tbuckley/cabot-search huggingface dataset:
Reversing T-cell Dysfunction and Exhaustion in Cancer
Authors: Hassane M. Zarour
Journal: Clinical Cancer Research (2016)

Abstract In the context of chronic antigen exposure in chronic viral infections and cancer, T cells become exhausted/dysfunctional. These exhausted T cells exhibit defective proliferative capacities and cytokine production, but are not totally inert and may exert lytic functions. Importantly, exhausted T cells upregulate multiple inhibitory receptors/immune checkpoints that bind to their ligands expressed by tumor cells and antigen-presenting cells in the tumor microenvironment (TME). Immune checkpoint blockades with anti-CTL antigen 4 (CTLA-4) and/or anti-programmed death 1 (PD-1) mAbs successfully reinvigorate tumor-infiltrating T lymphocytes and provide persistent clinical benefits to a large number of patients with advanced cancer. This great and long-awaited success for the immunotherapy of cancer has infused considerable enthusiasm in the field of oncology and fostered the development of combinatorial strategies to target the multiple mechanisms of tumor-induced T-cell dysfunction. Here, we review the critical immunoregulatory mechanisms driving T-cell exhaustion in the TME. We also discuss the development of promising combinatorial immunotherapies to counteract the mechanisms of tumor-induced T-cell dysfunction to improve the clinical efficacy of current immune checkpoint blockades. As our understanding of the mechanisms supporting tumor-induced T-cell dysfunction improves based upon preclinical and clinical studies, we expect that novel combinatorial immunotherapies will emerge to improve the clinical outcome of patients with advanced cancers. Clin Cancer Res; 22(8); 1856–64. ©2016 AACR. See all articles in this CCR Focus section, “Opportunities and Challenges in Cancer Immunotherapy.”
RBC and plasma levels of haloperidol and clinical response in schizophrenia
Authors: R C Smith, G Vroulis, A Shvartsburd, R Allen, N Lewis, J C Schoolar, M Chojnacki, R Johnson
Journal: American Journal of Psychiatry (1982)

The authors conducted a fixed-dose study of haloperidol blood levels and clinical response in schizophrenic in patients and found that those with steady-state RBC haloperidol levels in the range of 2.4--5.4 ng/ml showed greater improvement than those with lower or higher levels. They found a similar , although nonsignificant, curvilinear relationship between plasma haloperidol levels and clinical response. These findings suggest that the relationship between haloperidol blood levels and clinical response fits a therapeutic window for the treatment of schizophrenia.
Case 9-1994
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Anil K. Rustgi, Fiona Graeme-Cook
Journal: New England Journal of Medicine (1994)

Presentation of CaseAn 80-year-old woman was admitted to the hospital because of persistent gastrointestinal bleeding after a right colectomy.The patient had been in stable health until five months earlier, when chronic gastrointestinal bleeding began, and 12 transfusions of packed red cells were administered during the ensuing three months. She was admitted to another hospital, where examination with a fiberoptic esophagogastroduodenoscope, colonoscopic study to the level of the splenic flexure, and a barium-enema examination showed no bleeding site. A radionuclide red-cell scan suggested that the right side of the colon was the source of the bleeding, and a right . . .
Effect of Bilateral Adrenalectomy in a Patient with Massive Ascites and Postnecrotic Cirrhosis
Authors: Jerome Giuseffi, Emile E. Werk, Paul U. Larson, Leon Schiff, David W. Elliott
Journal: New England Journal of Medicine (1957)

THE problem of wasting ascites occurring in patients with cirrhosis of the liver is unsolved — both the pathogenesis of the ascites and its reliable cure. Recent observations have indicated the presence of an abnormal diathesis for sodium and water retention. The present report is concerned with the effect of bilateral adrenalectomy performed on a patient with unrelenting ascites and the alterations that occurred in water and electrolyte exchange.In many cases, ascites of cirrhosis is temporary or amenable to conservative medical management consisting largely of dietary salt restriction, adequate blood and plasma replacement and suitable diuresis. One must be . . .
GENO-16TO CATALOG THE MOLECULAR ALTERATIONS IDENTIFIED DURING GENOMIC ANALYSIS OF GLIOMAS AND THE UTILITY IN PERSONALIZING THERAPY
Authors: Aya Haggiagi, Christina Corpuz, Andrew Lassman, Fabio Iwamoto
Journal: Neuro-Oncology (2015)

