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Biomedical subjects

K Kelly

Publications and source records attributed to K Kelly.

At least 109 records · Page 6Linked to original sources
PubMed1997

Systemic investigational therapies as adjuvants to surgery in patients with operable lung cancer.

Early resection of lung cancers confined to the chest remains the best means of curing patients. Nonetheless, cure rates for resected patients are less than 50% overall, primarily due to the presence of occult distant metastases at the time of resection that subsequently manifest as relapse at distant sites. In approximately 20% of patients, local failure occurs within the chest. Chest radiotherapy reduces and nearly eliminates local failure, but does not improve survival or cure rates. Effective systemic chemotherapy is the cornerstone to improving survival and cure rates for early stage lung cancer. Recent studies showed that the preoperative use of cisplatin-based chemotherapy improved survival and 3-year disease-free survival in stage IIIA non-small cell lung cancer. New drugs such as paclitaxel and gemcitabine appear to improve survival in stages IIIB and IV non-small cell lung cancer. These agents will be tested in the surgical setting in the near future.

Carcinoma, Small Cell↗
PubMed1997

A phase I study of cisplatin, etoposide, and paclitaxel in small cell lung cancer.

This phase I study was designed to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with standard doses of cisplatin and etoposide for patients with untreated, extensive-stage small cell lung cancer. Secondary objectives were to determine the toxicities, response rate, response duration, and overall survival in this cohort. Twenty-four patients were enrolled into four dose levels. All patients received a fixed dose of cisplatin at 80 mg/m2 intravenously (IV) on day 1. The first group received etoposide 50 mg/m2 IV on day 1 and 100 mg orally on days 2 and 3, while all subsequent groups received etoposide 80 mg/m2 IV on day 1 and 160 mg/m2 orally on days 2 and 3. The paclitaxel starting dose was 135 mg/m2 IV over 3 hours and escalated to 175 mg/m2 and 200 mg/m2. Cycles were repeated every 21 days for a maximum of six cycles. Granulocyte colony-stimulating factor was not given prophylactically, but was allowed in subsequent cycles according to American Society of Clinical Oncology guidelines. Nineteen patients were evaluable for toxicity and 18 patients were evaluable for response. Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 18 of 19 patients (95%), but febrile neutropenia was uncommon and developed in four of 19 patients (21%). Dose-limiting peripheral neuropathy was observed at a paclitaxel dose of 200 mg/m2. Grade 4 nausea/vomiting and diarrhea were also noted at this dose level. Four patients had complete responses (22%) and 13 patients had partial responses (72%). The overall response rate was 94%, with a median survival of 11 months and a 2-year survival rate of 19%. This three-drug combination of paclitaxel with cisplatin and etoposide is highly active with acceptable toxicity. Neurotoxicity was dose limiting at 200 mg/m2 paclitaxel. Neutropenia was frequent but was not associated with significant morbidity. The recommended doses for future clinical trials are paclitaxel 175 mg/m2 IV over 3 hours on day 1 with cisplatin 80 mg/m2 IV on day 1 and etoposide 80/160 mg/m2 IV on day 1 and orally on days 2 and 3. Growth factor support should be used according to American Society of Clinical Oncology guidelines.

Aged↗
PubMed1997

High frequency of K-ras codon 12 mutations in bronchoalveolar lavage fluid of patients at high risk for second primary lung cancer.

A high frequency of K-ras mutations may indicate preneoplastic changes in the bronchial epithelium as a result of genotoxic injury. With the use of sensitive detection techniques, we report a higher prevalence of K-ras mutations in bronchoalveolar lavage than has been reported previously for lung cancer. A PCR/ligase chain reaction technique was used to determine K-ras codon 12 mutations in a group of 52 bronchoalveolar lavage specimens from patients at risk of a second lung cancer. Of the specimens examined, 84% contained at least one mutation in K-ras codon 12, corroborated by an allele-specific hybridization method. These results suggest that point mutations in K-ras codon 12 are widespread in the bronchial epithelium. Based on these preliminary findings, further evaluation of this efficient sensitive assay to monitor K-ras status should be conducted in larger clinical cohorts where clinical outcomes will ultimately be available. Such a trial will define the utility of K-ras codon 12 mutation status as a marker of lung cancer.

