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J J Lewis

Publications and source records attributed to J J Lewis.

At least 73 records · Page 4Linked to original sources
PubMed1997

Association of local recurrence with subsequent survival in extremity soft tissue sarcoma.

PURPOSE: The aim of this study was to analyze local recurrence in a large cohort of prospectively followed patients with primary extremity soft tissue sarcoma. In particular, we analyzed the correlation of local recurrence with subsequent metastasis and disease-specific survival. PATIENTS AND METHODS: Patients who underwent treatment for primary extremity soft tissue sarcoma from July 1982 through July 1995 at Memorial Sloan-Kettering Cancer Center were the subject of this study. Local recurrence, distant metastasis, and disease-specific survival were used as end points of the study. The influence of local recurrence on subsequent distant metastasis and disease-specific survival were examined using the Cox proportional hazards model. RESULTS: We treated 911 patients, of whom 297 (33%) developed recurrent disease. Local recurrence occurred in 116 patients (13%), metastasis in 167 (18%), and synchronous local recurrence and metastasis in 13 (2%). Of 116 patients who developed local recurrence, 38 subsequently developed metastasis and 34 died of disease. Metastasis after local recurrence was predicted in patients with initial high-grade (P = .005; risk = 3.5) or deep (P = .02; risk = 2.9) tumors. Tumor mortality after local recurrence was predicted in patients with initial high-grade (P = .007; risk = 3.7) or large (> 5 cm; P = .01; risk = 3.2) primary tumors. DISCUSSION: These findings suggest that there is a strong association of local recurrence with the development of subsequent metastasis and tumor mortality, and that local recurrence is a poor prognostic factor. It would seem prudent to consider patients who develop local recurrence and have high-grade tumors as being at high risk for systemic disease and therefore eligible for investigational adjuvant systemic therapy.

Arm↗
PubMed1997

Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management.

PURPOSE: Retroperitoneal soft tissue sarcomas are rare tumors. Studies characterizing long-term follow-up and patterns of recurrence are limited. The purpose of this analysis is to identify patterns of recurrence and prognostic factors associated with long-term survival after resection of retroperitoneal soft tissue sarcomas. METHODS: Between July 1, 1982, and June 30, 1990, 198 adult patients were identified from our prospective soft tissue sarcoma database carrying the diagnosis of retroperitoneal soft tissue sarcoma who were eligible for > or = 5 years of follow-up. Of these, 48 patients (25%) were documented to be alive > or = 5 years from the time of operation. Statistical analysis was by log-rank or Wilcoxon test for univariate analysis. Multivariate analysis was by the Cox model. RESULTS: The recurrence rate during the follow-up period was approximately 5% per year from the time of initial operation. Of the patients who were disease-free for > or = 5 years from initial surgery, 40% recurred by 10 years. Radiation therapy was the only factor significant (P = .02) for a reduction in the risk of local recurrence. Age < or = 50 years and high-grade tumors were significant factors (P = .003 and .009, respectively) for an increased risk of distant metastasis. Incomplete gross resection was the only factor significant for an increased risk of tumor mortality (P = .003). CONCLUSION: Complete surgical resection at the time of primary presentation is likely to afford the best chance for long-term survival. With long-term follow-up, it is clear that recurrence will continue to occur, and a 5-year disease-free interval is not a cure. Patients with an incomplete initial resection, age less than 50 years, and high-grade tumors are candidates for investigational adjuvant therapy.

Disease-Free Survival↗
PubMed1997

Adjuvant therapy for soft tissue sarcomas.

Primary therapy for soft tissue sarcoma is predicated on surgical resection with an adequate margin of normal tissue. For high-risk patients, local control is improved with postoperative adjuvant radiation or intraoperative brachytherapy. Despite the most recent meta-analysis or encouraging phase II data for neoadjuvant chemotherapy, there is no clearly proven role for adjuvant or neoadjuvant chemotherapy in the treatment of sarcoma. Nevertheless, distinct subpopulations of sarcoma patients are appropriate for consideration of investigational neoadjuvant/adjuvant chemotherapy due to their high risk of distant metastasis and potential for chemoresponsiveness.

Adult↗
PubMed1997

Priming for T-cell-mediated rejection of established tumors by cutaneous DNA immunization.