OBJECTIVE: To catalog the molecular alterations identified during genomic analysis of gliomas, and the utility in personalizing therapy. BACKGROUND: Recent advances in genomic analysis technologies using microarrays and next generation sequencing (NGS) have advanced our understanding of gliomas with a main goal to individualize therapy tailored to molecular and genomic profile of the tumor. One method is FoundationOne, a commercialized NGS-based assay panel designed to include all genes known to be somatically altered in solid tumors with periodic updates. DESIGN/METHODS: A retrospective study involved reviewing charts and Foundation Medicine results after IRB approval. RESULTS: We identified 45 patients with gliomas, WHO grades II-IV, from whom 45 tumors were analyzed. The FoundationOne results showed genomically significant alterations with available targeted therapy in 31/45 (68.8%). The most commonly identified alterations were in EGFR (33.3%, 15/45), including amplification (13), EGFRvIII mutation (7), other EGFR mutations (6) patients. Other frequently identified mutations involved PTEN (40%, 18/45), IDH1/2 (17.7%, 8/45), and FGFR3 (6.6%, 3/45). Therapy options and/or treatment changed based on the result in 15/45 (31.1%) of patients. Targeted therapy was tailored to EGFR in 12/15 (80%), FGFR3 mutation in 1/15 (6.6%), KDR amplification in 1/15 (6.6%) and NF1 in 1/15 (6.6%) of patients. Those therapies were either prescribed off-label (60%, 9/15) or as part of a clinical trial (40%, 6/15). Targeted therapy not offered most frequently due to enrollment in clinical trial not targeted to genetic alteration (8.8%, 4/45), good response on standard therapy (2%, 1/45), disease progression and death (2%, 1/45), international patients (2%, 1/45), and patient preference to seek alternative medicine internationally (2%, 1/45). CONCLUSIONS: Gliomas remain relatively resistant to approved therapies and using advanced technology in genetic analysis to individualize therapy is promising. The impact of targeting treatment based on individual key molecular alterations must be validated in prospective studies.
Initiation of Globin Synthesis in β-Thalassemia
Authors: Ronald G. Crystal, Norton A. Elson, Arthur Nienhuis, Abigail C. Thornton, W. French Anderson
Journal: New England Journal of Medicine (1973)

The mechanism of initiation of human globin chains was examined to determine if the initiation of protein synthesis is abnormal in β-thalassemia. Messenger RNA (mRNA) was isolated from the reticulocytes of normal adults, newborn infants and patients with β-thalassemia to study synthesis of alpha, beta and gamma chains. These isolated mRNA preparations were assayed in a cell-free system derived from rabbit reticulocytes. The initial dipeptides formed during the synthesis of the alpha and beta chains were determined. In normal subjects and patients with β-thalassemia the dipeptide for both the alpha and beta chains was found to be methionine-valine. The initial dipeptide for the gamma chain, determined in newborn infants and in patients with β-thalassemia, was methionine-glycine in both. All mRNA's studied shared a common requirement for methionyl-tRNAF (the specific initiator tRNA) and for the protein initiation factors. By these criteria, the mechanism of globin-chain initiation in β-thalassemia is normal. (N Engl J Med 288:1091–1096, 1973)
The Labyrinth of Congress
Authors: John K. Iglehart
Journal: New England Journal of Medicine (1993)

Congress in committee is Congress at work, as Woodrow Wilson once observed. That rule certainly applies now, as legislators, primed by President Bill Clinton and Hillary Rodham Clinton and pressured by a large array of private interests, intensify their scrutiny of the administration's ambitious proposal to reform the U.S. health care system. By the time the process concludes, the final product will bear only a slight resemblance to the original proposal, because according to history and current procedure, the executive branch proposes legislation and Congress disposes of it. Nevertheless, the Clintons have demonstrated in a masterly manner how to reach . . .
The availability of and satisfaction with palliative care services among VHA-based radiation oncologists.
Authors: George A. Dawson, Alice V. Cheuk, Shruti Jolly, Ruchika Gutt, Drew Moghanaki, Helen Fosmire, Stephen T. Lutz, Michael Philip Hagan, Mitchell Steven Anscher, Lori Hoffman-Hogg, Maria D. Kelly
Journal: Journal of Clinical Oncology (2014)

