Biomedical subjects

A K Stewart

Publications and source records attributed to A K Stewart.

At least 37 records · Page 2Linked to original sources

PubMed2001

Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study.

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

Adenoviridae↗

PubMed2001

Adenovirus-mediated human endostatin gene delivery demonstrates strain-specific antitumor activity and acute dose-dependent toxicity in mice.

Purified recombinant mouse endostatin protein has been reported to regress established murine solid tumors by inhibiting the proliferation of endothelial cells. To develop a clinical gene therapy strategy with endostatin, we cloned the cDNA of human endostatin by RT-PCR from human placenta. A 150-bp sequence encoding the IgG leader peptide was fused in frame to the 5' end of the endostatin cDNA and recombinant adenoviruses, AdENDO-YFP and AdENDO, carrying endostatin gene expression cassettes were rescued. AdENDO-YFP infects cultured mammalian cells at high efficiency and expresses a biologically active human endostatin in secreted form at high levels both in vitro and in vivo. When delivered in vivo, a strain-specific expression pattern was observed, with the highest and longest endostatin expression in 129/J mice. After systemic delivery of 2 x 10(9) PFU of AdENDO-YFP into 129/J mice, human endostatin expression was achieved at a mean value of 1.34 +/- 0.42 microg/ml of serum (n = 6) and inhibition of lung metastasis was observed in an EOMA tumor model. However, high dose intravenous delivery of AdENDO-YFP and AdENDO was associated with severe acute toxicity in recipient mice that included loss of weight, bleeding, and death of animals. These events were not observed with the injection of identical doses of a control adenovirus that did not contain the endostatin gene. Because the endostatin adenovirus-associated acute toxicity was also observed in immunodeficient NCRNU-M nude mice, the toxicity does not appear to be the result of the immunogenicity against human endostatin or the EYFP protein.

Adenoviridae↗

PubMed2001

Murine phosphatidylserine-specific phospholipase A1 (Ps-pla1) maps to chromosome 16 but is distinct from the lpd (lipid defect) locus.

We have previously generated a mouse transgenic line with an insertional mutation designated lpd that demonstrates a phenotype of hypertriglyceridemia and fatty liver. Since the recently identified phosphatidylserine-specific phospholipase A1 (PS-PLA1) demonstrates significant homology to triglyceride lipases, we reasoned that the mouse Ps-plaI gene may be the disrupted gene within the lpd locus. Using a rat PS-PLA1 cDNA sequence to search the EST database, we identified a mouse EST homolog AA839424. Sequencing analysis of AA839424 revealed a putative Ps-pla1 protein of 456 amino acids with extensive overall structural conservation with human and rat PS-PLA1 and with triglyceride lipases. Conserved sequences in Ps-pla1 include a lipase consensus sequences GxSxG, a catalytic triad, and eight of the ten conserved cysteine residues that are required for tertiary structure. Mouse Ps-plal carries a phosphatidylserine-binding motif that is absent in all triglyceride lipases. Using a mouse whole-genome radiation hybrid (WG-RH) mapping panel (T31), we mapped mouse Ps-pla1 to Chromosome (Chr) 16 between genetic markers D16Mit194 and D16Mit38, which is 17.1 cM centromeric to the lpd locus. On the basis of chromosome location, we conclude that Ps-pla1 and lpd are distinct genes in lipid metabolism.

Amino Acid Sequence↗

PubMed2001

Radiation-associated pneumonitis following autologous stem cell transplantation: predictive factors, disease characteristics and treatment outcomes.

