tbuckley/cabot-search huggingface dataset:
Phase I clinical trial of VTX-2337, a selective toll-like receptor 8 (TLR8) agonist, in patients with advanced solid tumors.
Authors: P. A. Cohen, D. W. Northfelt, G. J. Weiss, D. D. Von Hoff, K. Manjarrez, G. Dietsch, R. M. Hershberg, R. K. Ramanathan
Journal: Journal of Clinical Oncology (2011)

2537 Background: Toll-like receptors (TLRs) have emerged as attractive targets for anti-cancer immunotherapies. VTX-2337 is a novel, potent and selective small molecule (<500 MW) TLR8 agonist which activates myeloid dendritic cells, monocytes and NK cells to produce chemokines and Th1 polarizing cytokines, including TNFα, IL-12 and IFNγ. Such impacts induce innate and adaptive immune responses against tumor cells. VTX-2337 is the first selective TLR8 agonist studied in man. Methods: VTX-2337 was administered s.c. to 33 subjects with advanced solid tumors. weekly on Days 1, 8 and 15 of a 28d cycle. Using a modified Fibonacci dose escalation scheme, 8 cohorts of 3–8 patients received doses from 0.1 mg/m2 to 3.9 mg/m2. Pharmacokinetic (PK) and pharmacodynamic (PD)analyses were performed. Results: 19 males and 14 females with ECOG status 0-1 were enrolled. Median age was 65.0, and average time from diagnosis to study entry was 3.1 years. Common tumor types included colorectal (n=9), pancreatic (n=6) and melanoma (n=5). Grade 1 or 2 injection site reaction (85%), chills (58%), fever (42%) and flu-like symptoms (24%) were the most common drug-related adverse events, as expected from the pharmacology of the molecule. No drug-related hematologic or other laboratory toxicities were observed. The MTD was the highest dose tested (3.9 mg/m2), with one DLT of grade 3 hypotension in 1/6 evaluable subjects. Cmax values increased from 1.5 to 23.0 ng/mL and AUC0-∞ increased from 3.12 to 81.10 ng·hr/mL. Plasma levels of multiple immune mediators; including G-CSF, MCP-1, MIP1‐β and TNFα increased in a dose-dependent manner. PK and PD responses were accurately predicted from preclinical work in cynomolgus monkeys. There was no evidence of desensitization or augmentation of the PD response over multiple VTX-2337 doses. 25% of subjects experienced disease stabilization by RECIST at 8 weeks and received additional doses until progression. Conclusions: The TLR8 agonist VTX-2337 is safe and well tolerated, has a predictable PK profile and shows dose-dependent pharmacologic activity. Based on preclinical additive effects with various anticancer therapies, combination studies in multiple cancers are being initiated.
Pneumomediastinum and Severe Subcutaneous Emphysema
Authors: F G van der Kleij, J G Zijlstra
Journal: New England Journal of Medicine (2000)

Figure 1. A 76-year-old man with chronic obstructive pulmonary disease was admitted after a car accident. The initial clinical and radiographic evaluation showed no evidence of rib fractures or other chest trauma. Several hours later, his neck and upper chest became increasingly swollen. Crepitations were detected on palpation of the swollen areas. Respiratory failure developed (respiratory rate, 36 per minute; pulse rate, 120 per minute; and blood pressure, 120/75 mm Hg). A chest x-ray film showed pneumomediastinum (open arrows) and extensive subcutaneous emphysema (solid arrow) that appeared in part as a cast of the muscles of the upper chest wall. . . .
Case 20-1994
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Kenan E. Haver, Eugene J. Mark
Journal: New England Journal of Medicine (1994)

Presentation of CaseA girl five years and eight months old was admitted to the hospital because of a nodular lesion in the upper lobe of the left lung, recent bouts of fever, and a cough associated with pulmonary infiltrates.The child had been born after a full-term, uncomplicated first pregnancy and spontaneous vaginal delivery to a mother who had Hodgkin's lymphoma in remission; her mother had not received chemotherapy during the pregnancy. At the age of three years a cough and wheezing developed, and a diagnosis of asthma was made. One year later pneumonia was found on radiographic examination . . .
The Effect of Cost-Containment Policies on Rates of Coronary Revascularization in California
Authors: Kenneth M. Langa, Elliot J. Sussman
Journal: New England Journal of Medicine (1993)

