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Background Massive amounts of patient data are captured daily in electronic medical records (EMR). Utilizing the power of such large data may help identify disease associations and generate hypotheses that can lead to a better understanding of disease associations and mechanisms. We aimed to comprehensively identify and validate associations between inflammatory bowel disease (IBD) and concurrent comorbid diagnoses. Methods We performed a cross-sectional study using EMR data collected between 1986 and 2009 at a large tertiary referral center to identify associations with a diagnosis of IBD. The resulting associations were externally validated using the Truven MarketScan database, a large nationwide dataset of private insurance claims. Results A total of 6225 IBD patients and 31 125 non-IBD controls identified using EMR data were used to abstract 41 comorbid diagnoses associated with an IBD diagnosis. The strongest associations included Clostridiodes difficile infection, pyoderma gangrenosum, parametritis, pernicious anemia, erythema nodosum, and cytomegalovirus infection. Two IBD association clusters were found, including diagnoses of nerve conduction abnormalities and nonspecific inflammatory conditions of organs outside the gut. These associations were validated in a national cohort of 80 907 patients with IBD and 404 535 age- and sex-matched controls. Conclusion We leveraged a big data approach to identify several associations between IBD and concurrent comorbid diagnoses. EMR and big data provide the opportunity to explore disease associations with large sample sizes. Further studies are warranted to refine the characterization of these associations and evaluate their usefulness for increasing our understanding of disease associations and mechanisms.

BACKGROUND: Safety of anti-tumour necrosis factor-α (TNFα) therapy in people with a history of cancer and with an immune-mediated disease is unknown. We aimed to assess the risk of recurrence of initial cancer or development of a new primary cancer after treatment with anti-TNFα therapy.METHODS: In this Danish, population-based cohort study we recruited adults (≥18 years) with inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis and a primary cancer diagnosed between Jan 1, 1999 and Dec 31, 2016. Patients were recruited from the prospectively recorded Danish National Patient Registry and the Danish Cancer Registry. Participants were matched 1:10 between the treatment group who received anti-TNFα therapy and the control group (no anti-TNFα therapy) and we excluded individuals with a cancer diagnosed before their first anti-TNFα treatment (or before matching date for controls), individuals diagnosed with IBD, rheumatoid arthritis, or psoriasis after anti-TNFα initiation (or respective match date for controls), and individuals who received anti-TNFα with fewer than five matched controls. Using adjusted Cox proportional hazards regression, we estimated the primary outcome of development of recurrent or new primary cancer in patients who received anti-TNFα therapy compared with patients who did not receive this therapy, matched by sex, immune-mediated disease type, cancer type, and time from initial cancer diagnosis to first anti-TNFα registration.FINDINGS: Overall, 25 738 patients with immune-mediated disease and a history of cancer were identified. 434 patients who received anti-TNFα therapy after their initial cancer were matched to 4328 patients in the control group. During 18 752 person-years (median 5·6 years [IQR 2·8-7·9]) of follow up, 635 individuals developed recurrent or new primary cancer, 72 of whom had received anti-TNFα therapy and 563 of whom were in the control group. The median time between anti-TNFα treatment and recurrent or new primary cancer diagnosis was 2·8 years (IQR 1·7-5·4). The incidence of recurrent or new primary cancer development was 30·3 cases (95% CI 24·0-38·2) per 1000 person-years in the anti-TNFα treatment group and 34·4 cases (31·7-37·3) per 1000 person-years in the control group, yielding an adjusted hazard ratio of 0·82 (95% CI 0·61-1·11).INTERPRETATION: Use of anti-TNFα therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNFα therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. This observation might guide clinical decision making among providers treating immune-mediated diseases with anti-TNFα medications.FUNDING: None.

BACKGROUND: Clostridium difficile infection (CDI) is one of the most common hospital-acquired infections and is associated with significant morbidity and mortality. Since owning a cat or dog could enrich the gut microbiome, we hypothesized that it would be protective against CDI. AIMS: We conducted a survey study on patients tested for CDI in order to assess whether living in the presence of a pet is associated with a decreased risk of CDI. METHODS: We surveyed subjects aged 18–90 over a 14-month period using a retrospective case–control design. Subjects with CDI were matched by gender and age to patients who tested negative and had no prior history of CDI. A web-based survey was provided to subjects by mail or assisted by phone. Conditional logistic regression was used to assess for associations between CDI and the various risk factors. RESULTS: 205 CDI positive and 205 CDI negative subjects (response rate of 50.2%) were included. After matching for age and sex, living with a cat or dog was not associated with negative CDI testing. Exploratory multivariable modeling identified an unexpected association between positive CDI testing and high meat intake (OR 2.13, 95% CI 1.21–3.77) as well as between positive CDI testing and cat allergies (OR 1.88, 95% CI 1.02–3.46). CONCLUSION: Living with a cat or dog was not associated with negative CDI testing. Several novel risk factors for CDI have been identified including high meat intake and cat allergies.

Background & Aims Despite rescue therapy, more than 30% of patients with acute severe ulcerative colitis (ASUC) require colectomy. Tofacitinib is a rapidly acting Janus kinase inhibitor with proven efficacy in ulcerative colitis. Tofacitinib may provide additional means for preventing colectomy in patients with ASUC. Methods A retrospective case-control study was performed evaluating the efficacy of tofacitinib induction in biologic-experienced patients admitted with ASUC requiring intravenous corticosteroids. Tofacitinib patients were matched 1:3 to controls according to gender and date of admission. Using Cox regression adjusted for disease severity, we estimated the 90-day risk of colectomy. Rates of complications and steroid dependence were examined as secondary outcomes. Results Forty patients who received tofacitinib were matched 1:3 to controls (n = 113). Tofacitinib was protective against colectomy at 90 days compared with matched controls (hazard ratio [HR], 0.28, 95% confidence interval [CI], 0.10–0.81; P = .018). When stratifying according to treatment dose, 10 mg three times daily (HR, 0.11; 95% CI, 0.02–0.56; P = .008) was protective, whereas 10 mg twice daily was not significantly protective (HR, 0.66; 95% CI, 0.21–2.09; P = .5). Rate of complications and steroid dependence were similar between tofacitinib and controls. Conclusions Tofacitinib with concomitant intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC. Prospective trials are needed to identify the safety, optimal dose, frequency, and duration of tofacitinib for ASUC.

Infliximab can prevent colectomy in patients hospitalized with acute severe ulcerative colitis (ASUC). In cases of ASUC, fecal losses of infliximab may lead to low drug levels and reduced efficacy. To determine 90-day colectomy risk and postoperative complications in patients receiving single-dose and accelerated induction of infliximab for ASUC. We conducted a retrospective review of patients hospitalized with ASUC requiring infliximab therapy between 2013 and 2017 at the University of Michigan. Patients were excluded if they had an enteric infection, received an anti-TNF previously, or received cyclosporine during the same admission. The primary outcome was colectomy within 90 days of admission. Patients receiving single-dose induction infliximab were compared to those receiving accelerated rescue induction with two doses of infliximab prior to day 14. Administration of accelerated induction was guided by a protocol, suggesting administering a second dose of infliximab to those with only a partial response in CRP 3 days after the initial dose. Postoperative outcomes including 30-day readmission rates and complications were compared using descriptive statistics. From 2013 to 2017, 66 patients with ASUC met our criteria. Thirty-three received accelerated induction (50.0%). The colectomy rate in the accelerated induction group was 30.3% versus 24.2% in the single-dose induction group (p = 0.58). There was no detected difference in postoperative outcomes between the accelerated and single-dose rescue induction. In this retrospective review, 69.7% of those failing to respond to single-dose infliximab were able to avoid colectomy with an accelerated rescue induction strategy without worsening postoperative outcomes. Larger studies of accelerated dosing infliximab are needed.

Background and Aims Intestinal strictures are a common complication of Crohn’s disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. Methods We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). Results Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. Conclusions There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.

