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Results for “Pathologic response”

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At least 811 records · Page 45Linked to original sources

PubMed2004

Focused microwave phased array thermotherapy for ablation of early-stage breast cancer: results of thermal dose escalation.

BACKGROUND: Tumor ablation as a means of treating breast cancer is being investigated. Microwave energy is promising because it can preferentially heat high-water-content breast carcinomas, compared to adipose and glandular tissues. METHODS: This is a prospective, multicenter, nonrandomized dose-escalation study of microwave treatment. Thermal dose was measured as (1) thermal equivalent minutes (cumulative equivalent minutes; CEM) of treatment relative to a temperature of 43 degrees C and (2) peak tumor temperature. Microwaves were guided by an antenna-temperature sensor placed percutaneously into the tumor. Outcomes measured were pathologic response (tumor necrosis) side effects. RESULTS: Twenty-five patients (mean age, 57 years) were enrolled. The mean tumor diameter was 1.8 cm. Tumoricidal temperatures (>43 degrees C) were reached in 23 patients (92%). Tumor size was unchanged after thermotherapy (P = not significant). Pathologic necrosis was achieved in 17 (68%) patients. Complete necrosis of the invasive component was achieved in two patients. One hundred forty CEM is predictive of a 50% tumor response, and 210 CEM is predictive of a 100% tumor response (P =.003). Univariate linear regression predicts that peak tumor temperatures of 47.4 degrees C and 49.7 degrees C cause a 50% tumor response and a 100% tumor response, respectively. CONCLUSIONS: Thermotherapy causes tumor necrosis and can be performed safely with minimal morbidity. The degree of tumor necrosis is a function of the thermal dose. Future studies will evaluate the impact of high doses of thermotherapy on margin status and complete tumor ablation.

Breast Neoplasms↗

PubMed1993

[Carotid sinus massage in diagnosing syncope of unknown origin].

Carotid sinus massage (CSM) was performed in 44 patients (23 female, 21 male, mean age 52 years) with recurrent episodes of unexplained syncope and without any organic heart disease. The protocol of examination consisted of 5 s CSM performed unilaterally in supine, upright 60 degrees positions, after administration of propranolol (i.v. 0.1 mg/kg) and during autonomic inhibition (atropine i.v. 0.02 mg/kg after propranolol). The diagnosis of hypersensitive carotid sinus syndrome (HCSS) was established in case of pathologic response to CSM in supine and upright 60 degrees positions. Positive results of CSM was obtained in 15 (34%) examined patients. Cardioinhibitory form of HCSS was recognized in 9 and mixed form in 6 cases. Pathologically augmented carotid sinus reflex was provoked in 8 cases by massage of the right, in 4 cases of the left and in 3 both carotid sinuses. Maximal time of electrical asystole after CSM was 6300 ms while maximal decreased od systolic blood pressure was 70 mmHg. Intravenous administration of propranolol caused decrease of systolic blood pressure approximately 43 +/- 15 mmHg whereas the cardioinhibitory effect of CSM after this drug significantly was increased only in patients with a positive response to CSM in the supine or upright 60 degrees positions. Autonomic inhibition significantly decreased the cardioinhibitory effect of CSM without significant influence on its vasodepressive component.

Adult↗

PubMed1993

A human respiratory syncytial virus (RSV) primate model of enhanced pulmonary pathology induced with a formalin-inactivated RSV vaccine but not a recombinant FG subunit vaccine.

Human respiratory syncytial virus (RSV) is the leading cause of severe bronchiolitis and pneumonia in infants. RSV vaccine development has been stifled for the past 23 years because infants vaccinated with formalin-inactivated (FI) RSV have experienced exacerbated disease upon RSV infection. This exacerbated disease phenomenon is poorly understood, in part because of the lack of a primate model that exhibits a similar exacerbated disease state. Vaccination of African green monkeys with either FI RSV or a genetically engineered subunit vaccine termed FG glycoprotein reduced replication of challenge virus. However, only vaccination with FI RSV induced an enhanced pulmonary pathologic response to RSV infection. Pulmonary inflammatory scores in the FG glycoprotein-vaccinated monkeys were no greater than in monkeys vaccinated with adjuvant alone. This is the first demonstration of RSV vaccine-induced enhanced pathology in a primate and illustrates that a subunit vaccine has the potential of circumventing this exacerbated disease phenomenon.