High-dose therapy followed by autologous stem cell transplantation (ASCT) prolongs survival in patients with multiple myeloma and is relatively safe with treatment-related mortality rates of only 1-5%. Interstitial pneumonitis (IP) is normally an infrequent complication of ASCT with a reported incidence of 0-16%. Between 1992 and 1998, 94 myeloma patients at our center underwent ASCT using a high-dose regimen of etoposide (60 mg/kg), melphalan (160 mg/m2) and fractionated TBI 12 Gy. An unusually high incidence of IP (29/94 (31%)) was noted. Mortality in the IP patients was high at 45%. Patients developing IP were more frequently anemic than those who did not have pulmonary complications (hemoglobin <100 g/l) prior to transplant (P = 0.03) but no other pre-transplant factors were predictive (ie age, gender, smoking history, CMV status, pulmonary function, creatinine, beta2-microglobulin or C-reactive protein, prior cumulative chemotherapy or chest irradiation). A significantly lower IP rate was noted in 32 contemporaneous myeloma control patients conditioned with BU-CY without TBI at our center (3/32 (9%); P=0.03) and in 32 lymphoma control patients conditioned with the same melphalan and etoposide regimen minus the TBI (2/32 (6%); P = 0.003). In contrast, when using the same TBI-containing regimen in 32 concurrently treated lymphoma patients, an increase in IP similar to that seen in our myeloma cohort (7/32 (22%); P = 0.3) was noted. This strongly suggests that TBI is the predominant factor contributing to lung toxicity. We conclude that radiation-associated pneumonitis cannot be easily predicted by pretransplant variables. Therefore surveillance, early recognition and prompt therapy are recommended.

Adult↗

PubMed2001

Tricistronic viral vectors co-expressing interleukin-12 (1L-12) and CD80 (B7-1) for the immunotherapy of cancer: preclinical studies in myeloma.

Synergy between interleukin-12 (IL-12) and B7-1 (CD80) for cancer immunotherapy has previously been demonstrated in animal models of breast cancer, lymphoma, and multiple myeloma. With a view to human clinical application, tricistronic retroviral and adenovirus vectors co-expressing IL-12 (IL-12p40 plus IL-12p35) and CD80 were constructed by utilizing two internal ribosome entry site (IRES) sequences to link the three cDNAs. A murine stem cell virus (MSCV)-based retroviral vector (MSCV-hIL12.B7) utilized distinct IRES sequences from the encephalomyocarditis virus (EMCV) and the foot-and-mouth disease virus (FMCV), whereas Ad5-based adenovirus vectors contained transcriptional units with two EMCV IRES sequences under the control of murine (AdMh12.B7) or human (AdHh12.B7) cytomegalovirus promoters. AdMh12.B7 was found to consistently direct higher levels of IL-12 and CD80 expression than AdHh12.B7 following infection of a number of human tumor cell lines. In preclinical studies, the human myeloma cell line U266 was infected with MSCV-hIL12.B7 and a resulting clonal cell line, U/MSCV-h12.B7, was generated with stable expression of CD80 and secreting IL-12 at 1 ng/24 h/10(6) cells. By comparison, following AdMh12.B7 infection, 81% of infected U266 cells (U/AdMh12.B7) expressed CD80 and secreted IL-12 at 25-50 ng/24 h/10(6) cells. Both engineered myeloma cell lines stimulated enhanced allogeneic mixed lymphocyte proliferation and provoked increases in cytotoxic T-lymphocyte responses and gamma-interferon release from normal donor lymphocytes exposed to parental U266 cells. These results suggest potential clinical utility of AdMh12.B7 in immunotherapy strategies for the treatment of multiple myeloma and other cancers.

Adenoviridae↗

PubMed2001

Adenovector engineered interleukin-2 expressing autologous plasma cell vaccination after high-dose chemotherapy for multiple myeloma--a phase 1 study.

Eight multiple myeloma patients participated in a phase I trial evaluating the feasibility and safety of subcutaneous vaccination with adenovirus engineered, autologous plasma cells after high-dose therapy. Plasma cells were concentrated from bone marrow harvests by negative selection and high gradient magnetic separation. The mean plasma cell yield was 2.61 x 10(8). Transgene expression measured 48 h after plasma cell infection with an IL-2 expressing adenovirus averaged 2.95 ng/ml/10(6) cells. Vaccine production was successful for 88% of patients. Two months after high-dose therapy, six patients received from one to five injections of 3.5-9.0 x 10(7) cells/vaccine. Vaccines were well tolerated with only minor systemic symptoms reported. Injection with tumor cells induced a local inflammatory response consisting predominantly of CD8+ and/or TIA-1+ T-lymphocytes. Myeloma specific anti-tumor responses, assessed by interferon-gamma (IFN-gamma) release and cytotoxic T cell killing of autologous tumor cells, were not enhanced after vaccination in one evaluable patient. Clinical response, manifested as a decrease in serum paraprotein, was not observed in the one patient who had measurable disease at the time of vaccination. These results demonstrate that the generation of adenovector modified plasma cell vaccines is technically feasible and can be safely administered post-transplant. Further studies of immunlogic and clinical efficacy are required.