Background: Cytokines are being explored as a therapeutic strategy to modulate the tumor microenvironment and facilitate immunotherapy benefit in breast cancer. Here, we investigate a locoregional therapeutic approach whereby cytokines (IRX-2) are administered into the subcutaneous peri-areolar tissue (in an anatomic distribution similar to sentinel lymph node mapping) to facilitate immune cell recruitment/activation within the draining lymph nodes and tumor in ESBC. IRX-2 is derived from ex vivo phytohemagglutinin-stimulated lymphocytes and contains multiple cytokines including IL-1β, IL-2, TNF-α, IFN-γ, IL-6, IL-8, and GM-CSF, with stable concentrations from lot to lot. Preclinically, IRX-2 activates T-cells and natural killer (NK) cells, facilitates antigen presentation, and enhances activity of anti-PD-1/L1 in a SCC7 model. In a preceding head/neck squamous cell carcinoma phase I trial, perilymphatic IRX-2 was safe and increased TILs. Here, we report the final clinical results of a phase Ib trial evaluating the feasibility and immunologic activity of IRX-2 in ESBC. Methods: Beginning 21 days prior to surgical resection, enrolled operable patients with stage I-III ESBC (all subtypes) received the pre-operative IRX-2 regimen consisting of a single low-dose cyclophosphamide (300 mg/m2 to facilitate T-regulatory cell depletion), followed by 10 days of subcutaneous peri-areolar IRX-2 injections into the affected breast (1 mL × 2 at tumor axis and at 90°). Endpoints were feasibility (primary endpoint), stromal TIL (sTIL) count (pre-treatment versus post-treatment, blinded average of two pathologist reads using San Antonio H&E sTIL guidelines), PD-L1 expression (Nanostring) and enumeration of peripheral immune cells by flow cytometry. Results: All patients (n=16/16) completed and tolerated the regimen with no surgical delays or treatment-attributed grade III/IV toxicities. Common adverse events (occurring in >15% subjects) attributed to IRX-2 injections were: injection site reaction (grade 1, n=8/16), bruising (grade 1, n=7/16), and pain (grade 1, n=3/16). Common adverse events attributed to low-dose cyclophosphamide were: fatigue (grade 1, n=5/16) and nausea (grade 1/2, n=3/16). Treatment was associated with an increase in sTIL score (Wilcoxon signed-rank p=.04), with 4/10 sTIL-low tumors (0-10% score) re-categorized to sTIL-moderate (11-50% score). Increases in PD-L1 RNA expression were observed (Wilcoxon signed-rank p=.04) in 12/16 tumors (median 57% increase, range: -53% to 185% increase), as well as increases in Nanostring NK and Th1 cell signatures. In blood, increases in CD4 and CD8 effector T-cell activation (ICOS, HLA-DR, and CD38) and T-reg depletion were observed. Conclusions: IRX-2 was well tolerated with preliminary evidence of sTIL increase, PD-L1 upregulation, and peripheral lymphocyte activation. Based upon these data and preclinical evaluations demonstrating synergy with checkpoint inhibition, the IRX-2 regimen is being evaluated for clinical efficacy in conjunction with pembrolizumab and neoadjuvant chemotherapy (doxorubicin, cyclophosphamide, paclitaxel) in patients with stage II-III triple negative breast cancer. Citation Format: Pucilowska J, Egan JE, Berinstein NL, Moxon N, Aliabadi-Wahle S, Imatani JH, Conlin A, Acheson A, Massimino K, Martel M, Campbell M, Wu Y, Sun Z, Redmond W, Shah M, Urba WJ, Page DB. Perilymphatic IRX-2 cytokine therapy to enhance tumor infiltrating lymphocytes (TILs) and PD-L1 expression preceding curative-intent therapy in early stage breast cancer (ESBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-12.

Background Treatment of recurrent/refractory (r/r) DLBCL remains an unmet clinical need, and new effective and well-tolerated treatments are required. DPX-Survivac is a unique T cell activation therapy that targets survivin-expressing tumor cells and has shown anti-tumor activity in clinical trials. This trial is evaluating a novel immunotherapy combination with DPX-Survivac, intermittent low dose CPA and pembrolizumab. Methods ‘SPiReL’ is a Phase 2 non-randomized, open label, efficacy and safety study of a novel immunotherapy combination with DPX-Survivac (a unique T cell activation therapy that targets survivin-expressing tumor cells), intermittent low dose CPA and pembrolizumab, treatment regimen as described in figure 1. Subjects with r/r incurable DLBCL and survivin expression are eligible for participation. This study was approved by the Ontario Cancer Research Ethics Board, approval number 0981.ORR is assessed by modified Cheson criteria. For translational analyses, baseline and on-treatment PBMCs, along with tumor biopsy samples are collected from each subject. Survivin-specific systemic T cell responses are assessed using IFNγ-ELISPOT assay and tumour immune-infiltrate profile by multiplex-IHC. Results Twenty-two subjects have been enrolled to date, 19 are included in the intent to treat (ITT) population and 11 subjects are evaluable in the per protocol (PP) population. In the PP, the ORR is 63.6% including 3 CRs (27.3%), 4 PRs (36.4%) and the DCR is 81.8% (9/11). In the ITT, the ORR is 35% (7/19), and DCR is 52.0% (10/19). Preliminary results show that non-GCB subjects had a higher proportion of clinical response (4/8, 50%), compared to 3/10 (30%) in GCB subjects.DPX-Survivac-induced T cell responses were observed in 8/19 subjects (42.1%) including 6 subjects with clinical response (PR, CR), one SD and one PD. Multiplex-IHC analyses demonstrated baseline tumor PD-L1 expression in 6/7 subjects with a clinical response (85.7%, p Conclusions DPX-Survivac, intermittent low-dose CPA and pembrolizumab is generally well tolerated and can induce clinical responses in subjects with r/r DLBCL (7/11, 63.6% of evaluable subjects), including subjects with both non-GCB and GCB subtypes. Pre-treatment biopsies of clinical responders were characterized by higher baseline tumor PD-L1 expression and CD4 and CD8 infiltration. Extending this exploratory data in a larger cohort may define a r/r DLBCL patient population with a higher likelihood to respond to this novel combination immunotherapy. Trial Registration NCT03349450 Ethics Approval This study was approved by the Ontario Cancer Research Ethics Board, approval number 0981.

Background Coronavirus disease-2019 (COVID-19) is a global pandemic. Obesity has been associated with increased disease severity in COVID-19, and obesity is strongly associated with hepatic steatosis (HS). However, how HS alters the natural history of COVID-19 is not well characterized, especially in Western populations. Aims To characterize the impact of HS on disease severity and liver injury in COVID-19. Methods We examined the association between HS and disease severity in a single-center cohort study of hospitalized COVID-19 patients at Michigan Medicine. HS was defined by either hepatic steatosis index > 36 (for Asians) or > 39 (for non-Asians) or liver imaging demonstrating steatosis > 30 days before onset of COVID-19. The primary predictor was HS. The primary outcomes were severity of cardiopulmonary disease, transaminitis, jaundice, and portal hypertensive complications. Results In a cohort of 342 patients, metabolic disease was highly prevalent including nearly 90% overweight. HS was associated with increased transaminitis and need for intubation, dialysis, and vasopressors. There was no association between HS and jaundice or portal hypertensive complications. In a sensitivity analysis including only patients with liver imaging > 30 days before onset of COVID-19, imaging evidence of hepatic steatosis remained associated with disease severity and risk of transaminitis. Conclusions HS was associated with increased disease severity and transaminitis in COVID-19. HS may be relevant in predicting risk of complications related to COVID-19.

In the diabetic milieu, one way that oxidative stress contributes to processes leading to macrovascular disease is through the oxidative modification of high-density lipoprotein (HDL) particles, reducing their antioxidant and antiinflammatory properties. Despite the definitive role of oxidative stress in HDL dysfunction and the incidence of cardiovascular complications in diabetes, earlier clinical trials have failed to support the hypothesis that supplementation with antioxidant vitamins, including vitamin E, provides cardioprotection, even in the diabetic state. A prominent hypothesis for the null clinical trial results has been that antioxidant supplementation may benefit only specific populations susceptible to vascular disease. This chapter focuses on evidence surrounding the potentially protective effects of vitamin E on the HDL particle in one such population subgroup, namely, individuals with diabetes carrying the haptoglobin 2-2 genotype.

