tbuckley/cabot-search huggingface dataset:
Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF
Authors: Paul F Mercer, Hannah V Woodcock, Jessica D Eley, Manuela Platé, Michal G Sulikowski, Pascal F Durrenberger, Linda Franklin, Carmel B Nanthakumar, Yim Man, Federica Genovese, Robin J McAnulty, Shuying Yang, Toby M Maher, Andrew G Nicholson, Andy D Blanchard, Richard P Marshall, Pauline T Lukey, Rachel C Chambers
Journal: Thorax (2016)

Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose.We explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung.We provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF.Our data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-of-mechanism trial of this agent is currently underway.NCT01725139, pre-clinical.
Magnetic Resonance Cholangiopancreatography
Authors: Matthew A. Barish, E. Kent Yucel, Joseph T. Ferrucci
Journal: New England Journal of Medicine (1999)

Magnetic resonance cholangiopancratography (MRCP) is a radiologic technique that produces images of the pancreaticobiliary tree that are similar in appearance to those obtained by invasive radiographic methods, such as endoscopic retrograde cholangiopancreatography (ERCP). Originally described in 1991,1 MRCP takes advantage of the inherent contrast-related properties of fluid in the biliary and pancreatic ducts. Because MRCP does not require the administration of any exogenous contrast materials, it is an ideal imaging method for patients with allergies to iodine-based contrast materials or those with a general history of atopy. The interest in MRCP on the part of surgeons, gastroenterologists, and radiologists is . . .
Nail in the Brain
Authors: Kim Eagle, Michael Schwarzschild
Journal: New England Journal of Medicine (1993)

Figure 1. Nail in the Brain. “Scout” films for a computed tomographic scan of the head show a nail in the brain of a stuporous, inebriated man seen in the emergency department. Examination revealed a mild right hemiparesis, which persisted after he became sober and fully articulate. Nine hours after admission, the patient disclosed that during a depressive episode 12 years earlier, he had attempted suicide with a nail gun directed between his eyes. Aside from right-sided facial droop and a slight limp, the patient had been symptom-free since the suicide attempt; he had had neither seizures nor episodes of . . .
Impact of PET-CT Response on Survival Parameters Following Autologous Stem Cell Transplantation Among Patients with Multiple Myeloma: Comparison of Two Cut-Off Values
Authors: Meral Beksac, Mehmet Gunduz, Mehmet Ozen, Sule Mine Bakanay Ozturk, Ozlem Kucuk, Elgin Ozkan
Journal: Blood (2014)
The Regulation Strategy for Controlling Hospital Costs
Authors: William B. Schwartz
Journal: New England Journal of Medicine (1981)

Three regulatory mechanisms have been used to control the rise in hospital costs: assessments of patients' records by professional standards review organizations (PSROs), approval of capital expenditures by certificate-of-need agencies, and limits on hospital reimbursement by state rate-setting groups. The available evidence indicates that neither PSROs nor certificate-of-need programs have exerted an appreciable influence on costs. However, rate setting through mandatory "prospective reimbursement" appears to slow the growth of hospital expenditures and seems to be the only regulatory tool that has been effective. Any regulatory process that markedly restrains expenditures can ultimately be expected to affect patient care adversely and to create social and political tension within the health-care system.
Normal Serum Ferritin Concentrations in Precirrhotic Hemochromatosis
Authors: Jack R. Wands, John A. Rowe, Steve E. Mezey, Larry A. Waterbury, John R. Wright, June W. Halliday, Kurt J. Isselbacher, Lawrie W. Powell
Journal: New England Journal of Medicine (1976)

