Citations

Abstract Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.

Object The aim of this study was to determine whether ictal single-photon emission computed tomography (SPECT) is useful in localizing the site of seizure onset in patients in whom surgery for intractable epilepsy failed and who are being considered for repeated surgery. Methods Subtraction ictal SPECT coregistered to magnetic resonance imaging (SISCOM) studies were retrospectively analyzed in 58 patients who were being evaluated for possible repeated resection for intractable partial epilepsy between January 1, 1996, and October 31, 1999. All patients had persistent seizures subsequent to an initial resection and underwent another excision. The SISCOM-demonstrated abnormalities were classified as concordant, discordant, or indeterminate, compared with the localization of the epileptogenic zone revealed on video electroencephalography monitoring. The ability of SISCOM to predict operative outcome was also determined in patients who had undergone repeated surgical procedures. The SISCOM studies revealed a localized hyperperfused alteration in 46 (79%) of 58 patients. Forty-one (89%) of these 46 patients had a SISCOM-demonstrated alteration in the hemisphere of the previous epilepsy surgery. Imaging changes in 33 (72%) of the 46 patients were at the site of the previous focal cortical resection. Eight (17%) of the 46 had SISCOM-demonstrated abnormalities remote from the lobe in which surgery had been performed but in the ipsilateral hemisphere. The hyperperfusion focus was in the contralateral hemisphere in the remaining five patients (11%). The site of the epileptogenic zone was concordant with the SISCOM focus in 32 (70%) of 46 patients. Twenty-six patients underwent repeated resection and were followed up for a mean of 44 months thereafter; 11 of these patients (42%) had a significant reduction in seizure tendency. Only five patients (19%) were seizure free. Ten (50%) of 20 patients with a concordant SISCOM focus compared with none (0%) of three patients with a discordant focus had a favorable surgical outcome (p = 0.23). Conclusions The SISCOM method might be useful in the evaluation of, and the surgical planning for, patients with intractable partial epilepsy in whom previous resective treatment has failed and who are being considered for reoperation.

Object The authors reviewed the long-term outcome of focal resection in a large group of patients who had intractable partial nonlesional epilepsy, including mesial temporal lobe sclerosis (MTS), and who were treated consecutively at a single institution. The goal of this study was to evaluate the long-term efficacy of epilepsy surgery and the preoperative factors associated with seizure outcome. Methods This retrospective analysis included 399 consecutive patients who underwent epilepsy surgery at Mayo Clinic in Rochester, Minnesota, between 1988 and 1996. The mean age of the patients at surgery was 32 ± 12 years (range 3–69 years), and the mean age at seizure onset was 12 ± 11 years (range 0–55 years). There were 214 female (54%) and 185 male (46%) patients. The mean duration of epilepsy was 20 ±12 years (range 1–56 years). The preceding values are given as the mean ± standard deviation. Of the 399 patients, 237 (59%) had a history of complex partial seizures, 119 (30%) had generalized seizures, 26 (6%) had simple partial seizures, and 17 (4%) had experienced a combination of these. Preoperative evaluation included a routine and video-electroencephalography recordings, magnetic resonance imaging of the head according to the seizure protocol, neuropsychological testing, and a sodium amobarbital study. Patients with an undefined epileptogenic focus and discordant preoperative studies underwent an intracranial study. The mean duration of follow up was 6.2 ± 4.5 years (range 0.6–15.7 years). Seizure outcome was categorized based on the modified Engel classification. Time-to-event analysis was performed using Kaplan–Meier curves and Cox regression models to evaluate the risk factors associated with outcomes. Among these patients, 372 (93%) underwent temporal and 27 (7%) had extratemporal resection of their epileptogenic focus. Histopathological examination of the resected specimens revealed MTS in 113 patients (28%), gliosis in 237 (59%), and normal findings in 49 (12%). Based on the Kaplan–Meier analysis, the probability of an Engel Class I outcome (seizure free, auras, or seizures related only to medication withdrawal) for the overall patient group was 81% (95% confidence interval [CI] 77–85%) at 6 months, 78% (CI 74–82%) at 1 year, 76% (CI 72–80%) at 2 years, 74% (CI 69–78%) at 5 years, and 72% (CI 67–77%) at 10 years postoperatively. The rate of Class I outcomes remained 72% for 73 patients with more than 10 years of follow up. If a patient was in Class I at 1 year postoperatively, the probability of seizure remission at 10 years postoperatively was 92% (95% CI 89–96%); almost all seizures occurred during the 1st year after surgery. Factors predictive of poor outcome from surgery were normal pathological findings in resected tissue (p = 0.038), male sex (p = 0.035), previous surgery (p < 0.001), and an extratemporal origin of seizures (p < 0.001). Conclusions The response to epilepsy surgery during the 1st follow-up year is a reliable indicator of the long-term Engel Class I postoperative outcome. This finding may have important implications for patient counseling and postoperative discontinuation of anticonvulsant medications.

