tbuckley/cabot-search huggingface dataset:
Autoantibody‐Positive Healthy Individuals Display Unique Immune Profiles That May Regulate Autoimmunity
Authors: Samantha Slight‐Webb, Rufei Lu, Lauren L. Ritterhouse, Melissa E. Munroe, Holden T. Maecker, Charles G. Fathman, Paul J. Utz, Joan T. Merrill, Joel M. Guthridge, Judith A. James
Journal: Arthritis & Rheumatology (2016)

Objective Antinuclear antibodies (ANAs) are detected in ∼18% of females, yet autoimmune disease develops in only 5–8%. Immunologic differences between ANA‐positive healthy individuals and patients with systemic lupus erythematosus (SLE) may elucidate the regulatory mechanisms by which ANA‐positive individuals avoid transition to clinical autoimmune disease. Methods Healthy individuals (n = 790) were screened for autoantibodies specific for 11 antigens associated with lupus, systemic sclerosis, and Sjögren's syndrome. From this screening, 31 European American ANA‐positive healthy individuals were selected and demographically matched to ANA‐negative controls and SLE patients. Serum cytokine profiles, leukocyte subset frequency, and reactivity were analyzed by multiplex assays, immunophenotyping, and phosphospecific flow cytometry. Results Of 790 individuals screened, 57 (7%) were ANA‐positive. The majority of proinflammatory cytokines, including interferon‐γ (IFNγ), tumor necrosis factor, interleukin‐17 (IL‐17), and granulocyte colony‐stimulating factor, exhibited a stepwise increase in serum levels from ANA‐negative controls to ANA‐positive healthy individuals to SLE patients ( P &lt; 0.0001). IFNα, IFNβ, IL‐12p40, and stem cell factor/c‐Kit ligand were increased in SLE patients only ( P &lt; 0.05). B lymphocyte stimulator (BlyS) was elevated in SLE patients but decreased in ANA‐positive individuals ( P &lt; 0.001). Further, IL‐1 receptor antagonist (IL‐1Ra) was down‐regulated in SLE patients only ( P &lt; 0.0001). ANA‐positive individuals had increased frequencies of monocytes, memory B cells, and plasmablasts and increased levels of pSTAT‐1 and pSTAT‐3 following IFNα stimulation compared with ANA‐negative controls ( P &lt; 0.05). Conclusion ANA‐positive healthy individuals exhibit dysregulation in multiple immune pathways yet differ from SLE patients by the absence of elevated IFNs, BLyS, IL‐12p40, and stem cell factor/c‐Kit ligand. Further, severely decreased levels of IL‐1Ra in SLE patients compared with ANA‐positive individuals may contribute to disease development. These results highlight the importance of IFN‐related pathways and regulatory elements in SLE pathogenesis.
PWE-179 Cameron lesions as a cause of acute upper gastrointestinal bleeding and iron deficiency anaemia
Authors: N Papiamonis, K Fasoulakis, P Oustamanolakis, I Koutroubakis, E Kouroumalis
Journal: Gut (2015)

