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SummaryBackgroundAn association between bariatric surgery and development of de‐novo inflammatory bowel disease (IBD) has been observed.AimTo evaluate further the association among bariatric surgery, weight loss medications, obesity and new‐onset IBD.MethodsUsing Explorys, a population‐based Health Insurance Portability and Accountability Act compliant database, we estimated the prevalence of de‐novo IBD among patients treated with bariatric surgery (Roux‐en‐Y gastrojejunostomy, laparoscopic sleeve gastrectomy or gastric banding) (n = 60 870) or weight loss medications (orlistat, phentermine/topiramate, lorcaserin, bupropion/naltrexone and liraglutide) (n = 193 790) compared with obese controls (n = 5 021 210), between 1999 and 2018.ResultsThe prevalence of de‐novo IBD was lower among obese patients exposed to bariatric surgery (7.72 per 1000 patients) or weight loss medications (7.22 per 1000 patients) compared with patients with persistent obesity not exposed to these interventions (11.66 per 1000 patients, P < 0.0001). The risk reduction for de‐novo IBD was consistent across bariatric surgeries and weight loss medications with the exception of orlistat which was not associated with a reduction in risk for de‐novo IBD compared with the persistent obese control cohort.ConclusionObese patients undergoing treatment with bariatric surgery or weight loss medications are at a lower risk for developing de‐novo IBD compared with persistently obese controls not exposed to these interventions. These data suggest that obesity and ineffective management of obesity are risk factors for de‐novo IBD. Further research is needed to confirm these observations and understand potential mechanisms.

Abstract Background Heparin-induced thrombocytopenia (HIT) is an immune-mediated drug reaction in which heparin-dependant IgG antibodies (HIT-IgG) to heparin-platelet factor 4 complexes form with the potential for platelet activation with resultant thrombocytopenia (HIT) and thrombosis (HITT). The frequency of HIT-IgG formation and clinically apparent HIT or HITT varies considerably, according to the patient population (surgical versus medical) and type of heparin (unfractionated [UFH] vs low molecular weight [LMWH]). One large prospective study showed a frequency of HIT-IgG formation of 7.5% with clinical HITT in 34.5% of these orthopedic patients receiving prophylactic LMWH and corresponding figures in cardiac surgery patients receiving UFH were 50% and 2%, respectively [Warkentin et al. Blood2000;96: 1703]. Due to daily exposure to heparin flushes (UFH) and prophylactic LMWH (to prevent venoocclusive disease) hematopoietic stem cell transplant (HSCT) recipients may be at risk for HIT/HITT. However, due to anticipated post-transplant thrombocytopenia, clinical cases of HIT/HITT may be overlooked. We retrospectively determined the incidence of HIT-IgG formation and its clinical significance in this population. Methods: HIT-IgG was measured retrospectively using a commercially available ELISA kit in samples collected from patients prior to conditioning therapy and on day 14 post-HSCT. Medical records were reviewed to in order to determine the clinical significance (development of clinical HIT/HITT) in those with detectable HIT-IgG. Patients Samples from a total of 103 HSCT recipients with hematologic malignancy (including 25 myeloma, 17 lymphoma, 16 AML, 14 amyloid, 10 MDS, 10 ALL, 8 CML and 3 CLL) were tested, of which 52 and 49 underwent allogeneic and autologous HSCT, respectively. All patients were exposed to UFH flushes during line care. In addition, all allogeneic recipients received prophylactic subcutaneous dalteparin 5000U daily beginning with conditioning until engraftment. Conditioning regimens included high dose melphalan (n=34), cyclophosphamide/TBI (n=30), carmustine, etoposide, cytarabine, melphalan (n=15), busulfan/cyclophosphamide (n=9), fludarabine/melphalan (n=10) and fludarabine/TBI (n=4). The median age was 51.5 years (20–72) and 68 were male. Results: The median platelet count prior to initiation of conditioning therapy and at day 14 was 157 × 109/L (range: 10–672) and 40 × 109/L (range: 9–289), respectively. Prior to conditioning, two of 103 (1.9%) patients had a positive HIT-IgG assay, that became negative in one and equivocal in the other by day 14 post-HSCT, and one patient had an equivocal HIT assay that became negative by day 14. All 3 were autologous recipients. None of the previously negative patients had a positive HIT-IgG assay at day 14, although 3 patients (2 autologous and one allogeneic) had an equivocal result of uncertain significance. No patients developed clinical or symptomatic thrombosis (HITT). Conclusion: In spite of frequent exposure to heparin, the frequency of seroconversion is low, and in those patients with preexisting HIT-IgG, no patient developed symptomatic thrombosis, including the 2 patients with positive HIT IgG assays prior to conditioning. The low frequency of HIT-IgG formation may reflect the profound immunosuppression of the conditioning regimens employed. Nevertheless, in this population, a high index of clinical suspicion must be maintained.

