tbuckley/cabot-search huggingface dataset:
Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody
Authors: F. S. Hodi, A. Hoos, R. Ibrahim, K. Chin, H. Pehamberger, K. Harmankaya, S. O'Day, O. Hamid, R. Humphrey, J. Wolchok
Journal: Journal of Clinical Oncology (2008)

3008 Background: Ipilimumab represents a new class of immunotherapeutic agent. Antitumor activity (CR, PR, or SD) to ipilimumab in melanoma can take weeks to months and 3 main clinical patterns were observed: (1) immediate, (2) late (after progression; PD), and (3) in the presence of new lesions. Modified World Health Organization (mWHO) response criteria do not recognize the latter 2 patterns. PD by mWHO prompts cessation of treatment and follow-up. To capture the patterns of activity, novel or broader assessment criteria are needed. Methods: Patients (pts) with advanced melanoma in 3 phase II trials received 10 mg/kg ipilimumab induction dosing every 3 weeks (Q3W) × 4. Eligible pts continued maintenance therapy Q12W. Activity was assessed using conventional mWHO and novel immune-related response criteria (irRC) developed using the thresholds for response previously defined by conventional mWHO criteria. Contrary to mWHO, irRC (1) only considered measurable lesions (>1cm), (2) defined total tumor burden (TB) as the sum of index lesions identified at baseline and new lesions detected after baseline, (3) aimed for follow-up post PD to detect late activity. Pts with stable disease (SD) and slow decline in tumor volume >25% from baseline were included as clinically meaningful as they had objective activity without reaching the 50% threshold of PR. The totality of pts with an objective reduction of TB from baseline (CR, PR, SD with >25% decline) is reported. Results: 284 pts were evaluated. Conventional antitumor response rates (mWHO) in pts treated with 10 mg/kg ipilimumab monotherapy were 5.8%, 11.1%, and 15.8%, respectively. The totality of pts with an objective reduction of TB from baseline per irRC were 25.8%, 15.3%, and 30.9%, respectively. Conclusions: irRC may more accurately describe response to immunotherapy. Following pts for late response may avoid premature treatment cessation in pts with PD prior to response. Possible mechanisms underlying the clinical activity patterns are late effects of the immune system, sufficient availability of antigen for immune recognition, and increase of tumor volume through lymphocytic infiltration/edema before response. irRC need prospective validation and confirmation by survival data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Medarex Bristol-Myers Squibb, Medarex
Screening for Hemochromatosis
Authors: Jane F. Desforges, Corwin Q. Edwards, James P. Kushner
Journal: New England Journal of Medicine (1993)

In the United States the average daily intake of dietary iron ranges from 10 to 30 mg, but only about 1 mg is absorbed, to balance precisely the loss due to the sloughing of intact cells containing iron. Iron absorption can be increased if iron stores are depleted (usually through blood loss), and in genetically normal people absorption decreases with iron overload1,2 (usually from multiple transfusions). Iron balance is regulated at the absorptive step, but the mechanism by which the intestinal mucosa accomplishes this has not been defined. The defect responsible for hereditary hemochromatosis is malregulation of intestinal iron . . .
Photopheresis for the Prevention of Rejection in Cardiac Transplantation
Authors: M L Barr, B M Meiser, H J Eisen, R F Roberts, U Livi, R Dall'Amico, R Dorent, J G Rogers, B Radovancević, D O Taylor, V Jeevanandam, C C Marboe
Journal: New England Journal of Medicine (1998)

Photopheresis is an immunoregulatory technique in which lymphocytes are reinfused after exposure to a photoactive compound (methoxsalen) and ultraviolet A light. We performed a preliminary study to assess the safety and efficacy of photopheresis in the prevention of acute rejection of cardiac allografts.
Further Observations on Hyponatremia and Renal Sodium Loss Probably Resulting from Inappropriate Secretion of Antidiuretic Hormone
Authors: William B. Schwartz, Daniel Tassel, Frederic C. Bartter
Journal: New England Journal of Medicine (1960)