DNA immunization has been shown to elicit both antibody and CTL responses against antigens expressed by infectious organisms. Because CTL responses have been implicated in rejection of cancer, we investigated whether DNA immunization by particle bombardment using a gene gun could induce CTL responses that were capable of rejecting tumors in mice. DNA immunization by particle bombardment using genes encoding beta-galactosidase and ovalbumin primed mice to generate CTLs in two genetic backgrounds (DBA/2 and C57BL/6 strains, respectively). DNA immunization was more potent in inducing CTLs than immunization with an optimized regimen of ovalbumin peptide plus immune adjuvant. Immunity induced by DNA immunization protected mice against s.c. challenge with tumors expressing the beta-galactosidase antigen. Tumors were rejected even when DNA immunization was started 3 or 7 days after tumor challenge as tumors were becoming established. Tumor rejection required CD8(+) T cells, confirming a role for CTLs in vivo. These studies show that DNA immunization by particle bombardment can efficiently induce CTL responses that are capable of rejecting even established tumors.

Animals↗
PubMed1996

N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

Amides↗
PubMed1996

Invasive candidiasis in infants weighing more than 2500 grams at birth admitted to a neonatal intensive care unit.

BACKGROUND: Because invasive candidiasis in newborn infants admitted to a neonatal intensive care unit (NICU) occurs most frequently in very low birth weight infants, the incidence of invasive candidiasis and its clinical features in infants > 2500 g birth weight have not been well-described. METHODS: We retrospectively reviewed the medical records of all infants with birth weight > 2500 g admitted to our NICU from 1986 through 1993 who developed invasive candidiasis during their hospitalization. RESULTS: Seventeen of 3033 (0.6%) infants with birth weights > 2500 g admitted to the NICU developed invasive candidiasis. All 17 infants had a condition that required prolonged NICU hospitalization; 13 of 17 (76%) had a major congenital malformation. CONCLUSION: The incidence of invasive candidiasis in infants with birth weights > 2500 g requiring admission to a NICU was much less than has been reported for very low birth weight infants. This review points out that in infants with birth weights > 2500 g who develop invasive candidiasis, major congenital malformations are the most frequent underlying conditions responsible for prolonged NICU hospitalization.

Amphotericin B↗
PubMed1996

Soft tissue sarcomas.

Soft tissue sarcomas are relatively rare tumors with an annual incidence of 5000 to 6000 in the United States. The primary therapy is surgical resection with an adequate margin of normal tissue. For patients at high risk local control is improved with postoperative adjuvant radiation. Local recurrence rates vary depending on the anatomic site. In extremity lesions one third of patients will have locally recurrent disease with a median disease-free interval of 18 months. Treatment results for extremity local recurrence may approach those for primary disease. Isolated pulmonary metastases may be resected with 20% to 30% 3-year survival rates. Patients with sarcomas in other sites present similar but more difficult problems in terms of local control and management of disseminated disease. Patients with unresectable pulmonary metastases or extrapulmonary metastatic sarcoma have a uniformly poor prognosis and are best treated with systemic chemotherapy.

Female↗
PubMed1995

Definition of tumor antigens suitable for vaccine construction.

The treatment of cancer with tumor vaccines has been a goal of physicians and scientists ever since effective immunization against infectious disease with vaccines was developed. In the past, major tumor antigens had not been molecularly characterized. Recent advances are, however, beginning to define potential molecular targets and strategies and this had evolved with the principle that T-cell mediated responses are a key target for approaches to cancer immunization. In addition, these antigens are not truly foreign and tumour antigens fit more with a self/altered self paradigm, compared to a non-self paradigm for antigens recognized in infectious diseases. Potential antigens include the glycolipids and glycoproteins (e.g. gangliosides), the developmental antigens (e.g. MAGE, tyrosinase, melan-A and gp75) and mutant oncogene products (e.g. p53, ras, and HER-2/neu). Innovations for construction of cancer vaccines are emerging from these advances in molecular immunology and cancer biology. While vaccines against infectious agents are models for vaccine development, there are clearly distinct considerations and problems associated with cancer vaccines. One of the focal issues in designing active cancer immunotherapy is that cancer cells are derived from normal host cells. Thus, the antigenic profile of cancer cells closely mimics that of normal cells. How the immune system identifies and destroys cancer cells is therefore crucial. Clearly, the ultimate goal of tumor vaccine design is the generation of antigen-specific vaccines. The recent success identifying molecularly defined tumor antigens opens up potentially novel strategies for this approach. Vaccine possibilities include purified proteins and glycolipids, peptides, cDNA expressed in various vectors, and a range of immune adjuvants. The molecular and structural definition of tumor antigens provides an opportunity for cautious optimism that we are entering an era when we will soon begin to recapitulate the success of immunization against infectious disease.