Abstract E1496 is a phase III trial designed to evaluate the ability of 2 years (yr) of maintenance rituximab (MR) to prolong progression-free survival (PFS) after CVP (cyclophosphamide 1 G/m2 day [d] 1, vincristine 1.4 mg/m2 [max = 2 mg] d 1, prednisone 100 mg/m2 d 1–5) chemotherapy in stage III–IV follicular grade 1 and 2 and small lymphocytic lymphoma. After CVP treatment to maximum response, (6–8 cycles), stable and responding patients (pt) were randomized to MR (375 mg/m2 weekly x 4) every 6 months x 4 or observation (OBS). Stratification factors included histology, response and residual disease after CVP. With 3-yr median follow-up, survivals (from time of randomization, one-sided logrank p values) for all pt (n=304) favored MR for PFS (p = 3 x 10–8; hazard rate {HR} = 0.38 [0.28;0.54, 95% confidence intervals]) and OS (p = 0.09; HR = 0.66 [0.36–1.22]). Because the large majority of pt have FL and because rituximab efficacy is notably greater in FL, we focused in this report on the 237 FL pt. Median age was 58 yr, 65% were stage IV, 64% had marrow disease, 64% had high tumor burden and 37% had high-risk disease by the follicular lymphoma prognostic index. PFS after randomization was significantly longer for MR vs OBS (p = 3 x 10-7; HR = 0.39 [0.27;0.57]). The estimated PFS at 4 yr (~4.5 yr after start of treatment) was 56% for MR vs 33% for OBS. Differences in PFS were significant within the predefined strata and the differences were most significant in favor of MR for pt with high initial tumor burden and minimal residual disease after CVP. Overall survival was superior for MR (p = 0.03; HR = 0.51 [0.25;1.04]. Estimated OS at 4 yr (~4.5 years after start of treatment) was 88% for MR vs 72% for OBS. Of 33 deaths, 21 occurred on the OBS arm. These data demonstrate that maintenance rituximab not only significantly delays disease progression in FL compared with OBS but that a substantial proportion of patients treated with MR remain disease-free at 4 years after the completion of CVP. These are the first data to strongly suggest a survival benefit with a therapy that includes rituximab and CVP and the first to strongly suggest a survival benefit with maintenance rituximab in FL.

Abstract Introduction: Peripheral blood hematopoietic progenitor cell collection is a more popular source of stem cells for transplantation than bone marrow harvest. A number of automated cell separators exist which can be used to perform mononuclear cell collections. These separators collect varying amounts of other cells during the collection process, including them in the mononuclear cell product. Because of this, collection of mononuclear cells can result in significant reductions in platelet count and loss of red blood cells during the procedure. In order to minimize platelet transfusion support, we developed an algorithm to optimize mononuclear cell collections while minimizing platelet losses using the Gambro COBE Spectra and the Baxter Amicus Methods: Previously, patients were assigned randomly to any available apheresis machine. Starting August 2nd 2002, patients with a WBC count higher than 35×10 (9)/L were preferably assigned to Amicus for 5 hour collection with processing 1000 ml/cycle or as second choice Spectra for 5 hours run with maximum draw rate 65 ml/Min., for both instruments. If the WBC was lower than 35×10 (9)/L, the preferred machine would be Amicus for 5 hours run at 1400 ml/cycle with maximum draw rate 90ml/Min. or Spectra for 5 hours run with maximum draw 100 ml/Min. We reviewed the difference of pre and post procedure platelet counts of non Hodgkin’s Lymphoma patients undergoing stem cells collection for 6 months before and after the implementation of the above protocol from February 2002 till February 2003. All CBC were performed on the same Coulter analyzer. Results: 14 patients (2 on Amicus and 12 on Spectra) underwent stem cells collection before August 2nd, 2002. 13 patients (8 on Amicus and 5 on Spectra) were collected after this date. The Fisher’s exact test was used for this study. The median and mean differences in the first group were 141.5 ×10(9)/L and 135 ×10 (9)/L respectively (95% CI, p 0.0183). The second group had a median and mean of 45 ×10 (9)/L and 51 × 10(9)/L (95% I, p 0.0183). The minimum and maximum differences were 36 × 10(9)/L and 200 × 10(9)/L respectively in the first group and −19 ×10(9)/L and 121×10(9)/L for the second group. There was no difference in the numbers of the collections days in both groups in regard to the type of automated cell collector. Discussion: The implemented algorithm showed a net advantage. Even though none of the patients required blood transfusions, there was lesser drop of platelets counts with the new settings.

