Biomedical subjects
Publications and source records attributed to M Becker.
For clinical research and quality control in the treatment of patients with cleft lip and palate (CLP) we created a register based on commercially available computer components. In this report we present the logical organisation of the system and give some representative examples of its applicability. There is great potential for easy access to data, and presentation.
Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.
We investigated a method for a fully automatic identification and interpretation process for clustered microcalcifications in mammograms. Mammographic films of 100 patients containing microcalcifications with known histology were digitized and preprocessed using standard techniques. Microcalcifications detected by an artificial neural network (ANN) were clustered and some cluster features served as the input of another ANN trained to differentiate between typical and atypical clusters, while others were fed into an ANN trained on typical clusters to evaluate these lesions. The measured sensitivity for the detection of grouped microcalcifications was 0.98. For the task of differentiation between typical and atypical clusters an Az value of 0.87 was computed, while for the diagnosis an Az value of 0.87 with a sensitivity of 0.97 and a specificity of 0.47 was obtained. The results show that a fully automatic computer system was developed for the identification and interpretation of clustered microcalcitications in mammograms with the ability to differentiate most benign lesions from malignant ones in an automatically selected subset of cases.
OBJECTIVE: Endoscopic ultrasound (EUS) provides important information in the initial staging of patients with esophageal cancer. With recent modifications in chemoradiotherapy protocols, a significant number of patients have no residual tumor at esophagectomy. The high surgical morbidity and mortality might be avoided if complete response to chemoradiotherapy could be predicted. Previously published clinical trials, with relatively small patient numbers, have suggested that EUS may accurately stage esophageal cancer after chemoradiotherapy. The aim of this study was to verify the accuracy of EUS in staging esophageal cancer after effective chemoradiotherapy. METHODS: EUS staging was performed before and after concurrent cisplatin, 5-fluorouracil, and hyperfractionated radiotherapy in 59 patients with newly diagnosed esophageal cancer. All patients underwent subsequent esophagectomy and pathological staging. The accuracy of preoperative, postchemoradiotherapy EUS was evaluated in a retrospective fashion by comparison to pathological staging. RESULTS: After chemoradiotherapy, 18 patients (31%) had no residual disease at pathological staging (T0N0). However, EUS correctly predicted complete response to chemoradiotherapy (T0N0) in only three patients (17%). The accuracy of postchemoradiotherapy EUS for pathological T stage was only 37%, and its sensitivity for N1 disease was only 38%. EUS was unable to distinguish postradiation fibrosis and inflammation from residual tumor. CONCLUSION: When aggressive preoperative chemoradiotherapy is provided to patients with esophageal cancer, the predictive value of postchemoradiotherapy EUS is inadequate for use in clinical decision making.
Human herpesvirus 8 (HHV-8) (or Kaposi's sarcoma-associated herpesvirus) is implicated in the etiopathogenesis of Kaposi's sarcoma (KS) and certain lymphoproliferations. The introduction of more effective therapies to treat human immunodeficiency virus infection has led to a decline in the incidence of KS and also in the resolution of KS in those already affected. This suggests that cellular immune responses including cytotoxic T lymphocytes (CTLs) could play a vital role in the control of HHV-8 infection and in KS pathogenesis. Here we elucidate HLA class I-restricted, HHV-8-specific cellular immune responses that could be important in the control of HHV-8 infection and subsequent tumor development. We show the presence of CTLs against HHV-8 latent (K12), lytic (K8.1), and highly variable (K1) proteins in infected individuals.
OBJECTIVE: To compare dual therapy (omeprazole and amoxicillin) with triple therapy (omeprazole, amoxicillin, and clarithromycin) in the treatment of Helicobacter pylori infection. The efficacy of 1 mg/kg/day omeprazole was randomly compared with 2 mg/kg/day. STUDY DESIGN: 252 patients (median age, 11.0 years; range, 3-18) presenting with chronic abdominal pain underwent endoscopy and a 13C-urea breath test. Gastric biopsy specimens were taken for histological examination and for the rapid urease test. Patients were treated for two weeks: group A (n = 63) received amoxicillin (50 mg/kg; maximum, 2 g/day), group B (n = 73) received amoxicillin and clarithromycin (20 mg/kg; maximum, 1 g/day). Both groups were randomly treated with either 1 or 2 mg/kg omeprazole (maximum, 80 mg/day). Diagnostic procedures were repeated four weeks after the end of treatment. RESULTS: 11 patients were excluded; 136 patients were H pylori positive (56%), 105 of whom were re-examined after treatment. Helicobacter pylori was eradicated in 52% of group A and 83% of group B. The dose of omeprazole had no influence on the eradication rate. Specificity and sensitivity of the rapid urease test were 94% and 93%, respectively. Specificity and sensitivity of the 13C-urea breath test were 93% and 95%, respectively. CONCLUSIONS: Dual therapy can no longer be recommended. Triple therapy is more effective than dual therapy in the eradication of H pylori infection. The lower dose of 1 mg/kg omeprazole was as effective as 2 mg/kg.