Bronchoalveolar Lavage Fluid↗
PubMed1997

A phase I trial of paclitaxel plus carboplatin in untreated patients with advanced non-small cell lung cancer.

This Phase I study was designed to determine the maximally tolerated doses of paclitaxel (given as an outpatient 3-h infusion) plus carboplatin in advanced, untreated non-small cell lung cancer. Secondary objectives were to determine the response rate, response duration, and survival. Fifty-six patients were accrued, and all were evaluable for toxicity; 50 patients were assessable for response. Paclitaxel doses ranged from 135-250 mg/m2, whereas carboplatin dosing started at 250 mg/m2 and was escalated to 400 mg/m2. Patients received therapy on day 1 every 21 days for a maximum of six cycles. Prophylactic granulocyte colony-stimulating factor was not given initially but was allowed if grade 4 neutropenia developed. Neutropenia was the major toxicity observed (41% of patients; 16% of courses) and was dose related. However, febrile neutropenia was uncommon (4%), and no patient receiving growth factor developed subsequent grade 4 neutropenia. Only one patient developed grade 4 thrombocytopenia. No grade 4 neuropathy or grade 3 or 4 myalgias/arthralgias were reported. Grade 4 allergic reactions occurred in three patients (5%), and two patients sustained grade 4 cardiac toxicity (4%). Partial responses were observed in 13 of 50 patients (26%). One of 13 patients (8%) receiving paclitaxel at 135 mg/m2 and carboplatin (250-350 mg/m2) responded versus 12 of 37 patients (32%) receiving paclitaxel doses >/= 175 mg/m2 with carboplatin doses of 350-400 mg/m2. The median time to progression, median survival, and 1-year survival rates seemed to be dose related, with median times to progression of 6, 18, and 27 weeks; median survival of 13, 29, and 39 weeks; and 1-year survival rates of 15, 28, and 41% for the 135, 175-200, and 225-250 mg/m2 groups. We conclude that full doses of both paclitaxel and carboplatin can be given safely on an outpatient basis with 3-h paclitaxel infusions. Neutropenia is the most common toxicity; response rates and survival at higher dose levels were encouraging. Phase III trials to determine the optimal dose and infusion schedule of this combination are warranted, as are trials to compare paclitaxel/carboplatin to other active single agents or combination regimens.

Adult↗
PubMed1996

CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation.

CD97 is a receptor that spans the membrane seven times, a defining feature of G protein-coupled receptors. CD97 is predominantly expressed in leukocytes, but the function and accurate protein structure of this receptor have not been described. We show here that CD97 has the novel property among G protein-coupled receptors characterized to date of being processed intracellularly in either the endoplasmic reticulum or early Golgi from a proprotein into a noncovalently associated two-subunit structure that becomes expressed on the cell surface and is composed of a large extracellular protein (CD97alpha) and a seven-membrane spanning protein (CD97beta). CD97beta is part of an evolutionarily conserved subfamily of four proteins, including two Caenorhabditis elegans proteins of as yet unknown function, which is distinct from but most closely related to the glucagon receptor family. CD97alpha exists in three alternatively spliced isoforms that contain between three and five epidermal growth factor (EGF)-like repeats that are related to the calcium binding EGF-like repeats in the microfibril protein fibrillin. Leukocytes strongly positive for CD97 are concentrated at sites of inflammation relative to CD97 expression in normal lymphoid tissues. Soluble CD97alpha was found in body fluids from inflamed tissues, suggesting that a functional consequence of the CD97 heterodimeric structure is the stable existence of CD97alpha in a cellfree form. CD97 appears to be a multifunctional protein that may play a signal transduction role associated with the establishment or development of an inflammatory process.