We investigated 33 of 58 members of two families with latent or precirrhotic hemochromatosis to determine its pattern of inheritance and to evaluate the serum ferritin levels as an index of iron stores. In both families, the pattern of inheritance was as an autosomal dominant trait with incomplete expressivity. Mean serum ferritin values in the affected family members were 88.5 ng per milliliter (range, 28.0 to 201.9) for males and 65.2 ng per milliter (range 23.7 to 97.0) for females, which were no different from controls (P is less than 0.5). Furthermore, the serum ferritin values did not correlate with or reflect mobilizable iron stores, and there were no relations between the serum iron, iron-binding capacity and transferrin saturation (P is less than 0.2). Thus, serum ferritin concentrations in precirrhotic familial hemochromatosis appear to underestimate iron stores. Serum ferritin levels do not help to identify such patients with increased iron stores for therapeutic phlebotomy.
Cytotoxic chemotherapy with androgen deprivation for biochemically recurrent prostate cancer following radical prostatectomy: A retrospective review
Authors: D. M. Friedland, T. M. Feinstein, M. J. Braffet, J. B. Nelson
Journal: Journal of Clinical Oncology (2008)

16092 Background: PSA-only recurrences after radical prostatectomy (RP) present a common treatment dilemma. Most men respond to androgen deprivation therapy (ADT) but hormone refractory prostate cancer (PC) and metastases often develop. There is limited experience with chemotherapy plus ADT in this setting. Adding cytotoxic chemotherapy (CTX) offers the theoretical benefit of treating a latent hormone refractory clone early in the disease process. We reviewed an initial experience using CTX with ADT in men with biochemically recurrent PC. Methods: We conducted an IRB approved retrospective analysis of 24 patients with PC and detectable or rising PSA after RP by a single surgeon. No patients had metastases on bone scan or CT scan of the abdomen/pelvis. Treatment consisted of 1 year of ADT (LHRH agonist + androgen receptor blocker) and 4 cycles of CTX beginning near the start of ADT. Results: Treatment: from 2001–2007 all men completed 1 year of ADT and CTX consisting of: every 3 week docetaxel (72%), weekly docetaxel + estramustine (20%) or mitoxantrone (8%). Patient characteristics: median age 61 years (51–75); stage: pT2a (4%), pT2c (13%), pT3a (21%), pT3b (25%), TxN1 (38%); median Gleason score 8 (6–9); mean PSA pre-treatment 1.4 ng/ml (0.1–5.3). 50% of patients had recurrence and were treated within 9 months of RP. Response: Median follow-up 26.7 mo. 92% of patients achieved undetectable PSA lasting at least 4 weeks. Progression, defined as first recurrence of PSA, occurred in 50% at a median of 25.8 mo. (95% CI, 22.6–30). Metastases occurred in 21% at a median of 41.9 mo. (95% CI, 27.7–56.1). One patient died, due to a second malignancy. Conclusions: Randomized trials of ADT plus CTX for biochemically recurrent PC are lacking. This series demonstrated prolonged PSA control and a substantial time to development of metastasis, even in this high risk group (high Gleason score, high stage and short interval to PSA recurrence). CTX was tolerated well with the expected toxicities and no hospital admissions. This experience suggests chemohormonal therapy in this population is feasible with promising preliminary activity. Prospective studies are needed to determine whether this treatment is superior to ADT alone or watchful waiting. No significant financial relationships to disclose.
Treatment of Non–Small Cell Lung Cancer in the Older Patient
Authors: Apar Kishor Ganti, Mollie deShazo, Alva B. Weir, Arti Hurria
Journal: Journal of the National Comprehensive Cancer Network (2012)

Lung cancer is a disease of the elderly, with a median age at diagnosis of 70 years. However, there is a dearth of good quality evidence to guide treatment in this population and most of the data are extrapolated from younger patients. Current research is directed toward establishing simplified instruments to quantify fitness of older patients for various forms of therapy. Although current evidence suggests that outcomes after standard therapy are similar to those seen in younger patients, older patients have an increased incidence of adverse events. Until better predictive markers are available to guide treatment, therapy should be individualized using available instruments, including a comprehensive geriatric assessment. If an older patient is deemed to be fit, it is reasonable to use the treatment options recommended for younger individuals. This article summarizes the available data on the treatment of non–small cell lung cancer in the older patient.
Multimedia: Jackson Pollock
Authors: Sean A Spence
Journal: BMJ (1999)

