tbuckley/cabot-search huggingface dataset:
Successful Treatment of Immune Checkpoint Inhibitor–Induced Diabetes With Infliximab
Authors: Beckey Trinh, Marc Y. Donath, Heinz Läubli
Journal: Diabetes Care (2019)

We report a case of a 53-year-old male patient with melanoma who was treated with combination immune checkpoint blockade (ICB) with ipilimumab and nivolumab. The patient had advanced disease with metastasis to the liver, lung, and lymph nodes. After two doses of ICB, the patient developed hypocalcemia as a result of an immune-mediated hypoparathyroidism that was treated with calcium and vitamin D substitution. In addition, the patient suffered from immune-related colitis that required treatment with corticosteroids and two doses of infliximab. Combination immunotherapy led to a metabolic complete remission of the melanoma. After tapering corticosteroids, the patient was continued on nivolumab for several weeks. No abnormalities of blood glucose were noted until then in an otherwise lean patient with a BMI of 19.6 kg/m2. When the patient developed a seronegative oligoarthritis affecting the right knee and both ankles, he was treated with …
Paradoxical effect of regulatory T-cell density in the invasive margin on colon cancer disease-free survival.
Authors: Jamie Lombardo, Lynn Messersmith, Grant Williams, Annelies Hickerson, Jessica Campf, Ryan Collins, Robert Brady, George Earl Peoples, Guy T. Clifton
Journal: Journal of Clinical Oncology (2019)

47 Background: Increased numbers of FoxP3+ regulatory T cells (Treg), an immunosuppressive T cell subpopulation, in the tumor microenvironment (TME) has been associated with decreased recurrence risk in colon cancer. We assessed the association of Treg levels and disease-free survival (DFS) to confirm correlation with recurrence risk and to evaluate the impact on DFS in patients with colon cancer. Methods: Cases of colonic adenocarcinoma with endoscopic biopsies who had curative resection were collected from 2006-2016. The tissue sections were stained with FoxP3 immunohistochemical stain. FoxP3+ cells (Tregs) were counted with a digital imager software program and reported as cells per square mm. DFS from time of surgery was determined with a retrospective chart review. FoxP3 levels were compared with a Man-Whitney U test and DFS was compared with a Spearman’s test and regression. Results: 109 matched endoscopic biopsy colonic adenocarcinoma specimens were gathered. 94 cases had at least 4 months of follow up and were analyzed. The recurrence rate was 21.3% (20/94) with a median recurrence time of 13.5 months. The median time to follow up in patients with no recurrence was 39 (range 4-116) months. Tregs in those that recurred had a mean density of 152 (range 9-1267) at the invasive margin compared to 251 (range 15-485) in the cases that did not yet recur (p = 0.005). The same association was observed with Treg density in the center of the tumor (p = 0.03). In the cases that had a recurrence, there was a moderate, inverse correlation between Tregs at the invasive margin and time to recurrence (Spearman’s correlation coefficient = -0.46, p = 0.04.) A logarithmic inverse relationship between Tregs at the invasive margin and time to recurrence was observed (Correlation coefficient -0.63, p = 0.003). Conclusions: Treg density in endoscopic biopsies in colon adenocarcinoma is associated with recurrence risk, consistent with previously reported observations. Paradoxically, in patients who did recur, higher Treg density was associated with shorter time to recurrence. This discordant relationship of Treg density and colon cancer prognosis warrants further investigation.
Early progression of disease (POD24) as survival predictor in MALT lymphoma.
Authors: Annarita Conconi, Catherine Thieblemont, Luciano Cascione, Valter Torri, Barbara Kiesewetter, Gloria Margiotta-Casaluci, Gianluca Gaidano, Markus Raderer, Franco Cavalli, Armando Lopez-Guillermo, Peter W. M. Johnson, Emanuele Zucca
Journal: Journal of Clinical Oncology (2019)