<h3>Introduction</h3> Cameron lesions are linear corrosions or ulcers in gastric folds of the diaphragmatic part in patients with a large sliding hiatal hernia. They are found in about 5% of the patients with a known hiatal hernia and are subjected to upper GI endoscopy. Multiple possible causes have been reported such as mechanical trauma and exposure to acids or ischemia on a local vascular level. Cameron lesions are usually responsible for chronic blood loss and iron deficiency anaemia. <h3>Method</h3> In a period of two years (2012–2013) the data of all patients who were hospitalised for acute upper gastrointestinal (GI) bleeding or examined on regular basis for iron deficiency anaemia were reviewed. The cases with Cameron lesions during upper GI endoscopy and considered as the main cause of haemorrhage or anaemia were analysed concerning demographics, clinical characteristics and treatment. <h3>Results</h3> The data of 434 patients with acute upper GI bleeding (180 cases) or iron deficiency anaemia (254 cases) were analysed. 21 patients (4,8%, 10 males and 11 females) with Cameron lesions were identified, aged between 50–91 years (95% CI 63.1–72.9, median age 68 years). Clinical presentation was melaena (8 patients) haematemesis (4 patients) and iron deficiency anaemia (8 patients). 8 patients reported NSAID’s use. The size of the hiatal hernia ranged from 2 to 10 cm (95% CI 4–6, median diameter 5 cm), while the ulcer diameter ranged from 0.7 to 2 cm (median diameter 1.2 cm). Hemostasis was performed in 2 patients (adrenaline, clips) and all cases received PPI treatment. In all patients the lesions were found at the first esophagoduodenoscopy. No relapse of acute GI bleeding was reported on follow up. <h3>Conclusion</h3> Apart from iron deficiency anaemia, Cameron lesions may be responsible for acute upper GI bleeding. They should be sought in patients with a hiatal hernia where no other cause of haemorrhage or anaemia can be found. <h3>Disclosure of interest</h3> None Declared.
REGARD: A phase 3, randomized, double-blind trial of ramucirumab (RAM) and best supportive care (BSC) versus placebo (PL) and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression (PD) on first-line platinum- and/or fluoropyrimidine-containing combination therapy: Age subgroup analysis.
Authors: Charles S. Fuchs, Jiri Tomasek, Jae Yong Cho, Gianluca Tomasello, Chanchal Goswami, Lucas Vieira dos Santos, Giuseppe Aprile, David Ferry, Bohuslav Melichar, Mustapha Ali Tehfe, Eldar Topuzov, John Raymond Zalcberg, Ian Chau, Josep Tabernero, Yanzhi Hsu, Jonathan D. Schwartz, Minori Koshiji, Howard Safran
Journal: Journal of Clinical Oncology (2014)

4057 Background: The REGARD trial demonstrated significant improvements in overall survival (OS), progression free survival (PFS), and disease control rates in pts receiving RAM, a human IgG1 receptor targeted antibody. We examined outcomes by age (<65 and ≥65 years [yrs]). Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or PL plus BSC every 2 wks until PD, unacceptable toxicity, or death. Eligible patients had PD within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was OS. Secondary endpoints included PFS, 12-wk PFS rate, overall response rate (ORR) and safety. Results: 355 pts. were randomized; 227 were age <65 yrs (RAM 156; PL 71) and 128 were ≥ 65 yrs (RAM 82; PL 46).Baseline characteristics were well balanced between the treatment arms and subgroups. RAM efficacy was similar in younger and older patients. Median OS was 5.3 vs 4.1 m in the RAM:PL arms for pts <65 yrs and 5.2 vs 3.8 m in the RAM:PL arms for pts ≥65 yrs. The OS HR was 0.846 (95% CI, 0.611-1.171) in pts <65 years and 0.722 (95% CI 0.471-1.106) in pts ≥65 yrs (treatment-by-age group interaction p = 0.5569). Median PFS was 1.9 vs 1.3m in the RAM:PL arm for pts <65 yrs and 2.8 vs 1.4 m for Ram:PL for pts ≥65 yrs. The PFS HR was 0.450 (95% CI, 0.327-0.620) <65 yrs and 0.490 (95% CI, 0.319-0.752) (interaction p=0.9445). The incidence of Grade ≥3 adverse events was comparable between treatment arms for both age groups (55% vs 57% pts <65 yrs; 60% pts ≥65 yrs in both arms). The most frequent grade ≥ 3 AEs in ≥ 5% of pts RAM arm were: hypertension (7.8% RAM; 1.4% PL [<65 yrs] and 7.3% RAM; 4.4% PL [≥65 yrs]), abdominal pain (7.1% RAM; 4.3% PL [<65 yrs]), fatigue (7.3% RAM; 2.2% PL ≥ 65 yrs) and anemia (9.1% RAM; 7.1% PL [<65 yrs]. No specific AE was observed at grade ≥ 3 in > 10% of patients.Conclusions: When compared to placebo, RAM conferred similar improvements for OS and PFS between pts age < 65 yrs and those age ≥ 65; AE profiles were also similar for pts ≥ 65 and <65 yrs. Clinical trial information: NCT00917384.
A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)
Authors: T. F. Cloughesy, M. D. Prados, P. Y. Wen, T. Mikkelsen, L. E. Abrey, D. Schiff, W. K. Yung, Z. Maoxia, I. Dimery, H. S. Friedman
Journal: Journal of Clinical Oncology (2008)