Animals↗

PubMed2004

Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally advanced prostate cancer.

OBJECTIVES: To perform a Phase II trial of docetaxel administered on a weekly schedule for 6 weeks before radical prostatectomy (RP) in patients with locally advanced prostate cancer. METHODS: Treatment consisted of six doses of docetaxel 40 mg/m(2) intravenously administered weekly for 6 weeks followed by RP. Eligibility criteria included clinical Stage T2b, prostate-specific antigen (PSA) level 15 ng/mL or greater or Gleason sum 8 or greater, and no evidence of metastatic disease. The primary endpoint was feasibility and drug-related and surgical-related toxicities. Secondary endpoints included pre-RP PSA level, local response, pathologic outcomes, and time to PSA failure. RESULTS: Twenty-nine patients were entered; 80% completed all 6 weeks of therapy and 97% underwent RP. The median PSA level was 12 ng/mL (range 2.5 to 43.3), the median Gleason sum was 8 (range 6 to 9), and all had Stage T2b or greater disease. A statistically significant reduction in the prechemotherapy versus postchemotherapy mean PSA level was observed (12.00 +/- 1.86 ng/mL versus 8.42 +/- 1.63 ng/mL, P <0.03), with 79% of patients experiencing some reduction and 24% a more than 50% reduction in PSA level in response to docetaxel alone. No unexpected toxicities and no intraoperative complications occurred. Pathologic analysis demonstrated residual carcinoma in all cases. Three patients (11%) had organ-confined disease, and 26 (93%) had achieved an undetectable PSA postoperatively. At a median follow-up of 23 months (range 1.5 to 36), 20 patients were disease free with no additional therapy. CONCLUSIONS: This trial establishes the baseline effect of short-course high-dose docetaxel alone on locally advanced prostate cancer. Additional study of this paradigm with other agents alone and in combination with docetaxel seems warranted.

Aged↗

PubMed1998

Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae.

The vascular endothelium is uniquely positioned between the blood and tissue compartments to receive directly the fluid forces generated by the blood flowing through the vasculature. These forces invoke specific responses within endothelial cells and serve to modulate their intrinsic structure and function. The mechanisms by which hemodynamic forces are detected and converted by endothelia into a sequence of biological and even pathological responses are presently unknown. By purifying and subfractionating the luminal endothelial cell plasma membrane from tissue, we show, for the first time, that not only does mechanotransduction occur at the endothelial cell surface directly exposed to vascular flow in vivo but also increased flow in situ induces rapid tyrosine phosphorylation of luminal endothelial cell surface proteins located primarily in the plasmalemmal invaginations called caveolae. Increased flow induces the translocation of signaling molecules primarily to caveolae, ultimately activating the Ras-Raf-mitogen-activated protein kinase pathway. This signaling appears to require intact caveolae. Filipin-induced disassembly of caveolae inhibits both proximal signaling events at the cell surface and downstream activation of the mitogen-activated protein kinase pathway. With the molecular machinery required for mediating rapid flow-induced responses as seen in endothelium, caveolae may be flow-sensing organelles converting mechanical stimuli into chemical signals transmitted into the cell.

Animals↗

PubMed2002

Transcriptional control of cardiac allograft vasculopathy by early growth response gene-1 (Egr-1).

