tbuckley/cabot-search huggingface dataset:
Lack of correlation of eculizumab therapy in paroxysmal nocturnal hemoglobinuria (PNH) patients with myeloproliferative disorders, myelodysplastic syndromes, acute leukemias or aplastic anemia with long-term treatment
Authors: J. Schubert, N. S. Young MD, L. Luzzatto, R. A. Brodsky, G. Socié, R. P. Rother, S. A. Rollins, P. Hillmen
Journal: Journal of Clinical Oncology (2008)

7092 Background: PNH is a rare disorder characterized by bone marrow dysfunction and expansion of stem cell clones with somatic mutations in the PIG-A gene. Mutations in PIG-A result in deficiency of GPI-anchored proteins on the surface of blood cells including the complement inhibitor CD59. Lack of CD59 from PNH RBCs results in chronic hemolysis and leads to fatigue, thrombosis, anemia and poor quality of life. Development of myeloproliferative disorders, MDS, acute leukemias and AA/pancytopenia has been reported in PNH. In a previous retrospective analysis, 6.8% of patients developed either myeloid or lymphoid disorders and 1% developed acute leukemias. AA/pancytopenia has been reported to develop in PNH patients at a rate of ∼2%/year. Eculizumab prevents terminal complement activation and restores the PNH RBC clone resulting in improvements in anemia, thrombosis, fatigue, and quality of life. Eculizumab has been evaluated in 195 PNH patients initially enrolled in 1 of 3 parent trials who continued to receive drug in an extension trial (>382 patient years of exposure). Methods: Cell counts for RBCs, WBCs, platelets and neutrophils and leukocyte PNH clone size were assessed at baseline and at 18 mos. The frequency of MDS, leukemia and AA/pancytopenia was calculated across all eculizumab trials. Results: RBC, WBC, platelet and neutrophil counts did not change during 18 mos of eculizumab. PNH leukocyte clone size did not increase with eculizumab (median 96.7% at baseline vs 96.7% at 18 mos) suggesting that inhibition of complement does not destroy or result in the proliferation of PNH leukocyte clones. Additionally, the development of MDS (1/195 patients, 0.5%) and CMML (1/195 patients, 0.5%) during the treatment period was not increased over that expected. The case of CMML was attributed to a previously diagnosed high grade myelodysplasia. Interestingly, no new AA/pancytopenia cases developed during eculizumab, while 7–8 cases would have been expected from the reported rate. Conclusions: Long-term terminal complement inhibition with eculizumab does not increase myeloproliferative disorders, MDS, acute leukemias or AA/pancytopenia in PNH patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals Alexion Pharmaceuticals
Retrospective analysis of WSG AM01 tandem high dose chemotherapy trial in high risk primary breast cancer: A hypothesis generating study
Authors: U. A. Nitz, O. Gluz, A. Herr, E. Ting, S. Mohrmann, M. Frick, C. Jackisch, C. Poremba, W. Lindemann, R. Diallo-Danebrock
Journal: Journal of Clinical Oncology (2006)

