, C1QG, C1QR1, C1QTNF7, C1RL, C1S, C2, C3, C3AR1, C4BPA, C4BPB, C5, C5R1, C6, C7, C8B, C9, BF, CFH, CFHL5, CFHR1, CGHR4, CLU, CR1 (CD35), CR2 (CD21), DF, MASP2, MBL2, MCP (CD46), DAF (CD55), CD59 and SERPING1). Cox regression was used to estimate Hazard Ratios (HRs) for individual SNPs with EFS. The most prevalent homozygous genotype was used as the reference group, and each polymorphism was modeled individually as having a log-additive effect in the regression model. For gene-level analyses, we used a principal components based gene-level test. All models were adjusted for sex, FLIPI, follicular grade III, and initial treatment. Results. The median age at diagnosis was 61 years (range, 25-85). 57 (50%) of the patients had an event, at a median follow-up of 59 months (range, 33-73) for living patients. In gene-level analyses, CFH (p=0.004), CD55 (p=0.02), CFHR5 (p=0.02) and CFHR1 (p=0.02) were significant at p<0.05, and these genes had noteworthy q-values after consideration of multiple testing (q=0.04 for CFH and q=0.08 for CD55, CFHR5, and CFHR1). For CFH, 2 of the 11 tagSNPs (rs1329423, HR=0.46, p=0.001; and rs3766404, HR=2.0, p=0.003) were significantly associated with EFS, as was the nsSNP rs1065489 (amino acid change E936D: HR=0.39, p=0.004). For CD55, both tagSNPs (rs4844591, HR=0.58, p=0.03; and rs2564978, HR=0.58, p=0.03) were associated with EFS, as were 3 of 5 tagSNPs from CFHR5 (rs3748557, HR=0.52, p=0.03; rs12092294, HR=1.9, p=0.03; and rs6694672, HR=1.9, p=0.03) and the only tagSNP for CFHR1 (rs436719, HR=0.54, p=0.03). Conclusions. Genetic variation in CFH, CD55, CFHR5, and CFHR1 was associated with EFS in follicular lymphoma after adjustment for clinical variables. These genes are part of a gene cluster at 1q32-q32.1 involved in the regulation of C3. CD55 encodes a membrane complement regulatory protein which can allow tumor cells to evade complement attack. These results are being validated in a second set of SPORE patients. Support: P50 CA97274, R01 CA92153. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 140 Background: Peripheral T-cell lymphomas (PTCLs) have poor outcomes, and there is a lack of prognostic biomarkers and therapeutic targets to guide treatment. We recently proposed that the transcription factor, interferon regulatory factor-4 (IRF4, also called multiple myeloma oncogene-1 [MUM1]), might be oncogenic in PTCLs based on its expression in association with translocations between IRF4 and the T-cell receptor gene, TRA@. IRF4 is a therapeutic target in multiple myeloma, where high expression is a poor prognostic factor. In addition, at least two germline IRF4 single nucleotide polymorphisms (SNPs), rs12203592 and rs872071, are associated with IRF4 expression and disease risk and progression in various lymphoid neoplasms. However, the prognostic effects of IRF4/MUM1 expression and IRF4 SNPs in PTCLs are unknown. Methods: Forty seven newly diagnosed PTCL patients with available tissue were identified from the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource. There were 5 anaplastic large cell lymphomas, 14 cutaneous T-cell lymphomas (CTCLs), 6 cytotoxic T-cell lymphomas (cytTCLs: 4 extranodal NK/T-cell and 2 enteropathy type), and 22 PTCLs, not otherwise specified (NOS). Patients were diagnosed between September 2002 and February 2008 and systematically followed through March 2010 for overall survival (OS). Tumor cell IRF4/MUM1 expression was examined by immunohistochemistry on paraffin tissue sections (MUM1p clone; Dako). Positivity was defined as >30% of tumor cells with nuclear staining, as in previous studies. rs12203592 and rs872071 were genotyped in peripheral blood DNA. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for both IRF4/MUM1 expression and SNPs with OS. Chi-squared tests were used to assess the relationship between IRF4/MUM1 expression and IRF4 SNPs. Results: The median age at diagnosis was 60 years (range, 24–88). At a median follow-up of 62 months (range, 29–89), 22 (47%) of the patients had died. Fifteen (32%) of the 47 T-cell patients had IRF4/MUM1 positive tumors. IRF4/MUM1 positivity was associated with poorer overall survival (HR=4.3; 95% CI: 1.8–10.2; p=0.0008). This association was seen across PTCL subtypes, including PTCL, NOS (HR= 6.5; 95% CI: 1.5–27.7; p=0.01), CTCL (HR=13.4; 95% CI: 1.2–150.1; p=0.03), and cytTCL (HR=5.8; CI: 0.5–65.9; p=0.15). The minor allele (T) in SNP rs12203592 was positively associated with IRF4/MUM1 positivity in a dominant model, with IRF4/MUM1 expression in 60% of patients with CT or TT genotypes compared to 19% of patients with CC genotype (p=0.01). Patients with the CT/TT genotype at rs12203592 also had inferior overall survival (HR=3.7; 95% CI: 1.4–9.5; p=0.007). The rs872071 SNP showed no significant association with either IRF4/MUM1 expression (p=0.38) or overall survival (p=0.71). Conclusions: This study is the first to demonstrate that IRF4/MUM1 expression is poor prognostic factor in PTCLs. This association was observed across PTCL subtypes, including the most common subtype, PTCL, NOS. IRF4/MUM1 expression and poor survival in our patients also were associated with the minor allele (T) in the IRF4 SNP rs12203592; these findings are consistent with previous in vitro data showing the major allele (C) represses IRF4 promoter activity. Interestingly, rs872071 was not associated with IRF4/MUM1 expression or prognosis, similar to findings in multiple myeloma. In contrast, rs872071 is a risk and prognostic factor in chronic lymphocytic leukemia and classical Hodgkin lymphoma, diseases in which IRF4/MUM1 expression has been associated with favorable prognosis. IRF4/MUM1 expression is a poor prognostic factor in PTCLs. Disclosures: No relevant conflicts of interest to declare.

BACKGROUND: Controversy in performing hemorrhoidectomy and anal skin tag excision in patients with IBD stems from dated reports of nonhealing wounds resulting in proctectomy. OBJECTIVE: This study aimed to determine the safety of interventional management of hemorrhoids or anal skin tags in patients with Crohn’s disease or ulcerative colitis. DESIGN: This study is a retrospective review of patient records from 2000 to 2017. SETTING: The patient records were retrieved from a multistate health system. PATIENTS: Adult patients with IBD undergoing interventional management of hemorrhoids or skin tags were included. MAIN OUTCOME MEASURE: The primary outcome measured was the long-term requirement of proctectomy. RESULTS: Ninety-seven patients (n = 49 Crohn’s disease, 48 ulcerative colitis) underwent interventional management of hemorrhoids or anal skin tags (n =35 rubber band ligation, 27 anal skin tag excision, 21 hemorrhoidectomy, 14 excision/incision of thrombosed hemorrhoid). Thirty-day complications were observed in 5 patients (n = 4 urinary retention, 1 perianal abscess). Five patients with Crohn’s disease eventually required proctectomy at a median of 7 years after skin tag excision (range, 6 months to 10 years), but none were secondary to impaired wound healing. Two patients with ulcerative colitis who had previously undergone IPAA were subsequently diagnosed with Crohn’s disease of the pouch after skin tag excision. No other long-term complications were seen in patients with ulcerative colitis. LIMITATIONS: The study’s retrospective design does not allow identification of patients with IBD who underwent only medical management of their hemorrhoids. There is also selection bias in which patients were selected for interventional management of their disease. CONCLUSIONS: The requirement for proctectomy after hemorrhoidectomy/skin tag excision appears to be secondary to the natural disease course of perianal Crohn’s disease rather than perianal intervention. Selective hemorrhoidectomy and skin tag excision in patients with well-controlled luminal disease should be considered. See Video Abstract at http://links.lww.com/DCR/B55. HEMORROIDECTOMÍA ASOCIADA A LA EXCISIÓN DE PLICOMAS EN CASOS DE ENFERMEDAD INFLAMATORIA INTESTINAL: ¿ANUNCIO DE FATALIDAD O SIMPLEMENTE EVOLUCIÓN NATURAL DE LA ENFERMEDAD? ANTECEDENTES: Está controvertida la realización de una hemorroidectomía asociada a la excisión de plicomas ano-cutáneos en pacientes con enfermedad inflamatoria intestinal, así lo han demostrado informes detallados