7548 Background: Progression of disease within two years from start of therapy (POD24) is linked with poor outcome in follicular lymphoma. It is less clear whether POD24 affects overall survival (OS) also in extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). Methods: We analyzed the dataset of the IELSG19 clinical trial (training set) to determine whether POD24 is associated with inferior OS. The study population included 401 EMZL patients (131 randomly assigned to chlorambucil treatment, 138 to rituximab and 132 to chlorambucil plus rituximab). Reproducibility was analyzed in an independent cohort (validation set) of 218 patients who received systemic treatment (chemotherapy, immunotherapy or both). In both, training and validation sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without progression. Overall survival (OS) was calculated from disease progression in patients with POD24 and from 24 months after start of treatment in those without POD24 (reference group). Results: POD24 was observed in 69 of 401 patients of the IELSG19 study and 58 of 218 patients in the validation cohort. In the training set, the 10-year OS rates were 64% in the POD24 group and 85% in the reference group (HR = 2.42, 95%CI, 1.35-4.34; log-rank P = 0.002) and POD24 predicted poor outcome regardless of treatment type (multivariable Cox model, P = 0.003). The prognostic impact of POD24 was confirmed in the validation set, with 10-year OS rates of 48% in the POD24 group and 71% in the reference group (HR = 2.17, 95%CI, 1.20-3.93; log-rank P = 0.009). Conclusions: In patients with EMZL who received front-line systemic treatment, POD24 is associated with poorer survival and may represent a useful endpoint in future prospective clinical trial.
Expression of the type 3 InsP<sub>3</sub>receptor is a final common event in the development of hepatocellular carcinoma
Authors: Mateus T Guerra, Rodrigo M Florentino, Andressa Franca, Antonio C Lima Filho, Marcone L dos Santos, Roberta C Fonseca, Fernanda O Lemos, Matheus C Fonseca, Emma Kruglov, Albert Mennone, Basile Njei, Joanna Gibson, Fulan Guan, Yung-Chi Cheng, Meenakshisundaram Ananthanarayanam, Jianlei Gu, Jianping Jiang, Hongyu Zhao, Cristiano X Lima, Paula T Vidigal, Andre G Oliveira, Michael H Nathanson, Maria Fatima Leite
Journal: Gut (2019)

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca
Abstract 17876: Risk Factors and Thirty-day Adverse Events in Emergency Department Patients With Symptoms of Myocardial Ischemia With and Without Diabetes
Authors: Leonie L Rose Bovino, Vanessa Jefferson, Richard S Feinn
Journal: Circulation (2015)

Objective: To evaluate the association between diabetes and demographic and clinical characteristics and 30-day adverse cardiovascular events (return to the emergency department [ED] with signs and/or symptoms of acute myocardial ischemia, all-cause admission, acute myocardial infarction, use of reperfusion therapy, and all-cause mortality) in patients presenting to the ED with chest pain and/or symptoms suggestive of acute myocardial ischemia. Methods: We conducted a cross-sectional study of 163 adult patients presenting to the ED at a single hospital with symptoms of acute myocardial ischemia warranting evaluation with an electrocardiogram and a cardiac troponin test. We analyzed data collected 30±7 days after ED/hospital discharge from the index visit. Using chi-squared tests, we compared patients with a history of diabetes (n=65) to those without (n=98) on demographic and clinical characteristics and on 30-day adverse cardiovascular events. Findings: Patients with a history of diabetes were significantly more likely to be older (p&lt;.001), overweight (p=.003), have a history of coronary artery disease (p&lt;.001), heart failure (p=.016), and hyperlipidemia (p&lt;.001) than patients without a history of diabetes. We found a significant association between a history of diabetes and a composite of 30-day adverse cardiovascular events (p=.036). We also found a significant association between a history of diabetes and admission to the hospital within 30 days of the index visit (p=.015). Conclusion: Study findings emphasize the predominance of more modifiable and non-modifiable cardiovascular risk factors in patients with diabetes compared to those without diabetes among patients presenting to the ED with signs and/or symptoms of acute myocardial ischemia. Past research has demonstrated a strong association of optimal weight, glycemic, and blood pressure management with protective benefits in patients with diabetes. Tailored educational interventions in the ED may reduce modifiable risks in these patients, their hospital return rate, and likelihood of 30-day adverse cardiovascular outcomes.
Prostaglandin E2 (PGE2)–EP2 signaling negatively regulates murine atopic dermatitis–like skin inflammation by suppressing thymic stromal lymphopoietin expression
Authors: Yu Sawada, Tetsuya Honda, Satoshi Nakamizo, Saeko Nakajima, Yumi Nonomura, Atsushi Otsuka, Gyohei Egawa, Tomohiro Yoshimoto, Motonobu Nakamura, Shuh Narumiya, Kenji Kabashima
Journal: Journal of Allergy and Clinical Immunology (2019)
Comparative Effectiveness of New Approaches to Improve Mortality Risk Models From Medicare Claims Data
Authors: Harlan M. Krumholz, Andreas C. Coppi, Frederick Warner, Elizabeth W. Triche, Shu-Xia Li, Shiwani Mahajan, Yixin Li, Susannah M. Bernheim, Jacqueline Grady, Karen Dorsey, Zhenqiu Lin, Sharon-Lise T. Normand
Journal: JAMA Network Open (2019)