Abstract Background: Positive interim PET scans have been associated with inferior outcomes in DLBCL treated with chemotherapy, alone or with rituximab. In the ECOG 3404 study for bulky and advanced DLBCL, PET scans at baseline and after 3 R-CHOP are centrally reviewed by a single reader; those with positive scans cross-over to R-ICE after 4 R-CHOP, whereas those with negative scans continue on R-CHOP. The primary endpoint of E3404 is progression-free survival. To determine the reproducibility of interim PET scan interpretation, we convened an expert panel. Methods: Three external nuclear medicine physicians visually scored baseline and interim PET scans independently and blinded to other clinical information or outcome. ECOG study criteria were binary (0,1) based on residual disease in initially involved sites with uptake greater than the liver. London criteria were on a scale of 0–5, where 4–5 was positive, based on increased uptake relative to the liver. Overall scores and agreement among experts were evaluated for both criteria, with application of the kappa statistic to correct for chance. Results: Using the ECOG criteria, external reviewers were in complete agreement in 68% of 38 interim scans and completely agreed with the central review in the same 68% cases. Agreement among the experts was 71% employing the London criteria in these cases. The range of PET+ interim scans by reviewer was 16.8% to 34.2% (p=NS) by both ECOG and London criteria. The kappa statistic for overall pairwise correlation between readers was 0.445 (0.396–0.533) using ECOG and 0.502 (0.396–0.630) using London criteria – indicating moderate consistency. Areas of disagreement often, but not exclusively, related to bone disease, the shape and focality of residual uptake, splenic disease, and rare scans without CT-fusion. Conclusions: These data show that visual criteria, either ECOG or London in this series, for interim PET results are moderately reproducible among individual nuclear medicine experts. Our finding of variability among experts indicates the need for caution in interpreting interim PET results in studies and in practice. Review of all E3404 cases is planned after accrual is completed (projected 12/08). Other ongoing studies evaluating interim PET after 1–3 cycles of therapy, the application of quantitative criteria, and consensus panels may provide further valuable information.

Deborah Doniach MD, FRCP was born in Geneva, Switzerland in 1912. She attended high school at the Lycée Molière and medical school at the Sorbonne in Paris. Deborah married Israel (Sonny) Doniach in 1933. After the births of their two children, she resumed her studies at the Royal Free Hospital Medical School in London, graduating in 1945. After additional training in Immunopathology and Endocrinology, Dr. Doniach joined the faculty in the Department of Immunology at the Middlesex Hospital and rose to become Honorary Consultant Immunopathologist and full Professor of Clinical Immunology. During her career, Deborah enjoyed a long and fruitful collaboration with the chemist and immunologist Ivan Roitt. From their partnership sprang the seminal discovery that Hashimoto's thyroiditis is an autoimmune disease in which circulating antibodies target thyroglobulin, a normal thyroid protein. In addition, they demonstrated a separate antibody cytotoxic to thyrocytes, later found to target thyroid peroxidase. These novel insights ran counter to the prevailing scientific dogma contending that antibodies target only nonself antigens. Thus, the field of research into thyroid autoimmunity, and indeed into autoimmune diseases in general, was born. This work spawned a cadre of future investigators whose studies define our current understanding of thyroid autoimmunity and the broader spectrum of autoimmune disease. In her private life, Deborah was a free thinker who defied conventional norms of the day. She was vivacious, warm, and genuinely interested in everybody and everything. Deborah Doniach died on New Year's Day, 2004 at the age of 91.

In x‐ray computed tomography (CT), materials with different elemental compositions can have identical CT number values, depending on the mass density of each material and the energy of the detected x‐ray beam. Differentiating and classifying different tissue types and contrast agents can thus be extremely challenging. In multienergy CT, one or more additional attenuation measurements are obtained at a second, third or more energy. This allows the differentiation of at least two materials. Commercial dual‐energy CT systems (only two energy measurements) are now available either using sequential acquisitions of low‐ and high‐tube potential scans, fast tube‐potential switching, beam filtration combined with spiral scanning, dual‐source, or dual‐layer detector approaches. The use of energy‐resolving, photon‐counting detectors is now being evaluated on research systems. Irrespective of the technological approach to data acquisition, all commercial multienergy CT systems circa 2020 provide dual‐energy data. Material decomposition algorithms are then used to identify specific materials according to their effective atomic number and/or to quantitate mass density. These algorithms are applied to either projection or image data. Since 2006, a number of clinical applications have been developed for commercial release, including those that automatically (a) remove the calcium signal from bony anatomy and/or calcified plaque; (b) create iodine concentration maps from contrast‐enhanced CT data and/or quantify absolute iodine concentration; (c) create virtual non‐contrast‐enhanced images from contrast‐enhanced scans; (d) identify perfused blood volume in lung parenchyma or the myocardium; and (e) characterize materials according to their elemental compositions, which can allow in vivo differentiation between uric acid and non‐uric acid urinary stones or uric acid (gout) or non‐uric acid (calcium pyrophosphate) deposits in articulating joints and surrounding tissues. In this report, the underlying physical principles of multienergy CT are reviewed and each of the current technical approaches are described. In addition, current and evolving clinical applications are introduced. Finally, the impact of multienergy CT technology on patient radiation dose is summarized.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.