2010b Background: Effective 2nd-line therapies are absent in GBM leading to poor survival. VEGF upregulation is implicated in GBM tumorigenesis. In a single-arm PhII trial of BV + CPT in recurrent GBM, activity was demonstrated, warranting further investigation of clinical benefit of BV alone, and in combination with CPT (Vredenburgh J, JCO 2007). Methods: From June 2006 to Feb 2007, 167 patients (pts) with recurrent GBM were randomized 1:1 to BV (10 mg/kg q 2 wks) (Arm 1, n=85) or BV + CPT (340 mg/m2 if enzyme-inducing anti- epileptic drugs (AEDs) and 125 mg/m2 for non-AEDs) (Arm 2, n=82), stratified by KPS: 70–80, 90–100, and relapse (1st or 2nd). The co- primary endpoints were PFS6 (defined at 24-weeks) and objective response rate (ORR) determined by an independent radiology facility (IRF), with secondary endpoints of safety, PFS, and duration of response determined by IRF, and overall survival. The trial provided approximately 80% power to detect 13% improvement in PFS6 from an assumed rate of 15%, and 90% power to detect 13% improvement in ORR from assumed rates of 5% (Arm 1) and 10% (Arm 2) (2-sided significance level of 0.025). Results: Clinical outcomes are shown in Table 1. Median OS was based on 61.2% of deaths for BV alone and 67.1% of deaths for BV+CPT. One intracranial hemorrhage occurred in Arm 1 (Gr 1; 1.2%) and one in Arm 2 (Gr 4; 1.3%) during planned treatment period. The dose of corticosteroid required diminished from baseline to cycle 4 (Table 1). Benchmarking OS to that in a national GBM database is ongoing. Ä in KPS and neurocognitive function from baseline, and post-progression response will be presented. Conclusions: Both the PFS6 and OS of >9 months with BV alone or with CPT provides encouraging evidence of significant activity in this poor prognosis population. In addition, the reduction in corticosteroid use has the potential to provide benefit to patients. Randomized Subjects BV (n=85) BV + CPT (n=82) Median OS months (95% CI) 9.7 (8.2–11.8) 8.9 (7.8–11.9) PFS6 % (97.5% CI) 35.1 (23.2–47.0) 50.2 (36.6–63.8) ORR % (97.5% CI) 20 (12.7–29.5) 32.9 (23.4–43.5) Treated Subjects BV (n=84) BV + CPT (n=79) Grade >3 toxicities, % 47.6 67.1 Grade 5 AEs, % 2.4 1.3 BV discontinuation due to AEs, % 3.5 13.9 Corticosteroid dose (mg/kg) BV (n=84) BV + CPT (n=79) N, Mean (SD) Day 1 44, 7.3 (7.37) 46, 8.0 (4.96) Day 42 41, 5.0 (5.59) 44, 7.5 (5.71) Day 84 34, 3.1 (2.80) 34, 4.7 (3.68) Day 126 21, 2.7 (3.13) 21, 3.9 (2.60) Day 168 12, 1.1 (1.04) 15, 4.4 (4.13) No significant financial relationships to disclose.
Open label, randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC (T-FEC) versus the combination of paclitaxel and RAD001 followed by FEC (TR-FEC) in women with triple receptor-negative breast cancer (TNBC).
Authors: A. M. Gonzalez-Angulo, M. C. Green, J. L. Murray, S. L. Palla, K. H. Koenig, A. M. Brewster, V. Valero, N. K. Ibrahim, S. L. Moulder, J. K. Litton, D. J. Crawford, P. R. Flores, M. J. Dryden, W. F. Symmans, S. H. Giordano, L. Pusztai, A. Buzdar, G. B. Mills, G. N. Hortobagyi, F. Meric-Bernstam
Journal: Journal of Clinical Oncology (2011)