Risk adjustment models using claims-based data are central in evaluating health care performance. Although US Centers for Medicare & Medicaid Services (CMS) models apply well-vetted statistical approaches, recent changes in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding system and advances in computational capabilities may provide an opportunity for enhancement.To examine whether changes using already available data would enhance risk models and yield greater discrimination in hospital-level performance measures.This comparative effectiveness study used ICD-9-CM codes from all Medicare fee-for-service beneficiary claims for hospitalizations for acute myocardial infarction (AMI), heart failure (HF), or pneumonia among patients 65 years and older from July 1, 2013, through September 30, 2015. Changes to current CMS mortality risk models were applied incrementally to patient-level models, and the best model was tested on hospital performance measures to model 30-day mortality. Analyses were conducted from April 19, 2018, to September 19, 2018.The main outcome was all-cause death within 30 days of hospitalization for AMI, HF, or pneumonia, examined using 3 changes to current CMS mortality risk models: (1) incorporating present on admission coding to better exclude potential complications of care, (2) separating index admission diagnoses from those of the 12-month history, and (3) using ungrouped ICD-9-CM codes.There were 361 175 hospital admissions (mean [SD] age, 78.6 [8.4] years; 189 225 [52.4%] men) for AMI, 716 790 hospital admissions (mean [SD] age, 81.1 [8.4] years; 326 825 [45.6%] men) for HF, and 988 225 hospital admissions (mean [SD] age, 80.7 [8.6] years; 460 761 [46.6%] men) for pneumonia during the study; mean 30-day mortality rates were 13.8% for AMI, 12.1% for HF, and 16.1% for pneumonia. Each change to the models was associated with incremental gains in C statistics. The best model, incorporating all changes, was associated with significantly improved patient-level C statistics, from 0.720 to 0.826 for AMI, 0.685 to 0.776 for HF, and 0.715 to 0.804 for pneumonia. Compared with current CMS models, the best model produced wider predicted probabilities with better calibration and Brier scores. Hospital risk-standardized mortality rates had wider distributions, with more hospitals identified as good or bad performance outliers.Incorporating present on admission coding and using ungrouped index and historical ICD-9-CM codes were associated with improved patient-level and hospital-level risk models for mortality compared with the current CMS models for all 3 conditions.
Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma
Authors: Anja Mottok, Stacy S. Hung, Elizabeth A. Chavez, Bruce Woolcock, Adèle Telenius, Lauren C. Chong, Barbara Meissner, Hisae Nakamura, Christopher Rushton, Elena Viganò, Clementine Sarkozy, Randy D. Gascoyne, Joseph M. Connors, Susana Ben-Neriah, Andrew Mungall, Marco A. Marra, Reiner Siebert, David W. Scott, Kerry J. Savage, Christian Steidl
Journal: Blood (2019)
The i3+3 design for phase I clinical trials.
Authors: Yuan Ji, Meizi Liu
Journal: Journal of Clinical Oncology (2019)