Alternative Splicing↗
PubMed1996

Cell cycle kinetics and commitment in newborn, adult, and tumoral astrocytes.

In terms of cell cycle phases, mammalian astrocytes maintain the capacity to leave G0/G1 and enter S phase in response to brain injury or due to neoplastic transformation. This report compares proliferative behavior in vitro, particularly departure from G0, in three types of rat astroglial cells-newborn astrocytes, astrocytes from gelatin implants into the traumatized striata of adults, and astrocytoma cells (C6 glioma). Newborn and adult astrocytes demonstrated nearly identical proliferation kinetics as determined by peaks in cell number and rates of DNA synthesis. C6 glioma (C6G) proliferated more rapidly. Exit from G0 was examined by shift-down of serum from 10 to 0.1% for 48 h, followed by return to 10% at time 0. Synchronization of newborn and adult astrocytes in this way resulted in a 12 h lag phase (G0/G1) followed by a 6-10-fold surge in DNA synthesis and a corresponding increase in S-phase nuclei from < 15% to > 70%. Timing of S-phase commitment was established in late G1 by resistance to the inhibitors cycloheximide and mevinolin. Decay of commitment was assessed by addition of hydroxyurea (HU) at 10 h to cause accumulation at the G1/S boundary. Removal of HU after an additional 14, 16, and 20 h resulted respectively in these percentages of maximal S-phase DNA synthesis in newborn and adult astrocytes: 75 +/- 9, 60 +/- 8, 23 +/- 3, and 87 +/- 20, 62 +/- 7, 34 +/- 5. In contrast, synchronization of C6G resulted in a 6 h lag before a surge in DNA synthesis and an increase in S-phase nuclei from < 20% to 100%. Cell cycle commitment occurred earlier with C6G, and decay of commitment was not observed, even after 20 h of HU treatment. Thus, these in vitro techniques for cell cycle analysis are applicable to astrocytes obtained from developing and adult brain, and to at least some astroglioma cells. Furthermore, this comparative study showed that important cell cycle parameters differ markedly in the non-tumoral astrocytes and glioma cells. These differences could lead to strategies for selective targeting of the proliferation of neoplastic astroglia.

Animals↗
PubMed1996

Detection of K-ras oncogene mutations by polymerase chain reaction-based ligase chain reaction.

To evaluate a rapid multiplexed assay to detect three common K-ras codon 12 mutations, primer pairs complementary to the wild-type and mutant loci were developed and tested with lung cancer cell lines with previously identified mutation status. The sensitivity of detection of mutations was determined to be at least 1% using spiked samples containing K-ras codon 12 mutations. This assay was then used to evaluate prospectively K-ras status in airways of individuals at high risk of lung cancer by analysis of bronchoalveolar lavage (BAL) specimens from patients who have been previously treated for lung cancer. DNA was extracted from BAL specimen cell pellets, and PCR-based ligase chain reaction was performed for mutations in the first position of codon 12 of K-ras, with positive and negative controls. Of 10 BAL samples, 4 contained 1 mutation (GGT --> TGT), 1 contained 2 mutations (GGT --> TGT and GGT --> AGT), and the rest were wild-type. The BAL mutations were validated by cloning and screening with mutant-specific probes followed by confirmation sequencing.

Bronchoalveolar Lavage↗
PubMed1996

The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation.

Mitogen-activated protein (MAP) kinases can be grouped into three structural families, ERK, JNK, and p38, which are thought to carry out unique functions within cells. We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively. Here we characterize a new MAP kinase phosphatase, MKP-2, that is induced in human peripheral blood T cells with phorbol 12-myristate 13-acetate and is expressed in a variety of nonhematopoietic tissues as well. We show that the in vivo substrate specificities of individual phosphatases are unique. PAC1, MKP-2, and MKP-1 recognize ERK and p38, ERK and JNK, and ERK, p38, and JNK, respectively. Thus, individual MAP kinase phosphatases can differentially regulate the potential for cross-talk between the various MAP kinase pathways. A hyperactive allele of ERK2 (D319N), analogous to the Drosophila sevenmaker gain-of-function mutation, has significantly reduced sensitivity to all three MAP kinase phosphatases in vivo.