Adenoviridae↗

PubMed2001

Autotransplants for histologically transformed follicular non-Hodgkin's lymphoma.

Histological transformation from a follicular non-Hodgkin's lymphoma (NHL) to a higher grade lymphoma carries a poor prognosis despite treatment with aggressive anthracycline-based chemotherapy. We retrospectively analysed 35 patients with histologically transformed NHL who underwent high-dose therapy and autotransplantation at our centre. Patients up to 65 years old were eligible for autotransplant at the time of transformation or with subsequent relapses, provided that chemosensitivity to a salvage regimen could be demonstrated. All patients received high-dose therapy [etoposide 60 mg/kg, melphalan 160 mg/m2 and fractionated total body irradiation (TBI) 12 Gy] followed by unpurged autologous bone marrow or blood stem cell rescue. Most patients (69%) had advanced stage disease (stages 3--4) at transformation and bone marrow involvement was common (49%). Twenty-six (74%) patients were in partial remission (PR) and nine (26%) in complete remission (CR) at the time of transplant. Median duration from transformation to transplant was 10.9 months (range, 5.2 months--4.6 years). At a median follow up of 52 months after autotransplant, 19 (54%) patients had died. Causes of death were progressive lymphoma in nine patients (26%), treatment-related mortality (TRM) in seven (20%) and myelodysplasia in three (8%). Only five patients in our cohort were > 60 years old, but all died as a result of treatment-related causes (mostly pulmonary infections). Five-year overall survival and progression-free survival from time of transplant were 37% and 36% respectively. Using multivariate analysis of factors including gender, age, stage, extranodal disease, disease bulk, B symptoms, number of prior therapies, relapse status and CR/PR status at transplant, only advanced age significantly predicted for survival from autotransplant (P = 0.002). Our survival data are comparable to previous reports of autotransplantation for transformed NHL and suggest a benefit over standard chemotherapy alone in selected patients. However, our high TRM cautions the use of aggressive therapy, including TBI, in patients over 60 years old.

Adult↗

PubMed2001

Male sexual function after autologous blood or marrow transplantation.

Although endocrine dysfunction has been reported in survivors of allogeneic bone marrow transplantation (alloBMT), data for autologous BMT (autoBMT) recipients are lacking. Because information on male potency in particular is scanty, we prospectively assessed male sexual function after autoBMT. We identified 16 men who were < or =50 years of age at the time of evaluation and disease free for at least 6 months after autoBMT. Nine had Hodgkin's disease, 4 had acute myelogenous leukemia, and 3 had non-Hodgkin's lymphoma. Blood samples were assayed for luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Patients were surveyed with a modified version of the Pyschosocial Adjustment to Illness Scale regarding erectile dysfunction and loss of interest in sexual activities. Seventy five percent of the men reported normal interest in sexual activities and 87.5% reported normal erectile function; however, 4 of 16 reported a moderate loss of interest in sexual activities, and another 2 of 16 reported frequent loss of erectile function. All 4 men with decreased libido and both men with impaired erectile function had Hodgkin's disease. Fourteen (88%) of 16 patients had an elevated FSH level, 7 (47%) of 15 had elevated LH, and 6 (38%) of 16 had decreased testosterone levels. Decreased testosterone levels correlated with a moderate or total loss of libido (P = .008) and a diagnosis of Hodgkin's disease (P = .01). Thus, after transplantation, most men have abnormal levels of gonadotrophins. Decreased levels of testosterone and symptoms of sexual dysfunction correlated with a diagnosis of Hodgkin's disease and may be related to the induction and salvage therapy received prior to autoBMT.

Adult↗

PubMed2001

Regulation of AE2 anion exchanger by intracellular pH: critical regions of the NH(2)-terminal cytoplasmic domain.