IN a previous report1 metabolic studies were presented on 2 patients with bronchogenic carcinoma and normal renal and adrenal function, who were found to have severe hyponatremia with renal sodium loss. The urine was persistently hypertonic to the serum, and contraction of body-fluid volume did not occur as sodium depletion and hypotonicity of the serum progressed. As an explanation for these findings, it was postulated that the underlying process induced a sustained, inappropriate secretion of antidiuretic hormone and that the syndrome was a consequence of the resulting expansion of body-fluid volume.This paper presents metabolic studies in a third patient . . .
O6-Methylguanine-Dna Methyltransferase (Mgmt) Cut-Off Methylation Level Determined By Pyrosequencing and Clinical Outcome in Patients with Glioblastoma Multiforme (Gbm): a Single-Institution Experience
Authors: L. Gurrieri, S. Rizzato, M. Macerelli, G. De Maglio, F. Pisa, E. Masiero, G. Aprile, A. Follador, S. Pizzolitto, G. Fasola
Journal: Annals of Oncology (2014)
An update of phase I data from RTOG 0211: A phase I/II clinical study of gefitinib+ radiation for newly-diagnosed glioblastoma (GBM) patients
Authors: A. Chakravarti, W. Seiferheld, H. I. Robins, A. Guha, D. Brachman, W. Curran, A. Choucair, M. Mehta
Journal: Journal of Clinical Oncology (2004)

1571 Background: The Radiation Therapy Oncology Group (RTOG) initiated a Phase I/II clinical study of the EGFR tyrosine kinase inhibitor, Gefitinib, in combination with radiation for newly diagnosed GBM patients. This report is an update of Phase I toxicity data. Methods: Patients entered on RTOG 0211 were stratified into two groups based on whether they were on enzyme-inducing anticonvulsant drugs (EIACDs:Group I) or not (non-EIACDs: Group II). The planned Gefitinib dose escalation during radiation was from 250 to 750mg in Group I and 250 to 500mg in Group II in 250 mg increments. A standard 3+3 design was used to evaluate dose-limiting toxicities (DLTs), which were defined as designated acute (<90 days) toxicity events. Results: A total of 18 patients in Group I (16 eligible and analyzable) and 13 patients in Group II (12 eligible and analyzable) were included in this update. In Group I, no DLTs were observed up to 750 mg. One subject in Group I had late (>90 days) Grade 3 elevation of SGOT. In Group II, one subject experienced a Grade 3 elevation of SGOT at the 250 mg dose level within 90 days. At the 500 mg dose level in Group II, one patient had late Grade 3 elevation of SGOT and one patient had acute Grade 4 elevation of SGOT. Other observed side-effects (e.g. fatigue, skin rash, headaches, seizures) did not fit the definition of DLTs or were deemed to be unrelated to Iressa. Conclusions: Gefitinib in combination with radiation appears to be well-tolerated in GBM patients at the dose levels examined. Further dose escalation is being planned for Group I, given the favorable side-effect profile in EIACD patients in this, as well as previously reported studies in the setting of recurrent disease. For non-EIACD patients, the Phase II component of the study has been initiated at the 500 mg dose level. No significant financial relationships to disclose.
Thiotepa for autologous hematopoietic stem cell transplantation for solid tumors
Authors: Ritsuro Suzuki, Yoshiyuki Takahashi, Masami Inoue, Heiwa Kanamori, Yoshiko Hashii, Hisashi Sakamaki, Yoshiko Atsuta, Koji Kato, Keisei Kawa, Seiji Kojima
Journal: Annals of Oncology (2015)
Case 33-1991
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, M. Lahav, J.C. Sullinger
Journal: New England Journal of Medicine (1991)

Case Records of the Massachusetts General Hospital from The New England Journal of Medicine — Case 33-1991 — A 74-Year-Old Man with Severe Vascular Disease, Chronic Lymphocytic Leukemia, and Loss of Vision in the Left Eye
S82 ‘The Kiss of death’ – Calcineurin inhibitors prevent actin-dependent lateral transfer of Aspergillus fumigatus in necroptotic human macrophages
Authors: A Shah, S Kannambath, S Herbst, A Rogers, M Carby, A Reed, S Mostowy, S Shaunak, D Armstrong-James
Journal: Thorax (2015)