Animals↗
PubMed1993

Management of unresectable malignant endocrine tumors of the pancreas.

Malignant endocrine tumors of the pancreas are a heterogenous group of tumors with a multipotential secretory capacity. The lesions are generally slow growing with a relatively long life expectancy from the time of diagnosis. Death results from a combination of local and metastatic disease and the sequelae of excess hormone secretion. While potentially successful curative resections are rare, long term survival is frequently possible based on the rate of growth and the inhibition of the bioactive effects of the secretory products of the tumor. Regional control with palliative surgical debulking and transcatheter arterial embolization of hepatic metastases has an important role in terms of symptomatic relief and long term survival. These tumors respond frequently to chemotherapy. Combination chemotherapy is more effective than single agent treatment. Preliminary information suggests that leukocyte interferon is useful in treatment, but this agent still requires careful prospective evaluation. While current data do not support the use of octreotide for an antitumor effect, it is capable of producing prompt and substantial symptomatic relief with minimal side effects in a large proportion of patients with functional malignant endocrine tumors of the pancreas. Many advances have been made in the recognition, diagnosis and management of patients with malignant endocrine tumors of the pancreas. Additional basic cellular research is necessary to define the molecular and cell biologic factors of these tumor cells. Particular facets that require further understanding include their basic cytogenetic abnormality, regulation of peptide production and the role of peptides and other growth factors in endocrine, paracrine and autocrine regulatory relationships. The answers to these questions will hopefully promulgate the discovery of improved cytotoxic agents, better peptide pharmacotherapeutic agents and improve the overall management of patients with unresectable malignant endocrine tumors of the pancreas.

Adenoma, Islet Cell↗
PubMed1992

Dephosphorylation of cAMP-dependent protein kinase regulatory subunit in stimulated parietal cells.

The phosphorylation of endogenous proteins was investigated in subcellular fractions prepared from isolated rabbit parietal cells incubated with either cimetidine (unstimulated) or a combination of histamine and forskolin (maximally stimulated). Phosphorylation of endogenous proteins in subfractions was then assessed in a post hoc assay using [gamma-32P]ATP as a phosphate donor in vitro. The Mg(2+)-dependent incorporation of [32P]phosphate into a 52-kDa protein (pp52M) was observed in the 4,000 g membrane fraction from stimulated but not unstimulated cells. The pp52M protein was identified as the type II regulatory subunit of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (RII) by isoelectric focusing, comigration with cAMP-binding proteins, and immunoprecipitation. Incorporation of [32P]phosphate into RII in the in vitro assay in the presence of Zn2+ was apparent in the 4,000 g membrane from stimulated but not unstimulated cells. The results thus suggested that, on stimulation, RII in membrane was dephosphorylated. Incorporation of [32P]phosphate into membrane-associated RII was completely abolished in the presence of 10 microM cAMP. The decrease in RII phosphorylation in membrane from stimulated cells assayed in the presence of cAMP was due to a phosphoprotein phosphatase activity that was completely inhibited by okadaic acid (1 microM). The results indicate that stimulation of parietal cells with histamine and forskolin results in the dephosphorylation of membrane bound RII by a protein phosphatase that is also membrane associated. Furthermore, okadaic acid inhibited histamine-stimulated accumulation of [14C]aminopyrine into isolated parietal cells without altering stimulated increases in cAMP. Thus protein phosphatase may be a significant regulator of parietal cell function.

Adenosine Triphosphatases↗
PubMed1992

Surgical therapy of acute esophageal variceal hemorrhage.