55 Background: Palliative care services enhance quality of life in patients with advanced malignancies and are an integral component of multidisciplinary cancer care. They provide symptom control and psychosocial support for patients and family members. A survey in non-VHA cancer centers showed that despite availability of palliative care programs, there was wide variability in the use of these services (Hui et al, JAMA 2010). Palliative care services are a component of the VHA medical benefits package. We sought to determine the ease of access to palliative care services and provider satisfaction among VHA Radiation Oncologists. Methods: VHA-based Radiation Oncologists were identified using the National VHA Radiation Oncology list serve group. All practicing Radiation Oncologists were surveyed to determine the extent of Palliative Care Services available to them and to measure their level of satisfaction with these services. Eighty two surveys were electronically mailed to practitioners at the 38 active VHA Radiation Oncology sites, followed by a reminder phone call.This survey was conducted over a four week period in May of 2014. Results: Sixty four of the 82 surveys distributed over the 4 week period, or 78% were completed. They represent 89% (34/38) of VHA Radiation Oncology Services. All respondents had Palliative Care Services available to them and 98% were happy with the services rendered by the Palliative Care teams. Conclusions: All VHA-based Radiation Oncologists who responded to this survey have access to local VHA based Palliative Care Services. This represented 82% of VHA Radiation Oncology practitioners and 98% were satisfied with the services rendered. Further studies should explore the scope and extent of palliative care involvement including when these services are integrated into the management of patients with advanced malignancies, availability of outpatient palliative care services and variations in care delivery. Radiation therapy is utilized in over 50% of patients with malignancy, often in advanced disease for symptom management and standard guidelines integrating radiotherapy and palliative care should be developed.
Fever with seizure and confusion
Authors: R Nandhagopal
Journal: BMJ (2016)

A 41 year old previously healthy man presented with a six day history of fever, headache, and vomiting, followed by two episodes of staring spells and unresponsiveness and secondarily generalised tonic-clonic seizures. In the emergency department he was restless, inattentive, and not oriented to time, place, and person (Glasgow coma score 10/15; best eye opening response (E): 3; best motor response (M): 5 and best verbal response (V):2). He had neck stiffness; Kernig’s sign was positive and his ocular fundi were normal. He had no limb weakness or ataxia and deep tendon reflexes and plantar reflexes were normal. He tested negative for HIV1/2 antigen and antibody. His blood coagulation profile and platelet count were normal. An initial unenhanced computed tomogram of the brain found no contraindications for lumbar puncture. Analysis of cerebral spinal fluid (CSF) showed glucose 3.4 mmol/L (reference range 2.2-3.9 mmol/L; corresponding blood glucose was 5.8 mmol/L), protein 2.59 g/L (0.15-0.45 g/L), 450×106 white blood cells/L (100% lymphocytes; 0-5×106), and 40×106 red blood cells/L. Gram staining of the CSF was negative and bacterial culture was sterile. A confirmatory microbiological test was performed on his CSF and computed tomography of the brain repeated the second week after the onset of symptoms (fig 1⇓).



Fig 1  Unenhanced cranial computed tomograms at the level of the temporal lobe (A) and insula (B)



1.  What abnormalities are seen in fig 1⇑?

2.  How do you interpret the …
Improving end-of-life communication between primary and secondary care within respiratory medicine
Authors: Alison C. Boland, Claire Hodgekiss, Fiona Hicks, Annette Edwards, Ian J. Clifton
Journal: European Respiratory Journal (2015)

We read with interest the editorial about "Improving palliative care for patients with COPD" [1] and the subsequent article by Meffet et al. [2]. We would like to highlight the results of our study looking at the impact of initiatives to improve communication with primary care in relation to end-of-life care (EoLC). Improving end-of-life care for respiratory and COPD patients through better communication from secondary care <http://ow.ly/U3ecw>
TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors
Authors: Laurie Menger, Anna Sledzinska, Katharina Bergerhoff, Frederick Arce Vargas, Julianne Smith, Laurent Poirot, Martin Pule, Javier Herrero, Karl S. Peggs, Sergio A. Quezada
Journal: Cancer Research (2016)

Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern. To overcome PD-L1-mediated immunosuppression and reduce CPI-associated toxicities, we used TALEN technology to render tumor-reactive T cells resistant to PD-1 signaling. Here, we demonstrate that inactivation of the PD-1 gene in melanoma-reactive CD8(+) T cells and in fibrosarcoma-reactive polyclonal T cells enhanced the persistence of PD-1 gene-modified T cells at the tumor site and increased tumor control. These results illustrate the feasibility and potency of approaches incorporating advanced gene-editing technologies into ACT protocols to silence immune checkpoints as a strategy to overcome locally active immune escape pathways. Cancer Res; 76(8); 2087-93. ©2016 AACR.
The predictive factors for relapse of Krukenberg tumor after removal of primary cancer
Authors: T. K. Park, S.-H. Kim, D. J. Chung, S. H. Noh, N. K. Kim, N. H. Cho, J. K. Roh
Journal: Journal of Clinical Oncology (2004)

5098 Background: The aim of this study was to evaluate the relationship between the relapse free interval of Krukenberg tumor in patients with stomach and colon cancer and factors such as clinical characteristics, operative findings of primary cancer, and expression of matrix metalloproteinase-2, -9 known to be related to cancer metastasis. Methods: From Jan. 1986 to Dec. 2001, 54 patients diagnosed of Krukenberg tumor were enrolled in this study. Informations regarding patient characteristics, operative findings of primary cancer, and the relapse free intervals were acquired from medical records and 32 currently available paraffin blocks of pathologic specimen were stained with MMP-2 and -9. Results: For stomach cancer, the mean age of surgery group was 38.2 9.7 years and relapse free interval was 11.7 mon. 33 patients(86.8%) were younger than 50 years old and 24 patients(63%) had bilateral tumors. For colon cancer, the mean age of surgery group was 51.7 11.6 years and relapse free interval was 4.8 mon. 10 patients(62.5%) were over 50 years old and 9 patients(56.2%) had unilateral tumor. However, factors such as age, histologic classification of primary cancer, histologic differentiation, Lauren classification(stomach cancer), maximal diameter of cancer, location of primary cancer, number of positive lymph nodes, Duke's stage(colon cancer) and relapse free interval of Krukenberg tumor were not significantly different in both groups. Nevertheless, although the depth of invasion of stomach cancer had no significant relation with relapse free interval of Krukenberg tumor, the depth of colon cancer invasion correlated inversely with relapse free interval. No association between MMP-2 or -9 with relapse free interval of Krukenberg tumor was found. Conclusions: The prophylactic oophorectomy for menopausal patients to relieve the burden of secondary debulking operation, and early detection and meticulous follow up of ovarian status for premenopausal patients to overcome the problems arising from prophylactic oophorectomy should be considered. Furthermore, colon cancer patients with deep invasion should undergo prophylactic oophorectomy to prevent disease relapse. No significant financial relationships to disclose.
Lack of Effect of Induced Menses on Symptoms in Women with Premenstrual Syndrome
Authors: Peter J. Schmidt, Lynnette K. Nieman, Gay N. Grover, Kari L. Muller, George R. Merriam, David R. Rubinow
Journal: New England Journal of Medicine (1991)

No physiologic abnormality of the luteal phase has been consistently demonstrated in women with premenstrual syndrome (PMS). Using the progesterone antagonist mifepristone, we truncated the late luteal phase of the menstrual cycle in a blinded fashion to evaluate the relation of the events of the late luteal phase to the symptoms of PMS.
Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate
Authors: C. D. Blanke, G. D. Demetri, M. Von Mehren, M. C. Heinrich, B. L. Eisenberg, J. Fletcher, C. L. Corless, E. Wehrle, K. B. Sandau, H. Joensuu
Journal: Journal of Clinical Oncology (2006)