The role of intracellular pH (pH(i)) in regulation of AE2 function in Xenopus oocytes remains unclear. We therefore compared AE2-mediated (36)Cl(-) efflux from Xenopus oocytes during imposed variation of extracellular pH (pH(o)) or variation of pH(i) at constant pH(o). Wild-type AE2-mediated (36)Cl(-) efflux displayed a steep pH(o) vs. activity curve, with pH(o(50)) = 6.91 +/- 0.04. Sequential NH(2)-terminal deletion of amino acid residues in two regions, between amino acids 328 and 347 or between amino acids 391 and 510, shifted pH(o(50)) to more acidic values by nearly 0.6 units. Permeant weak acids were then used to alter oocyte pH(i) at constant pH(o) and were shown to be neither substrates nor inhibitors of AE2-mediated Cl(-) transport. At constant pH(o), AE2 was inhibited by intracellular acidification and activated by intracellular alkalinization. Our data define structure-function relationships within the AE2 NH(2)-terminal cytoplasmic domain, which demonstrates distinct structural requirements for AE2 regulation by intracellular and extracellular protons.

Acids↗

PubMed2001

Regulation of Na+-independent Cl-/HCO3- exchangers by pH.

Among human bicarbonate transporters, two major gene families encode Na-independent Cl(-)/HCO(3)(-) exchangers: the SLC4 anion exchanger (AE) family, and the SLC26 "sulfate permease" anion transporter family. The SLC4 AE family contains at least three genes, and comprises a subfamily within the larger and phylogenetically more ancient bicarbonate transporter superfamily that includes the Na bicarbonate cotransporters (NBC) and the Na-driven Cl/base exchangers. Mutations in the human AE1 gene cause autosomal dominant spherocytic anemia and distal renal tubular acidosis of both dominant and recessive forms. Anemia is also associated with AE1 mutations in mouse, cow, and zebrafish. Naturally occurring mutations in the human AE2 and AE3 genes have not been detected. The SLC26 family in humans consists of at least 10 members, and includes anion exchangers which exchange chloride for bicarbonate, hydroxyl, sulfate, formate, iodide, and/or oxalate. Mutations in three of these genes cause hereditary disease, including chondrodysplasia (SLC26A2, DTD), diarrhea (A3, down-regulated in adenoma/chloride-losing diarrhea protein: DRA/CLD), and goiter/deafness syndrome (A4, pendrin). Little is known about the acute regulation of these modulators of intracellular and compartmental pH and volume.

Animals↗

PubMed2000

Patterns of care for patients with primary differentiated carcinoma of the thyroid gland treated in Germany during 1996. U.S. and German Thyroid Cancer Group.