PURPOSE: To evaluate the usefulness of neoadjuvant chemotherapy and radiation therapy before esophagectomy for invasive cancer of the esophagus or gastroesophageal junction (GEJ). MATERIALS AND METHODS: The authors conducted a retrospective analysis of 154 patients who underwent esophagectomy for invasive cancer between September 1, 1991, and December 31, 1995. The end points evaluated were overall, disease-free, local-regional relapse-free, and systemic relapse-free survival. RESULTS: Seventy of the 154 patients received neoadjuvant combined-modality therapy (CMT) consisting of concurrent cisplatin and fluorouracil administration and accelerated, hyperfractionated radiation therapy. The remaining 84 patients underwent immediate esophagectomy. With a median follow-up of 34.7 months, the 3-year overall, disease-free, and distant metastatic relapse-free survival rates were 38.0%, 41.9%, and 56.0%, respectively. Although neoadjuvant therapy did not appear to prevent distant metastases, there was a dramatic effect on local control. After CMT, the 5-year local control rate was 90% compared to 64% after surgery (P < .001). Tumors in the GEJ recurred more frequently (P = .01); however, multivariate analysis showed CMT was the only independent predictor of local control. Postoperative mortality was 15.7% after CMT versus 5.9% without CMT (P = .05). CONCLUSION: Local control of esophageal cancer is excellent following neoadjuvant chemotherapy and radiation therapy. However, the effects of CMT on overall and disease-free survival are less clear due to significant differences between the treatment groups.
The Wisconsin Quality of Life Index (W-QLI) is a multidimensional model for measuring quality of life. This model assumes that quality of life is comprised of 9 dimensions: life satisfaction, occupational activities, psychological well-being, physical health, social relations, economics, activities of daily living, symptoms, and the patient's own goals. The W-QLI takes into account the different perspectives of the patient, the patient's family, and the clinician, both currently and over time. An accompanying taxonomy and patient outcome report can be used in clinical practice to group the patient's goals and to track the attainment of the goals over time, as well as to show the agreements and disagreements between the patient and clinician in terms of how satisfied each is with the patient's progress. The W-QLI, taxonomy, and outcome report can also incorporate the service provider's goals and can be used to examine program results.
We have established new human sarcoma lines and examined their sensitivity to common antitumor drugs and expression of putative multidrug resistance (MDR) proteins. Eighty-two sarcoma samples were transplanted in nude mice. Fourteen of these sarcomas were established as tumor cell lines. We determined a chemosensitivity profile to antitumor drugs (MDR drugs = doxorubicin, mitoxantrone, and vincristine; non-MDR drugs = cisplatin, ifosfamide, and bleomycin) for each tumor line in vivo. Response to chemotherapy with doxorubicin and ifosfamide was observed in 30-50% of these tumor lines. Our results obtained with xenotransplants are similar to the results documented in clinical trials in which doxorubicin and ifosfamide are effective in 30-50% of the patients. Furthermore, we examined expression of MDR-relevant markers like P-glycoprotein, MDR-associated protein, lung resistance protein, and mdr1 mRNA in these xenotransplants. A relationship between mdr1 mRNA expression and response to doxorubicin was demonstrated in >90% of our tumor lines. In six sarcomas with mdr1 mRNA expression, five were resistant against doxorubicin and cross-resistant against several other drugs, whereas from eight sarcomas, which lacked detectable mdr1 mRNA, seven were sensitive to doxorubicin and other drugs. We found lung resistance protein or MDR-associated protein expressed in three resistant and mdr1 mRNA-positive sarcomas. These results demonstrate that mdr1 mRNA expression is a putative marker for drug resistance in our sarcoma lines. We conclude, therefore, that inherent P-glycoprotein expression might be also responsible for drug resistance occurring in treatment of patients with sarcomas. The established tumor lines are useful for additional investigations on mechanisms of drug resistance in sarcomas and as models for preclinical screening of new antitumor drugs.