Expression of the zinc finger transcription factor early growth response gene-1 (Egr-1) is triggered rapidly after mechanical vascular injury or after a precipitous drop in ambient oxygen, whereupon it induces the expression of diverse gene families to elicit a pathological response. Initially characterized as an early response transcriptional activator, the role of Egr-1 in more chronic forms of vascular injury remains to be defined. Studies were designed to examine whether Egr-1 induction may serve as a causal link between early preservation injury and delayed vascular consequences, such as coronary allograft vasculopathy (CAV). The preservation and transplantation of heterotopic murine cardiac allografts strongly induce Egr-1 expression, leading to increased expression of its downstream target genes, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and platelet-derived growth factor A chain. Expression of these Egr-1-inducible gene targets is virtually obliterated in homozygous Egr-1-null donor allografts, which also exhibit attenuated parenchymal rejection and reduced CAV as long as 60 days. Congruous data are observed by treating donor hearts with a phosphorothioate antisense oligodeoxyribonucleotide directed against Egr-1 before organ harvest, which blocks subsequent expression of Egr-1 mRNA and protein and suppresses the late development of CAV. These data indicate that Egr-1 induction represents a central effector mechanism in the development of chronic rejection characterized by CAV. Blocking the expression of this proximal transcription factor solely at the time of organ harvest elicits beneficial delayed consequences for the cardiac allograft.

Animals↗

PubMed1997

Regulation of cytochromes P450 during inflammation and infection.

Hepatic P450 activities are profoundly affected by various infectious and inflammatory stimuli, and this has clinical and toxicological consequences. Whereas the expression of most P450s in the liver is suppressed, some are induced. Many of the effects observed in vivo can be mimicked by pro-inflammatory cytokines and IFNs, and P450s are differentially regulated by these agents. Therefore, different cytokine profiles and concentrations in the vicinity of the hepatocyte in different models of inflammation may result in qualitatively and quantitatively different effects on populations of P450s. In addition to cytokines, glucocorticoids may have an important role in P450 regulation in stress conditions, including that caused by inflammatory stimuli. Although in many cases the decreases in activity are due primarily to a down-regulation of P450 gene transcription, it is likely that modulation of RNA and protein turnover, as well as enzyme inhibition, contributes to some of the observed effects. The mechanisms whereby these effects are produced may also vary with both the P450 under study and the time course of the effect. The complexity of the P450 response to inflammation and infection means that all of the above factors must be considered when trying to predict the effect of a given infectious or inflammatory condition on the clinical or toxic response of humans or animals to an administered drug or toxin. The question of whether the down-regulation of the hepatic P450 system to inflammation or infection is a homeostatic or pathological response cannot be answered at present. It is difficult to discern the physiological benefit of reducing hepatic P450 activities, unless it is to prevent the generation of reactive oxygen species generated by uncoupled catalytic turnover of the enzymes. On the other hand, as we proposed some years ago [64], the suppression of P450 may be due to the liver's need to utilize its transcriptional machinery and energy for the synthesis of APPs involved in the inflammatory response. In that case, one could ask why the organism has gone to the trouble of employing differential mechanisms for suppression of P450. One answer could be that the response evolved after the divergence of many of the P450 genes, necessitating the evolution of multiple redundant mechanisms for P450 suppression. In contrast to the down-regulation of P450s in the liver, the induction of several forms in this and other tissues suggests a more specific homeostatic role of these effects, e.g., in generation or catabolism of bioactive metabolites.

Animals↗

PubMed2005

Inhibitors of TLR-9 act on multiple cell subsets in mouse and man in vitro and prevent death in vivo from systemic inflammation.

In parallel with the discovery of the immunostimulatory activities of CpG-containing oligodeoxynucleotides, several groups have reported specific DNA sequences that could inhibit activation by CpG-containing oligodeoxynucleotides in mouse models. We show that these inhibitory sequences, termed IRS, inhibit TLR-9-mediated activation in human as well as mouse cells. This inhibitory activity includes proliferation and IL-6 production by B cells, and IFN-alpha and IL-12 production by plasmacytoid dendritic cells. Our studies of multiple cell types in both mice and humans show the optimal IRS to contain a GGGG motif within the sequence, and the activity to require a phosphorothioate backbone. Although the GGGG motif readily itself leads to formation of a tetrameric oligodeoxynucleotide structure, inhibitory activity resides exclusively in the single-stranded form. When coinjected with a CpG oligodeoxynucleotide in vivo, IRS were shown to inhibit inflammation through a reduction in serum cytokine responses. IRS do not need to be injected at the same site to inhibit, demonstrating that rapid, systemic inhibition of TLR-9 can be readily achieved. IRS can also inhibit a complex pathological response to ISS, as shown by protection from death after massive systemic inflammation induced by a CpG-containing oligodeoxynucleotides.

