Biomedical subjects

Jeffrey W Sherman

Publications and source records attributed to Jeffrey W Sherman.

5 recordsLinked to original sources

PubMed2006

Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies.

OBJECT: Convection-enhanced delivery (CED) is an increasingly used novel local/regional delivery method targeted directly to tissue. It relies on a continuous pressure gradient for distribution of therapeutic agents into the interstitial space, with administration of the infusate over a few days. Cintredekin besudotox (also known as IL13- PE38QQR) is a recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium, which targets malignant glioma cells. METHODS: Cintredekin besudotox was administered via intraparenchymal CED after resection of supratentorial recurrent malignant glioma. The safety and toxicity profile was reviewed for 53 patients in whom infusion catheters had been placed; 51 of them received CED of the study drug. Adverse events were categorized based on time of onset in relation to CED, and the causal relationship with catheter placement or delivery of cintredekin besudotox. Catheters were placed in 53 patients, although only 51 of them received cintredekin besudotox. Most adverse events related to catheter placement or the study drug originated from the central nervous system. Three symptomatic windows were defined: the first one was between surgical procedure and CED; the second was during CED and up to 1 week after its completion; and the third window was 2 to 10 weeks after treatment. Those windows generally reflected adverse events related to surgical procedures, mass effect from infusate, and drug effect on tumor-infiltrated and normal brain parenchyma, respectively. CONCLUSIONS: The symptomatic windows identified in this study apply to any CED clinical trials, particularly those in which chimeric cytotoxins are used, and will help to determine the most likely underlying pathophysiological process causing symptoms. This information, in turn, will help to prevent adverse events or minimize their severity. Those events also have implications for dose escalation and outcome measures.

Adult↗

PubMed2006

Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies.

PURPOSE: Raf proteins are key elements of growth-related cellular signaling pathways and are a component of cancer cell resistance to radiation therapy. Antisense oligonucleotides to c-raf-1 permit highly selective inhibition of the gene product and offer a strategy for sensitizing cancer cells to radiation therapy. In this dose escalation study, we evaluated the safety of combined liposomal formulation of raf antisense oligonucleotide (LErafAON) and radiation therapy in patients with advanced malignancies. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated with LErafAON in a phase I dose escalation study while receiving palliative radiation therapy. Drug-related and radiation-related toxicities were monitored. Pharmacokinetics and expression of c-raf-1 mRNA and Raf-1 protein were determined in peripheral blood mononuclear cells. RESULTS: Seventeen patients with palliative indications for radiation therapy were entered into this study. Thirteen patients received daily infusions of LErafAON and four received twice-weekly infusions. Radiation therapy was delivered in daily 300-cGy fractions over 2 weeks. Patients tolerated radiation, and no unexpected radiation-related side effects were observed. Drug-related reactions (grade > or =2), such as back pain, chills, dyspnea, fatigue, fever, flushing, and hypertension, were observed in most patients and were managed by premedication with corticosteroids and antihistamines. Serious adverse events occurred in five patients, including acute infusion-related symptoms, abnormal liver function tests, hypoxia, dehydration, diarrhea, esophagitis, fever, hypokalemia, pharyngitis, and tachypnea. Twelve of 17 patients were evaluable for tumor response at completion of treatment; four showed partial response, four showed stable disease, and four experienced progressive disease. The intact rafAON was detected in plasma for 30 minutes to several hours. Six patients with partial response or stable disease were evaluable for c-raf-1 mRNA and/or Raf-1 protein expression. Inhibition of c-raf-1 mRNA was observed in three of five patients. Raf-1 protein was inhibited in four of five patients. CONCLUSION: This is the first report of the combined modality treatment using antisense oligonucleotides with radiation therapy in patients with advanced cancer. A dose of 2.0 mg/kg of LErafAON administered twice weekly is tolerated with premedication and does not enhance radiation toxicity in patients. The observation of dose-dependent, infusion-related reactions has led to further modification of the liposomal composition for use in future clinical trials.

Abdominal Pain↗

PubMed2006

Automatic and controlled components of judgment and decision making.

The categorization of inductive reasoning into largely automatic processes (heuristic reasoning) and controlled analytical processes (rule-based reasoning) put forward by dual-process approaches of judgment under uncertainty (e.g., K. E. Stanovich & R. F. West, 2000) has been primarily a matter of assumption with a scarcity of direct empirical findings supporting it. The present authors use the process dissociation procedure (L. L. Jacoby, 1991) to provide convergent evidence validating a dual-process perspective to judgment under uncertainty based on the independent contributions of heuristic and rule-based reasoning. Process dissociations based on experimental manipulation of variables were derived from the most relevant theoretical properties typically used to contrast the two forms of reasoning. These include processing goals (Experiment 1), cognitive resources (Experiment 2), priming (Experiment 3), and formal training (Experiment 4); the results consistently support the author's perspective. They conclude that judgment under uncertainty is neither an automatic nor a controlled process but that it reflects both processes, with each making independent contributions.

Analysis of Variance↗

PubMed2005

Separating multiple processes in implicit social cognition: the quad model of implicit task performance.

The authors argue that implicit measures of social cognition do not reflect only automatic processes but rather the joint contributions of multiple, qualitatively different processes. The quadruple process model proposed and tested in the present article quantitatively disentangles the influences of 4 distinct processes on implicit task performance: the likelihood that automatic bias is activated by a stimulus; that a correct response can be determined; that automatic bias is overcome; and that, in the absence of other information, a guessing bias drives responses. The stochastic and construct validity of the model is confirmed in 5 studies. The model is shown to provide a more nuanced and detailed understanding of the interplay of multiple processes in implicit task performance, including implicit measures of attitudes, prejudice, and stereotyping.

Automatism↗

PubMed2005

Prejudice and stereotype maintenance processes: attention, attribution, and individuation.

Three experiments examined the relationship between prejudice and processing of stereotypic information. Higher levels of prejudice were associated with greater attention to and more thorough encoding of stereotype-inconsistent than stereotype-consistent behaviors but only when processing capacity was plentiful (Experiments 1 and 3). High-prejudice participants attributed consistent behaviors to internal factors and inconsistent behaviors to external forces (Experiment 2). Together, these results suggest that high-prejudice people attend carefully to inconsistent behaviors to explain them away but only if they have sufficient resources to do so. Results also showed that low-prejudice but not high-prejudice participants formed individuated impressions by integrating the implications of the target's behaviors (i.e., individuating). High levels of prejudice appear to be associated with biased encoding and judgment processes that may serve to maintain stereotypes.

Adult↗