1016 Background: TNBC is an aggressive disease and the only subtype with no specific targeted therapy. PI3K pathway activation occurs frequently in TNBC and confers susceptibility to mTOR inhibitors as RAD001. mTOR inhibition synergistically enhances taxane-induced cytotoxicity in breast cancer cells including TNBC in vitro and in vivo. Methods: We conducted a single institution phase II study in patients (pts) with primary TNBC randomized to T-FEC (paclitaxel 80mg/m2 IV weekly for 12 weeks, followed by 5FU 500mg/m2, epirubicin 100mg/m2, and cyclophosphamide 500mg/m2 every 3 weeks for 4 cycles) vs TR-FEC (paclitaxel 80mg/m2 IV and RAD001 30mg PO weekly for 12 weeks, followed by 5FU 500mg/m2, epirubicin 100mg/m2, and cyclophosphamide 500mg/m2 IV every 3 weeks for 4 cycles). Clinical endpoints included 12-week response rate (12wk RR, complete or partial response), pathological complete response (pCR), and toxicity. Tumor samples were collected to assess molecular changes in the PI3K pathway, at baseline, 48-hours, 12-weeks and at surgery (data not presented). Results: 62 pts were registered, and 50 were randomized from August 2007 to August 2010: 27 received T-FEC and 23 received TR-FEC. Median age was 48 (range 31−75). 12wk RR by ultrasound were (8/27) 29.6% vs (11/23) 47.8% for T-FEC and TR-FEC respectively (p=0.15 one-sided). At the time of submission, the last pt was scheduled for surgery; pCR data will be presented at the meeting. Main NCI grade 3/4 toxicities included anemia 4% vs. 13% (P=0.322), leukopenia 11% vs. 17%, (P=0.689), rash/desquamation 7% vs. 9%, (P>0.999), vomiting 4% vs. 13% (P=0.322), in T-FEC and TR-FEC respectively. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. Conclusions: The addition of RAD001 to paclitaxel in the neoadjuvant setting was well tolerated. TR was associated with a higher 12wk RR rate than T; this did not reach statistical significance given our small sample size. Larger, studies are warranted to study this combination. Biomarker analysis in ongoing to further optimize patient selection.
Studies in the Home Treatment of Streptococcal Disease
Authors: Daniel N. Mohler, David G. Wallin, Edward G. Dreyfus, Henry J. Bakst
Journal: New England Journal of Medicine (1956)

PATIENTS with streptococcal pharyngitis were formerly treated by the Home Medical Service of the Massachusetts Memorial Hospitals with a seven-day course of penicillin by mouth. However, when it became apparent that more than a third of these patients were failing to take the full prescribed course of penicillin, it was decided to change to intramuscular injections of benzathine penicillin.1 There have been many favorable reports in the recent literature concerning the effectiveness of a single injection of benzathine penicillin G for the treatment of infections with the beta-hemolytic streptococcus.2 3 4 A single injection of 600,000 units of this repository penicillin has . . .
Lifetime Use of Nursing Home Care
Authors: Peter Kemper, Christopher M. Murtaugh
Journal: New England Journal of Medicine (1991)