Lower rates of use of resources have been reported for the treatment of hospitalized patients covered by Medicaid than for privately insured patients. Cost-containment policies may exacerbate such differences in the use of hospital resources. We studied patients with ischemic heart disease who received care at nonfederal hospitals in California in 1983 (the year a Medicaid cost-containment program was implemented), in 1985, or in 1988. Within this sample of patients, we compared the rates of coronary revascularization (coronary-artery bypass surgery or coronary angioplasty) among patients covered by Medicaid, patients with private insurance covering fee-for-service care, and patients enrolled in a health maintenance organization (HMO).
Disseminated Osteomyelitis from Mycobacterium ulcerans after a Snakebite
Authors: Michael Hofer, Bernard Hirschel, Philip Kirschner, Maurice Beghetti, Andre Kaelin, Clair-Anne Siegrist, Susanne Suter, Andreas Teske, Erik C. Bottger
Journal: New England Journal of Medicine (1993)

Atypical mycobacteria have been widely recognized as human pathogens only since the 1950s1. Multiple organs can be involved, in particular the skin and bones. However, disseminated infection is usually observed only in immunodeficient hosts. We describe a boy with an apparently normal immune system, who nevertheless had debilitating multifocal osteomyelitis associated with a growth-deficient acid-fast microorganism. The microorganism was identified as Mycobacterium ulcerans by DNA amplification and subsequent determination of the nucleic acid sequence. Case Report The patient, born in November 1985, was the fourth child of a farmer from West Africa. In 1989 he was bitten on his . . .
Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ
Authors: Susan M. Love
Journal: JAMA Oncology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Multimedia: The Spine and Medical Negligence
Authors: Patrick Hoyte
Journal: BMJ (1999)

R W Porter


Bios Scientific, £19.95, pp 200 




ISBN 1 85996 126 6

———————

Rating: ★★★★

Since 1991 the cost of medical negligence in the United Kingdom has risen fivefold—it costs the NHS over £300m a year. Fortunately, there is no evidence of any fall in clinical standards. The proportion of claims that are settled with payment of compensation to patients has in fact fallen from 34% in 1975 to 25% in 1997.

The medical profession cannot afford to be complacent, however, and even less so can orthopaedic surgeons, who regularly feature at the top of tables of claims. Clinical risk management is here to stay, and NHS trusts are adopting programmes of risk management to reduce the number of accidents to patients.

Professor Porter has done his colleagues great service in setting out the important issues surrounding consent, counselling, operative technique, and pitfalls where mismanagement can cause major neurological damage and costly disability.

The chapters on why patients sue, the legal process, informed consent, and risk management are worthy of any medicolegal textbook, but I was particularly taken with the many case reports emphasising the dangers behind clinical scenarios.

Four messages emerge: reliance on conservative surgery when anything more could not guarantee a better result; the importance of patient selection for difficult revisional surgery, coupled with the choice of an experienced centre; the great need for informed consent about difficult and highly technical procedures; and the obligation to educate patients about the reality of medical practice, as medicine cannot completely remedy every clinical problem.

Responding to a lawsuit may be one of the most stressful times of a doctor’s life. Some allegations will be ill-founded because the undesirable outcome stemmed from the natural course of the disease or from a well known and unavoidable complication, but much morbidity and the consequent litigation is avoidable—how nice to be told how in such a measured and effective way.
Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants
Authors: Andrew Perkins, Xiangmin Xu, Douglas R. Higgs, George P. Patrinos, Lionel Arnaud, James J. Bieker, Sjaak Philipsen
Journal: Blood (2016)