Background Fecal calprotectin (fCAL) is a noninvasive biomarker used to differentiate between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Methods A multicenter prospective case–control study evaluating the BÜHLMANN fCAL enzyme-linked immunosorbent assay (ELISA) was conducted in 478 subjects. Sensitivity, specificity, predictive values, and area under the receiver operator characteristic (AuROC) curve are reported and compared to another device. Results In differentiating IBD from IBS, the BÜHLMANN fCAL ELISA is very sensitive (93.3%) at a cutoff 160 μg/g (AuROC 0.933). Conclusions The BÜHLMANN fCAL ELISA demonstrates excellent discriminating between IBD and IBS.

Five-year overall survival for high-risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high-risk follicular lymphoma. Front-line treatment with chemo-immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio- immunotherapy with 90-Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5-year overall survival for intermediate and high-risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio-immunotherapy. Three months post radio-immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo-immunotherapy and converted to complete response after radio-immunotherapy. The 5-year progression-free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow-up of 48 months (range 3-84 months). Post radio-immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%-36% and 10%-24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B-cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562.

INTRODUCTION: COVID-19 is a global pandemic However, the effects of underlying liver disease on COVID-19 in the United States is not well described We investigated whether COVID-19 was associated with elevations in liver enzymes or hepatic decompensation in patients with underlying hepatic steatosis METHODS: We retrospectively reviewed the charts of consecutive adults with RT-PCR positive for COVID-19 treated at Michigan Medicine between March 1 and April 30, 2020, who had ultrasound, computed tomography, or magnetic resonance imaging >30 days before COVID-19 diagnosis Hepatic steatosis was defined based on imaging Outcomes were: (1) peak ALT or bilirubin following COVID-19 diagnosis, (2) ALT >2 or = times upper limit of normal (ULN), defined as the higher of baseline ALT or 19 U/L in women and 30 U/L in men, (3) jaundice defined as bilirubin >2 or 4mg/ dl, and (4) new/worsening ascites or encephalopathy We conducted regressions with the above outcomes as dependent variables and hepatic steatosis as the primary predictor, adjusting for age, sex, race, recent healthcare exposure, body mass index, hypertension, dyslipidemia, and diabetes These regression models were logistic for outcomes of abnormal ALT or bilirubin, and linear for maximal ALT or bilirubin RESULTS: Of patients with prior imaging, 80/159 (50 3%) had steatosis Overall, 89% of patients were hospitalized, 51% were admitted to intensive care, and 16% died 14% had chronic liver disease other than NAFLD, 5% had cirrhosis, and 2 7% had prior liver decompensation with ascites, variceal bleeding, or hepatic encephalopathy Patients with steatosis were older, had higher body mass index, and were more often Black than those without steatosis (Table 1) Baseline ALT and total bilirubin were higher in the steatosis group (Table 1) Hepatic steatosis was associated with increased incidence of ALT >2x ULN (OR 2 93 [1 23-6 97]) or >5x ULN (OR 6 21 [1 45-26 62]), and with peak ALT (beta 39 7 [7 85-71 49]) (Table 2) Hepatic steatosis was not associated with increased bilirubin (Table 2) Rates of new/worsening ascites and encephalopathy were very low: 1 3% and 2 5%, respectively, with no difference based on NAFLD status (P >0 4 for both) CONCLUSION: Hepatic steatosis is associated with acute hepatocellular injury with COVID-19 infection Steatosis was not associated with jaundice Rates of new/worsening ascites or hepatic encephalopathy were very low and unrelated to steatosis status

Irritable bowel syndrome (IBS) is a common gastrointestinal condition with a heterogeneous pathophysiology. An altered gut microbiome has been identified in some IBS patients, and fecal microbiota transplantation (FMT) has been suggested to treat IBS. We performed meta-analyses and systematic review of available randomized controlled trials (RCTs) to evaluate the efficacy of FMT in IBS.We performed a systematic literature search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. Selection criteria included RCTs of FMT vs placebo using FMT excipients or autologous FMT in IBS. Meta-analyses were conducted to evaluate the summary relative risk (RR) and 95% confidence intervals (CIs) of combined studies for primary outcome of improvement in global IBS symptoms as measured by accepted integrative symptom questionnaires or dichotomous responses to questions of overall symptom improvement.Among 742 citations identified, 7 were deemed to be potentially relevant, of which 4 studies involving 254 participants met eligibility. No significant difference in global improvement of IBS symptoms was observed at 12 weeks in FMT vs placebo (RR = 0.93; 95% CI 0.48-1.79). Heterogeneity among studies was significant (I = 79%). Subgroup analyses revealed benefits of single-dose FMT using colonoscopy and nasojejunal tubes in comparison with autologous FMT for placebo treatment (number needed to treat = 5, RR = 1.59; 95% CI 1.06-2.39; I = 0%) and a reduction in likelihood of improvement of multiple-dose capsule FMT RCTs (number needed to harm = 3, RR = 0.54; 95% CI 0.34-0.85; I = 13%). Placebo response was 33.7% in nonoral FMT RCTs and 67.8% in capsule FMT RCTs. The Grading of Recommendations Assessment, Development and Evaluation quality of the body of evidence was very low.Current evidence from RCTs does not suggest a benefit of FMT for global IBS symptoms. There remain questions regarding the efficacy of FMT in IBS as well as the lack of a clean explanation on the discrepant results among RCTs in subgroup analyses.

Background: Recurrent/refractory (r/r) DLBCL presents a major treatment challenge, especially in the setting of patients who are ineligible for, or relapsing after, potentially curative treatments such as autologous stem cell transplant (ASCT) and chimeric antigen receptor T cell (CAR-T) therapy. Efficacious treatment options that are well-tolerated and easily accessible in this population represent a critical unmet medical need. DPX-Survivac is a targeted T cell activation therapy against cancers expressing survivin. Survivin plays an essential role in cancer biology and represents a target of choice to disrupt tumour progression. DPX-Survivac's mechanism of action relies on its ability to generate robust and durable survivin-specific T cells that migrate to, infiltrate and kill tumour cells. DPX-Survivac is administered with intermittent, low dose cyclophosphamide (CPA) used as an immunomodulator. In nonclinical studies, treatment with DPX-Survivac increases PD-L1 and PD-1 expression providing the rationale for combination with pembrolizumab. Methods: "SPiReL" is a Phase 2 non-randomized, open label, efficacy and safety study. Subjects with r/r DLBCL with confirmed survivin expression are eligible for participation. Subjects must also be ineligible for potentially curative therapy. The treatment and testing regimen is shown in the figre below. The primary objective of SPiReL is to document a minimum Objective Response Rate (ORR) of 24% (in 6/25 subjects) using the modified Cheson criteria (2007). Secondary objectives include safety, duration of response and time to next treatment. Exploratory endpoints include T cell response, tumour immune cell infiltration, and biomarker analysis. Results: At data cut-off, 22 subjects have been enrolled in the study. The median age is 75.5 years (50-82). Thirteen of 22 subjects (59.1%) are GCB sub-type, 8 subjects (36.4%) are non-GCB and 1 subject (4.5%) has primary cutaneous DLBCL, leg type. The median number of prior therapies is 2 (1-7), with 4 subjects having previously undergone ASCT and 5 subjects with transformed disease. Of the 22 enrolled subjects, 8 are not evaluable per protocol for clinical efficacy due to early disease progression. Four subjects are active on treatment, 3 of which have not yet reached the first time point for assessment. Clinical outcome was analyzed for the Full Analysis Set (FAS) (n=19) and in the Per Protocol (PP) analysis (n=11). Of 11 subjects in the PP, 7 subjects (63.6%) have achieved an objective response, meeting the study's primary endpoint; 3 subjects (27.3%) with a CR and 4 subjects (36.4%) with a PR. Three subjects (27.3%) achieved SD and thus clinical benefit was demonstrated in 10/11 (90.9%) of evaluable subjects. Two subjects (18.2%) have completed the 1 year treatment period, 8 subjects (72.7%) discontinued treatment due to disease progression, and 1 subject (9.2%) discontinued treatment due to an unrelated Adverse Event (AE). Including the entire FAS, the objective response rate was 7/19 (36.8%). This treatment combination is well-tolerated, only 11% of Treatment Related AEs (TRAEs) were assessed as Grade 3 or higher. The majority of the Grade 1 and 2 TRAEs were Injection Site Reactions (ISRs) related to DPX-Survivac. Ten serious AEs were reported, of which 3 were considered related to study treatment. No subjects have discontinued study treatment due to a TRAE. Analyses of peripheral blood T cell responses to survivin by ELISpot assay shows that 7/7 subjects who achieved an objective response have survivin-specific T cell response. One subject with PD also showed a survivin-specific T cell response, supporting the mechanism of action and the role of DPX-Survivac in anti-tumor activity. Summary: DPX-Survivac and low dose CPA in combination with pembrolizumab, demonstrates promising clinical activity in recurrent/refractory DLBCL with 10/11 (90.9%) of evaluable subjects deriving clinical benefit with minimal toxicity. The primary endpoint of this study has been reached with 7/11 (63.6%) of evaluable subjects achieving an objective response warranting further exploration of DPX-Survivac in this population. Enrollment is continuing to further define the patient population most likely to benefit from this well-tolerated therapy. Figure 1 Disclosures Bence-Bruckler: Merck: Membership on an entity's Board of Directors or advisory committees. Forward:Seattle Genetics: Research Funding; IMV: Research Funding; Merck: Research Funding; Astellas: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; IMV: Membership on an entity's Board of Directors or advisory committees; Calgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Stewart:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Teva: Honoraria. Bramhecha:IMV Inc.: Current Employment. Conlon:IMV Inc.: Current Employment. OffLabel Disclosure: Keytruda (pembrolizumab). Indicated for use in melanoma, nonÃÆ'Ã'¢Ã¢ââ'¬Å¡Ã¢â€šâ'¬ÃƒÂ¢Ã¢â€šâ'¬Ã…“small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite instability-high (MSI-H) or a mismatch repair deficient (dMMR) solid tumor, gastric or gastroesophageal junction (GEJ) adenocarcinoma, squamous cell carcinoma of the esophagus, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma (MCC), and renal cell carcinoma (RCC).

