Citations

Abstract Sterol excretion in the spontaneously atherosclerosis‐susceptible White Carneau (WC) pigeon, the Silver King (SK) pigeon and the Show Racer (SR) pigeon was studied by thin layer chromatography (TLC), argentation TLC and gas liquid chromatography. Unlike man and the chicken, these pigeons excreted no coprostanol or coprostanone derivatives of sterols. Moreover incubation of 14 C‐labeled cholesterol with pigeon feces indicated that, also unlike man and the chicken, these pigeons are unable to convert it to coprostanol. Bacteriologic examination revealed the absence of gram‐negative anaerobic flora and of members of the genus Bifidobacterium in both the WC and SR pigeons. On the other hand, one of the two SK pigeons examined showed evidence of the presence of both Bacteroids fragilis and B. bifidum in the upper intestinal tract. Although no qualitative experiments were performed, no unusual characteristics of the aerobic flora were noted in these pigeons. In addition, analysis of human stool specimens indicated a “normal” bowel flora. The flora of the intestinal tract of the chicken is similar to that of the human. Because of this similarity, it appears that differences in environment (living conditions, diets) between the human and the chicken are of little consequence. The results obtained in this study suggest the possibility that the anaerobic gram‐negative flora and sponsible, at least in part, for the chemical conversion of cholesterol to coprostanol.

Abstract Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

Purpose Epidermal growth factor receptor/human epidermal growth factor receptor 1 and ligand expression is common in biliary cancers (BILI) and may be associated with worse outcome. The primary objective of this study was to determine the proportion of patients with advanced BILI who were progression-free at 6 months. Methods Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally. Results Forty-two patients with BILI were enrolled. The median age was 67 years (range, 33 to 82 years). Fifty-two percent of patients had Eastern Cooperative Oncology Group performance status of 1. Fifty-seven percent of patients had received prior chemotherapy for advanced BILI. HER1/EGFR expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%; 95% CI, 7% to 31%) were progression free at 6 months. Three patients had partial response by Response Evaluation Criteria in Solid Tumors Group classification of duration 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral HER1/EGFR expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash. Conclusion Results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. Additional studies with erlotinib as a single agent and in combination with other targeted agents are warranted in this disease.

Abstract Further analyses from the Women's Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture. Introduction: The Women's Health Initiative provided evidence that conjugated equine estrogen (CEE) can significantly reduce fracture risk in postmenopausal women. Additional analysis of the effects of CEE on BMD and fracture are presented. Materials and Methods: Postmenopausal women 50–79 years of age with hysterectomy were randomized to CEE 0.625 mg daily (n = 5310) or placebo (n = 5429) and followed for an average 7.1 years. Fracture incidence was assessed by semiannual questionnaire and verified by adjudication of radiology reports. BMD was measured in a subset of women (N = 938) at baseline and years 1, 3, and 6. A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk. Results: CEE reduced the risk of hip (hazard ratio [HR], 0.65; 95% CI, 0.45–0.94), clinical vertebral (HR, 0.64; 95% CI, 0.44–0.93), wrist/lower arm (HR, 0.58; 95% CI, 0.47–0.72), and total fracture (HR, 0.71; 95% CI, 0.64–0.80). This effect did not differ among strata according to age, oophorectomy status, past hormone use, race/ethnicity, fall frequency, physical activity, or fracture history. Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms (HR, 0.86; 95% CI, 0.68–1.08). CEE also provided modest but consistent positive effects on BMD. The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk (lowest risk: HR, 0.81; 95% CI, 0.62–1.05; mid risk: HR, 1.09; 95% CI, 0.92–1.30; highest risk: HR, 1.04; 95% CI, 0.88–1.23; interaction, p = 0.42). Conclusions: CEE reduces the risk of fracture and increases BMD in hysterectomized postmenopausal women. Even among the women with the highest risk for fractures, when considering the effects of estrogen on other important health outcomes, a summary of the burden of monitored effects does not indicate a significant net benefit.

AbstractMetastatic renal cell carcinoma (RCC) is an aggressive disease refractory to most existing therapeutic modalities. Identifying new markers for disease progression and drug targets for RCC will benefit this unmet medical need. We report a subset of clear cell and papillary cell RCC aberrantly expressing the lymphocyte activation marker CD70, a member of the tumor necrosis factor superfamily. Importantly, CD70 expression was found to be maintained at the metastatic sites of RCC. Anti-CD70 antibody-drug conjugates (ADC) consisting of auristatin phenylalanine phenylenediamine (AFP) or monomethyl auristatin phenylalanine (MMAF), two novel derivatives of the anti-tubulin agent auristatin, mediated potent antigen-dependent cytotoxicity in CD70-expressing RCC cells. Cytotoxic activity of these anti-CD70 ADCs was associated with their internalization and subcellular trafficking through the endosomal-lysosomal pathway, disruption of cellular microtubule network, and G2-M phase cell cycle arrest. The efficiency of drug delivery using anti-CD70 as vehicle was illustrated by the much enhanced cytotoxicity of antibody-conjugated MMAF compared with free MMAF. Hence, ADCs targeted to CD70 can selectively recognize RCC, internalize, and reach the appropriate subcellular compartment(s) for drug release and tumor cell killing. In vitro cytotoxicity of these ADCs was confirmed in xenograft models using RCC cell lines. Our findings provide evidence that CD70 is an attractive target for antibody-based therapeutics against metastatic RCC and suggest that anti-CD70 ADCs can provide a new treatment approach for advanced RCC patients who currently have no chemotherapeutic options. (Cancer Res 2006; 66(4): 2328-37)

Dieser zweiteilige Artikel stützt sich auf ein vergleichendes und beschreibendes Modell, anhand dessen sich die Wahrnehmungen der Symptombelastung von Lungenkrebspatientinnen und -patienten und die Einschätzungen der sie hauptsächlich pflegenden Angehörigen im familiären Rahmen untersuchen lassen. Der zweite Teil beschreibt die Resultate der qualitativen Komponente dieser Untersuchung. Eine Auswahl von 37 Paaren, die aus Patient/in und pflegendem Familienmitglied bestanden, füllte die McCorkle and Young Symptom Distress Scale (SDS) aus. Die Gesamtresultate der pflegenden Angehörigen korrelierten mäßig1 mit jenen der Patienten (r = 0.71; P < 0.001). Bei 10 der 13 Symptome fanden sich keine bedeutsamen Unterschiede in der Einstufung. Pflegende sollten sich daher bewußt sein, daß die pflegenden Angehörigen die Symptombelastung von Lungenkrebspatienten bei mindestens 10 der 13 auf der SDS aufgeführten Symptome zuverlässig einschätzen. Dies ist vor allem dann von großer Bedeutung, wenn der Patient oder die Patientin selbst nicht in der Lage ist, über seine/ihre Symptombelastung zu sprechen.