AbstractBackgroundPatients with papillary thyroid carcinoma (PTC) may suffer recurrence despite thyroidectomy and complete radioiodine (RAI) ablation. Reoperation is vitally dependent on accurate and complete disease localization, typically utilizing cervical ultrasonography (US) and/or computed tomography. Our aim was to determine the comparative value of F18‐fluorodeoxyglucose positron emission tomography (PET) to US for localization of locoregional recurrence in patients who underwent reoperation for recurrent PTC.MethodsFrom 1999 to 2004, 30 patients who underwent re‐exploration and 100 nonoperated patients who were investigated with PET for possible recurrent PTC were reviewed. The surgical group [9 males, 21 females; mean age = 50 years (range = 18–84 years)] all had received RAI ablation. Preoperative thyroid‐stimulating hormone (TSH), thyroglobulin (Tg), and location of metastasis were recorded for each imaging study and surgical exploration. All separate sites that contained disease pathologically must have been identified by imaging for a patient to be considered true positive (TP).ResultsPET scans were TP in 43%, false positive in 7%, false negative (FN) in 50%, and had a sensitivity of 46%. Comparable US results were 86%, 10%, 3%, and 96%. Of the 15 patients with FN PET scans, 13 had lymph node metastasis less than 2 cm in diameter, 11 had Tg ≤ 10 μg/L, and the TSH < 20 in 13. In only 3 of the 30 (10%) patients was PET deemed to add value.ConclusionsAt least with suppressed TSH, PET scanning in reoperative PTC patients appears to offer modest benefit beyond high‐resolution US.

Abstract Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true “CNS signature” because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

Heart failure with normal ejection fraction occurs in elderly patients with hypertensive heart disease. We hypothesized that, in such patients, mineralocorticoid receptor activation accelerates the types of ventricular and vascular remodeling and dysfunction believed important in the transition to heart failure. We tested this hypothesis by administering deoxycorticosterone acetate (DOCA) without salt loading or nephrectomy to elderly dogs with experimental hypertension. Elderly dogs were made hypertensive by renal wrapping. After 5 weeks, dogs were randomly assigned to DOCA (1 mg/kg per day IM; old hypertensive [OH]+DOCA; n=11) or not (OH; n=11) for 3 weeks. At week 8, conscious echocardiography and hemodynamic assessment under anesthesia were performed. DOCA resulted in further increases in conscious blood pressure ( P <0.05) without increases in cardiac output or diastolic volume. In the conscious state, effective arterial elastance ( P <0.05) and systemic vascular resistance ( P =0.06) were increased, and systemic arterial compliance ( P <0.05) was decreased in OH+DOCA animals. After anesthesia, instrumentation, and autonomic blockade, blood pressure was lower, whereas left ventricular (LV) systolic elastance, LV diastolic stiffness, and ex vivo myofiber diastolic stiffness were increased in OH+DOCA animals. LV collagen was increased in OH+DOCA animals ( P <0.05 for all), but LV mass, LV brain natriuretic peptide, and titin isoform profiles were not. Neither aortic stiffness nor aortic structure was altered in OH+DOCA animals. These findings suggest that age and hypertensive heart disease enhance sensitivity to exogenous mineralocorticoid administration and that mineralocorticoid receptor activation could contribute to the transition to heart failure in elderly persons by promoting increases in LV diastolic and systolic stiffness.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regulates the local level of glucocorticoids, has been suggested to be involved in the development of obesity. A definitive functional role for 11β-HSD1 in adipogenesis, however, remains to be established. We developed 3T3-L1 cell lines stably transfected with a small hairpin RNA (shRNA) targeting 11β-HSD1. A shRNA containing two nucleotide substitutions was used as a control. Silencing of 11β-HSD1 substantially attenuated the accumulation of lipid droplets and the expression of adipogenesis marker genes, which was induced by a mixture containing either corticosterone or dexamethasone. Silencing of 11β-HSD1 increased the concentration of 11-dehydrocorticosterone in the culture supernatant but did not significantly affect the levels of corticosterone or dexamethasone. Translocation of glucocorticoid receptors to the nucleus in response to glucocorticoids was significantly attenuated by silencing 11β-HSD1. The number of cells entering the S phase of the cell cycle following the induction of adipogenesis was significantly reduced by silencing 11β-HSD1. 11β-HSD1 shRNA delivered by lentiviral vectors after the induction of differentiation, however, did not affect the progression of adipogenesis. These results indicate that 11β-HSD1 plays a significant functional role in the initiation of 3T3-L1 adipogenesis and provide new mechanistic insights into the role of 11β-HSD1 in the development of obesity and related diseases.