INTRODUCTION: Coronavirus disease (COVID)-19 is a global pandemic that carries significant morbidity and mortality However, the effect of COVID-19 on liver disease, and vice versa, is not well-characterized in the United States Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition associated with metabolic disease including diabetes and obesity We examined the association between NAFLD and COVID19 disease severity in a large cohort of patients METHODS: We retrospectively reviewed a cohort of 396 consecutive adult patients with RT-PCR positive for COVID-19 between March 1 and April 30, 2020 at Michigan Medicine NAFLD was defined as either prior imaging evidence of steatosis or hepatic steatosis index >36 for Asians or >39 for non-Asians, with no history of alcohol abuse The primary outcome was disease severity based on admission to intensive care, intubation, death, or the World Health Organization (WHO) ordinal scale We used multivariable logistic regression to assess the predictors of intensive care, intubation, or death and linear regression for disease severity on WHO ordinal scale NAFLD was the primary predictor and models were adjusted for age, sex, race, recent healthcare exposure, hypertension, and dyslipidemia RESULTS: The median age was 60 5 years, 52% were male, 46% were Black, 41% were White and 54% had NAFLD Of 396 patients, 86% were hospitalized, 45% required intensive care, 30% required intubation, and 14% died 213 (54%) patients had NAFLD Patients with NAFLD were older (65 vs 57 years;P < 0 001), had higher body mass index (34 5 vs 26 4;P < 0 001), and higher prevalence of diabetes (45% vs 34%;P = 0 039) than those without NAFLD (Table 1) NAFLD was independently associated with increased odds of requiring admission to the intensive care unit (odds ratio [OR] 1 66 [1 06-2 62], P = 0 027) and intubation (OR 2 46 [1 50-4 04], P < 0 001), as well as higher WHO ordinal scale (beta 0 43 [0 03-0 84], P = 0 036) There was no significant association between NAFLD and death (OR 0 84 [0 46-1 67], P = 0 62) (Table 2 ) CONCLUSION: Our study shows that patients with NAFLD were more likely to develop severe disease with COVID-19 (Table Presented)

Introduction: Recurrent/refractory diffuse large B cell lymphoma (DLBCL) remains an area of unmet clinical need. Although autologous stem cell transplant (ASCT), and more recently chimeric antigen receptor (CAR) T cell therapy, have made a significant impact, many patients are ineligible for these treatments due to advanced age, comorbidities, or financial or geographical limitations, or they have relapsed following these treatments. Survivin, a novel target in DLBCL, is overexpressed in approximately 60% of untreated DLBCL with higher rates in relapsed disease. DPX-Survivac, a T cell activating therapy, elicits a strong and prolonged immune response against tumors expressing survivin. DPX-Survivac is combined with pembrolizumab, an anti-PD-1 checkpoint inhibitor, and intermittent low dose cyclophosphamide (CPA), used for an immunomodulatory effect. Pre-clinical studies have demonstrated increased efficacy of this DPX-based drug combination in controlling of tumor growth in murine tumor models, resulting in improved survival (Weir et al. J Immunother Cancer 2016). Methods: "SPiReL" is a Phase 2 non-randomized, open label, efficacy and safety study. Subjects with recurrent/refractory DLBCL with confirmed survivin expression are eligible for participation. Participants must also be ineligible for curative therapy. Study treatment includes administering two doses of 0.5 mL of DPX-Survivac 3 weeks apart followed by up to six 0.1 mL doses every 8 weeks. Intermittent low dose cyclophosphamide is administered orally at 50 mg twice daily for 7 days followed by 7 days off. Pembrolizumab 200 mg is administered every 3 weeks. Study participants continue active therapy for up to one year or until disease progression, whichever occurs first. The primary objective is to document the response rate to this treatment combination using modified Cheson criteria. Secondary objectives include duration of response and safety. Exploratory endpoints include T cell response, tumor immune cell infiltration, and gene expression analysis. Enrollment is ongoing with a goal of up to 25 subjects in this national, multi-center study. Trial design is shown below the text. Results: At the time of data cut-off, 23 subjects have been screened and 12 have been enrolled. The demographics of enrolled subjects include: median age is 75.5 years (50-82), with 3 male subjects participating. The median number of prior therapies is 2.5 (1-6), with 4 subjects having previously undergone ASCT. The median time from diagnosis to screening is 31 months (8-151). Of the 12 enrolled subjects, 3 were not evaluable for clinical efficacy due to early disease progression. One subject has not yet reached the first time point for assessment. In the Per Protocol analysis of 8 evaluable subjects ("PP", N = 8); as compared to a Full Analysis Set ("FAS", N = 11); 7 of 8 subjects (PP = 87.5%) demonstrated clinical benefit, including 6 with tumor regressions (FAS = 63.6%); 2 subjects (PP = 25%) achieved a complete response, 1 of whom has completed the 1 year study period (FAS = 18.2%); 3 subjects (PP = 37.5%) had a partial response (FAS = 27.3%); and 3 (PP = 37.5%) had stable disease remaining on study for 4, 6 and 8 months (FAS = 27.3%). This treatment combination is well-tolerated with mostly grade 1 and 2 adverse events reported; a single grade 3 maculopapular rash and 1 case of grade 4 cytopenia has been observed. Of the 23 screened subjects, survivin expression analysis was performed on 18 subjects. All of the 18 samples analyzed were survivin positive, with a range of 60%-100% of lymphoma cells expressing survivin. Preliminary analysis of peripheral blood T cell responses to survivin by ELISPOT assay shows 2 of 4 subjects had strong survivin-specific T cell responses. Both of these subjects had clinical responses. Summary: DPX-Survivac, in combination with pembrolizumab and low dose cyclophosphamide, demonstrates clinical activity and a favorable safety profile in recurrent/refractory DLBCL with 87.5% of evaluable subjects deriving clinical benefit, including 2 complete responses (25%) and 3 partial responses (37.5%) to date. Enrollment is continuing to further explore the synergistic effect of this combination in this population. Figure Disclosures Berinstein: Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Keytruda (pemroblizumab) is approved for use to treat Melanoma, Metastatic, Non-Small Cell Lung Cancer, Head and Neck Cancer, Hodgkin's Lymphoma, Urothelial Carcinoma, Gastric Cancer, Cervical Cancer, Hepatocellular Carcinoma, Merkel Cell Carcinoma, Renal Cell Carcinoma, and Small Cell Lung Cancer. In this trial, it is being used to treat Diffuse Large B-Cell Lymphoma.