3066 Background: Other than the 3+3 design, new model-based statistical designs like the mTPI design (Ji and Wang, 2013, JCO) are alternative choices for oncology dose-finding trials, including immune oncology dose-finding trials (Atkins et al., 2018, Lancet Oncology). One major criticism of the 3+3 design is that it is based on simple rules, does not depend on statistical models for inference, and leads to unsafe and unreliable operating characteristics. However, the rule-based nature allows 3+3 to be easily understood and implemented in practice, making it practically attractive and friendly. Can friendly rule-based designs achieve great performance seen in model-based designs? For four decades, the answer has been NO. Methods: We propose a new rule-based design called i3+3, where the letter "i" represents the word "interval". The i3+3 design is based on simple but more clever rules that account for the variabilities in the observed data. In short, the i3+3 design simply asks clinicians to compare observed toxicity rates with a prespecified toxicity interval, and make dose escalation decisions according to three simple rules. No sophisticated modeling is needed and the entire design is transparent to clinicians. Results: We compare the operating characteristics for the proposed i3+3 design with other popular phase I designs by simulation. The i3+3 design is far superior than the 3+3 design in trial safety and the ability to identify the true MTD. Compared with model-based phase I designs, i3+3 also demonstrates comparable performances. In other words, the i3+3 design possesses both simplicity and transparency of the rule-based approaches, and the superior operating characteristics seen in model-based approaches. An online R Shiny tool is provided to illustrate the i3+3 design, although in practice it requires no software to design or conduct a dose-finding trial using the design. Conclusions: The i3+3 design could be a practice-altering method for the clinical community. It may increase the safety and efficiency of dose finding trials.
Phase II study of preemptive high dose chemotherapy and autologous stem cell transplantation for lymphoma based on early FDG-PET scanning
Authors: Y. L. Kasamon, R. Wahl, H. Ziessman, E. Garrett-Mayer, R. J. Jones, R. F. Ambinder, I. W. Flinn, L. J. Swinnen
Journal: Journal of Clinical Oncology (2006)

7561 Background: [ 18 F] FDG-PET after only 2–4 cycles of initial chemotherapy is highly prognostic in patients (pts) with aggressive lymphoma, with reported relapse rates of 71–100% if PET demonstrates residual viable disease. We hypothesized that midtreatment PET could optimize pt selection for preemptive transplantation through early risk stratification. Methods: A phase II, single center trial was activated in 2/2004. Pts with newly diagnosed aggressive non-Hodgkin’s lymphoma underwent PET-CT on days 11–20 of cycle 2 or 3 of (R)CHOP. Regardless of IPI, pts whose PET was considered positive for macroscopic residual lymphoma received 2 cycles of (R)ESHAP or (R)ICE, followed by autologous transplantation (busulfan-cyclophosphamide conditioning). Pts with negative interim PET completed standard therapy. We aimed to transplant ≥20 pts to detect a ≥25% absolute improvement in 2-year event-free survival (EFS) to 45%, versus 20% in a historical cohort of PET positive pts who did not receive early transplantation (85% power and two-sided alpha of 0.05). An ongoing imaging analysis of gradations of FDG uptake, scored as 0 to 4+, will be correlated with outcome. Results: As of 1/6/2006, 41 evaluable pts have been accrued, 39 with large B-cell lymphoma (8 primary mediastinal), 1 follicular large cell, 1 peripheral T-cell. Median age at diagnosis was 50 (20–78); 26 pts were stage III or IV. Twenty-five pts (61%) had a positive midtreatment PET. Of 26 pts with IPI of 0–2, 17 (65%) had positive PET; of 13 pts with IPI of ≥3, 8 (62%) were positive; 2 pts had undetermined IPI. The actuarial 1-year EFS from the time of midtreatment imaging is 78% for the group as a whole, 69% for PET positive pts, 81% for PET negative pts. Twenty pts have completed transplant, and 2 were ineligible because of early disease progression. Two transplant recipients have relapsed. Treatment-related mortality has been limited to 1 death from veno-occlusive disease. Conversion from PET positive to negative at initial post-transplant assessment occurred in 68%. The actuarial 1-year EFS after transplantation at 10 month median follow-up is 82%. Conclusions: Immediate intensification of therapy for poor-risk pts identified by midtreatment PET has been feasible and so far very promising. [Table: see text]
Extraordinary increase in West Nile virus cases and first confirmed human Usutu virus infection in Hungary, 2018
Authors: Anna Nagy, Eszter Mezei, Orsolya Nagy, Tamás Bakonyi, Nikolett Csonka, Magdolna Kaposi, Anita Koroknai, Katalin Szomor, Zita Rigó, Zsuzsanna Molnár, Ágnes Dánielisz, Mária Takács
Journal: Eurosurveillance (2019)

