Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy: a prospective clinical study.

BACKGROUND: The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy. METHODS: In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity. RESULTS: The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01). CONCLUSIONS: To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively.

The agricultural mechanization controversy.

Attorneys of California Rural Legal Assistance are suing the University of California on behalf of 19 farm workers, alleging that publicly funded mechanization research displaces farm workers, eliminates small farmers, hurts consumers, impairs the quality of rural life, and impedes collective bargaining. This article reviews the evidence and finds that it does not support the charges. The mechanization lawsuit is important because applied research by universities is often authorized by legislation stipulating multiple goals, leaving researchers and universities vulnerable to lawsuits alleging that only some of the legislative goals are being pursued.

Transcription of class III genes: formation of preinitiation complexes.

Class III genes require multiple cellular factors for transcription by RNA polymerase III; these genes form stable transcription complexes, which in the case of Xenopus 5S genes are correlated with differential expression in vivo. The minimal number and identity of the factors required to form both stable and metastable complexes on three class III genes (encoding, respectively, 5S RNA, transfer RNA, and adenovirus VA RNA species) were determined. Stable complex formation requires one common factor, whose recognition site was analyzed, and either no additional factors (the VA gene), a second common factor (the transfer RNA gene), or a third gene-specific factor (the 5S gene). The mechanism of stable complex formation and its relevance to transcriptional regulation were examined in light of the various factors and the promoter sequences recognized by these factors.

Androgen deprivation leads to increased carbohydrate metabolism and hexokinase 2-mediated survival in Pten/Tp53-deficient prostate cancer.

Prostate cancer is characterized by a dependence upon androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) is the accepted treatment for progressive prostate cancer. Although ADT is usually initially effective, acquired resistance termed castrate-resistant prostate cancer (CRPC) develops. PTEN and TP53 are two of the most commonly deleted or mutated genes in prostate cancer, the compound loss of which is enriched in CRPC. To interrogate the metabolic alterations associated with survival following ADT, we used an orthotopic model of Pten/Tp53 null prostate cancer. Metabolite profiles and associated regulators were compared in tumors from androgen-intact mice and in tumors surviving castration. AR inhibition led to changes in the levels of glycolysis and tricarboxylic acid (TCA) cycle pathway intermediates. As anticipated for inhibitory reciprocal feedback between AR and PI3K/AKT signaling pathways, pAKT levels were increased in androgen-deprived tumors. Elevated mitochondrial hexokinase 2 (HK2) levels and enzyme activities also were observed in androgen-deprived tumors, consistent with pAKT-dependent HK2 protein induction and mitochondrial association. Competitive inhibition of HK2-mitochondrial binding in prostate cancer cells led to decreased viability. These data argue for AKT-associated HK2-mediated metabolic reprogramming and mitochondrial association in PI3K-driven prostate cancer as one survival mechanism downstream of AR inhibition.

Optical spectroscopy for the classification of malignant lesions of the bronchial tree.

Optical spectroscopy may be used for in vivo, noninvasive distinction of malignant from normal tissue. The aim of our study was to analyze the accuracy of various optical spectroscopic techniques for the classification of cancerous lesions of the bronchial tree. We developed a fiberoptic instrument allowing the measurement of autofluorescence spectroscopy (AFS), diffuse reflectance spectroscopy (DRS), and differential path length spectroscopy (DPS) during bronchoscopy. Spectroscopic measurements were obtained from 191 different endobronchial lesions (63 malignant and 128 nonmalignant) in 107 patients. AFS, DRS, and DPS sensitivity/specificity for the distinction between malignant and nonmalignant bronchial lesions were 73%/82%, 86%/81%, and 81%/88%, respectively. All three optical spectroscopic modalities facilitate an increase of the positive predictive value of autofluorescence bronchoscopy for the detection of endobronchial tumors. Even better results were obtained when the three spectroscopic techniques were combined.

Thermal stability of the thermoluminescence trap structure of bentonite.

This work reports about the thermal stability of the blue thermoluminescence (TL) of a well-characterised natural bentonite from Almeria (Spain). The main interest of this clay, mainly composed of montmorillonite, is because of its application in the field of high-level radioactive waste (HLW) repository in deep-lying rocks. As observed in other aluminosilicates, bentonite exhibits a very complex structure of the emission spectra based on a wide broad maximum peaked at approximately 265 degrees C that can be associated to physico-chemical processes such as dehydroxylation processes, consecutive breaking linking of bonds, formation of hydrolysed ions and redox reactions. The thermal stability tests performed at different temperatures confirm a continuum in the distribution of traps. Hence, the glow curve analysis methods commonly used for synthetic materials based on single discrete traps cannot be applied for this material and the kinetic parameters were fitted assuming an exponential distribution of trapped electrons.