Rabea Asleh,1,2 Alexandros Briasoulis,3 Elliot M Berinstein,1 Joshua B Wiener,1 Mohan Palla,4 Sudhir S Kushwaha,2 Andrew P Levy1 1Bruce and Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel; 2Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA; 3Division of Cardiovascular Diseases, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; 4Department of Cardiology, Detroit Medical Center, Wayne State University, Detroit, MI, USA Objectives: The objectives of the study were to compile and summarize the data from all of the clinical trials designed to examine the association between haptoglobin (Hp) genotype and incidence of cardiovascular (CV) events in patients with diabetes mellitus (DM) and to assess the impact of vitamin E treatment on CV outcomes according to the Hp genotype.Background: The Hp genotype could serve as a predictive biomarker to DM patients who may benefit from vitamin E therapy.Methods: The electronic databases MEDLINE, PubMed, EMBASE and the Cochrane Library for Central Register of Clinical Trials were searched systematically using the following MESH terms: “haptoglobin genotype”, “diabetes mellitus” and “cardiovascular events”.Results: Overall, 13 studies fit the inclusion criteria for this analysis, yielding a large study population that included 6,161 patients without Hp 2-2 and 4,684 patients with Hp 2-2. The analysis of these studies showed that the incidence of CV events in DM patients with the Hp 2-2 genotype was significantly increased as compared to non-Hp 2-2 patients in all three subgroups of case–control (OR: 2.2, 95% CI: 1.3–3.6; P=0.003), cohort (OR: 1.3, 95% CI: 1.2–1.5; P=0.001) and randomized controlled trials (OR: 1.6, 1.2–2.2; P=0.005). Among patients with the Hp 2-2 genotype, administration of vitamin E was associated with lower rates of CV events (OR: 0.66, 95% CI: 0.45–0.95; P=0.025). Further investigation into the association between Hp 2-2 and myocardial infarction, stroke, mortality and end-stage renal disease was also performed.Conclusion: The Hp genotype is a risk factor for CV events in patients with DM, and administration of vitamin E appears to offer a low cost and accessible means of reducing CV events and mortality in this population. Keywords: haptoglobin genotype, diabetes mellitus, vitamin E, cardiovascular disease, antioxidants, HDL dysfunction

Cryptococcal peritonitis is an under-recognized disease that is an important cause of mortality in end-stage liver disease. We report a 43-year old male with decompensated cirrhosis secondary to refractory autoimmune hepatitis on immunosuppression with hepatocellular carcinoma who developed cryptococcal peritonitis. The patient subsequently developed ischemic bowel and multisystem organ failure secondary to abdominal compartment syndrome, leading to rapid deterioration and death. Frequently, these patients experience delays in diagnosis and treatment, which leads to a rapid and high mortality. This case report synthesizes data regarding the optimal approach for screening and managing patients with cryptococcal peritonitis and proposes a pathogenic mechanism of mortality with implications for improved treatment in the future.

Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed—median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Background: Dose-modified (dm) CODOX-M/IVAC is commonly used for Burkitt lymphoma (BL) and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and BL (BCL-U; previously Burkitt-like lymphoma-BLL). Methods: We evaluated the clinical characteristics, outcomes and prognostic markers in patients treated with dmCODOX-M/IVAC+/- rituximab (R) at a single academic center. Results: 31 patients with BL (n = 21) or BCL-U (n = 10) were included. The median age was 45, and 90% were high risk. The 2-year overall survival (OS) and progression-free survival (PFS) were 69% and 62%, respectively, with no differences between BL and BCL-U. By multivariable analysis, rituximab use was significantly associated with improved OS (Hazard Ratio 0.15; 95% CI 0.04 - 0.56) while elevated LDH (Hazard Ratio 2.84, 95% CI 1.52 - 5.29) and rituximab use (Hazard Ratio 0.054, 95% CI 0.01 - 0.32) predicted PFS. Conclusion: DmCODOX-M/IVAC+/- R chemotherapy provides equivalent survival for both BL and BCL-U patients. The addition of rituximab improves overall and progression free survival and is recommended.

Despite compelling evidence regarding the importance of oxidant stress in the development of vascular complications and observational studies suggesting that vitamin E may be protective from these complications, multiple clinical trials have failed to show benefit from vitamin E supplementation in the prevention of vascular complications in diabetes. One possible explanation for this failure of vitamin E may have been inappropriate patient selection. This review seeks to provide the clinical evidence and mechanistic basis for why a subset of individuals defined by their haptoglobin (Hp) genotype may derive cardiovascular protection by vitamin E supplementation. Clinical trial data from the HOPE, ICARE, and WHS studies is presented showing a pharmacogenomic interaction between the Hp genotype and vitamin E on the development of CVD. Specifically, in individuals with diabetes and the Hp2-2 genotype, vitamin E has been shown to be associated with an approximately 35% reduction in CVD. Cardioprotection by vitamin E in individuals with the Hp2-2 genotype appears to be mediated in part by an improvement in HDL functionality as demonstrated in three independent trials in both type 1 diabetes and type 2 diabetes. Vitamin E may provide benefit in reducing CVD in Hp2-2 individuals with diabetes. However, in order for this pharmacogenomic algorithm to be accepted as a standard of care and used clinically, an additional large prospective study will need to be performed.

Patients with mantle cell lymphoma (MCL) have a particularly poor prognosis when treated with standard chemotherapy, with a median overall survival of only 3 years. These patients have therefore been considered for first-line treatment with more aggressive or experimental strategies, such as high-dose therapy (HDT) with autologous stem cell transplantation (ASCT). While high rates of clinical remission have been achieved with HDT/ASCT, this procedure alone is not believed to be curative and different treatment strategies are being developed to improve outcomes in this group of patients. Single-agent rituximab is active in both newly diagnosed and relapsed MCL and therefore the addition of rituximab to chemotherapy regimens and/or HDT/ASCT may enhance their efficacy. Outside the transplantation setting, rituximab plus chemotherapy has been shown to be highly active in MCL, and preliminary data from randomized trials suggest that the combination may yield superior results compared with chemotherapy alone. The addition of rituximab to transplantation protocols appears to be a very promising strategy for patients with MCL, given as an in vivo purge before HDT/ASCT and/or as posttransplant maintenance therapy. Two phase II clinical trials with rituximab given as an in vivo purge during stem cell mobilization and as posttransplant immunotherapy in patients with previously untreated MCL have generated very promising data. Rituximab is an important addition to cytotoxic therapy and with HDT/ASCT represents a highly active therapy that may be superior to conventional treatment or HDT/ASCT alone in MCL. Randomized prospective studies and longer follow-up are needed to determine whether these regimens can achieve longer survival or possibly cure in this disease.

In the pre-rituximab era, transformation of indolent B-cell lymphoma to diffuse large B-cell lymphoma (DLBCL) was associated with an extremely poor outcome and a median post-transformation survival ranging from 1 to 2 years. We evaluated the impact of rituximab-cyclophosphamide, adriamycin, vincristine, prednisone (R-CHOP) on the survival outcomes of transformed lymphoma compared with de novo DLBCL. Between 2002 and 2010, 317 DLBCL patients who were consecutively diagnosed and treated with R-CHOP were identified at our institution. Patients with transformed lymphoma were included if they had not previously received R-CHOP. Patient characteristics, treatment, and outcome data were retrospectively collected. Sixty patients (19 %) had transformed lymphoma of which 37 (62 %) had transformed from follicular lymphoma, 50 (83 %) were chemotherapy naïve, and 58 (96 %) were rituximab naïve at the time of treatment. With a median follow-up of 31.4 months, 231 patients achieved either complete response or complete response unconfirmed (73 %) with no significant difference between de novo DLBCL (n = 192, 75 %) and the transformed group (n = 39, 65 %) (P = 0.25). Six patients (15 %) relapsed in the transformed group at a median time to relapse of 29.3 months. The 2-year and 5-year overall survivals for all patients were 82 and 72 %, respectively. The overall and progression-free survivals for transformed lymphoma and de novo DLBCL were not statistically different (P = 0.45 and P = 0.38, respectively). With R-CHOP chemotherapy, the prognosis of transformed lymphoma in patients with minimal chemotherapy exposure for indolent disease is similar to that of de novo DLBCL.