BACKGROUND: To determine current patterns of care and disease characteristics for patients with thyroid carcinoma, a Patient Care Evaluation Study was initiated in 1996 in the U.S. and Germany. This project addresses ongoing concerns with respect to the diagnostic evaluation and treatment of patients diagnosed with thyroid carcinoma and raises questions concerning how physicians are interpreting current standards and acting on the basis of these recommendations. METHODS: Patients with primary thyroid carcinoma were entered into a prospective multicenter observational study with free choice of treatment (no control group) between January 1, 1996 and December 31, 1996 in Germany. This resulted in a total of 2537 cases under observation and analysis; 1685 patients had papillary carcinoma (66.4%), 691 had follicular carcinoma (27.2%), 70 had medullary carcinoma (2.8%), and 91 had anaplastic carcinoma (3.6%). The 2376 patients with carcinoma of either papillary or follicular histology were included in the current analysis. RESULTS: The major symptoms reported for patients with papillary and follicular thyroid carcinoma was neck mass (reported in 76% and 79%, respectively) followed by dysphagia (reported in 25% and 27%, respectively), stridor (reported in 9% and 14%, respectively), and neck pain (reported in 7% and 8%, respectively). Greater than 50% of the patients with papillary thyroid carcinoma were reported to have American Joint Committee on Cancer/International Union Against Cancer Stage I disease. Between 37-39% of the follicular carcinoma patients had Stage I and Stage II disease. Only slight differences in the diagnostic approach to patients with papillary or follicular carcinoma were noted. The majority of patients underwent an ultrasound of the thyroid region (78.1%), which was suggestive of carcinoma in only 39% of the cases. A thyroid scan was performed on 76.6% of patients, and the results were suggestive of carcinoma in 44.8% of the individuals. In contrast, fine-needle aspiration biopsy of the thyroid is highly recommended in the current Clinical Practice Guidelines (CPG) but results were obtained in only 27.4% of the patients. Total thyroidectomy without lymph node dissection was the most commonly used surgical procedure in the treatment of patients with papillary and follicular thyroid carcinoma. Only approximately 2% of patients at low risk in the group with Stage I disease were treated with a lobectomy. In 80% of the patients with Stage I papillary thyroid carcinoma and approximately 90% of those patients diagnosed with Stage II, III, and IV disease treating physicians chose to utilize radioiodine as adjuvant treatment after disease-directed surgery. External beam radiation was added to the treatment regimen for many patients diagnosed with Stage III and IV disease (30% in patients with papillary thyroid carcinoma and 33% in patients with follicular thyroid carcinoma). CONCLUSIONS: To the authors' knowledge no single effective diagnostic test for thyroid carcinoma currently is available and in the majority of cases a combination of ultrasound, thyroid scan, or fine-needle aspiration biopsy together with the clinical findings (e.g., thyroid mass) led to a diagnosis of carcinoma. The authors suspect that the high prevalence of concomitant pathologic findings such as goiter, even in the healthy population in Germany, reduces the accuracy of all diagnostic test methods and may account for the frequent use of imaging techniques. The majority of patients underwent a total or near-total thyroidectomy. Total thyroidectomy with radical lymph node dissection was used very frequently in those patients with papillary thyroid carcinoma (22%). German physicians tend to surgically treat early stage thyroid carcinoma somewhat more radically than recommended in the CPG. With respect to other treatment options employed as part of the first course of treatment, radioiodine appears to play the most important role. [See commentary o

Adenocarcinoma, Follicular↗

PubMed2000

Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study.

BACKGROUND: The American College of Surgeons Commission on Cancer (CoC) has conducted national Patient Care Evaluation (PCE) studies since 1976. METHODS: Over 1500 hospitals with CoC-approved cancer programs were invited to participate in this prospective cohort study of U.S. thyroid carcinoma cases treated in 1996. Follow-up will be conducted through the National Cancer Data Base. RESULTS: Of the 5584 cases of thyroid carcinoma, 81% were papillary, 10% follicular, 3.6% Hürthle cell, 0.5% familial medullary, 2.7% sporadic medullary, and 1.7% undifferentiated/anaplastic. Demographics and suspected risk factors were analyzed. Fine-needle aspiration of the thyroid gland (53%) or a neck lymph node (7%), thyroid nuclear scan (39%), and ultrasound (38%) constituted the most frequently utilized diagnostic modalities. The vast majority of patients with differentiated thyroid carcinoma presented with American Joint Committee on Cancer Stage I and II disease and relatively small tumors. For all histologies, near-total or total thyroidectomy constituted the dominant surgical treatment. No lymph nodes were examined in a substantial proportion of cases. Residual tumor after the surgical event could be documented in 11% of cases, hypocalcemia in 10% of cases, and recurrent laryngeal nerve injury in 1.3% of cases. Complications were most frequently associated with total thyroidectomy combined with lymph node dissection. Thirty-day mortality was 0.3%; when undifferentiated/anaplastic cancer cases were eliminated, it decreased to 0.2%. Adjuvant treatment, probably underreported in this study, consisted of hormonal suppression (50% overall) and radioiodine (50% overall). CONCLUSIONS: In addition to offering information concerning risk factors and symptoms, the current PCE study compliments the survival information from previous NCDB reports and offers a surveillance snapshot of current management of thyroid carcinoma in the U.S. Identified opportunities for improvement of care include 1) more frequent use of fine-needle aspiration cytology in making a diagnosis; 2) more frequent use of laryngoscopy in evaluating patients preoperatively, especially those with voice change; and 3) improved lymph node resection and analysis to improve staging and, in some situations, outcomes.