Tate Gallery, London, until 6 June

  Jackson Pollock was the quintessential “action painter.” A muscular man stooping over canvasses he’d laid on the ground, he dripped and flung paint in the white T shirt and faded jeans immortalised in iconic portraits. He had appropriated this “uniform” long before Bruce Springsteen wore it. Indeed, his very “Americaness” prompted claims that he was not a great painter at all but a stooge for the New York art scene elite, set up to rival the European tradition, in particular Picasso. Certainly, it is difficult to overlook the resemblance to the work of the Spaniard in many of Pollock’s early and middle paintings.

Pollock breaks free only when he puts aside representation altogether and enters the abstract realm (violently). It begins with the Mural he painted for the heiress Peggy Guggenheim one apocryphal New Year’s night (1943-4). In fact, the painting could not have been completed in one “campaign” or the colours would have bled into each other on the canvass; the life of Pollock lends itself to legend from beginning to end.

He was born in Cody, Wyoming, in 1912, the youngest of five brothers. His father made a series of business errors and spent periods working away from home, living the itinerant life in working gangs, where violence and alcoholism were common. Jackson was the third brother to become an artist, but he lacked the technical facility of his siblings. His early style is brutish and ordinary, and his young adulthood is more notable for his drinking, fighting, and failing with women. He was at pains to prove his masculinity. He believed that he would be an artist, a belief as much to do with acquiring an identity as expressing a point of view. He progressed through a series of attachments to father figures—some of them artists who encouraged him and others critics who saw in him something they could mould.

Periods of relative tranquillity and creativity accompanied Pollock’s time in Jungian analysis and the early years of his marriage to Lee Krasner. But when his forging ahead into newer forms of abstraction began to falter he resorted to drink, and his demons returned. 

Seeing all of Pollock’s oeuvre in one exhibition is a profoundly moving experience. The colours, the brio, cry out to be seen. The complexity of synapses floods these rooms; an abstract language seared with emotion. And then there is the last phase as he scrambles for new forms, his powers failing; the “black” series presages a coming storm.

Jackson Pollock died in a car crash on an empty road. He was 44. He had been drinking all day.
The role of surgery and radiotherapy in treatment of soft tissue sarcomas of the head and neck region: Review of 30 cases
Authors: F. Tas, M. Fayda, G. Aksu, F. Y. Agaoglu, A. Karadeniz, E. Darendeliler, M. Altun, K. Uygun
Journal: Journal of Clinical Oncology (2007)

20507 Background: To evaluate the role of surgery and radiotherapy in the treatment of soft tissue sarcomas of the head and neck region Methods: Thirty adult patients with head and neck soft tissue sarcoma were retrospectively analyzed. The most frequent histopathologic subtypes were chondrosarcomas (27%) and malignant fibrous histiocytoma (20%). The surgical resection was performed in 25 of the 30 patients (83%). Negative surgical margins could be achieved only in 9 of 25 patients (36%). Ten patients had marginal resection (40%) and 6 patients (24%) had gross residual disease after the surgery. All patients in the surgical resection arm received postoperative radiotherapy except two patients. Results: Five-year local control rates for patients with negative surgical margins (n=9), microscopically positives (n=10), gross residual disease (n=6) and inoperable (n=5) cases were 64%, 70%, 20% and 0% respectively. The median disease free survivals were 26.6 months, 17.7 months, 8.4 and 5.5 months. However, there was no significant difference in local control between patients with negative or microscopically positive disease who receive postoperative radiotherapy (71% vs 70%). The higher dose of radiotherapy (= 60Gy) was found to be associated with a longer local control (p=0.048). The local control rates were lower in patients with grade 2–3 tumors as compared with grade 1 tumors (44% vs. 83%). The median overall survival of whole group was 31 months. Median survivals of patients receiving both surgery and radiotherapy with negative and microscopically positive margins were significantly better than patients who were not treated with surgery (34.8 and 36 months vs. 13.3 months). In univariate analysis grade 1–2 vs. 3, had statistically significant 5-year survival difference (64% vs. 14%, p=0.003). The presence of local relapse had clear negative effect on survival (absent vs. present 66% vs. 7%, p=0.0003). Conclusions: Our results and the findings in the literature confirm that the optimal treatment of head and neck soft tissue sarcomas is complete surgical excision. Postoperative adjuvant radiotherapy clearly improves local control however the high locoregional failure rates still indicate the need for improved treatment strategies. No significant financial relationships to disclose.
Lipid Modulation of Mammary Tumor Cell Cytolysis: Direct Influence of Dietary Fats on the Effector Component of Cell-Mediated Cytotoxicity&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: I K Thomas, K L Erickson
Journal: JNCI Journal of the National Cancer Institute (1985)