665 Background: The WSG AM 01 trial is the first one to report superiority of HDC in terms of DFS and OS in patients with &gt;9 positive axillary lymph nodes. Retrospectively we tried to identify patient subgroups with maximum benefit from HDC. Methods: 403 patients were randomized to tandem HDC or to dose-dense conventional chemotherapy (DD). 236 tumors were available for central pathologic review (117/119). A panel of 34 markers were determined by IHC in TMA. Kaplan-Meier, Log rank and Cox proportional hazard models were used for uni- and multivariate analysis. We choose K-means clustering with K=5 and using Manhattan distance as similarity measure. Results: Pts: n=236 (HDC/DD): mean age 47.3/47.4 yrs, mean tumor sizes 3.5/3.4cm, mean positive lymph nodes 17.2/17.0, HR+ 55%/53%, G3 44%/35%. HDC was superior to DD (p=0.02). Multivariate analysis demonstrated a significant correlation for grading, tumor size, PR+. HR &gt; 2 were reported for the following markers: Her2neu+, p53+, bcl2−, Ck 5/6 and 17+, Ck8−, c-kit+, vimentin+, ETR 1/2, BCRP+. Triple negative tumors (TN) (31%) had a large benefit from HDC (HR DD vs. HD: 3.06, 95%CI:1.41–6.06). Groups identified by K-means clustering could be attributed to luminal-A-(31%), luminal-B-(27%), her2-(11%), basal like-(11%) type and a so far undefined proliferative group (20%) characterized mainly by the absence of specifying markers. Interestingly, the proportion of the above mentioned molecular subtypes within of high risk populations very similar to those reported for less selected populations. Her2, basal-like and the undefined proliferative group had significantly worse outcome when compared to luminal tumors (p&lt;0.01). Very poor prognosis if treated by conventional CT was observed in basal like (HR DD vs HD=2.66 95%CI: 0.9–7.9) und the undefined group (HR=1,72, 95%CI:0.92–3.21), where most of the TN tumors were found. Conclusions: Tandem HDC is superior to DD conventional CT for treatment of HRBC. The largest benefit from high dose chemotherapy was reported for younger patients with TN poor differentiated tumors, &gt;2cm. Negative hormone receptor status, p53+, bcl2−, MIB/p16+ and BCRP+ predicted benefit from dose intensification. Subgroups are small and may help to generate further hypothesises. No significant financial relationships to disclose.
P279 The Female Disadvantage in UK CF Registry Data 2008–2013
Authors: S Hippolyte, R Keogh, S MacNeill, N Simmonds, U Griesenbach
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> The UK Cystic Fibrosis (CF) registry has been in its current form since 2006 offering annual review data comprising of detailed demographic and clinical information on 99% of the UK CF population (&gt;10,000 individuals). Whilst widely accepted that FEV<sub>1</sub> and BMI are well-validated predictors of disease severity and outcome, the role of gender in CF remains debated. In some studies <i>Pseudomonas aeruginosa </i>(PsA) infection occurred earlier in females with a resulting deterioration in FEV<sub>1</sub>. Here, we use CF registry data (2008–2013) to assess whether a female disadvantage in FEV<sub>1</sub>or BMI exists in the UK population and whether PsA status differs by gender. This is the most complete UK CF registry gender-based analysis to date. <h3>Methods and results</h3> Cross-sectional analysis of data from 2010 and 2013 supported decreased female survival (decreasing female prevalence with sequential age groups; 2013 p = 0.0001). It also highlighted lower BMI percentiles and more underweight (BMI &lt;19) individuals amongst females (21.9%; males 13.6%: p = &lt;0.0001), even when adjusted for lung function. Females had worse lung function compared to males, particularly in adolescence; (females: mean FEV<sub>1</sub> 71.3% at 16–19 yrs (CI 69.2–73.4), males: 78.9% (CI 76.9–81.0); p &lt; 0.0001). Females had higher absolute rates (57.1% on any intravenous antibiotics; 44.8% males) and greater total duration of intravenous antibiotic use across all adult age groups (p &lt;). Females had higher rates of CF-related diabetes from 16–29 years (females 28.2%, males 17.7%: p &lt; 0.005), itself independently associated with worse prognosis. On full analysis from 2008–2013 the age at which chronic PsA was first reported occurred earlier in females (mean 15.5 yrs 95% CI 14.9–16.1) than males (16.7 yrs; 95% CI 16.1–17.3) p = 0.01. <h3>Conclusions</h3> Disease severity appears worse in CF females compared to males on cross-sectional analysis of data from 2010 and 2013. Females have earlier PsA infection and lower BMI, both of which are individually associated with worse outcomes and increased intravenous antibiotic use. Females also have reduced lung function, and receive more treatment. These data suggest a persistent and measurable gender difference in the UK CF population which we aim to explore more closely in longitudinal analysis.
The Combined Effect of Cortisone and Partial Protein Depletion on Wound Healing
Authors: Charles W. Findlay, Edward L. Howes
Journal: New England Journal of Medicine (1952)

MANY investigators have reported retardation of wound healing by cortisone or ACTH.1 2 3 4 5 6 7 They have noted the depressant action on many phases of healing, including vascular growth, fibro-plasia and the deposition of normally staining extracellular material. Relative absence of the inflammatory elements but only slight slowing of epithelization has also been observed. These observations were made on different laboratory animals, using different methods of wounding.There have been, however, several clinical reports on patients with burns and surgical wounds that healed normally in the presence of ACTH or cortisone administration.8 9 10 11 12 13 Some have attributed this difference to inadequate or too infrequent administration . . .
CD205-TLR9-IL-12 axis contributes to CpG-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells
Authors: Xin Hou, Xiaolei Hao, Meijuan Zheng, Congfei Xu, Jun Wang, Rongbin Zhou, Zhigang Tian
Journal: Cellular and Molecular Immunology (2016)