<h3></h3> Invasive fungal infections are a major cause of mortality in solid-organ transplantation where steroids and calcineurin inhibitors form the core of immunosuppression. Our group has previously shown in established hydrocortisone-based mouse models of invasive aspergillosis that calcineurin inhibitors increase mortality through effects on the innate immune response.<sup>1</sup> As alveolar macrophages present the primary resident innate immune cell in the airways responsible for fungal clearance, we perform a detailed study of the role of the calcineurin pathway in the human macrophage response to <i>A. fumigatus </i>(AF). We show that the calcineurin-NFAT pathway is highly activated in the human lung transplant alveolar macrophage response to AF with inhibition resulting in impaired fungal clearance. Calcineurin inhibition leads to delayed phagocytosis, reduction in reactive-oxygen species production and an impairment of a novel actin-dependent process of lateral transfer of swollen AF conidia between human macrophages. Further characterisation reveals that transfer of AF occurs during macrophage necroptosis with subsequently around 50% control of germination in the receiving macrophage. To understand the calcineurin-dependent mechanism, next generation RNA sequencing was performed which confirms that calcineurin inhibition impairs the macrophage programmed cell death immune response. Utilising phosphoproteomics we additionally show that calcineurin inhibition impairs dephosphorylation of vasodilator-stimulated phosphoprotein (VASP), an important actin regulatory protein which promotes actin filament formation. High-resolution confocal microscopy confirms that VASP strongly co-localises to AF conidial phagocytosis and facilitates lateral transfer through tunnel-like structures. Lastly, we utilise a zebrafish model of invasive aspergillosis to confirm the in-vivo relevance of AF macrophage lateral transfer. In conclusion our data shows the importance of the calcineurin pathway in the macrophage innate immune response to AF and highlights a novel calcineurin-actin dependent host defense mechanism which may have significant implications on persistence and dissemination within solid organ transplantation. To our knowledge this is the first report of a host-mediated cell-cell transfer mechanism for any pathogen. <h3>Reference</h3> 1 Herbst S, Shah A, Mazon Moya M, Marzola V, Jensen B, Reed A, <i>et al</i>. Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. <i>EMBO Mol Med</i>. 2015;<b>7</b>(3):240–58
Resin Uptake of I<sup>131</sup>-Labeled Tri-Iodothyronine as a Test of Thyroid Function
Authors: Manuel Nava, Leslie J. De Groot
Journal: New England Journal of Medicine (1962)

THE thyroid hormones, thyroxine and tri-iodothyronine (T3), circulate in plasma bound in dissociable linkage to specific proteins. The hormone-binding proteins defined to date consist of thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA) and albumin.1 2 3 4 5 Collectively these may be referred to as thyroid-hormone-binding protein (TBP). Albright et al.6 demonstrated that TBP in the serum of hypothyroid subjects is less saturated, and that of hyperthyroid subjects more saturated, than the serum of euthyroid subjects. Hamolsky and his co-workers7 introduced a method for evaluating the saturation of the TBP by studying the incorporation in vitro by the human erythrocyte of I131-labeled . . .
Ibrutinib increased survival more than chlorambucil in older patients with untreated chronic lymphocytic leukemia
Authors: Frederick R. Aronson
Journal: Annals of Internal Medicine (2016)

ACP Journal Club19 April 2016Ibrutinib increased survival more than chlorambucil in older patients with untreated chronic lymphocytic leukemiaFrederick R. Aronson, MDFrederick R. Aronson, MDNew England Cancer Specialists, Scarborough, Maine, USA (F.R.A.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2016-164-8-044 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationBurger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-37. https://pubmed.ncbi.nlm.nih.gov/26639149Clinical Impact RatingsGeriatrics: Oncology: References1 Woyach JA, Ruppert AS, Rai K, et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies. J Clin Oncol. 2013;31:440-7. [PMID: 23233702] Google Scholar2 Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-10. [PMID: 24401022] Google Scholar3 Hillmen P, Robak T, Janssens A, et al; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385:1873-83. [PMID: 25882396] Google Scholar Author, Article, and Disclosure InformationAffiliations: New England Cancer Specialists, Scarborough, Maine, USA (F.R.A.)This article was published at Annals.org on 5 April 2016. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 April 2016Volume 164, Issue 8Page: JC44KeywordsAdverse eventsChronic lymphocytic leukemiaLymphomaProgression free survivalPurinesSafetySurvival analysisToxicityTyrosine kinase inhibitors ePublished: 19 April 2016 Issue Published: 19 April 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Radio-Guided Lymph Node Mapping in Bladder Cancer Using SPECT/CT and Intraoperative γ-Probe Methods
Authors: Wojciech Połom, Marcin Markuszewski, Wojciech Cytawa, Piotr Lass, Marcin Matuszewski
Journal: Clinical Nuclear Medicine (2016)