For understanding the mechanism by which fatty acids promote mammary tumor growth, experiments were designed to determine the influence of dietary fat concentration and saturation on both effector (Ef) and target (Ta) cells in an allogeneic antitumor cell-mediated immune response. Exposure of cytotoxic T-lymphocytes (CTL) to different fatty acids led to significant changes in the subsequent cytolytic capacity of these cells after both primary and secondary immunization. An increase in both saturated (SF) and polyunsaturated (PUF) fats led to decreased cytotoxic function after primary immunization. After a secondary challenge, the suppressive influence of SF was significantly greater than that of PUF, compared to that of the control diet containing essential fatty acids as the only fat source. This response was mediated by a direct effect on the CTL and not through an increase in suppressor or a decrease in Ef or helper cell frequency. In contrast, manipulation of the fatty acid environment of the Ta mammary tumor cells in vivo or in vitro had no significant effect on their susceptibility to lymphocyte-mediated cytotoxicity. Therefore, dietary fats may mediate their effect by a direct influence on the immunocompetent lymphocyte and not on the Ta mammary tumor cell.
Novel phase II study design of MORAb-003, a monoclonal antibody against folate receptor alpha in platinum-sensitive ovarian cancer in first relapse
Authors: M. Phillips, D. Armstrong, R. Coleman, S. Weil, J. Arseneau, D. Glenn, L. Puls, N. Senzer, J. Torres, A. White
Journal: Journal of Clinical Oncology (2007)

5583 Background: Folate receptor alpha (FRA) is over-expressed in the majority of epithelial ovarian cancers (EOC) but largely absent from normal tissue. MORAb-003 (M3) is a humanized monoclonal antibody to FRA. Binding of M3 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-positive tumor cell killing; and suppresses tumor growth in xenograft models. High-dose M3 is non-toxic in monkeys. A phase 1 study showed no significant AEs and suggestions of efficacy in platinum-resistant EOC. This phase 2 efficacy study will determine the efficacy of M3 in platinum-sensitive EOC in first relapse, either as a single agent (SA) in asymptomatic relapse, or in combination with platinum and taxane (P/T) in symptomatic relapse, and to maintain a second response. Methods: Subjects with EOC in first relapse are eligible. For CA125 elevation without symptoms (± measurable disease) the subject receives SA M3 until progression. For symptomatic relapse the subject receives P/T and M3. Subjects with CR or PR receive SA M3 maintenance therapy with the objective of prolonging the second remission longer than the first. Endpoints include CA125 and CT scans. ORR and PFS will be determined for each arm. Results: To date, 15 subjects have been treated, 8 in combination therapy and 7 on single-agent M3. No significant drug-related adverse events have been reported. All subjects treated with the combination of M3 and P/T for symptomatic relapse who have reached at least the first evaluation point have achieved a normalization of CA125 and reduction of tumor size (CR or PR) by CT scan using RECIST criteria, including 3 of 3 subjects with first remissions of 6 to 9 months. Early responses have been observed in the SA M3 treatment arm. Conclusions: This first phase 2 study will determine the efficacy of M3, either as SA or in combination with P/T chemotherapy to achieve a meaningful response rate in EOC in first relapse, and to maintain the second remission longer than the subject’s own first remission. These data will be used to define the most effective phase of disease in which to use M3, and to focus a pivotal study on the area of greatest efficacy. The early results continue to demonstrate activity of M3 in EOC. No significant financial relationships to disclose.
Vidarabine versus Acyclovir Therapy in Herpes Simplex Encephalitis
Authors: Richard J. Whitley, Charles A. Alford, Martin S. Hirsch, Robert T. Schooley, James P. Luby, Fred Y. Aoki, Daniel Hanley, Andre J. Nahmias, Seng-Jaw Soong
Journal: New England Journal of Medicine (1986)