Until recently our approach to analyzing human genetic diseases has been to accurately phenotype patients and sequence the genes known to be associated with those phenotypes; for example, in thalassemia, the globin loci are analyzed. Sequencing has become increasingly accessible, and thus a larger panel of genes can be analyzed and whole exome and/or whole genome sequencing can be used when no variants are found in the candidate genes. By using such approaches in patients with unexplained anemias, we have discovered that a broad range of hitherto unrelated human red cell disorders are caused by variants in KLF1, a master regulator of erythropoiesis, which were previously considered to be extremely rare causes of human genetic disease.
Diffuse Glomerulonephritis Associated with Infected Ventriculoatrial Shunt
Authors: Gunnar B. Stickler, Myung H. Shin, Edmund C. Burke, Keith E. Holley, Ross H. Miller, William E. Segar
Journal: New England Journal of Medicine (1968)

Of six patients with diffuse glomerulonephritis and associated infected ventriculoatrial shunt, three had improved renal function after removal of the infected shunt, and three died from Central-nervous-system disease. The renal disease probably resulted from an immunologic response to the staphylococcal infection rather than from direct bacterial embolization of the kidney.
Lithium erythrocyte/plasma ratio as a predictor of response
Authors: A Flemenbaum, R Weddige, J Miller
Journal: American Journal of Psychiatry (1978)

The authors measured RBC/plasma lithium ratios in 33 patients with primary diagnoses of unipolar depression (N=20), bipolar depression (N=9), schizo-affective psychosis (N=2), and alcoholism (N=2). Subjects rated as having marked or moderate improvement at follow-up (average = 17.1 months) tended to have high ratios (greater than or equal to .41), whereas all 9 patients rated as minimally improved were in the low-ratio group. Although further research with larger samples, controls, and longer follow-up is necessary, the results suggest a predictive value for the RBC/lithium ratio.
Case 28-1983
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, James M. Richter, G. Richard Dickersin
Journal: New England Journal of Medicine (1983)

Presentation of CaseA 35-year-old woman was admitted to the hospital because of abdominal pain and a mass.She was well until eight months earlier, when she began to have diffuse, crampy abdominal pain. She was seen at another hospital, where a mixture of phenobarbital and belladonna alkaloids was prescribed, with temporary improvement. The pain recurred and worsened after the ingestion of fatty foods. Seven months before admission she came to this hospital, where physical examination was negative. The hematocrit was 29.9 per cent, the white-cell count 7900, and the erythrocyte sedimentation rate 40 mm per hour. The urea nitrogen . . .
Rational Intravenous Doses of Theophylline
Authors: Paul A. Mitenko, Richard I. Ogilvie
Journal: New England Journal of Medicine (1973)

Physiologic responses to intravenously administered theophylline were determined in nine hospitalized asthmatic subjects. In each patient incremental theophylline plasma concentration plateaus were attained at which pulmonary-function changes related to drug administration were examined. Continuous improvement in vital capacity and first-second forced expiratory volume was observed over the plasma range of theophylline concentration of 5 to 20 mg per liter. The improvement varied directly with the logarithm of the plasma concentration. A safe and effective dosage regimen for intravenous theophylline can be based on these observations. After a loading dose of aminophylline, 5.6 mg per kilogram given intravenously, 0.9 mg per kilogram per hour can be given as a maintenance dose. This amount will result in a plasma theophylline concentration of approximately 10 mg per liter for 95 per cent of patients and in recovery from some 30 to 40 per cent of reversible pulmonary-airway obstruction. (N Engl J Med 289:600–603, 1973)
A phase I study of GC33, a recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma (HCC).
Authors: A. X. Zhu, P. J. Gold, A. B. El-Khoueiry, T. A. Abrams, H. Morikawa, T. Ohtomo, P. A. Philip
Journal: Journal of Clinical Oncology (2011)