Lymph outflow from bladder tumor differs between individuals, making the prediction of the metastatic landing sites difficult. A "blind" template of lymphadenectomy has been tested as a solution to this problem. We believe that it is feasible to find methods enabling more precise lymph nodes (LNs) evaluation. The aims of our study were to evaluate the possibility of LNs mapping in case of muscle invasive bladder cancer (MIBC) and to compare the 2 methods of their detection.Our study group consisted of 38 cN0 MIBC patients. Lymph nodes mapping was performed by SPECT/CT lymphoscintigraphy using Tc-nanocolloid, followed by intraoperative verification with γ-ray probe. Lymph nodes with increased radiotracer uptake (hot spots) were removed, and then pelvic LNs dissection was conducted. Lymph nodes resected as hot spots and LNs resected with lymphadenectomy were separately examined by a pathologist.An average of 3 hot spots (range, 1-5) were identified in each case. For 36 of 38 patients, both preoperative SPECT/CT and intraoperative γ-probe evaluation results were obtained. Ninety-five percent of hot spots were found distally and caudally to the uretero-iliac crossing; 5% were found proximal. Lymph nodes outside the pelvic LNs dissection area did not contain metastases. In 2 patients, metastases were found in LNs without increased radiotracer uptake, and the observed hot spots contained no metastases.Radio-guided LNs mapping in case of MIBC is feasible. Preoperative detection of hot spots using SPECT/CT and intraoperative γ-ray detection probe gives similar results.
Microarray analysis in pulmonary hypertension
Authors: Julia Hoffmann, Jochen Wilhelm, Andrea Olschewski, Grazyna Kwapiszewska
Journal: European Respiratory Journal (2016)

Microarrays are a powerful and effective tool that allows the detection of genome-wide gene expression differences between controls and disease conditions. They have been broadly applied to investigate the pathobiology of diverse forms of pulmonary hypertension, namely group 1, including patients with idiopathic pulmonary arterial hypertension, and group 3, including pulmonary hypertension associated with chronic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. To date, numerous human microarray studies have been conducted to analyse global (lung homogenate samples), compartment-specific (laser capture microdissection), cell type-specific (isolated primary cells) and circulating cell (peripheral blood) expression profiles. Combined, they provide important information on development, progression and the end-stage disease. In the future, system biology approaches, expression of noncoding RNAs that regulate coding RNAs, and direct comparison between animal models and human disease might be of importance.
Determination of peritoneal transport characteristics with 24-hour dialysate collections
Authors: M V Rocco, J R Jordan, J M Burkart
Journal: Journal of the American Society of Nephrology (1994)

Although the 24-hour collection of dialysate provides a very accurate measure of the adequacy of dialysis, it is not known if it can also determine peritoneal membrane transport characteristics. In this prospective study, 101 24-hour dialysate collections were immediately followed by a standard peritoneal equilibration test (PET). Four- and 24-h dialysate-to-plasma (D/P) ratios were determined for creatinine and urea. The correlation coefficients between these two tests were 0.86 for the adjusted D/P creatinine and 0.71 for the D/P urea, whereas the standard errors of estimate were 0.054 and 0.060, respectively. Patients were classified into one of four transport groups on the basis of the mean and standard deviation of the adjusted D/P creatinine values, and these values were similar to those generated from the PET data. Rates of ultrafiltration were also defined for patients undergoing 2.0- and 2.5-L dwells. A survey of a subset of these patients demonstrated that the 24-h collection was preferred to the PET for determining transport characteristics. Therefore, the 24-h dialysate collection can be used to monitor both peritoneal membrane transport characteristics and adequacy. This technique, which has been named the "dialysis adequacy and transport test," has the potential for significant cost savings when it is used for the routine follow-up of both peritoneal transport and adequacy of dialysis.
Forcible Medication for Courtroom Competence — The Case of Charles Sell
Authors: George J. Annas
Journal: New England Journal of Medicine (2004)