Adjuvants, Immunologic↗

PubMed2005

Adenosine A2A receptors and metabotropic glutamate 5 receptors are co-localized and functionally interact in the hippocampus: a possible key mechanism in the modulation of N-methyl-D-aspartate effects.

Hippocampal metabotropic glutamate 5 receptors (mGlu5Rs) regulate both physiological and pathological responses to glutamate. Because mGlu5R activation enhances NMDA-mediated effects, and given the role played by NMDA receptors in synaptic plasticity and excitotoxicity, modulating mGlu5R may influence both the physiological and the pathological effects elicited by NMDA receptor stimulation. We evaluated whether adenosine A2A receptors (A(2A)Rs) modulated mGlu5R-dependent effects in the hippocampus, as they do in the striatum. Co-application of the A(2A)R agonist CGS 21680 with the mGlu5R agonist (RS)-2-chloro-s-hydroxyphenylglycine(CHPG) synergistically reduced field excitatory postsynaptic potentials in the CA1 area of rat hippocampal slices. Endogenous tone at A(2A)Rs seemed to be required to enable mGlu5R-mediated effects, as the ability of CHPG to potentiate NMDA effects was antagonized by the selective A(2A)R antagonist ZM 241385 in rat hippocampal slices and cultured hippocampal neurons, and abolished in the hippocampus of A(2A)R knockout mice. Evidence for the interaction between A(2A)Rs and mGlu5Rs was further strengthened by demonstrating their co-localization in hippocampal synapses. This is the first evidence showing that hippocampal A(2A)Rs and mGlu5Rs are co-located and act synergistically, and that A(2A)Rs play a permissive role in mGlu5R receptor-mediated potentiation of NMDA effects in the hippocampus.

Adenosine↗

PubMed2001

Systemic therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cancer worldwide. Most patients present at a stage when surgical resection is no longer possible, and face a dismal prognosis. Locoregional and intra-arterial treatments are feasible and effective only in selected patients with disease confined to the liver. For patients with extrahepatic disease or a blocked portal venous system, systemic chemotherapy is the only treatment option available. Systemic therapy has not been successful in the past, with very low response rates to single-agent chemotherapy. Recently, however, there have been reports that combination chemotherapy with currently available agents may make some initially unresectable tumors resectable and, in some cases, induce complete pathologic responses. This has led to a reconsideration of systemic therapy for HCC, the current status of which is described in this review.

Antineoplastic Agents↗

PubMed2006

Real-time RT-PCR analysis of human histidine decarboxylase, a new marker for several types of leukemia and cancer.

Histamine is involved in different physiological and pathological responses, such as immune response, gastric acid secretion or neurotransmission, as either angiogenesis or cancer. Histidine decarboxylase (HDC) catalyzes the formation of histamine from histidine. HDC has been suggested as a new marker for neuroendocrine differentiation, inflammatory pathologies and several leukemia and highly malignant forms of cancer, such as melanoma and small cell lung carcinoma. In the present work, we describe the use of Syber Green-based quantitative real-time RT-PCR to determine the expression of histidine decarboxylase in human cells and tissue. As an internal control, glyceraldehyde 3-phosphate dehydrogenase was also amplified. The linear dynamic range of the assay covered 4 orders of magnitude for HDC amplification. The detection limit was 0.1 ng of total RNA extracted from HMC-1 cells. This method is simple, rapid, sensitive, and quantitative, and allows for the specific identification of cells and tissue expressing HDC, stressing its potential diagnostic usefulness in malignancies in which HDC is described as a new marker.