As many as 25% of patients diagnosed with ulcerative colitis are hospitalized with an episode of acute severe ulcerative colitis (ASUC).1 The standard of care for patients hospitalized with ASUC relies on rapid induction with intravenous (IV) corticosteroids. Up to 30% of patients do not respond to corticosteroids alone.2 Rescue therapy with infliximab or cyclosporine has been shown to reduce rates of colectomy to 20% by 90 days.3,4 This still represents a significant rate of treatment failure, which leads to an unplanned and irreversible surgery. In recent years, increasing numbers of patients admitted with ASUC have already failed infliximab therapy, highlighting the need for additional treatment options for these patients. Tofacitinib is a rapidly acting, oral, small-molecule Janus kinase inhibitor that was recently approved by the Food and Drug Administration for treatment of ulcerative colitis.5 We present the first reported use of off-label, high-intensity tofacitinib in 4 patients admitted to our institution with ASUC predicted to fail medical management.

Central nervous system (CNS) prophylaxis for diffuse large B-cell lymphoma (DLBCL) is controversial with even less evidence in the era of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. We reviewed the impact of CNS prophylaxis in DLBCL patients treated with R-CHOP at a tertiary care centre over a 7-year period. CNS prophylaxis was recommended for 'higher risk' patients and consisted of intrathecal methotrexate and/or high-dose methotrexate. Of 214 patients 12·6% received CNS prophylaxis. With a median follow-up of 27 months, eight patients (3·7%) developed CNS relapse (75% isolated to the CNS and 62·5% as parenchymal brain disease) at a median time of 17 months. Patients who did not receive CNS prophylaxis had lower events (2·7%) than those who did (11·1%). Half of the CNS relapses occurred in testicular lymphoma patients, 75% of whom had received CNS prophylaxis. In multivariate analysis, testicular involvement was the only significant prognostic factor for CNS relapse (hazard ratio 33·5, P < 0·001). In conclusion, CNS relapse in DLBCL appears to present as a later, more isolated parenchymal event and at a lower rate in the rituximab era compared with historical data. R-CHOP may negate the need for CNS prophylaxis with the exception of testicular lymphoma.

7 Background: The IRX-2 biologic is an injectable immunotherapy containing cytokines derived from stimulated lymphocytes. In preclinical models, IRX-2 activates T-cells, natural killer (NK) cells, macrophages, and dendritic cells, and facilitates maturation of antigen-presenting cells. Stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved outcomes in early stage breast cancer (ESBC), and neoadjuvant IRX-2 increased TILs in a head/neck squamous cell carcinoma trial. We conducted a phase Ib trial to evaluate the feasibility/activity of IRX-2 in ESBC. Methods: Beginning 21 days prior to surgical resection, enrolled operable patients with stage I-III ESBC received the pre-operative IRX-2 regimen consisting of a single low dose of cyclophosphamide (300 mg/m2 to facilitate T-regulatory cell depletion), followed by 10 days of subcutaneous peri-areolar injections of IRX-2 into the affected breast (1 mL × 2 at tumor axis and at 90°). Endpoints were feasibility (primary), sTIL count (secondary), and immune monitoring by flow cytometry and immune transcriptome analysis (Nanostring PanCancer Immune Panel). Results: As of October 2017, 12 patients are enrolled and evaluable. All patients received all planned injections with no treatment-related surgical delays, complications, or grade III/IV toxicities. Treatment was associated with a mean 52% relative increase in sTILs (range –25% to +166%, p = 0.02). RNA expression profiling revealed the greatest increases in Th1 cell signature (mean +28.5%, range -5.3% to +283%), but also increases in CD8+, NK, and DC signatures. PDL1 RNA expression increased in 10/12 patients (mean +131.5%, range –83% to +1112%). In blood, increases in T-cell activation markers (ICOS, HLADR, and CD38) and T-reg depletion were observed at 1-month follow-up. Conclusions: Peri-lymphatic IRX-2 was well tolerated with preliminary evidence of sTIL recruitment, PDL1 upregulation, and peripheral lymphocyte activation. Study enrollment is ongoing, including patients for a pre-neoadjuvant-chemotherapy triple-negative ESBC cohort. Clinical trial information: NCT02950259.

Follicular lymphoma (FL) is a unique disease characterised by a long natural history and responsiveness to many different therapies. We have reviewed the prognostic significance of the quality of both clinical and molecular responses for patients with FL. We have found that, as might be expected, patients who achieve a complete clinical response to treatment have a better prognosis than patients who achieve an incomplete or a partial response. However, unlike aggressive lymphomas, treatments that produce a higher frequency of complete responses do not result in better survival outcomes than treatments that produce lower complete response rates. Recent improvements in technologies have enabled quantitative monitoring of responses at the molecular level and at much higher degrees of sensitivity than can be obtained at the clinical level. Although these data are very heterogeneous and have many limitations, data are emerging that demonstrate that achieving molecular remissions after standard dose chemotherapy, high dose chemotherapy or various immunotherapies may have prognostic significance for patients with FL. With sensitive, quantitative, standardised and reproducible tools for molecular monitoring and with the combination of novel targeted biological therapies, we are approaching an era, where the potential to cure patients with FL is being turned into a reality.

Background Little is known about the pharmacokinetics of rituximab in an autologous stem cell transplant (ASCT) setting. Patients and methods We evaluated serum rituximab levels in 26 patients with follicular or mantle cell lymphoma treated with a combination of ASCT and immunotherapy. Patients received nine infusions of rituximab (375 mg/m2): one dose as an ‘in vivo purge’ prior to stem cell collection, and two 4-week cycles at 8 and 24 weeks following ASCT. Pre- and post-infusion serum rituximab levels were measured during the purging dose, with doses 1 and 4 of both sets of maintenance rituximab cycles, and 12 weeks and 24 weeks following treatment. Results Rituximab levels were detectable after the first infusion, and peaked at a mean concentration of 463.8 µg/ml after the final dose. Levels remained detectable 24 weeks after completion of treatment. There was a trend toward higher rituximab levels in patients with follicular lymphoma. Serum concentrations achieved during the maintenance cycles were similar to levels observed in patients with measurable lymphoma treated during ‘the pivotal trial’. No correlation was observed between serum rituximab levels achieved in the minimal disease state and the risk of later clinical relapse, nor with the ability to achieve a molecular remission following ASCT. Conclusions The finding that patients treated in minimal disease states and at the time of active disease both achieve similar final serum rituximab concentrations after four infusions suggests that the pharmacokinetics are complex, and may not necessarily correlate with disease burden. The precise factors influencing rituximab clearance in patients with lymphoma are unresolved, and this remains an area of active research.

High-dose therapy with stem-cell transplantation is a potentially curative therapy for younger patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) and is also under investigation in relapsed indolent NHL. There are, however, risks associated with this treatment strategy. Autologous stem-cell transplantation (ASCT) continues to be associated with a high risk of relapse, while graft-versus-host disease is a major limiting factor with allogeneic stem-cell transplantation. The presence of minimal residual disease (MRD) in the harvested, re-infused stem cells, or remaining in the patient following chemotherapy, is associated with relapse after ASCT. As a result, monitoring and eradicating MRD has become a major focus of many studies in NHL. Rearrangement and overexpression of the bcl-1 and bcl-2 genes are the hallmarks of mantle-cell and follicular lymphoma, respectively, and evidence suggests that they are promising surrogate markers of MRD. Polymerase chain reaction analysis is a sensitive methodology used to monitor the status of occult lymphoma cells bearing these genetic aberrations, and results from trials of ASCT have shown that clearance of bcl-1/JH- and bcl-2/JH-positive cells following treatment is associated with a significant improvement in outcome. Rituximab, the anti-CD20 monoclonal antibody, is increasingly used for in vivo purging and can effectively eradicate bcl-1/JH- and bcl-2-positive cells. If the encouraging preliminary results with rituximab are maintained with a longer follow-up, this agent could play a pivotal role in improving outcome after stem-cell transplantation in NHL.