sobre la no cicatrisación de las heridas conllevando a una proctectomía. OBJETIVO: Determinar los margenes de seguridad en casos de tratamiento instrumental de hemorroides asociadas a la excisión de plicomas ano-cutáneos en pacientes portadores de colitis ulcerosa o enfermedad de Crohn. DISEÑO: Revisión retrospectiva de historias clinicas de pacientes entre 2000 y 2017. ENTORNO: Servicio Multiestatal de Salud. PACIENTES: Adultos con enfermedad inflamatoria intestinal sometidos a tratamiento instrumental de hemorroides asociado a la excisión de plicomas ano-cutáneos. RESULTADO PRINCIPALES: Requisitos a largo plazo para una proctectomía. RESULTADOS: Noventa y siete pacientes (49 con enfermedad de Crohn, 48 con colitis ulcerosa) se sometieron a un tratamiento instrumental de hemorroides asociada a la excisión de plicomas ano-cutáneos (35 ligadura con bandas elásticas, 27 excisión de plicomas ano-cutáneos, 21 hemorroidectomías, 14 excisiones / incisiones de hemorroides trombosadas) Se observaron complicaciones a los 30 días en cinco pacientes (4 con retención urinaria, 1 absceso perianal). Cinco pacientes con enfermedad de Crohn requirieron proctectomía en una media de 7 años después de la excisión de los plicomas ano-cutáneos (rango, 6 meses a 10 años), pero ninguno fue secundario a la mala cicatrización de la herida. Dos pacientes con colitis ulcerosa que previamente se habían sometido a una anastomosis colo-anal protegia por ilestomía fueron diagnosticados posteriormente con enfermedad de Crohn localizada en la ostomía después de la excisión de plicomas ano-cutáneos. No se observaron complicaciones a largo plazo en pacientes con colitis ulcerosa. LIMITACIONES: El diseño retrospectivo del estudio no permite la identificación de pacientes con enfermedad inflamatoria intestinal que se sometieron únicamente al tratamiento médico de las hemorroides. También existe un sesgo de selección de pacientes escogidos para tratamiento instrumental de la enfermedad hemorroidaria. CONCLUSIONES: El requisito de proctectomía después de la hemorroidectomía / excisión de plicomas anocutáneos parece ser secundario al curso de la enfermedad natural de la enfermedad de Crohn perianal en el sitio de la intervención perianal. Se debe considerar la hemorroidectomía selectiva y la excisión de plicomas ano-cutáneos solo en pacientes con enfermedad endoluminal controlada. Vea el video del resumen en http://links.lww.com/DCR/B55.

Abstract BACKGROUND Postoperative readmissions are a significant driver of variation in bundled care costs associated with cervical spine surgery. OBJECTIVE To determine the factors predicting the cost of readmission episodes following elective anterior cervical discectomy and fusion (ACDF). METHODS We queried the Healthcare Cost and Utilization Project Nationwide Readmissions Database for patients undergoing elective ACDF during 2012 to 2015. Multivariable linear regression was performed to establish the factors associated with the cost of each 30-/90-d readmission episode. RESULTS A total of 139 877 and 113 418 patients met inclusion criteria for the evaluation of 30- and 90-d readmissions, respectively. Among these, the national rates of 30- and 90-d readmission after an elective ACDF were 3% and 6%, respectively. The median cost of a 30- and 90-d readmission episode was $6727 (IQR: $3844-$13 529) and $8507 (IQR: $4567-$17 460), respectively. Relative predictor importance analysis revealed that the number of procedures at index admission (IA), length of stay at IA, and time elapsed between index surgical admission and readmission were the top predictors of both 30- and 90-d readmission costs (all P < .001). Although cervical myelopathy accounted for only 3.6% of all 30-d readmissions, it accounted for the largest share (8%) of 30-d readmission costs. CONCLUSION In this analysis from a national all-payer database, we determined the factors associated with the cost of readmissions following elective ACDF. These results are important in assisting policymakers and payers with a better risk adjustment in bundled care payment systems and for surgeons in implementing readmission cost-reduction efforts.