Options for the management of patients with acute variceal hemorrhage must be compared for their ability to stop bleeding and prevent rebleeding, for their safety, and for their impact on hepatic reserve. Pharmacologic treatment may stop bleeding in up to 50% of patients, but cannot prevent rebleeding. Balloon tamponade controls bleeding in 90% of patients but is only transiently effective and may cause complications. Immediate sclerotherapy may stop acute bleeding and may provide chronic control with repeated treatments. However, patients who fail to respond to such measures must be submitted for surgical intervention. Emergency portosystemic shunt or esophageal transection represent the current procedures of choice for these patients. Surgery may also prove more cost effective than repeated sclerotherapy as primary therapy in a select group of patients with a high risk of rebleeding. Ultimately, however, primary pharmacologic therapy or hepatic transplantation to correct the pathophysiology underlying the esophageal variceal hemorrhage must be developed and refined if the natural history of this disease is to be substantially altered.

Acute Disease↗
PubMed1992

Correlates of aldosterone-induced increases in Cai2+ and Isc suggest that Cai2+ is the second messenger for stimulation of apical membrane conductance.

Studies were performed on monolayers of cultured A6 cells, grown on permeable filters, to determine the second messenger system involved in the aldosterone-induced increase in electrogenic sodium transport. Addition of aldosterone (1 microM) to the solution bathing the basal surface of cells caused both an increase in Isc and threefold transient rise in intracellular calcium Cai2+ after a delay of approximately 60 min. Because both events were inhibited by actinomycin D and cyclohexamide, they appeared to require transcriptional and translational processes. Addition of BAPTA to the bathing media to chelate Cai2+ reduced Isc and the delayed Cai2+ transient; 50 microM BAPTA inhibited Isc and the rise in Cai2+ by greater than 80%. Further studies suggested that the action of aldosterone to increase Isc may be dependent on a calcium/calmodulin-dependent protein kinase, because W-7 and trifluoperazine reduced the aldosterone-induced Isc in a dose-dependent manner. Taken together, these observations suggest that calcium is a second messenger for the action of aldosterone on sodium transport, and suggest, for the first time, that agonists which bind to intracellular receptors can utilize, via delayed processes dependent on de novo transcription and translation, intracellular second messenger systems to regulate target cell function.

Aldosterone↗
PubMed1991

Redistribution of 23 kDa tubulovesicle-associated GTP-binding proteins during parietal cell stimulation.

Small GTP-binding proteins are important regulators of intracellular traffic. The presence of several small GTP-binding proteins was documented in subfractions of rabbit parietal cells. Upon maximal stimulation of the cells with a combination of histamine and forskolin, one 23 kDa GTP-binding band was observed to decrease in a 50,000 g membrane fraction while increasing in 4000 g membranes. The 23 kDa band resolved into one major and two minor species on two-dimensional gels. GTP-binding species of 23 kDa, 24 kDa and 25 kDa were present in purified preparations of tubulovesicles. The three isoelectric species of the 23 kDa proteins observed in parietal cell 50,000 g microsomes were enriched in tubulovesicle preparations. None of the tubulovesicle-associated GTP-binding proteins were substrates for ADP-ribosylation by a preparation of botulinum D toxin. These results indicate that tubulovesicles contain discrete small GTP-binding proteins which redistribute during parietal cell stimulation.

Adenosine Diphosphate Ribose↗
PubMed1990

Effects of epidermal growth factor on signal transduction in rabbit parietal cells.

The aim of this study was to elucidate the cellular mechanisms of action of epidermal growth factor (EGF) inhibition of parietal cell secretion. EGF effects on histamine- and carbachol-stimulated [14C]aminopyrine (AP) uptake and intrinsic factor (IF) secretion were evaluated in isolated rabbit parietal cells. EGF inhibited histamine-stimulated [14C]AP uptake and IF secretion through a reduction in stimulated adenosine 3',5'-cyclic monophosphate (cAMP) levels. EGF decreased the phosphorylation of a cytosolic 30-kDa, histamine-stimulated, cAMP-dependent protein kinase substrate. These effects on histamine-stimulated activation were reversed by pertussis toxin preincubation. EGF inhibited carbachol-stimulated [14C]AP uptake and IF secretion, but did not alter the carbachol-stimulated Ca2+ transient. These results indicate that EGF inhibits histamine-stimulated secretion through the inhibitory Gi guanosine 5'-triphosphate-binding protein and carbachol-stimulated secretion through a mechanism independent of the activation of an increase in intracellular Ca2+.