Adenocarcinoma, Follicular↗

PubMed2000

White cells 2: impact of understanding the molecular basis of haematological malignant disorders on clinical practice.

The molecular basis of many leukaemias is now known, allowing precise diagnosis. Treatment of chronic myeloid leukaemia is now possible by targeting of the BCR-ABL tyrosine kinase. The underlying molecular abnormalities in acute leukaemias allow the outlook for individual patients to be assessed at diagnosis and therapy tailored accordingly. Analysis of V(H) genes in B-cell malignant disorders allows these to be placed in the hierarchy of B-cell development and may provide prognostically valuable information.

Acute Disease↗

PubMed2000

Germline CDKN2A mutation implicated in predisposition to multiple myeloma.

Germline mutations of the CDKN2A (p16(INK4A)) tumor suppressor gene predispose patients to melanoma and pancreatic carcinoma. In contrast, mutations of the murine CDKN2A gene predispose BALB/c mice to pristane-induced plasmacytoma. We describe here a family in which a germline mutation of CDKN2A is present in 4 individuals who developed melanoma as well as in a fifth family member who is suffering from multiple myeloma. To determine whether the CDKN2A mutation predisposed the myeloma patient to her disease, we carried out loss of heterozygosity studies on sorted bone marrow from this individual and observed loss of the wild type CDKN2A allele in the malignant plasma cells. We suggest that germline mutations of CDKN2A may predispose individuals to a wider variety of malignancy than has been hitherto reported, but that the expression of these cancers may depend heavily on the genetic background of the patient. (Blood. 2000;95:1869-1871)

Animals↗

PubMed2000

The National Cancer Data Base Report on treatment patterns for hepatocellular carcinomas: improved survival of surgically resected patients, 1985-1996.

BACKGROUND: The Commission on Cancer data from the National Cancer Data Base (NCDB) has previously reported data evaluating time trends in various cancers, including such elements as stage of disease at diagnosis, treatment, and survival for multiple tumor sites. In this report, data collected from 1985, 1986, 1990, 1991, 1995, and 1996 for primary hepatocellular carcinoma (HCC) tumors are presented. METHODS: The data presented in this review were collected from hospital cancer registries from across the U.S. Eight calls for data have yielded a total 6.9 million cases for the years 1985-1996, including 1158 HCC cases in 1985-1986, 3319 cases in 1990-1991, and 5683 cases in 1994-1995 from hospital cancer registries across the U. S. These data represent approximately 4.3%, 11.2%, and 14.8% of the estimated cases of carcinomas of the liver and biliary tract diagnosed in the U.S. in each of the three respective time periods. RESULTS: The outcome for patients diagnosed with HCC remains poor, with only 10% of patients with American Joint Committee on Cancer Stage I disease surviving 5 years. Approximately 50% of patients received no therapy for their HCC, even those with early stage disease. Over these three time periods, the use of chemotherapy appears to have decreased. Among patients diagnosed with Stage II and III disease a difference in survival was noted between those treated with surgery only and those treated with chemotherapy only. Women appear to have a limited survival advantage over men. CONCLUSIONS: In spite of an overall poor prognosis, subsets of patients with HCC appear to benefit from surgical resection/ablation of their tumor. The decreasing use of chemotherapy and the early reports of newer ablative techniques (e.g., cryotherapy) suggest that other treatment modalities are emerging. These NCDB data provide a baseline for HCC treatment from which prospective studies are being developed to assess the newer treatments as well as the underlying causes.

Adult↗

PubMed2000

Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis.

The t(4;14) translocation occurs in 25% of multiple myeloma (MM) and results in both the ectopic expression of fibroblast growth factor receptor 3 (FGFR3) from der4 and immunoglobulin heavy chain-MMSET hybrid messenger RNA transcripts from der14. The subsequent selection of activating mutations of the translocated FGFR3 by MM cells indicates an important role for this signaling pathway in tumor development and progression. To investigate the mechanism by which FGFR3 overexpression promotes MM development, interleukin-6 (IL-6)-dependent murine B9 cells were transduced with retroviruses expressing functional wild-type or constitutively activated mutant FGFR3. Overexpression of mutant FGFR3 resulted in IL-6 independence, decreased apoptosis, and an enhanced proliferative response to IL-6. In the presence of ligand, wild-type FGFR3-expressing cells also exhibited enhanced proliferation and survival in comparison to controls. B9 clones expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed increased phosphorylation of STAT3 and higher levels of bcl-x(L) expression than did parental B9 cells after cytokine withdrawal. The mechanism of the enhanced cell responsiveness to IL-6 is unknown at this time, but does not appear to be mediated by the mitogen-activated protein kinases SAPK, p38, or ERK. These findings provide a rational explanation for the mechanism by which FGFR3 contributes to both the viability and propagation of the myeloma clone and provide a basis for the development of therapies targeting this pathway.