Despite the growth in the number of Americans in nursing homes, there are only limited data on the total amount of time that people spend in such facilities. We estimate the amount of time the average person spends in nursing homes over his or her lifetime (lifetime nursing home use), using data from the National Mortality Followback Survey of the next of kin of a sample of persons 25 years of age or older who died in 1986. On the basis of these data, we estimated the likelihood that Americans will use nursing home care during the course of their lifetimes and the total duration of such care. Current data on life expectancy were then used to reweight the sample to project lifetime nursing home use for those who became 65 years old in 1990.Of those who died in 1986 at 25 years of age or older, 29 percent had at some time been residents in a nursing home, and almost half of those who entered a nursing home spent a cumulative total of at least one year there. The probability of nursing home use increased sharply with age at death: 17 percent for age 65 to 74, 36 percent for age 75 to 84, and 60 percent for age 85 to 94. For persons who turned 65 in 1990, we project that 43 percent will enter a nursing home at some time before they die. Of those who enter nursing homes, 55 percent will have total lifetime use of at least one year, and 21 percent will have total lifetime use of five years or more. We also project that more women than men will enter nursing homes (52 percent vs. 33 percent), and among them, more women than men will have total lifetime nursing home use of five years or more (25 percent vs. 13 percent).Our projections indicate that over a lifetime, the risk of entering a nursing home and spending a long time there is substantial. With the elderly population growing, this has important implications for both medical practice and the financing of long-term care.
Pamidronate for Bone Pain from Osteolytic Lesions in Langerhans'-Cell Histiocytosis
Authors: Karo Arzoo, Saeed Sadeghi, Vinod Pullarkat
Journal: New England Journal of Medicine (2001)

To the Editor: Bernard and coworkers (March 8 issue) 1 conclude that recombinant human activated protein C (drotrecogin alfa [activated]) is efficacious in patients with sepsis.The placebo and treatment groups appeared to be closely matched, with one important exception: the interval between the diagnosis of sepsis and the administration of appropriate antibiotic therapy.The authors state only that appropriate antibiotic therapy was started within 48 hours of the diagnosis of severe sepsis.It is axiomatic that the more severe the sepsis, the more important the requirement for prompt administration of appropriate antibiotic therapy.In a study of gram-negative bacterial sepsis in mice, we demonstrated that each hour that appropriate antibiotic therapy was delayed resulted in progressive increases in mortality. 2After a delay of three to eight hours, depending on the bacterial species, mortality by day 4 was no longer reducible.Windows of antibiotic effectiveness can also close so rapidly during severe sepsis in humans that even prompt initiation of antibiotic therapy may not reduce mortality significantly. 3 We agree that difficulty determining the time of onset of sepsis is a major impediment to progress in clinical trials, whereas animal models do not pose this problem. 4Nevertheless, because each hour of delay in initiating appropriate antibiotic therapy in patients with severe sepsis may affect the outcome, the greatest possible precision must be used in showing that this factor is similar in the study groups before any differences in outcome are attributed to other antisepsis treatments.In a previous trial in-volving sepsis, the investigators applied this principle, performing a statistical analysis to compare the study groups.
Megaloblastic Erythropoiesis and Acquired Hemolysis in Sickle-Cell Anemia
Authors: Herman L. Oliner, Paul Heller
Journal: New England Journal of Medicine (1959)