Aminopyrine↗
PubMed1990

Inhibition of parietal cell H+ secretion by transforming growth factor alpha: a possible autocrine regulatory mechanism.

Transforming growth factor-alpha (TGF alpha) and TGF alpha/epidermal growth factor receptor messenger ribonucleic acid have recently been demonstrated in isolated parietal cells. The aim of this study was to investigate the effects of TGF alpha on basal and stimulated secretion in vitro with the isolated rabbit parietal cell model. Acid secretion was assessed indirectly with cell uptake of carbon 14-labeled aminopyrine [( 14C]AP). TGF alpha (10(-11) to 10(-7) mol/L) had no effect on unstimulated [14C]AP uptake. TGF alpha dose dependently inhibited histamine (10(-5) to 10(-6) mol/L)-stimulated but not forskolin (10(-5) to 10(-7) mol/L)-stimulated [14C]AP uptake. This effect on histamine-stimulated activation was reversed by pertussis toxin (200 ng/ml) before incubation. TGF alpha had no effect on carbachol (10(-5) to 10(-6) mol/L)-stimulated [14C]AP uptake. Specific HCO3-buffer studies demonstrated that these observations were independent of extracellular buffer and possible TGF alpha effects on intracellular pH. Our data indicate that TGF alpha inhibits acid secretion by specifically uncoupling histamine/cyclic adenosine monophosphate transduction at the guanosine triphosphate-binding protein. TGF alpha, unlike epidermal growth factor, has no effect on carbachol stimulation, which suggests a qualitative difference between the biologic actions of TGF alpha and epidermal growth factor. Possible autocrine-paracrine modulation of histamine stimulation by TGF alpha invokes a novel regulatory mechanism of parietal cell secretion.

Aminopyrine↗
PubMed1989

A micromethod for the assay of cellular secretory physiology: application to rabbit parietal cells.

A micromethod for investigating secretory physiology in isolated cells was evaluated. The method utilized a specially designed polycarbonate incubation chamber to provide constant oxygenation to cells incubating in a 96-well microtiter plate. Cells were rapidly separated from media by vacuum filtration. Isolated parietal cells were utilized to demonstrate the versatility of the method for assay of intracellular accumulation of [14C]-aminopyrine, secretion of intrinsic factor into the medium, and assay of intracellular cAMP. Histamine stimulated the uptake of [14C]aminopyrine and intrinsic factor secretion in a sustained and linear fashion. At the end of the 2-h period uptake of aminopyrine and secretion of intrinsic factor were increased 17- and 5-fold, respectively. This response to histamine was accompanied by a rapid and sustained 3-fold rise in intracellular cyclic AMP. In contrast, carbamylcholine caused a transient increase in [14C]aminopyrine accumulation and intrinsic factor secretion which was most pronounced during the first 10 min and had almost ceased by 30 min. Carbamylcholine had no effect on intracellular cAMP levels. This new method, which can handle 400 replicates using parietal cells from the fundic mucosa of a single rabbit, is suitable for studying the time course of intracellular events which accompany general secretory processes.

Aminopyrine↗
PubMed1989

Pancreastatin: a novel peptide inhibitor of parietal cell signal transduction.

The direct inhibition of secretion by pancreastatin was investigated in rabbit isolated parietal cells. Pancreastatin exerted no influence on basal aminopyrine uptake. Pancreastatin inhibited histamine stimulated aminopyrine uptake through a decrease in intracellular cAMP. Pancreastatin inhibition of histamine stimulated uptake was blocked in the presence of pertussis toxin. Pancreastatin also inhibited the carbachol stimulated increase in aminopyrine accumulation. However, the effects of pancreastatin on carbachol stimulation were not reversed by pertussis toxin. Pancreastatin did not alter the carbachol induced increase in cytosolic free calcium. Thus, pancreastatin appears to inhibit parietal cell signal transduction at multiple points along the second messenger pathways.

Aminopyrine↗