Apoptosis↗

PubMed2000

Esophageal cancer: results of an American College of Surgeons Patient Care Evaluation Study.

BACKGROUND: The last two decades have seen changes in the prevalence, histologic type, and management algorithms for patients with esophageal cancer. The purpose of this study was to evaluate the presentation, stage distribution, and treatment of patients with esophageal cancer using the National Cancer Database of the American College of Surgeons. STUDY DESIGN: Consecutively accessed patients (n = 5,044) with esophageal cancer from 828 hospitals during 1994 were evaluated in 1997 for case mix, diagnostic tests, and treatment modalities. RESULTS: The mean age of patients was 67.3 years with a male to female ratio of 3:1; non-Hispanic Caucasians made up most patients. Only 16.6% reported no tobacco use. Dysphagia (74%), weight loss (57.3%), gastrointestinal reflux (20.5%), odynophagia (16.6%), and dyspnea (12.1%) were the most common symptoms. Approximately 50% of patients had the tumor in the lower third of the esophagus. Of all patients, 51.6% had squamous cell histology and 41.9% had adenocarcinoma. Barrett's esophagus occurred in 777 patients, or 39% of those with adenocarcinoma. Of those patients that underwent surgery initially, pathology revealed stage I (13.3%), II (34.7%), III (35.7%), and IV (12.3%) disease. For patients with various stages of squamous cell cancer, radiation therapy plus chemotherapy were the most common treatment modalities (39.5%) compared with surgery plus adjuvant therapy (13.2%). For patients with adenocarcinoma, surgery plus adjuvant therapy were the most common treatment methods. Disease-specific overall survival at 1 year was 43%, ranging from 70% to 18% from stages I to IV. CONCLUSIONS: Cancer of the esophagus shows an increasing occurrence of adenocarcinoma in the lower third of the esophagus and is frequently associated with Barrett's esophagus. Choice of treatment was influenced by tumor histology and tumor site. Multimodality (neoadjuvant) therapy was the most common treatment method for patients with esophageal adenocarcinoma. The use of multimodality treatment did not appear to increase postoperative morbidity.

Aged↗

PubMed2000

Human herpesvirus 8 (KSHV) contamination of peripheral blood and autograft products from multiple myeloma patients.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), has recently been identified within the bone marrow dendritic cells of multiple myeloma (MM) patients. This virus contains homologues to human cytokines such as IL-6 that could potentially stimulate myeloma cell growth and contribute to disease pathogenesis. Since mobilization chemotherapy may increase circulating dendritic cell numbers, we searched for HHV-8 in peripheral blood mononuclear cells (PBMCs) before and after mobilization chemotherapy given to MM patients. Furthermore, we determined if autograft purging using the CEPRATE SC device would reduce the percentage of HHV-8 infected stem cell products. Only two of the 39 PBMC samples collected prior to mobilization chemotherapy contained PCR detectable virus, yet nine of 37 PBMCs collected on the first day of leukapheresis had detectable HHV-8 (P = 0.016). HHV-8 was more frequently identified in autograft products before vs after Ceprate SC selection (40% vs 15%, P = 0.016). Although the role HHV-8 plays in myeloma pathogenesis remains unclear, these results imply that mobilization chemotherapy increases the numbers of circulating HHV-8-infected dendritic cells within the peripheral blood. In addition, CD34 selection of autograft products in MM patients may reduce the reintroduction of virally infected cells following high-dose chemotherapy. Bone Marrow Transplantation (2000) 25, 153-160.

Antigens, CD34↗