Biomarkers, Tumor↗

PubMed1989

Beyond morality: the need for psychodynamic understanding and treatment of responses to the AIDS crisis.

The purpose of this paper is to identify a broad range of issues that both impact, and are impacted by, psychiatric intervention in AIDS and AIDS-related cases, with a special concern towards emphasizing the need for application of a psychodynamic perspective, in the understanding and treatment of pathological responses to the AIDS crisis. As a cornerstone of the psychiatric model, psychodynamic evaluation and treatment can provide a breadth of focus and depth of understanding crucial to a resolution of some of the deeper psychosocial aspects involved in the reaction to and spread of the AIDS virus. A case example is used to illustrate psychodynamic factors which precluded the patient's ability to choose monogamy, and which contributed to the "transmission" of a cyclic pattern of psychodynamic pathology.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Characterisation of the advanced glycation endproduct receptor complex in the retinal pigment epithelium.

AIMS: Advanced glycation endproducts (AGEs) accumulate with ageing and may have a significant impact on age related dysfunction of the retinal pigment epithelium (RPE). Many of the cellular effects of AGEs in other cell types are mediated through AGE binding proteins. The aim of this study was to characterise the AGE receptor complex in RPE cells in vitro and to focus on the role of the R3 component (galectin-3) as the primary effector of the complex. METHODS: Primary cultures of bovine RPE cells and the human D407 RPE cell line were exposed to AGE modified albumin. Receptor expression was determined using mRNA analysis by quantitative real time RT-PCR and protein characterisation by western blotting. Immunocytochemical analysis examined the cellular localisation of the various components of the AGE receptor complex. The role of the galectin-3 receptor component was examined by transfection and overexpression using the D407 cell line and analysis of soluble AGE-R3 by ELISA. RESULTS: All three components of the AGE receptor complex were expressed by bovine and human RPE cells. AGE exposure upregulated two components of the receptor complex and also induced significant RPE expression of VEGF mRNA (p<0.05). RPE D407 cells stably transfected to overexpress galectin-3 showed less VEGF induction. In non-transfected RPE which were exposed to AGEs, there was less soluble galectin-3 protein released into the medium (p<0.05), a response that was not evident in transfected cells. CONCLUSION: A conserved AGE receptor complex is evident in primary cultures of bovine RPE cells and also in a human cell line. These cells show a pathological response to AGE exposure, an effect which appears to be modulated by the galectin-3 component of the receptor complex.

Animals↗

PubMed2006

A Phase I study of weekly intravenous oxaliplatin in combination with oral daily capecitabine and radiation therapy in the neoadjuvant treatment of rectal adenocarcinoma.

PURPOSE: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. METHODS AND MATERIALS: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly x 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction x 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. RESULTS: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m2/week) had a dose-limiting diarrhea. One of 6 patients at DL (-)1 (capecitabine 725 mg/m2 p.o., b.i.d.; oxaliplatin 50 mg/m2/week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). CONCLUSIONS: Capecitabine 725 mg/m2 p.o., twice daily in combination with oxaliplatin 50 mg/m2/week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.

Administration, Oral↗

PubMed1991

A 90-day continuous vapor inhalation toxicity study of JP-8 jet fuel followed by 20 or 21 months of recovery in Fischer 344 rats and C57BL/6 mice.