Gut-derived bacterial products contribute to liver inflammation and injury during chronic hepatitis B virus infection; however, the underlying mechanisms remain obscure. In this study, hepatitis B surface antigen transgenic (HBs-Tg) mice and their wild-type (WT) control C57BL/6 mice were injected with CpG-oligodeoxynucleotides (ODNs) to mimic the translocation of gut microbial products into the systemic circulation. We found that, compared with the WT mice, the HBs-Tg mice were oversensitive to CpG-ODN-induced liver injury, which was dependent on natural killer T (NKT) cells. CpG-ODN injection enhanced the expression of Fas ligand (FasL) on NKT cells. In addition, hepatocytes from the HBs-Tg mice expressed higher levels of Fas than did those from the WT mice, which was further augmented by CpG-ODN. Interaction of Fas and FasL was involved in the cytotoxicity of NKT cells against hepatocytes in the HBs-Tg mice. Moreover, Kupffer cells in the HBs-Tg mice expressed higher levels of CD205 and produced greater amounts of interleukin (IL)-12 than did those in the WT mice. Finally, the depletion of Kupffer cells, neutralization of IL-12 or specific silencing of CD205 on Kupffer cells significantly inhibited CpG-ODN-induced liver injury and NKT activation in the HBs-Tg mice. Our data suggest that CD205-expressing Kupffer cells respond to CpG-ODNs and subsequently release IL-12 to promote NKT cell activation. Activated NKT cells induce liver damage through the Fas signaling pathway in HBs-Tg mice.
Case 9-2012
Authors: Donald S. Kaufman, Anthony L. Zietman, W. Scott McDougal, Douglas M. Dahl, Mukesh G. Harisinghani, Chin-Lee Wu
Journal: New England Journal of Medicine (2012)

A 67-year-old man was seen in the cancer center of this hospital because of elevated prostate-specific antigen for 6 years. One of six transrectal prostate-biopsy specimens showed a tiny focus of well-differentiated adenocarcinoma. A diagnostic procedure was performed.
PWE-123 Adaptive immune responses in ALF
Authors: W Khamri, AE Anderson, RD Abeles, G Auzinger, W Bernal, C Willars, JH Robinson, G Lombardi, MR Thursz, J Wendon, CG Antoniades
Journal: Gut (2015)

<h3>Introduction</h3> Acute liver failure (ALF) is characterised by an overwhelming hepatic necrosis, imuneparesis and susceptibility to infections. To date, a number of defects in innate immune responses have been identified but defects in adaptive immune responses remain unexplored. The aims of this study were to evaluate whether impairment in adaptive immune responses could also account for the immuneparesis and infection susceptibility in ALF. <h3>Method</h3> CD4<sup>+ </sup>T-cell-subsets in peripheral blood mononuclear cells (PBMCs) from 20 ALF patients and 10 healthy controls (HC) were determined using multicolor flow cytometry. CD45RA/RO were used to differentiate naïve and memory CD4<sup>+ </sup>T-cells. Expression or lack of expression of CD45RO/CCR7 was used to determine effector memory (T<sub>EM</sub>) subset. Negative regulators of T cell activation (CTLA-4) were analysed. Specific CD4<sup>+ </sup>T-cell antigen-recall responses to a pool of HLA class II-restricted T cell epitopes were examined <i>in vitro </i>in the presence or absence of anti-CTLA-4 blocking antibody. CD4<sup>+ </sup>T-cell proliferation was assessed by flow cytometry and IL-2 secretion by ELISA. Soluble CTLA-4 (sCTLA-4) in sera samples were measured using ELISA. <h3>Results</h3> Whilst overall percentages of circulating CD4+ T lymphocytes were expanded in ALF (p=0.03), we report a significant reduction in the frequency of memory CD4<sup>+ </sup>T-cell population (p=0.01). MELD score correlated negatively with the proportion of CD4<sup>+</sup>T-cells (r=-0.462, p=0.06). Furthermore, T<sub>EM</sub>population was significantly reduced in ALF in comparison to HC (p=0.04). This reduction was highly significant in patients with a poor outcome (p=0.002). CTLA-4 expressing CD4<sup>+ </sup>T-cells were significantly higher in ALF compared to HC (p=0.0001). Similarly, levels of sCTLA-4 in the sera of ALF were significantly elevated (p= 0.02). ALF (n = 4) showed a defect in proliferative responses to recall antigens compared to HC (n = 3) (p = 0.05). However, blockade of CTLA-4-4 was sufficient to restore antigen-recall responses defined by increased T cell proliferation (p=0.05) and IL-2 secretion (0 vs 20.84 pg/ml). <h3>Conclusion</h3> Our novel data identify defects in function of circulating CD4<sup>+ </sup>T-cell subsets in ALF with a significant increase in the CTLA-4 expressing CD4<sup>+ </sup>T-cells, a phenotype with an inhibitory functional aspect. Proof-of-principle experiments indicate that blocking CTLA-4, a crucial immune checkpoint, may be a promising immunotherapeutic target to boost adaptive immune responses and reduce susceptibility to infection in ALF patients. <h3>Disclosure of interest</h3> None Declared.
Prosthesis Following Hemipelvectomy
Authors: John F. Cooper, Grantley W. Taylor
Journal: New England Journal of Medicine (1949)