We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of >10, 7 to 10, and ≤6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis. (N Engl J Med 1986; 314:144–9.)
Laminectomy plus Fusion versus Laminectomy Alone for Lumbar Spondylolisthesis
Authors: Zoher Ghogawala, James Dziura, William E. Butler, Feng Dai, Norma Terrin, Subu N. Magge, Jean-Valery C.E. Coumans, J. Fred Harrington, Sepideh Amin-Hanjani, J. Sanford Schwartz, Volker K.H. Sonntag, Fred G. Barker, Edward C. Benzel
Journal: New England Journal of Medicine (2016)

The comparative effectiveness of performing instrumented (rigid pedicle screws affixed to titanium alloy rods) lumbar spinal fusion in addition to decompressive laminectomy in patients with symptomatic lumbar grade I degenerative spondylolisthesis with spinal stenosis is unknown.In this randomized, controlled trial, we assigned patients, 50 to 80 years of age, who had stable degenerative spondylolisthesis (degree of spondylolisthesis, 3 to 14 mm) and symptomatic lumbar spinal stenosis to undergo either decompressive laminectomy alone (decompression-alone group) or laminectomy with posterolateral instrumented fusion (fusion group). The primary outcome measure was the change in the physical-component summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36; range, 0 to 100, with higher scores indicating better quality of life) 2 years after surgery. The secondary outcome measure was the score on the Oswestry Disability Index (range, 0 to 100, with higher scores indicating more disability related to back pain). Patients were followed for 4 years.A total of 66 patients (mean age, 67 years; 80% women) underwent randomization. The rate of follow-up was 89% at 1 year, 86% at 2 years, and 68% at 4 years. The fusion group had a greater increase in SF-36 physical-component summary scores at 2 years after surgery than did the decompression-alone group (15.2 vs. 9.5, for a difference of 5.7; 95% confidence interval, 0.1 to 11.3; P=0.046). The increases in the SF-36 physical-component summary scores in the fusion group remained greater than those in the decompression-alone group at 3 years and at 4 years (P=0.02 for both years). With respect to reductions in disability related to back pain, the changes in the Oswestry Disability Index scores at 2 years after surgery did not differ significantly between the study groups (-17.9 in the decompression-alone group and -26.3 in the fusion group, P=0.06). More blood loss and longer hospital stays occurred in the fusion group than in the decompression-alone group (P<0.001 for both comparisons). The cumulative rate of reoperation was 14% in the fusion group and 34% in the decompression-alone group (P=0.05).Among patients with degenerative grade I spondylolisthesis, the addition of lumbar spinal fusion to laminectomy was associated with slightly greater but clinically meaningful improvement in overall physical health-related quality of life than laminectomy alone. (Funded by the Jean and David Wallace Foundation and others; SLIP ClinicalTrials.gov number, NCT00109213.).