The author discusses the legal and ethical issues raised by the 2003 Supreme Court decision in the case of former dentist Charles Sell. The case focused on the legality of the forcible administration of psychiatric medication for the purpose of making a defendant competent to stand trial. The Court ruled that when certain criteria were met, a judge could order involuntary medication to restore competence. The Court, however, did not permit the forcible treatment of Sell, because these criteria had not been met.
Abstract 17001: Reconstituted High-density Lipoprotein (CSL-111) Infusion Improves Post-ischemic Heart Function Through Modulating the Acute Inflammatory Response and Angiogenesis
Authors: Adele Richart, Sarah Heywood, Medini Reddy-luthmoodoo, Alaina K Natoli, Helen Kiriazis, Xiao-Jun Du, Andrew Siebel, Bronwyn Kingwell
Journal: Circulation (2015)

Aims: High-density lipoprotein (HDL) has multiple actions which may benefit post-ischemic heart function. We have shown in patients with type 2 diabetes that a single infusion of reconstituted HDL (rHDL, CSL-111) reduces inflammation1 including the number of circulating monocytes, neutrophils and lymphocytes. Whether such effects may contribute to improved heart function after ischemia and reperfusion is unknown. This study aimed to determine the effect of HDL on post-ischemic inflammatory response and heart function in insulin resistant mice. Methods and Results: A left coronary artery ligation model was used to study acute ischemia (30min) and reperfusion (I/R) in mice fed a chow (CD) or high fat diet (HFD) for 8 weeks. A single intravenous bolus of rHDL (CSL-111; 80mg/kg) or placebo (saline) was delivered at the time of reperfusion. At 15 days post I/R, rHDL increased ejection fraction from 40±3% to 48±2% in both diet groups (p=0.004). rHDL also increased stroke volume (p=0.002) and cardiac output in both diet groups (p=0.015). Histological analysis revealed that rHDL increased the myocardial capillary density by 22±4% and 15±4% in CD and HFD mice respectively (p=0.0007; p=0.042). However, rHDL did not alter cardiomyocyte hypertrophy. Interestingly, rHDL infusion modulated acute post-ischemic inflammatory response by decreasing the total number of circulating leucocytes (p=0.030) and neutrophils (p=0.005) in both diet groups 1 day following I/R. However, rHDL reduced the number of circulating monocytes (p=0.044) and B lymphocytes (p=0.009) only in HFD mice. In both diet groups, at 3 days post-I/R, rHDL reduced recruitment of leukocytes into the heart including monocytes (p=0.038, p=0.014), neutrophils (p=0.005, P=0.020), T lymphocytes (p=0.044, p=0.018) and B lymphocytes (p=0.043, p=0.010). Moreover, rHDL decreased the proportion of B lymphocytes recruited into the heart in HFD mice only (p=0.040), highlighting its strong anti-inflammatory effect particularly in the insulin-resistant state. Conclusion: A single infusion of rHDL at time of reperfusion improves post-ischemic heart function through modulation of angiogenesis and acute inflammatory response in insulin-resistant mice.
Arteriovenous Fistula Complicating Lumbar-Disk Surgery
Authors: John A. Spittell, Pasquale J. Palumbo, J. Grafton Love, F. Henry Ellis
Journal: New England Journal of Medicine (1963)

IN spite of the frequency of intervertebral-disk operations since the description of the procedure by Mixter and Barr1 in 1934 it was not until 1945 that the first vascular complication of such treatment — an arteriovenous fistula between the right common iliac artery and the inferior vena cava — was reported by Linton and White.2 Studies3 , 4 in which surgeons were polled regarding the occurrence of vascular injury during removal of lumbar disks have indicated that it is not so rare as one might expect; the most recent poll4 reported 106 vascular complications, including laceration of arteries or veins and traumatic . . .
<b>Pregnant women in war zones</b>
Authors: A D Akol, S Caluwaerts, A D Weeks
Journal: BMJ (2016)

Forgotten victims, killed by violence and by a lack of available care 

Death from violent conflict is a little acknowledged cause of maternal mortality. In times of war, the focus is usually on the male soldiers—yet an estimated 140 000 women die in conflict every year.1 An unknown proportion of these women are pregnant at the time of death, adding to the estimated 303 000 women already expected to die annually in pregnancy and childbirth.2

War aggravates an existing high maternal mortality rate by destroying health services and preventing access to them. Health services may even become targets, as seen in the recent massacre of 11 Medecins Sans Frontieres (MSF) health workers in Syria3 and the bombing of Kunduz trauma hospital in Afghanistan.4

There is also increasing evidence of violence directed specifically against pregnant women. A British war surgeon, David Nott, witnessed a heavily pregnant woman being targeted …