The long median survival time of patients with follicular non-Hodgkin's lymphoma (NHL), means that the efficacy of new treatments are difficult to assess in the short term. Bcl-2 is an inhibitor of apoptosis and overexpression of the bcl-2 gene in the blood or bone marrow is a feature in up to 85% of patients with follicular NHL. Levels of bcl-2+ cells in the peripheral blood or bone marrow therefore are a useful measure of disease status in such patients and can be detected by polymerase chain reaction (PCR). Complete bcl-2 clearance from the bone marrow (molecular remission) following autologous stem cell transplant (ASCT) for follicular NHL is considered to be an important prognostic factor for disease-free survival. Tumour cell contamination of the stem cell grafts used in ASCT is commonly associated with relapse. This can be addressed by purging the stem cell harvest prior to transplantation. Various methods of in vitro purging after stem cell collection have been shown to reduce the level of contamination but yield is invariably reduced and grafts remain bcl-2 positive. However, in vivo purging with rituximab during the process of collection has been used to obtain bcl-2-negative stem cell harvests without compromising the yield. Rituximab is a monoclonal antibody licensed for treatment of relapsed and refractory low-grade or follicular NHL. Rituximab targets the CD20 antigen, which is found on cells of the B cell lineage. When used for in vivo purging it depletes the peripheral blood of CD20-positive cells and prevents contamination by lymphoma cells. Molecular remission, as measured by bone-marrow bcl-2 clearance, has been achieved in 7/7 patients with follicular NHL at 1 year after treatment with ASCT using rituximab as an ‘in vivopurse’, followed by rituximab maintenance. Early clinical outcomes are also encouraging. Bone Marrow Transplantation (2002) 29, Suppl. 1, S14–S17. doi:10.1038/sj.bmt.1703297

Follicular lymphoma (FL) is characterized by an initial response to treatment with inevitable relapse. We evaluated chemoimmunotherapy resistance (CIR resistance) including transformation. We identified patients who received rituximab combination therapy for symptomatic FL. CIR resistance was defined as disease progression during rituximab-based chemoimmunotherapy, rituximab maintenance or within 6 months of treatment completion. Our primary outcome was time to early progression (CIR resistance). Between July 2006 and April 2010, 132 patients met the inclusion criteria and 22 (16.7%) demonstrated CIR resistance with a median follow-up of 33 months. High-risk Follicular Lymphoma International Prognostic Index (FLIPI) score was predictive of CIR resistance (hazard ratio [HR] 2.43; 95% confidence interval [CI], 1.4-4.1; p = 0.001). Overall, eight patients (36.3%) transformed (biopsy-proven), with no transformation in the chemoimmunotherapy responder group. Median overall survival in the CIR resistant group was 47 months. Patients with CIR resistance had high rates of histologic transformation and shorter survival with poor response to next therapy.

Background: Although the natural history of follicular lymphoma is indolent with a median overall survival of about 12-15 years, the disease is heterogeneous. The 5 and 10 year overall survival (OS) of low, intermediate and high risk FLIPI is 91%, 78% and 53% and 71%, 51% and 36% using standard rituximab-based treatment. 5-year progression-free survival (PFS) is 80%, 70% and 48% respectively. Methods: Based upon this we conducted an investigator-initiated single-centre Phase II trial of intensified therapy with CHOP-R followed by (90)Y ibritumomab tiuxetan consolidation and 24 months of rituximab maintenance as treatment for patients with intermediate and high-risk newly diagnosed symptomatic follicular lymphoma. 33 patients were enrolled. Results: The addition of (90)Y ibritumomab tiuxetan was well tolerated but resulted in asymptomatic grade 3 or 4 thrombocytopenia and neutropenia in11-36% and 10-24% of patients between weeks 2-8 post (90) Y. After 9 years of follow-up (median follow-up 61 months) the 0S for intermediate and high risk FLIPI was 95% and 78%. The 5 year PFS was 79% and 64% for intermediate and high risk FLIPI, respectively. Responses at three months post consolidation were as follows: 3/33 (9%) achieved CR, 25/33(76%), achieved CRU, 1/33(3%) had PR, and 1/33(3%) had PD. Three patients did not receive (90)Y ibritumomab tiuxetan due to disease progression 2/33(6%), or death 1/33(3%). Of 19 patients who had a molecular marker for their lymphoma, 18 (95%) achieved molecular remissions in peripheral blood with CHOP-R therapy. Nine (47%) of these patients have been recently assessed for MRD and remain in molecular remission. The therapy resulted in decreased levels of IgG, IgM and IgA below the lower normal level in 33%, 40% and 23% of patients respectively post therapy. These levels did not recover in most of these patients. B cells were depleted to undetectable levels during therapy including rituximab maintenance. In 18 evaluable patients only 11 recovered normal B cell counts post maintenance rituximab. There was no correlation between normal B-cell recovery and Ig levels. Many patients with low or no B cell counts had normal IgG levels, whereas some patients who regained normal B cell counts were still unable to reach normal Ig levels. No patient developed human anti-mouse antibody. Immunity to measles, mumps, or rubella was retained post therapy. Patients did not have significant infections or opportunistic infections (although 2 developed Grade 1 shingles post (90)Y ibritumomab tiuxetan) and none required IVIG. Conclusions: We conclude that this intensified regimen is highly active in cyto-reducing lymphoma in high and intermediate risk FLIPI follicular lymphoma patients. The toxicity is tolerable although a significant percentage of patients will end up with persistent asymptomatic reductions in B cells and serum Ig. Only randomized trials will determine whether this regimen enhances outcome over standard of care in this higher risk follicular lymphoma population. References: 1.Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Nooka AK, Nabhan C, Zhou X, Taylor MD, Byrtek M, Miller TP, Friedberg JW, Zelenetz AD, Link BK, Cerhan JR, Dillon H, Sinha R, Shenoy PJ, Levy D, Dawson K, Hirata JH, Flowers CR. Ann Oncol. 2013 Feb;24(2):441-8. doi: 10.1093/annonc/mds429. Epub 2012 Oct 5 2.Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting. van de Schans SA, Steyerberg EW, Nijziel MR, Creemers GJ, Janssen-Heijnen ML, van Spronsen DJ. Ann Oncol. 2009 Oct;20(10):1697-702. doi: 10.1093/annonc/mdp053. Epub 2009 Jun 23. PMID: 19549712 Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding.

Treatment outcomes were documented for 204 adult patients with clinical Stage I-II Hodgkin's disease who were treated with risk-adapted ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiotherapy (RT) at the Toronto-Sunnybrook Regional Cancer Centre between 1984 and 1994. Forty-nine patients with clinical Stage I disease (excluding bulky mediastinal presentations) and 50 patients with a combination of clinical Stage IIA disease, age 50 years or less, and favourable pathology (lymphocyte predominant or nodular sclerosing histology) were identified as low risk and treated with RT alone to 35 Gy. One hundred and five high-risk patients were treated with chemotherapy (86 with ABVD) followed by RT to 25 Gy. The 7-year cause-specific, overall and disease-free survivals were 95%, 90% and 75% respectively for the low-risk cohort, and 91%, 90% and 88% respectively for the high-risk cohort. In-field relapses accounted for 50% of the failures in both groups. Sixteen of 24 (67%) patients with RT failure and 6/14 (43%) with combined modality therapy (CMT) failure were salvaged. Twenty-eight per cent of the patients treated with RT and 21% of those treated with CMT developed hypothyroidism by 7 years. Fatal complications were recorded in 6% of the low-risk patients managed with RT and 8% of high-risk patients managed with CMT. Septic death and second malignancy accounted for the majority of treatment-related fatalities. Risk-adapted therapy emphasizing RT alone for selected patients with favourable prognostic factors and CMT based on ABVD provides excellent long-term disease control. Further treatment refinements, including the wider application of CMT with lower doses of chemotherapy and RT, will be required to reduce the rate of fatal complications to more acceptable levels.