Background During the 2018 WNV transmission season, similarly to other endemic areas in Europe, a large number of human West Nile virus (WNV) infections were reported in Hungary. Aims We summarise the epidemiological and laboratory findings of the 2018 transmission season and expand experiences in flavivirus differential diagnostics. Methods Every patient with clinical suspicion of acute WNV infection was in parallel tested for WNV, tick-borne encephalitis virus and Usutu virus (USUV) by serological methods. Sera, whole blood and urine samples were also tested for the presence of viral nucleic acid. Results Until the end of December 2018, 215 locally acquired and 10 imported human WNV infections were notified in Hungary. All reported cases were symptomatic; most of them exhibited neurological symptoms. In a large proportion of tested individuals, whole blood was the most appropriate sample type for viral nucleic acid detection, but because whole blood samples were not always available, testing of urine samples also extended diagnostic possibilities. In addition, the first human USUV infection was confirmed in 2018 in a patient with aseptic meningitis. Serological cross-reactions with WNV in different serological assays were experienced, but subsequent molecular biological testing and sequence analysis identified Europe lineage 2 USUV infection. Conclusion Careful interpretation and simultaneous application of different laboratory methods are necessary to avoid misdiagnosis of human USUV cases. Expansion of the laboratory-confirmed case definition criteria for detection of viral RNA in any clinical specimens to include urine samples could increase diagnostic sensitivity.
Phase I trial of a novel DNA vaccine in patients (pts) with smoldering Waldenstrom macroglobulinemia (sWM).
Authors: Sheeba K. Thomas, Soungchul Cha, Sapna R Parshottam, Sheetal S Rao, Jasper B. Olsem, Brandon N. Crumpton, Lei Feng, Hans Chulhee Lee, Elisabet Esteve Manasanch, Donna M. Weber, Krina K. Patel, Robert Z. Orlowski, Sattva Swarup Neelapu, Larry W. Kwak
Journal: Journal of Clinical Oncology (2019)

8050 Background: Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given pt’s B-cell lymphoma are unique to that tumor, and thus are a tumor-specific marker. This study aims to use an idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies. Administered vaccine used recombinant plasmid DNA encoding a fusion protein, consisting of autologous lymphoma scFv (pt-specific idiotype) and human CCL20 (macrophage inflammatory protein-3 alpha - MIP-3α) chemokine. Targeted delivery of this fusion protein to APCs, and subsequent processing and presentation, is hypothesized to break tolerance and generate an immune response against the idiotype, promoting eradication of antigen-expressing B-cell lymphoma cells. Methods: Pts with sWM received 3 i.d. vaccinations of pt-specific DNA vaccine at 4-week (wk) intervals (wks 0, 4 and 8). Two dose levels (500µg; 2500µg) were evaluated in a 3+3 design. Primary objective: to evaluate the vaccine’s safety and identify it’s MTD. Secondary objectives: 1) to assess immunogenicity of the vaccine 2) to determine time to symptomatic WM. Results: Between 1/2016 - 1/2019, 9 pts (7 men) were treated (500 µg: n = 3; 2500µg: n = 6). Median age at enrollment was 67 yrs (range 56-78); median time from diagnosis to 1 st vaccination was 26.5 mos (8.8-120.9). MYD88 L265P + (6 pts). CXCR4 WHIM + (1 pt). With median follow up of 26.5 months (range: 8-36.4), all pts remain alive. Seven have stable disease; 2 progressed to symptomatic WM (8 mos. (1pt) and 26 mos. (1pt) from 1 st vaccination). All pts completed planned therapy. No DLTs or Grade 4 AEs occurred. Ten mos. after the 3 rd vaccination, 1 pt had a grade 3 pleural effusion and leukopenia with an increase in rheumatoid factor (23.1 IU/mL [normal range 0.0-15.9]) and ANA titer of 1:80; all resolved within 2 mos. Grade 1-2 AEs ( &gt; 3pts): leukopenia (6), nausea (5), anemia (4), increased creatinine (4), fatigue (4). Conclusions: Idiotype (scFv-CCL20) DNA vaccine therapy appears to be safe in pts with sWM. Results of immunogenicity assays are underway, and will inform whether tumor specific immune responses are induced. Additional follow up is required to determine time to symptomatic WM. Clinical trial information: NCT01209871.