9528 Background: Imatinib achieves tumor control in most pts with advanced GIST, but the durability of remissions has not been well described. We now present an updated long-term analysis of a randomized phase II trial first presented in 2001, with a median follow-up of 52 months. Methods: 147 pts with unresectable or metastatic malignant GIST were randomized to treatment with daily dosing of imatinib, 400 or 600 mg po. Results: Two pts (1%) achieved a complete response, 98 (67%) achieved a partial response (PR), and 23 (16%) exhibited stable disease (SD) as their best response. Median time-to-response was 13 weeks (95% CI; 12–23 weeks), but one quarter of pts responded after 23 weeks. No significant response differences were seen between the two dose levels tested. The median duration of response was 27 months, and median overall survival was 58 months. Pts with SD or PR had similar 4-year survival rates (64% versus 62%). KIT and/or PDGFRA mutational analyses were obtained in 87% of patients, and the mutational status was highly significant in predicting outcome. GISTs harboring KIT mutations in exon 11, exon 9, and with no detectable mutations in KIT or PDGFRA demonstrated PR rates of 87%, 48%, and 0%, respectively. The median survival for pts with exon 11 KIT mutations has not yet been reached, and it was 45 months for those with exon 9 mutations. Conclusions: While late progression can be seen in GIST pts treated with imatinib, the majority of pts derive benefit. Survival in those achieving SD parallels those with PRs. Late responses are often seen in pts with initial SD, and responses in general are of lasting duration. In particular, pts with KIT mutations in exon 11 (the most common exon affected) have very high response rates and favorable long term survival. [Table: see text]
PWE-144 7-year experience of two stage minimally invasive oesophagectomy with intrathoracic anastomosis (mio-2) in a single uk centre
Authors: F Noble, T Underwood, D Sharland, J Byrne, J Kelly
Journal: Gut (2015)

<h3>Introduction</h3> The 2014 report of the National OesopahgoGastric Cancer Audit (NOGCA) identified an increasing number of patients who were treated with minimally invasive (MIO) or hybrid operations (41.5%). Overall complications were similar to open surgery, but a significant increase in anastomotic leak (AL) after MIO was identified (11.7% vs. 6.7%). Totally minimally invasive oesophagectomy with intrathoracic anastomosis (MIO-2) has been performed at University Hospital Southampton NHS Foundation Trust since 2008 and we present a review of this consecutive series. <h3>Method</h3> A prospectively collected database of clinic-pathological and operative variables from consecutive patients undergoing oesophagogastric resection between January 1, 2005 and February 27, 2015 was reviewed. Statistical analysis was performed in SPSS. <h3>Results</h3> 147 patients (78% male, 22% female) underwent MIO-2, beginning in June 2008. Patient demographics were: median age 67 years (33–85), median BMI 26 (16–37), ASA 1 6.8%, ASA 2 64.6%, ASA 3 27.9%, ASA 4 0.7%. One patient had surgery for achalasia and 3 for HGD/Tis; the remainder had invasive cancer. 65% of patients had T3 disease on preoperative staging, with 65.3% having evidence of lymph node involvement (N1+). Median operative duration was 319 min (180–530 min) and median blood loss of 205 ml (0–5000 ml). In 11 (7.5%) cases the thoracic component was converted to open. There were 3 in-patient deaths (2.0%) including one intraoperative mortality. Major complications (Clavien-Dindo 3–4) were observed in 19% of cases with 11 anastomotic leaks (7.5%) and a reoperation rate of 9.6%. An R0 resection was achieved in 81.9% of cases with a median lymph node yield of 21 (2–62). Median length of hospital stay was 11 (6–96) days. <h3>Conclusion</h3> MIO-2 can be performed in the UK with acceptable perioperative morbidity, mortality, and oncological efficiency. <h3>Disclosure of interest</h3> F. Noble: None Declared, T. Underwood Grant/Research Support from: MRC, D. Sharland: None Declared, J. Byrne: None Declared, J. Kelly: None Declared.
Aneurysms of the Splenic Artery
Authors: Thomas H. Palmer
Journal: New England Journal of Medicine (1950)

THE recognition of aneurysms of the splenic artery is important since death from spontaneous hemorrhage ultimately occurs in the majority of cases and since these aneurysms may be completely excised at an elective time without jeopardizing the blood supply of vital organs. Because of the rarity of this lesion aneurysm of the splenic artery is almost never considered in the differential diagnosis of diseases that produce similar signs and symptoms. Elective surgical extirpation of the aneurysm has been successful in a high percentage of cases, but the number of patients operated upon before rupture has occurred has been small. The . . .