The kerosene-type jet fuel, JP-8, consists of a complex mixture of aliphatic and aromatic hydrocarbons. Because of the utility of JP-8, studies have been conducted to identify the potential long-term consequence of occupational inhalation exposure. Fischer 344 rats and C57BL/6 mice of both sexes were exposed to JP-8 vapors at 0, 500, and 1,000 mg/m3 on a continuous basis for 90 days, then followed by recovery until approximately 24 months of age. Occurrence of necrotizing dermatitis associated with fighting resulted in an increase in mortality in mice (male greater than female) during the 2 week to 9 month post-exposure recovery period. The male rat kidney developed a reversible ultrastructural increase in size and propensity for crystalloid changes of phagolysosomal proteinic reabsorption droplets in the proximal convoluted tubular epithelium. A specific triad of persisting light microscopic renal lesions occurred but functional change was limited to a decrease in urine concentration compared to controls that persisted throughout the recovery period. The response is comparable to the chronic effect of lifetime exposure of the male rat to unleaded gasoline, d-limonene, and p-dichlorobenzene, except for the absence of tubular tumorigenesis. The active toxicologic response presumably must occur over a greater proportion of the male rat's life span for the tumor component of this male rat hydrocarbon nephropathy syndrome. The predictiveness for humans must be questioned, since the pathologic response to JP-8 involved only one tissue in one sex of one species, and since the male rat response appears to be linked to an inherent renal protein peculiarity.

Administration, Inhalation↗

PubMedDate not supplied

[Development of the steady-state cortical visual evoked response in children].

Steady-state VEPs responses (pattern reversal stimulation) have been studied by the application of frequency analysis with Fourier methods. Authors examined with this method a group of children aged from 4 to 12 years, without ophthalmological or neurological pathologies. Responses evaluation is based on the number of harmonic frequency components and also on the power spectra of the first two components. Frequency analysis shows a well proportioned responses development that can be considered as a good index of visual function growth.

Child↗

PubMed2006

Prognostic factors for disease-free survival in patients with T3-4 or N+ rectal cancer treated with preoperative chemoradiation therapy, surgery, and intraoperative irradiation.

PURPOSE: Fluoropyrimidine-radiosensitizing agents in conjunction with preoperative radiotherapy have proven to induce tumor and nodal downstaging effects, sphincter preservation promotion, and mid-term favorable survival rates. Intraoperative electron beam radiation therapy may improve pelvic control in patients with locally advanced rectal cancer stages. Potential predictive factors for response and disease-free survival, with intense local multidisciplinary approach, are analyzed. METHODS AND MATERIALS: One hundred fifteen patients with rectal cancer were treated with oral 5-fluorouracil or Tegafur with preoperative radiotherapy, surgery, and intraoperative electron beam radiation therapy to identify potential pre- and on-treatment characteristics that might be of prognostic value for disease outcome. Univariate and multivariate analyses were performed. RESULTS: Older patients and those treated with Tegafur were more likely to achieve a major histologic response, categorized as persistence of minimal residual microscopic disease foci in the surgical specimen ("mic" response). Factors unfavorably associated with disease-free survival in the multivariate model were male gender and persistence of macroscopic disease in the rectal wall ("mac" response). Accordingly, 3-year disease-free survival rates in the groups of patients with 0, 1, or 2 of these risk factors were 100%, 81%, and 53%, respectively (p < 0.001). CONCLUSIONS: Females with an intense pathologic response (pT(mic) residue) to preoperative chemoradiotherapy have an excellent 3-year disease-free survival. This information might be of interest for stratification of patients in the development of adjuvant treatment trials.

Adenocarcinoma↗

PubMed2003

The restaging issue.

Patients with persisting involvement of mediastinal lymph nodes after neo-adjuvant therapy have a poor prognosis and do not benefit from surgical resection. Precise restaging after induction treatment is important to determine further treatment and prognosis. Computed tomography (CT) and magnetic resonance imaging (MRI) have a low accuracy in predicting response after induction therapy. Positron emission tomography (PET) has a high sensitivity to detect residual viable disease in the primary tumour but not in the mediastinal lymph nodes. Invasive staging remains necessary to precisely assess mediastinal response. Remediastinoscopy, although technically difficult, has an accuracy of 80% and provides histological proof of mediastinal downstaging. In this way, it is a useful procedure to select patients for thoracotomy after induction therapy. The ultimate overall pathologic response can only be determined by thoracotomy with excision of the primary tumour, hilar and mediastinal lymph nodes.

Carcinoma, Non-Small-Cell Lung↗