4085 Background: Glypican 3 (GPC3) belongs to a family of cell-surface heparan sulfate proteoglycans and is specifically expressed in HCC. In this phase I study, we examined the safety, tolerability, and pharmacokinetics (PK) of GC33, a recombinant, humanized monoclonal antibody against GPC3, in patients (pts) with advanced HCC. Methods: Key eligibility criteria included pts with histologically confirmed measurable advanced HCC, ECOG PS ≤ 1, Child-Pugh A/B, adequate organ function, and available tumor tissues for GPC3 testing by IHC. This study was performed to determine the maximum tolerated dose of GC33 given intravenously weekly. Results: Twenty pts were evaluated at 4 dose levels (2.5, 5.0, 10, and 20 mg/kg): median age=62 yrs (range 50-78), M/F=16/4, ECOG PS 0/1=10/10, HCV/HBV/Alcohol/other=10/4/3/1, Child-Pugh A/B=13/7. Fifteen pts (75%) had received prior sorafenib. Treatment was well tolerated at all dose levels without dose-limiting toxicities (DLTs). Grade 3/4 treatment related events in first 4 weeks were anemia (5%) and lymphopenia (5%). Grade 1-2 infusion reactions were seen in 35% of patients after the first infusion. Other all grades common toxicities included fatigue (45%), pyrexia (40%), and diarrhea (35%). Stable disease (SD) was observed in 7 patients. Non-linear PK was seen with t1/2of 4-7 days at 10-20 mg/kg. Trough plasma concentrations reached steady state within 3-6 doses. An exploratory analysis revealed longer SD in pts with positive GPC3 membranous staining than in pts with negative staining. Conclusions: GC33 can be safely administered intravenously up to 20 mg/kg weekly. No DLTs were encountered. Fatigue, infusion reactions and lymphopenia were the most common adverse events. SD was associated with positive GPC3 expression. The study is currently ongoing to assess the efficacy signal in a well defined cohort of 12 patients with Child-Pugh A and positive GPC3 membranous staining.
Costs and Effectiveness of Routine Therapy with Long-Term Beta-Adrenergic Antagonists after Acute Myocardial Infarction
Authors: Lee Goldman, S.T. Benjamin Sia, E. Francis Cook, John D. Rutherford, Milton C. Weinstein
Journal: New England Journal of Medicine (1988)

We analyzed the costs and effectiveness of routine therapy with beta-adrenergic antagonists in patients who survived an acute myocardial infarction. On the basis of data pooled from the literature, this form of therapy resulted in a 25 percent relative reduction annually in the mortality rate for years 1 to 3 and a 7 percent relative reduction for years 4 to 6 after a myocardial infarction. The estimated cost of six years of routine beta-adrenergic-antagonist therapy to save an additional year of life was $23,400 in low-risk patients, $5,900 in medium-risk patients, and $3,600 in high-risk patients, assuming that the entire benefit of earlier treatment is lost immediately after six years. Under a more likely assumption--that the benefit of six years of treatment wears off gradually over the subsequent nine years--the estimated cost of therapy per year of life saved would be $13,000 in low-risk patients, $3,600 in medium-risk patients, and $2,400 in high-risk patients. As compared with coronary-artery bypass grafting and the medical treatment of hypertension, routine beta-adrenergic-antagonist therapy has a relatively favorable cost-effectiveness ratio.
Pharmacists Contribute to Safe Management in Outpatient Cancer Chemotherapy
Authors: Hirotoshi Iihara, Masashi Ishihara, Hironori Fujii, Minako Nishigaki, Maya Yamada, Chiaki Yoshimi, Mayu Takahashi, Takao Takahashi, Kazuhiro Yoshida, Yoshinori Itoh
Journal: Annals of Oncology (2014)
Control of Acute Alcoholism with Prochlorperazine
Authors: Joseph Thimann, Joseph W. Gauthier
Journal: New England Journal of Medicine (1959)

ONE of the chief aims in the present-day treatment of the acutely ill alcoholic patient is to provide adequate symptomatic control of severe acute intoxication, delirium tremens, the withdrawal symptoms and postdelirious agitation. Ideal therapy should control these withdrawal symptoms without increasing excessively the already existing cortical depression.Withdrawing alcohol gradually has been found to be an inefficient method, and most sedatives and central relaxants are contraindicated during this period because they increase central depression or confusion, may be habit forming or may mask signs of organic illness. Certain ataraxic drugs, however, have proved effective in the control of symptoms . . .
Incidence, severity, and management of anemia during concurrent chemoradiation for head and neck cancer
Authors: A. M. Choudhury, T. Tanvetyanon
Journal: Journal of Clinical Oncology (2004)