Prognostic value of pre-operative glucose-corrected maximum standardized uptake value in patients with non-small cell lung cancer after complete surgical resection and 5-year follow-up.

INTRODUCTION: In this study we evaluated the value of pre-operative glucose corrected maximum standard uptake value (GC-SUVmax) as prognostic factor in patients with early stage non-small cell lung cancer (NSCLC) after complete surgical resection. METHODS: This study was designed as a retrospectively evaluated single center study with prospective data registry. Inclusion criteria were: histologically proven stage I NSCLC, 18F-FDG-PET/CT scan prior to surgery, complete resection (R0) and follow up in our outpatient department. Exclusion criteria were: history of malignancy other than NSCLC, diabetes and (neo) adjuvant therapy. Follow up period was 5 years. RESULTS: Between 2006 and 2008 a total of 33 patients (16 males, 17 females) met the inclusion criteria. SUVmax and GC-SUVmax were strongly correlated (Spearman's ρ = 0.97). Five-year overall survival (OS) rate was 70 % (95 % CI = 56-87 %). Patients who died within 5 years of follow up had significantly higher pre-operative GC-SUVmax (median = 10.6, IQR = 8.3-14.4) than patients who were alive at 5-year follow up (median = 6.4, IQR = 3.0-9.8), p = 0.04. SUVmax showed similar differences: 10.4 (8-12.9) vs. 6.6 (3.0-8.8), p = 0.047. The area under the receiver-operating characteristic (ROC) curve at 5 years was 0.70 (95 % CI = 0.50-0.90) for GC-SUVmax and 0.71 (95 % CI = 0.51-0.91) for SUVmax (p = 0.75). CONCLUSION: Pre-operative FDG tumor uptake in patients with NSCLC is predictive for survival after complete surgical resection. GC-SUVmax, as an additional value to SUVmax, may better approach competitive inhibition of FDG and glucose in tumors, however, in this study this potential advantage, if any, was very small.

Improving the specificity of fluorescence bronchoscopy for the analysis of neoplastic lesions of the bronchial tree by combination with optical spectroscopy: preliminary communication.

Detection of malignancies of the bronchial tree in an early stage, such as carcinoma in situ (CIS), augments the cure rate considerably. It has been shown that the sensitivity of autofluorescence bronchoscopy is better than white light bronchoscopy for the detection of CIS and dysplastic lesions. Autofluorescence bronchoscopy is, however, characterized by a low specificity with a high rate of false positive findings. In the present paper we propose to combine autofluorescence bronchoscopy with optical spectroscopy to improve the specificity of autofluorescence imaging, while maintaining the high sensitivity. Standard autofluorescence bronchoscopy was used to find suspect lesions in the upper bronchial tree, and these lesions were subsequently characterized spectroscopically using a custom made fiberoptic probe. Autofluorescence spectra of the lesions as well as reflectance spectra were measured. We will show in this preliminary report that the addition of either of these spectroscopic techniques decreases the rate of false positives findings, with the best results obtained when both spectroscopic modalities are combined.

Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma.

The outcome of children, adolescents and young adults (CAYA) with poor-risk recurrent/refractory lymphoma is dismal (⩽30%). To overcome this poor prognosis, we designed an approach to maximize an allogeneic graft vs lymphoma effect in the setting of low disease burden. We conducted a multi-center prospective study of myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT), followed by a reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (AlloHCT) in CAYA, with poor-risk refractory or recurrent lymphoma. Conditioning for MAC AutoSCT consisted of carmustine/etoposide/cyclophosphamide, RIC consisted of busulfan/fludarabine. Thirty patients, 16 Hodgkin lymphoma (HL) and 14 non-Hodgkin lymphoma (NHL), with a median age of 16 years and median follow-up of 5years, were enrolled. Twenty-three patients completed both MAC AutoSCT and RIC AlloHCT. Allogeneic donor sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched siblings (n=6). The incidence of transplant-related mortality following RIC AlloHCT was only 12%. In patients with HL and NHL, 10 year EFS was 59.8% and 70% (P=0.613), respectively. In summary, this approach is safe, and long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC AlloHCT in the majority of cases.

Circulating estradiol, estrone and gonadotropin levels following the administration of orally active 17beta-estradiol in postmenopausal women.