This study was designed to evaluate the efficacy and toxicity of dose intensifying DHAP (dexamethasone, cytarabine and cisplatin) salvage chemotherapy by adding mitoxantrone with GM-GSF support in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL). From March 1992 to January 1995, 22 patients with intermediate and high grade (aggressive) NHL refractory or relapsed after adriamycin containing chemotherapy regimens were treated with M-DHAP+GM-CSF, (dexamethasone 40 mg i.v. days 1-4, cisplatin 100 mg/m2 i.v. by continuous infusion over 24 hours on day 1, cytarabine 2 gm/m2, i.v. every 12 hours for 2 doses on day 2, mitoxantrone 10 mg/m2 i.v. on days 3 and 4 and GM-CSF 250-500 microg/m2 s.c. daily beginning day 5 until absolute neutrophil count recovery. Most patients had poor prognostic factors including primary refractory disease (18/22), bulky disease (12/22), elevated LDH (9/22), or bone marrow involvement (8/22). All 22 patients were evaluable. The overall response rate was 41% (CR 23% and PR 18%). There were three toxic deaths, all related to sepsis. Median progression free survival (PFS) and overall survival (OS) rates were 5.2 months and 11.8 months respectively. At the same time of the analysis two patients were alive after high-dose therapy and bone marrow transplant at 34 and 36 months follow-up and two were alive with disease. The maximal acceptable dosage of mitoxantrone was 10 mg/m2 x 2 due to serious hematologic toxicity. Treatment delays and dose reductions compromised delivering the optimal dose intensity of M-DHAP. A poor prognostic group of patients with refractory or recurrent aggressive lymphoma, many of whom were not eligible for high-dose therapy and stem cell transplantation were treated with repeated cycles of dose intensified DHAP with growth factor support. Although M-DHAP had therapeutic activity even in patients considered to have primary refractory disease, myelosuppression was dose limiting and frequently limited the number of cycles. Therefore, if M-DHAP is to be further evaluated, therapeutic results may be improved further by incorporating strategies to reduce myelotoxicity such as the use of growth factors to reduce platelet transfusion requirements or the use of autologous stem cell support after each cycle.

Because of evidence that failure to deliver full dose CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) may compromise the outcome of elderly patients with aggressive non-Hodgkin's lymphoma (NHL), we attempted to deliver full dose CHOP to these patients. The objective of this review was to assess the relative received dose intensity (ARRDI), toxicity and outcome of elderly patients treated with curative intent with CHOP at our centre. Charts were reviewed of all patientsor = 65 years with newly diagnosed aggressive NHL referred to the Toronto-Sunnybrook Regional Cancer Centre (TSRCC) for initial management from 1990-1995 before routine use of G-CSF. Sixty eligible patients were identified. 31 received CHOP +/- radiation (XRT), 9 other curative treatment and 20, palliative treatment. The mean ARRDI calculated on 29/31 patients receiving CHOP was .86; 41%=1.0, 24%=.90-.99, 14%=.75-.89 and 21%=.75. During 141 cycles of CHOP. 17 (12%) episodes of febrile neutropenia (FN) occurred in 14 (45%) patients and other grade 3/4 toxicity occurred in10% of patients. There were 3 (10%) toxic deaths. Sixteen (52%) patients required a total of 29 admissions to hospital for FN (59%) or other causes. Of the 31 patients, 16 (52%) achieved a complete remission (CR), 7 (23%) a partial remission-1 (PR-1), 2 (6%) a partial remission-2 (PR-2), 1 (3%) had no response (NR), 2 (6%) had progressive disease and 3 (10%) were not evaluable (NE). The median progression free survival (PFS) and overall survival (OS) were (16+) months and (24.5) months respectively. We found that physician biases resulted in the selection of; younger patients (median 71 vs. 80 years), patients with a better ECOG performance status (or =2, 13% vs. 50%) and patients with less co-morbid illness (42% vs. 90%) for attempt at curative treatment with CHOP chemotherapy. Age was never the sole reason for offering palliative treatment. In conclusion, a subset of patients over the age of 65 with aggressive NHL, who have a good performance status and minimal co-morbid illness can tolerate full dose CHOP chemotherapy without G-CSF support. Future strategies should emphasize full dose treatment with curative intent with minimization of both hematologic and non-hematologic toxicity. Clinical studies are required to determine whether routine G-CSF support will reduce toxicity or improve outcome in this group of patients.

Summary Background Monoclonal antibodies are being utilized for treatment of patients with low-grade non-Hodgkin’s lymphoma as well as other cancers. Results from phase I and II clinical studies has shown that the chimeric monoclonal antibody Rituximab has minimal toxicity and significant therapeutic activity in low grade non-Hodgkin’s lymphoma. Patients and methods We have recently reported on a multicentre pivotal phase III clinical trial involving 166 patients with recurrent low-grade lymphoma who were treated with four infusions of Rituximab. Eighty patients (48%) achieved objective responses including 10 patients (6%) with complete responses. Overall, 126 patients (76%) had a ≥ 20% reduction in overall tumor size. The median response duration and time to progression are 11.6 and 13.2 months, respectively. The infusional and long term toxicities were limited. Results In this report we describe the pharmacokinetic data obtained on these patients. Measurable concentrations of Rituximab were detected in all patients after the first infusion and increased throughout the treatment course. The half-life of the monoclonal antibody increased from 76.3 hours after the first infusion to 205.8 hours after the fourth infusion and was concomitant with a four-fold decrease in the antibody clearance. At three months and six months post-treatment, the median Rituximab serum levels were 20.3 μg/ml (range 0.0 to 96.8 μg/ml in 104 patients) and 1.3 μg/ml (range 0.0–28.7 μg/ml in 13 patients), respectively. A statistically significant correlation was found between the median antibody concentration and response for multiple time points during the treatment and followup. The mean serum antibody concentration was also inversely correlated with measurements of tumor bulk and with the number of circulating B cells at baseline. Conclusions We conclude that Rituximab is therapeutically effective against B-cell lymphoma. Pharmacokinetic data suggests that certain subsets of patients may possibly benefit from increased dosing and studies to address this are currently underway.

We have studied, as part of a group of international multicenter phase II clinical trials, the toxicity and effectiveness of CAMPATH1H administered intravenously three times a week in an outpatient setting to patients with recurrent or progressive low grade lymphoma. We report here on the toxicity and therapeutic results of the first seven patients treated before the study was closed prematurely because of unacceptable toxicity. Classical complete or partial responses of treatment were seen in three of seven patients. One complete response lasted 8.5 months and the other complete response is ongoing at 1 year. Responses occurred in nodal sites as well as in skin and peripheral blood. The first three or four antibody infusions in each patient was associated with grade 1 or 2 side-effects including rigor, fever, facial flushing, nausea, vomiting, hives, wheezes, hypotension, and/or diarrhea but these subsequently decreased or disappeared. The most significant toxicity was profound lymphopenia and associated infection, usually viral. Six of seven patients had culture or serologically documented infections and four patients had two or more such episodes. All infections responded to temporary discontinuation of antibody therapy and appropriate antiviral or antibiotic agents. We conclude that CAMPATH1H monoclonal antibody has therapeutic activity against low grade non-Hodgkin's lymphoma but that this activity is limited by marked lymphopenia and an unacceptably high frequency of serious infection at the dose and schedule used in this trial.

PURPOSE The purpose of this review was to assess the outcome of patients with non-Hodgkin's lymphoma (NHL) who achieve an incomplete or slow response to front-line chemotherapy and to determine whether salvage treatment with intensive combination chemotherapy with or without autologous bone marrow transplantation (ABMT) is successful in such patients. METHODS A comprehensive literature search of studies using combination chemotherapy for the front-line therapy of advanced-stage intermediate- and high-grade NHL and for salvage therapy of patients with a partial response (PR) was reviewed. RESULTS The median survival duration of patients with a PR ranged between 5 to 14 months, while the median survival duration of patients with a complete response (CR) was not reached in many studies. For patients in CR, the probability of survival at 24 months ranged between 0.79 to 1, while for patients in PR it ranged from 0 to 0.31. The rapidity of a response to front-line therapy was often found to be of prognostic importance. Patients who relapsed after a PR to front-line therapy had similar outcomes to intensive salvage therapy as those who relapsed after a CR. ABMT performed immediately after a PR to induction therapy, before progressive disease occurred, resulted in high CR rates in nonrandomized studies. CONCLUSION Patients with aggressive NHL who experience a PR or who respond slowly to front-line chemotherapy have a poor prognosis. Early introduction of dose-intensive salvage therapy before the development of progressive disease may benefit patients with a PR and requires testing in randomized clinical trials.