Animals↗
PubMed1996

Atypical presentation of preeclampsia in high-order multifetal gestations.

OBJECTIVE: To describe our experience with preeclampsia in high-order multifetal gestations. METHODS: Records for all triplet and quadruplet pregnancies delivered after 24 weeks' gestation from January 1988 through June 1994 were reviewed. All patients were treated with bed rest from 20 weeks' gestation onward and received corticosteroids weekly beginning at 24 weeks. Tocolytics were used as needed. RESULTS: Twenty-one triplet and eight quadruplet pregnancies were studied. The mean gestational age at delivery was 32.3 and 27.9 weeks, and mean birth weights were 1547 and 1028 g, respectively. Seventeen of 29 patients developed preeclampsia, 14 of the 21 triplet mothers and three of the eight quadruplet mothers. Among 16 patients who were delivered for preeclampsia, only eight had blood pressure (BP) elevation before delivery, whereas ten had epigastric pain, visual disturbances and/or headache; nine had elevated liver enzyme levels; and seven had low platelet counts. Only three patients had proteinuria, and only six had edema. Five women developed the syndrome of hemolysis, elevated liver enzymes, and low platelets postpartum, all of whom had normal BP before delivery. Two patients developed preeclampsia after delivery. A total of 95 infants were delivered, all by cesarean, of whom 93 (98%) survived. CONCLUSION: Preeclampsia is common in high-order multifetal gestations and often presents in an atypical manner. Hypertension is not always the presenting sign, and symptoms consistent with severe preeclampsia and abnormal laboratory values predominate.

Adult↗
PubMed1996

Peptide amidating activity in human bronchoalveolar lavage fluid.

Monitoring respiratory epithelial biology may reveal individuals with incipient lung cancer. The expression of neuroendocrine (NE) markers in pulmonary epithelium is thought to be central to lung development, repair of injury and may contribute to carcinogenesis. In this study, we evaluate several candidate NE markers to determine the feasibility of prospective analysis of clinical specimens. The potential NE markers include the enzyme L-DOPA decarboxylase (DDC), the neuropeptide gastrin releasing peptide (GRP), and peptidyl-glycine alpha-amidating monooxygenase (PAM), the bifunctional enzyme responsible for the final bioactivation step of many neuropeptides. A comparison of PAM activity and DDC levels in 30 lung cancer cell lines indicated that peptide amidating activity may be an indicator of NE status. Bronchoalveolar lavage (BAL) fluid from subjects at risk of developing second primary lung cancer and from volunteers was obtained. The activity of the first PAM enzyme, peptidylglycine alpha-hydroxylating monooxygenase (PHM), ranged from not detectable to 507 pmol/h/mg protein in 57 specimens. The second PAM enzyme, peptidylamidoglycolate lyase (PAL), ranged from not detectable to 414 pmol/h/mg protein in 56 specimens. Using cluster analysis by the average linkage method, a group of enzyme values with PHM greater than 230 pmol/h/mg protein was determined. Long-term follow-up of these patients for new second primary lung cancers may help to determine the potential predictive value of PAM detected in the BAL fluid.

Biomarkers, Tumor↗
PubMed1996

Ethics and the police surgeon: compromise or conflict?

Police surgeons play an important role in the British criminal justice system. Professionally located between the two worlds of medicine and the law, they face ethical dilemmas which derive from the dual nature of their role. The development of the police surgeon service has seen the emergence of three further dualisms within the police surgeon role. These are the forensic-therapeutic divide, the specialist-generalist division, and the issue of dependence or independence with regard to the police. These internal dualisms are discussed and their implications explored. Attention then turns to a consideration of three issues which demonstrate the nature of the ethical dilemmas facing the British police surgeon: the particular articulation of the (police) doctor-patient relationship, the matter of consent, and the subject of confidentiality. Both these ethical issues and the nature of the police surgeon role are explored through the primary analysis of survey and interview data collected from a national sample of police surgeons and police services, and the secondary analysis of key documents on the police surgeon, the paper concludes that specific ethical guidance is needed to address the forensic aspects of the police surgeon role.