Ingestion of a single tablet containing 2 mg micronized 17beta-estradiol (E-2) produced marked increases in the serum concentrations of E-2 and estrone (E-1) in 9 postmenopausal women. The rise in circulating E-2 became significant within 2 h, reached a maximum (110 pg/ML; 437% increase) at 5 h, and remained significantly elevated at 8 h posttreatment. By 24 h, the serum E-2 concentration was not significantly different than baseline. In contrast, a more rapid (within 1 h) and pronounced (4-fold) increase in the serum concentration of E-1 was observed. This rise continued until a peak (467 pg/ml; 2000%) was reached 6 h posttreatment. Thereafter, the serum E-1 concentration declined progressively but was still significantly elevated (140 pg/ml; P smaller than 0.01) 24 h after treatment. Serum concentrations of FSH AND LH were significantly decreased within 6 and 3 h, respectively and both gonadotropins remained significantly suppressed 24 h following the ingestion of E-2. The ratios of circulating E-1: E-2 reported herein (ca. 3-6) were much higher than those observed by other investigators following iv E-2 (I.E., smaller than 1). Thus the data indicate that micronized E-2 peros is readily absorbed and that during this process a significant portion of the hormone is converted to E-1 by the gstrointestinal tract. In addition, 2 mg oral E-2 exerts significant biologic activity as assessed by serum gonadotropin suppression.

Graft-versus-leukemia-induced complete remission following unrelated umbilical cord blood transplantation for acute leukemia.

A 15-year-old female received an unrelated three of six HLA antigen matched umbilical cord blood (UCB) transplant for refractory, relapsed T-cell ALL. Conditioning consisted of TBI, melphalan, and anti-thymocyte globulin (ATG), with cyclosporin A (CsA) and solumedrol for GVHD prophylaxis. She engrafted and a day 34 bone marrow aspirate showed 100% donor cells and no evidence of leukemia. The post-transplant course was complicated by mild grade I acute GVHD involving skin, and limited chronic GVHD of the gut which resolved with the addition of 1 mg/kg/day of steroids to her CsA prophylaxis. One hundred and ninety days after transplantation the patient developed pancytopenia and was subsequently found to have a leukemic relapse. Immunosuppression was discontinued and she was started on G-CSF and erythropoietin. Moderate skin and gut GVHD developed which was treated with both topical and low-dose oral steroids. Over the next few weeks she became transfusion independent and a follow-up bone marrow aspirate showed complete remission. She continued in complete remission for 4 months, at which time localized leukemic relapse was found in a soft tissue breast mass in spite of continued bone marrow remission. While the patient ultimately died of progressive disease, this case demonstrates that mismatched UCB in conjunction with G-CSF is capable of generating a GVL effect that can induce a complete remission.

Toxicity, pharmacology and feasibility of administration of PEG-L-asparaginase as consolidation therapy in patients undergoing bone marrow transplantation for acute lymphoblastic leukemia.

We attempted to administer PEG-L-asparaginase (PEG-L-A) following hematologic recovery to 38 patients undergoing autologous or allogeneic marrow transplantation for acute lymphoblastic leukemia (ALL). Twenty-four patients (12 of 22 receiving allogeneic and 12 of 16 receiving autologous transplants) received between one and 12 doses of PEG-L-A, including nine who completed the planned 12 doses of therapy. The toxicities encountered were similar to those observed in non-transplanted patients undergoing therapy with PEG-L-A and included allergic reactions, pancreatitis, weight loss, hypoalbuminemia, and low levels of anti-thrombin III. Of the 24 who received the drug, eight remain in remission. Of 12 patients in second remission at the time of transplantation who received PEG-L-A, five of seven who received allogeneic and two of five who received autologous transplants remain in remission, 16+ to 46+ months from transplant. While PEG-L-A could be administered to most of the patients undergoing marrow transplantation for ALL, most patients either relapsed while receiving the drug or developed toxicities which resulted in abbreviated courses. At this time, we cannot recommend PEG-L-A as single agent, post-BMT chemotherapy.

High-dose fractionated total-body irradiation, etoposide and cyclophosphamide for treatment of malignant lymphoma: comparison of autologous bone marrow and peripheral blood stem cells.