AbstractBackgroundHuman pegivirus (HPgV) is a single-strand RNA virus belonging to the Flaviviridae. Although no definitive association between HPgV infection and disease has been identified, previous studies have suggested an association of HPgV viremia with risk of lymphomas.MethodsWe conducted a systematic review and meta-analysis, including 1 cohort study and 14 case-control studies, assessing the association of HPgV viremia with adult lymphomas. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, overall and by geographic region and lymphoma subtype.ResultsThe overall OR for lymphoma was 2.85 (95% CI, 1.98–4.11), with statistically significantly elevated ORs observed in 8 of 15 studies. There was a small amount of heterogeneity among studies (I2 = 28.9%; Q = 18.27, P = .16), and the funnel plot provided no evidence for publication bias. The strongest association with lymphoma risk was observed for studies from Southern Europe (OR, 5.68 [95% CI, 1.98–16.3]), whereas weaker ORs (with 95% CIs) were observed for studies from North America (2.24 [1.76–2.85]), Northern Europe (2.90 [.45–18.7), and the Middle East (2.51 [.87–7.27]), but all of similar magnitude. Participants with HPgV viremia had statistically significantly increased risks (OR [95% CI]) for developing diffuse large B-cell (3.29 [1.63–6.62]), follicular (3.01 [1.95–4.63]), marginal zone (1.90 [1.13–3.18]), and T-cell (2.11 [1.17–3.89]) lymphomas, while the risk for Hodgkin lymphoma (3.53 [.48–25.9]) and chronic lymphocytic leukemia (1.45 [.45–4.66]) were increased but did not achieve statistical significance.ConclusionsThis meta-analysis supports a positive association of HPgV viremia with lymphoma risk, overall and for the major lymphoma subtypes.

SummaryIbrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Abstract Background: Operative maneuvers to increase mesenteric length during ileal pouch-anal anastomosis (IPAA) are frequently utilized in adults, but limited data exist on the need for their use in children. Materials and Methods: A retrospective chart review of children (age <18) considered for IPAA creation at two affiliated tertiary referral centers from 2007 to 2017 was conducted, and patient factors, operative details, and 30-day postoperative complications were abstracted. Body mass index (BMI) was normalized to BMI percentile-for-age-and-sex and classified as underweight (BMI <5th percentile), healthy weight (5th ≤ BMI percentile <85th), or overweight/obese (BMI ≥85th percentile). Maneuvers were identified from operative notes. Univariate analysis and multivariable logistic regression were performed to determine independent factors associated with the use of maneuvers. Results: A total of 94 patients underwent attempt at IPAA creation, which was successful in 91 (97%). Fourteen (15%) of 91 patients were classified as overweight or obese. The 3 failures occurred secondary to inability to reach in 3 patients, with specific mention of patients' obesity in 2 and pouch ischemia in 1. Sixty (66%) patients required maneuvers to lengthen the mesentery. Overweight/obese patients required maneuvers more often than nonoverweight/obese patients (93% versus 61%, P = .03). There were no differences in 30-day maximum Clavien-Dindo scores between patients with and without maneuvers performed ( P = .83). Being overweight/obese was an independent risk factor for requiring maneuvers (odds ratio: 9.3, 95% confidence interval: 1.1–82.8) after adjusting for age, sex, height, operative stage, and surgeon. Conclusion: Surgeons should be prepared to perform mesenteric lengthening maneuvers when operating on pediatric patients to ensure minimal tension on the IPAA, and more so when operating on obese children. Whether these maneuvers have an impact on long-term pouch function is undetermined.

Abstract In this month's CME article, an analysis of over 1300 patients with diffuse large B-cell lymphoma (DLBCL), Wang et al demonstrate that the approximately 13% of patients with concurrent indolent lymphoma at diagnosis had the same prognosis as those patients with isolated DLBCL.