A MAJOR problem in the rehabilitation of patients subjected to hemipelvectomy has been the adaptation of a suitable prosthetic appliance. Owing to the rarity of this type of amputation, both the surgeon and the artificial-limb manufacturer have had few opportunities to clarify the problem. The purpose of this report is to present an efficient prosthetic appliance of this character and to record a case of its successful use.In the last half century 138 cases of hind-quarter amputation have been reported in the literature. This radical surgical procedure was first performed successfully in 1895 by Girard1 and later standardized by . . .
Meningococcal Pericarditis without Meningitis Presenting as Tamponade
Authors: Robert A. Herman, Herbert A. Rubin
Journal: New England Journal of Medicine (1974)

PERICARDITIS complicating meningococcal meningitis is an uncommon but documented entity.1 2 3 4 Isolated meningococcal pericarditis without meningitis or meningococcemia presenting as cardiac tamponade, as in the following case, is exceedingly rare.Case ReportAn 18-year-old boy was well until two days before admission, when fever, rigors and drenching sweats developed. On the day before admission he noted sharp, substernal, pleuritic chest pain that was aggravated by the supine position or ingestion of food, but relieved by sitting upright. He sought medical advice because of progressive dyspnea and orthopnea.He denied headache, stiff neck and skin rash, as well as symptoms of urethritis, . . .
Studies on Some Actions of Sulphated Polysaccharides on Arteriosclerosis (III) : CLINICAL USE OF DEXTRAN SULPHATE
Authors: Kozo Yamada, Humio Kuzuya, Masatoshi Noda, Takeshi Oguri
Journal: Circulation (1961)

The repeated intravenous administration of dextran sulphate which we synthesized decreased serum total cholesterol, especially free cholesterol in several patients, without the prolongation of clotting time of blood.
Prevention of Reactivated Herpes Simplex Infection by Human Leukocyte Interferon after Operation on the Trigeminal Root
Authors: George J. Pazin, John A. Armstrong, Man Tai Lam, George C. Tarr, Peter J. Jannetta, Monto Ho
Journal: New England Journal of Medicine (1979)

Microneurosurgical procedures on the trigeminal-nerve root are often followed by reactivation of herpes simplex virus infection, manifested by herpes labialis or oropharyngeal herpesvirus shedding or both. In a double-blind study of the ability of human leukocyte interferon to prevent this reactivation, patients with a history of herpes labialis were given 7 x 10(4) U of interferon per kilogram of body weight per day or placebo for five days beginning on the day before operation. In 18 patients treated with placebo, herpes labialis developed in 10, and virus shedding in the oropharynx in 15. In 19 patients treated with interferon, lesions developed in five, and shedding in eight. The frequency of reactivation as measured by lesions or positive throat cultures or both was significantly reduced by interferon (P less than 0.05). Of 127 daily throat-wash cultures in the placebo group, 42 per cent were positive for herpesvirus, but of 134 in the interferon group, only 9 per cent were positive (P less than 0.001). We conclude that interferon at a well-tolerated dosage reduces reactivation of latent herpes simplex virus infection after a potent operative stimulus.
The Red Baron
Authors: Thomas P. Duffy
Journal: New England Journal of Medicine (1992)

A 33-year-old naval pilot was admitted to Yale–New Haven Hospital in early 1992 because he had been coughing up blood and passing bloody urine for two days. He gave a history of Goodpasture's syndrome manifested by hemoptysis and hematuria, which had initially been diagnosed and treated in March 1990 at the naval base where he was stationed. The diagnosis was established serologically and by renal biopsy, and he was treated with plasmapheresis, cyclophosphamide, and steroids, resulting in remission of the condition until July 1991. He had a relapse at that time and was successfully treated with the same regimen.The . . .
Soundings: Deliver us from evil
Authors: Imre Loefler
Journal: BMJ (2006)

Randomised controlled trials examining the effectiveness of prayer as a life saving intervention have become commonplace. All suffer from methodological shortcomings. What is prayer? Whom do the prayers address? How does one make sure that the person who claims to have prayed has done so? How does one know that the prayer did not pray for the opposite outcome? Are there people who can pray better than others? Does prayer come in doses? And if prayer is effective, what about cursing—is that equally effective?