Consecutive patients with non-Hodgkin's lymphoma (NHL, n = 133) or Hodgkin's disease (HD, n = 20) were treated with 12.0 Gy of fractionated total body irradiation, etoposide 60 mg/kg, and CY 100 mg/kg followed by infusion of autologous hematopoietic stem cells. Seventy-nine patients received purged (n = 62) or unpurged BM (n = 17), and 74 received unpurged PBSCs alone (n = 56) or with BM (n = 18). The median day for achieving a sustained granulocyte count of 0.5 x 10(9)/I was 14 range (7-66) for BM recipients and 10 (7-30) for PBSC +/- BM recipients (P = 0.03). A platelet count of 20 x 10(9)/I was achieved at a median of day 24 (6-145) in BM recipients and day 11 (range, 7-56) in PBSC +/- BM recipients (P = 0.007). The median number of platelet units transfused was 86 (0-1432) for BM recipients and 30 (6-786) for PBSC +/- BM recipients (P = 0.001). The median number of hospital days was 36 (10-88) for BM recipients and 27 (14-76) for PBSC +/- BM recipients (P = 0.0001). The unadjusted Kaplan-Meier (KM) estimates of survival, event-free survival (EFS) and relapse at 2 years were 0.57, 0.45 and 0.43 for patients receiving BM and 0.55, 0.36 and 0.59 for patients receiving PBSC +/- BM. After adjusting for confounding variables, the estimated relative risk (RR) of death from any cause was 0.92 (P = 0.75), of relapse was 1.25 (P = 0.39), of non-relapse mortality was 0.71 (P = 0.42) and of mortality and/or relapse was 1.17 (P = 0.48) for patients receiving PBSC +/- BM as compared to BM. For 46 patients with NHL receiving unpurged PBSC alone, the unadjusted KM estimate of relapse was 0.61 compared with 0.48 for 52 comparable patients receiving purged BM, while the RR for relapse for patients receiving unpurged PBSCs was 1.37 (P = 0.33) after adjusting for other significant covariates. These data confirm previous observations that patients who receive PBSC +/- BM have faster engraftment, fewer transfusions and shorter hospital stays than patients who receive only BM. There were no statistically significant differences between the two groups in survival, relapse, death from causes other than relapse and event-free survival.

Micronized 17 beta-estradiol for oral estrogen therapy in menopausal women.

Micronized 17beta-estradiol (E2) was used as oral replacement therapy in 369 patients with estrogen deficiency and related menopausal symptoms. Over 95 percent of 319 patients evaluable for efficacy gained satisfactory relief of their symptoms from cyclic (on 21 days/off 7 days) E2 therapy. Approximately 77 percent required no adjustment of their initial daily dose, viz, 1 mg (5 or less hot flushes per day) or 2 mg (6 or more flushes daily). In addition, 80 percent (58/72) of the patents who did not obtain adequate control from their starting dose were successfully titrated, either upward to a maximum of 4 mg/day or downward for maintenance. Overall, a higher percentage of patients were treated successfully with 2 mg daily (209/319; 66 percent) than with 1 mg/day (22 percent). About 8 percent of the patients required 3 or 4 mg daily, while 4 percent failed to derive adequate benefit from micronized E2. Oral E2 therapy was well tolerated; hence, the attrition rate due to side effects or lack of control was only 6 percent (22/369). Moreover, all laboratory fingings were within normal limits, even in patients treated with E2 for over 12 months. Coincidental endometrial changes were found in 9 patients, all of whom had received long-term (9 months-3 years) estrogen therapy prior to entering this study. Thus, the stste of the endometrium should be determined before any estrogens are given for the monopause. It is concluded that micronized E2 is highly efficacious, well accepted, and safe for oral estrogen-replacement therapy in menopausal women.

Estradiol, estrone, and gonadotropin levels after use of vaginal estradiol.

The vaginal absorption of 0.5-mg tablets of micronized estradiol was evaluated in postmenopausal women. In a single-dose study, one hour after insertion, a 5.3-fold rise in mean serum estradiol levels and 1.5-fold rise in mean serum estrone levels were observed. Mean levels of luteinizing hormone and follicle-stimulating hormone were significantly depressed. In a three-week alternate-day regimen, mean serum levels of estradiol were consistently two to three times greater than those of estrone 12 hours after insertion. Vaginal absorption of micronized estradiol tablets into the systemic circulation was found to be rapid and efficient. The vaginal route was acceptable and well tolerated by patients. In addition, the major conversion of estradiol to estrone that follows oral or sublingual administration was reduced. The vagina may be a preferred alternate route for estrogen replacement therapy in selected patients.

Vascular access in a University transplant and dialysis program. Results, costs, and manpower implications.