Confidentiality↗
PubMed1996

Role of gamma-delta T cells in murine Chlamydia trachomatis infection.

The role of gamma-delta T cells in host resistance to Chlamydia trachomatis was characterized by using a murine model of pneumonia caused by the mouse pneumonitis agent (MoPn), murine C. trachomatis. At days 3 and 7 after infection, gamma-delta T-cell-deficient knockout mice had significantly higher levels of MoPn in the lungs than did immunologically intact controls. At day 20, paradoxically, gamma-delta T-cell-deficient mice were more resistant to MoPn than were controls. This increased resistance was not due to an increased production of toxic cytokines or interleukin-10 in controls on that day. Gamma-delta T cells play a role in protection early in MoPn infection, but they may be deleterious later in infection, as has been observed in models of salmonella and trypanosome infection.

Animals↗
PubMed1996

A general method for the detection of large CAG repeat expansions by fluorescent PCR.

The expansion of a tandemly repeated trinucleotide sequence, CAG, is the mutational mechanism for several human genetic diseases. We present a generally applicable PCR amplification method using a fluorescently labelled locus specific primer flanking the CAG repeat together with paired primers amplifying from multiple priming sites within the CAG repeat. Triplet repeat primed PCR (TP PCR) gives a characteristic ladder on the fluorescence trace enabling the rapid identification of large pathogenetic CAG repeats that cannot be amplified using flanking primers. We used our method to test a cohort of 183 people from myotonic dystrophy families including unaffected subjects and spouses. Eighty five clinically affected subjects with expanded alleles on Southern blot analysis were all correctly identified by TP PCR. This method is applicable for any human diseases involving CAG repeat expansions.

Child↗
PubMed1996

Phase I study of cisplatin, etoposide, and paclitaxel in patients with extensive-stage small cell lung cancer: a University of Colorado Cancer Center study.

This phase I study investigated the maximum tolerated dose of cisplatin, etoposide, and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in 18 patients with advanced small cell lung cancer. Cisplatin (80 mg/m2) and etoposide (50 or 80 mg/m2 intravenously and 100 or 160 mg/m2 orally) were infused concomitantly 30 minutes after a 3-hour infusion of paclitaxel (135, 175, or 200 mg/m2). This order of administration was known to cause less toxicity than the reverse order. Granulocyte colony-stimulating factor was given as necessary. Overall, complete responses were observed in 33% of evaluable patients and partial responses were seen in 67%. No patient progressed during therapy. Median survival exceeded 12 months, with 53% of patients alive at 1 year. Untreated patients in similar health survive approximately 6 to 16 weeks. Hematologic toxicities were seen most frequently, and neutropenia was seen most often and was the most severe. Febrile neutropenia occurred in one patient; grade 4 thrombocytopenia did not occur at all. Nonhematologic toxicity was mild. Nausea and vomiting generally were well controlled, and there were no instances of severe allergic reaction. Although the maximum tolerated dose has not yet been defined, one of two patients in the group receiving the highest doses encountered a dose-limiting toxicity. Thus, we expect to recommend the following dosages for further study: cisplatin 80 mg/m2, etoposide 80 mg/m2, and paclitaxel 175 mg/m2. All patients had an objective response and one third had a complete response, compared with 10% of patients in most series. We conclude that paclitaxel can be added safely to full doses of cisplatin and etoposide with encouraging efficacy, and recommend a randomized trial be undertaken to compare the two-drug regimen with the three-drug regimen.

Antineoplastic Agents, Phytogenic↗