5563 Background: Anemia, causing tumor hypoxia, can reduce the efficacy of radiation therapy (RT), particularly in patients with head and neck cancer (HNC). Low average weekly nadir hemoglobin (AWNH) has been associated with increased cancer recurrence. The incidence, severity, and management of anemia, including the use of erythropoietin or blood transfusion, during concurrent chemoradiation for HNC is unknown. Methods: Medical records of patients with unresectable HNC who were treated with concurrent chemoradiation during 1999–2003 were reviewed. Patients with less than 10% planned radiation dosage, impaired renal function, or cancers of the paranasal sinuses or parotid glands were excluded. Results: Forty-eight patients were included for analyses. Mean age was 59.9 years; 95.6% had stage III or stage IV disease. Mean radiation dose was 65.0 Gy. The incidence of anemia was very high: 70.8% had hemoglobin below 10 g/dl; 91.6% below 12 g/dl; mean nadir hemoglobin was 9.0 g/dl; AWNH was 10.7 g/dl. No patients received erythropoietin during RT. Total episodes of transfusion was 1.8 per patient; 19/48 (39.6%) were transfused at least once. Mean lowest hemoglobin threshold of transfusion was 7.4 g/dl. The first transfusion occurred at about 3.2 weeks since initiation of radiation. Total blood transfused were 3.3 units per patient. Transfused patients had significantly lower hemoglobin at baseline compared with non-transfused counterparts (10.8 vs 12.4 g/dl, p=0.002). Patients who received multiple chemotherapeutic agents concurrently with radiation were more frequently transfused than did patients receiving single-agent platinum (47% vs 10%, p=0.03). Most patients who did not receive transfusion remained anemic at the conclusion of RT; 51% had hemoglobin below 12 g/dl; 86.2% below 10 g/dl. Conclusions: Anemia during concurrent chemoradiation for HNC was prevalent. AWNH was critically low, potentially causing insensitivity to RT. Our patients were mainly managed by transfusion; however, the intensity of transfusion was less than desirable. Further studies using adequate transfusion and/or erythropoietin to improve tumor control are warranted No significant financial relationships to disclose.
Is the Continual Reassessment Method superior to the standard 3+3 dose escalation scheme?
Authors: A. Iasonos, E. R. Riedel, D. R. Spriggs
Journal: Journal of Clinical Oncology (2008)

2559 Background: Bayesian phase I designs have received increased attention. The objective is to determine if the Continual Reassessment Method (CRM) is superior to the standard 3+3 dose escalation scheme (SM) in terms of sample size, precision and study duration. Methods: Comparisons were carried out through 1,000 simulated trials under different scenarios by varying the number of dose levels from 5 to 8 and the location of the true MTD. The hyperbolic tangent was assumed as the dose-toxicity curve and the target toxicity rate was 25%. Four Bayesian designs were evaluated: original CRM; CRM that is restricted in no more than one dose level increase; two-stage CRM that follows an arbitrary escalation plan at the beginning of the trial until a DLT is observed and then switches to CRM; and CRM in cohorts of three patients. CRM was assessed in two alternative schemes: with a fixed sample approach of 20 patients or with a stopping rule that halts the trial when a specified amount of precision around the estimated toxicity rate at the MTD (ETR) is reached. Standard endpoints were evaluated: accuracy, precision, safety, total sample size, and minimum study duration. Results are independent of the increment between dose levels. Results: SM found the true MTD on average 20% (range 8–28%) fewer times compared to CRM-based methods in almost all scenarios. All CRM-based methods treated more patients at the MTD compared to SM (42% vs 11%) except when the true MTD is at the second dose level (36 vs 35%). Number of DLTs was the smallest under the SM. CRM and SM are similar in terms of total sample size when testing 5 dose levels, although SM requires shorter duration. As the number of dose levels increases to 8, CRM completes the trial faster than SM when used with a fixed sample of 20 patients; except when the MTD is among the lower levels. Using the stopping rule approach with a maximum of 30 patients, 66–78% of trials have not met the required precision around the ETR. Conclusions: All CRM-based methods are an improvement over SM in terms of accuracy and optimal dose allocation, except when the true MTD is among the lower levels. When the number of dose levels is limited (eg 5), a sample of 20 is sufficient by both methods in order to find the MTD. However, a sample size of 20–30 is not sufficient to achieve a narrow confidence interval around the ETR. No significant financial relationships to disclose.