Prayer research is not science. Nor is it doing a service to religion. Whatever prayer is, it is certainly not akin to a drug, a procedure, or a psychotherapy session, yet it is harmless.

What is not harmless is a new influence emerging from US Christian fundamentalism that accuses the medical and nursing professions of preventing people from attaining the supposed purpose of life—the state of holiness.

The theological argument is this: holiness is available only to those who repent and who are, at the time of their death, at peace with God. Sedatives and analgesics are said to interfere with the process of repenting in two ways.

People who have been fully sedated, who are semi-conscious, even those who just sleep, cannot repent. If they die without repenting they will miss the chance of becoming holy, they might not be called to glory, and this will be the fault of those who administered the drugs.

The second and more sinister charge made against the use of drugs is as follows. The claim is that pain and suffering are meted out partly as punishment, partly as admonishment. A person who has no pain, who does not suffer, who may be happy, does not think of repenting, of the need to prepare for holiness.

This theological attack is aimed at the heart of medical care. For giving comfort is one of the core values of medical care, and analgesia is an essential part of giving comfort.

Denying analgesia to someone who is in pain, or sedatives to someone whose suffering cannot otherwise be alleviated, is cruel and uncharitable.

The alleviation of suffering is the noblest among doctors' and nurses' responsibilities, and so they must vigorously resist intrusions and indoctrinations of this kind.
Feasibility of a combination of high dose chemotherapy ifosfamide, carboplatin, etoposide (ICE) plus stem cells and bevacizumab in refractory sarcoma and germ cell tumors
Authors: K. Jordan, T. Kegel, L. P. Mueller, I. Kinitz, H. J. Schmoll
Journal: Journal of Clinical Oncology (2005)

9070 Background: High-dose chemotherapy (HD) with ICE for 1 up to 4 cycles represents a frequently used salvage regimen for solid tumors refractory to standard dose (SD) chemotherapy. However, the activity of HD-ICE is only moderate particularly in sarcoma or in germ cell tumors unresponsive to SD -ICE. Bevacizumab (B) has some activity in sarcoma and another antiangiogenetic agent, thalidomide in refractory germ cell tumor. Furthermore B has been shown to increase the antitumor efficacy of chemotherapy in colorectal cancer, an effect which might not only be limited to 5 FU based chemotherapy. Therefore the combination of bevacizumab with sequential/intermediate/high-dose chemotherapy might be of interest. To evaluate the potential risk of the combination of HD-ICE + B we are currently performing a feasibility study in pts with progressive sarcoma and germ cell cancer. Methods: To date 5 pts (4 sarcomas, 1 germ cell tumor, including 1 pt with brain metastasis) progressive after SD-ICE (ifosfamid 1,5 g/m2 d1–3, carboplatin 150mg/m2 d1–3, etoposide 150 mg/m2 d1–3) received HD-ICE (ifosfamid 3 g/m2 d1–3, carboplatin 300mg/m2 d1–3, etoposide 300 mg/m2 d1–3) in combination with B (7,5 mg/kg - 10mg/kg) d1 with stem cell support, q 3 weeks. 5 pts were evaluable for toxicity and 4 for response. A total of 5 pts and 12 cycles (c) of chemotherapy (range 1–5) are evaluated to date. Median age was 29y (range 22–38y); female:male 2:3, ECOG 0/1 (5 pts). Results: NCI-CTC grade 3/4 toxicities: Thrombocytopenia 12/12 c, Neutropenia 12/12, nausea/vomiting 1/12, acute ifosfamide encephalopathy 1/12. In one cycle G1 epistaxis occured. There was no hypertension, mucositis over G1, no severe sustained bleeding and no thromboembolic event or severe infection. Efficacy: 1 CR, 1 PR and 2 SD were seen. Conclusions: The addition of B to HD-ICE in pts with refractory solid malignancy has interesting activity without significant increase of toxicity in particular thrombopenic bleeding and acute encephalopathy, even in the pts with brain metastasis. The study is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Hoffmann-La Roche