Vascular access has become the most common operation performed at North Carolina Memorial Hospital, Chapel Hill. Three hundred vascular access procedures performed between 1971 and 1975 were reviewed as to results, costs, and manpower commitment. Subcutaneous radial arterial venous fistula was the procedure of choice, with a 67% two-year patency and the lowest incidence of complications. An average of 1.7 operations per patient was necessary to maintain access. Patients used an average of 19 hospital days per year of dialysis for vascular access and an average of 35 hospital days per year of dialysis for all medical problems. Cost of hospitalization averaged $6,818 per patient per year of dialysis, and for vascular access alone averaged $3,452 per patient per year of dialysis. To create and maintain vascular access, 1,000 hours of operating room time were required, at an expense of $200,000. Vascular access in support of patients undergoing chronic hemodialysis requires a massive commitment of dollars, time, and personnel.

Relative agonist potencies of C2-substituted analogues of adenosine: evidence for adenosine A2B receptors in the guinea pig aorta.

Nine C2-substituted adenosine analogues that are potent and selective for the A2-adenosine receptor were tested for their ability to induce relaxations of the guinea pig aorta. Compounds tested were 2-phenylethoxyadenosine (PEA), 2-phenylethoxy-5'-N-ethylcarboxamidoadenosine (PENECA), 2-cyclohexylethoxyadenosine (CEA), 2-fluorophenylethoxyadenosine (FPEA), 2-methoxyphenylethoxyadenosine (MPEA), 2-naphthylethoxyadenosine (NEA), 2-phenylaminoadenosine (CV-1808), 2-phenylethylaminoadenosine (PEAA) and 2-carboxyethylphenethylamino-5'-N-ethylcarboxamidoadenosine (CGS21680). The responses to these agents were compared to those of three standard adenosine receptor agonists, 5'-N-ethylcarboxamidoadenosine (NECA), N6-cyclohexyladenosine (CHA) and R-N6-phenylisopropyladenosine (R-PIA). The C2-ethoxyadenosine analogues were 30- to 140-fold less potent than NECA and the C2-amino-substituted analogues were 250 to 1000-fold less potent than NECA at inducing relaxations of the guinea pig aorta. All of the analogues were also less potent than the A1-selective agonist R-PIA. However, only responses to NECA were competitively antagonized by the non-selective adenosine receptor antagonist 8-phenyltheophylline (8-PT), pKB = 6.83 +/- 0.05. The results suggest that the C2-substituted analogues produce relaxations of the guinea pig aorta through a combination of actions at A2-adenosine receptors and at xanthine resistant sites. The lack of potency of these analogues at activating the xanthine sensitive A2-receptors in the guinea pig aorta suggests that these adenosine receptors may be of the A2b-subtype.

Evidence that adenosine receptors in the dog left atrium are not of the typical A1 or A2 adenosine receptor subtypes.

The adenosine receptors from the isolated dog left atrium were characterized using the non-selective agonists 5'-N-ethyl-carboxamidoadenosine (NECA) and adenosine, the A1-selective agonist N6-R-phenylisopropyladenosine (R-PIA), and the A2 adenosine receptor agonist C2-naphthylethoxyadenosine (NEA). The potency order of the agonists in the dog left atrium was NECA greater than adenosine greater than R-PIA = NEA. This potency order was the same as that found in the guinea pig aorta (A2) but different from that in the guinea pig left atrium (A1). In the guinea pig left atrium the potency order was NECA greater than R-PIA greater than adenosine much greater than NEA. The negative inotropic responses to NECA in the dog left atrium were antagonised by the non-selective antagonist 8-phenyltheophylline (8-PT) and the A1-selective antagonists 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and N6-endonorbornan-2-yl-9-methyladenine (N-0861), giving pKB values of 6.3, 7.3 and 5.1, respectively. These values are significantly different from those estimates determined in either the guinea pig left atrium or guinea pig aorta. The potency order of the agonists and the relatively low potencies of the A1-selective antagonists suggests that the adenosine receptors in the dog left atrium are not of the classical A1 adenosine receptor subclass and may instead be more closely related to the A2 adenosine receptor.

Adenosine agonists for the prevention of restenosis?

Balloon angioplasty involves the simultaneous activation of platelets and neutrophils. Activated platelets release mitogenic substances that cause smooth muscle cell proliferation and thereby contribute to restenosis. Activated neutrophils activate platelets and activated platelets activate neutrophils. Therefore the simultaneous activation of both cell types may be responsible for the exaggerated repair mechanisms resulting in restenosis of coronary blood vessels. Adenosine inhibits neutrophil activation, platelet activation and smooth muscle cell proliferation and stimulates endothelial cell proliferation predominantly through activation of A2A-receptors. Adenosine and A2A-selective agonists may be useful in the prevention of restenosis following balloon angioplasty.