THE bone marrow of patients with sickle-cell anemia usually shows normoblastic hyperplasia. In the case reported below, which was complicated by an extracorpuscular hemolytic state, the bone marrow was found to be megaloblastic on three occasions. This combination, to our knowledge, has not been described previously.Case ReportA 30-year-old Negro gas-station attendant was admitted to the hospital on August 7, 1957, because of weakness, lightheadedness, blurred vision and marked fatigue of 2 weeks' duration. Bowel function was normal. He had been well previously, except for an automobile accident in 1954 that had resulted in multiple fractures of several long . . .
Investigation Of Fresh Tissue and Effusion Samples From Immunocompromised Hematologic Patients Suspected For Invasive Fungal Infection With An Aspergillus-specific PCR Is a Promising Tool For Identifying Invasive Aspergillosis
Authors: Mark Reinwald, Birgit Spiess, Werner J. Heinz, Claus Peter Heussel, Hartmut Bertz, Oliver A. Cornely, Joachim Hahn, Thomas Lehrnbecher, Michael Kiehl, Hans Jürgen Laws, Hans-Heinrich Wolf, Rainer Schwerdtfeger, Beate Schultheis, Alexander Burchardt, Michael Klein, Matthias Dürken, Bernd Claus, Frank Schlegel, Margit Hummel, Wolf-Karsten Hofmann, Dieter Buchheidt
Journal: Blood (2013)
Psychiatric illness and irritable bowel syndrome: a comparison with inflammatory bowel disease
Authors: E A Walker, P P Roy-Byrne, W J Katon, L Li, D Amos, G Jiranek
Journal: American Journal of Psychiatry (1990)

Structured psychiatric interviews and psychological self-report measures were administered to 28 patients with irritable bowel syndrome and 19 patients with inflammatory bowel disease. Significantly more of the patients with irritable bowel syndrome had lifetime diagnoses of major depression, somatization disorder, generalized anxiety disorder, panic disorder, and phobic disorder. They had significantly more medically unexplained somatic symptoms, and most had suffered from psychiatric disorders, particularly anxiety disorders, before the onset of their irritable bowel symptoms.
Why is one arm stronger than two arms? IgG4 antibodies in IgG4-related autoimmune pancreatitis
Authors: Julia Mayerle, Markus M Lerch, Andreas Greinacher
Journal: Gut (2016)

In this issue, Shiokawa et al 1 recapitulated the approach, previously established in pemphigus vulgaris,2 of passive transfer of IgG1 and IgG4 purified from patients with autoimmune pancreatitis (AIP) type 1 into neonatal Balb/c mice. These patients suffered from IgG4-related disease (IgG4-RD).

IgG4-RD is a novel clinical entity that includes a growing number of medical conditions that have the following features in common: diffuse organ swelling or focal mass formation, sclerosing storiforme (whirl-like) fibrosis with a lymphoplasmacytic infiltrate rich in IgG4-bearing plasma cells and elevated levels of serum IgG4. The disease usually responds well to steroid treatment and is predominantly diagnosed in elderly men.3 ,4 IgG4-RD is poorly understood but is currently classified as an autoimmune disease because of its association with autoantibody formation. However, so far there has been no evidence that the autoantibodies reported in IgG4-RD contribute directly to the pathogenesis.5 In many autoimmune disorders, which are unequivocally T-cell-driven, autoantibodies such as antinuclear antibodies and rheumatoid factor are detected, but such antibodies are not necessarily responsible for the tissue damage resulting in autoimmune disease, which is rather primarily induced by T cells. While T cells are likely also important for IgG4-RD (although it is still debated whether Th1 or Th2 cytokines ultimately drive the disease process6 ,7), the present study provides solid evidence that in IgG4-RD-associated AIP IgG4 is more than just a biomarker, or an epiphenomenon, but a driver and also a modulator of the disease.

Total IgG from patients with IgG4-RD resulted in injury to the pancreas and salivary glands of the mice. …
Lymphosarcoma in Childhood
Authors: Saul A. Rosenberg, Henry D. Diamond, Harold W. Dargeon, Lloyd F. Craver
Journal: New England Journal of Medicine (1958)

IN the course of a review of the experience at the Memorial Center for Cancer and Allied Diseases with the group of cancers known generally as lymphosarcoma, an analysis has been made of these diseases as seen in children. This study covers a period of thirty years, from January 1, 1928, to January 1, 1958, and includes all cases seen at this institution in which the probable clinical onset of the disease occurred before January 1, 1953, thus providing a follow-up period of at least five years for all studied material. Where pertinent, the manifestations and course of the diseases . . .