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A calculated 3-D model of the kinase domain of the epidermal growth factor receptor (EGF-R) protein-tyrosine kinase (PTK) was used to develop a pharmacophore model for ATP-competitive inhibitors and, subsequently, a new class of selective EGF-R kinase inhibitors. CGP 59326A, a highly selective and potent inhibitor of the EGF-R in vitro, inhibited the proliferation of EGF-R-expressing epithelial lines, while having little anti-proliferative activity against EGF-R-negative lines. In contrast to previously described inhibitors, CGP 59326A had potent and selective in vivo anti-tumor activity at well-tolerated doses against EGF-R-expressing tumors (e.g., ED50 of 0.78 to 1.5 mg/kg for inhibition of A431 tumor growth). CGP 59326A inhibited growth of human tumor xenografts expressing the EGF-R but showed little activity against EGF-R-negative xenografts. Combination of CGP 59326A with cytotoxic agents resulted in tumor regression and cures. The high selectivity and attractive biological profile of CGP 59326A suggest that it could have therapeutic value in the treatment of proliferative diseases which involve mitogenic signaling from the EGF-R.
A candidate tumor suppressor gene, DPC4, located at 18q21.1, has recently been shown to be inactivated in half of pancreatic adenocarcinomas. The close developmental relationship of the pancreas and biliary tract prompted us to determine the role of DPC4 in the multistep carcinogenesis of biliary tract carcinoma. A search for mutations in the genomic sequence of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational polymorphism analysis. Five of 32 (16%) primary biliary tract carcinomas had point mutations in the DPC4 sequence. Interestingly, inactivation of DPC4 was especially common in carcinomas originating from the common bile duct (four of eight specimens analyzed), suggesting an important role for DPC4 in the development of this subtype of biliary tract tumor.
The desirability of inducing cytotoxic T cell responses to defined epitopes in humans has led to the development of a variety of recombinant delivery systems. Recombinant protein particles derived from a yeast retrotransposon (Ty) and the modified Ankara vaccinia (MVA) virus can deliver large epitope strings or even whole proteins. Both have previously been administered safely in humans. Immunization with recombinant Ty and MVA containing a single Plasmodium berghei class I-binding epitope provided 95% sterile protection against malaria in mice. The sequence of immunization, Ty followed by MVA, was critical to elicit high levels of IFN-gamma-producing cells and protection. The reciprocal sequence (MVA/TY) or homologous boosting was not protective. Both constructs (Ty and MVA) contain the H-2Kd-restricted pb9 CTL epitope from the circumsporozoite protein of P. berghei among a string of 8-15 human P. falciparum-derived CTL epitopes restricted through 7 common HLA alleles as well as widely recognized CD4 T cell epitopes. Thus, the novel recombinant Ty/MVA prime/boost combination with these constructs provides a safe alternative for evaluation for human vaccination against P. falciparum malaria.
Phycoerythrin 545 from the cryptomonad alga, Rhodomonas lens, has been crystallized under a wide variety of conditions. Although this type of photosynthetic light-harvesting protein is water soluble, detergents were always required for crystallization. The crystals were typically poorly ordered, or ordered in only two dimensions. However, crystals that were well-ordered in three dimensions could be obtained under two different conditions. Both used polyethylene glycol as precipitant and the detergent lauryldimethylaminoxide, but the additives that were critical for obtaining well-ordered crystals were propionamide in one case and Cs+/Br- in the other. Crystals obtained in the presence of propionamide have the space group P2(1)2(1)2(1), with cell constants of a = 85.6 angstroms, b = 108.2 angstroms, and c = 131.0 angstroms, and contain two dimers [i.e., 2 x (alpha2beta2)] in the asymmetric unit. They show diffraction to at least 3.0 angstroms resolution. The crystals grown with Cs+/Br- are nearly isomorphous. Both types of crystals show intense, strongly polarized fluorescence, suggesting that energy transfer in the crystals is highly efficient. This should provide a basis for quantitative investigation of the role of exciton interactions in energy transfer in cryptomonad phycobiliproteins.
The anticancer drug carboplatin has been monitored in rats during treatment by means of in vivo 195Pt NMR spectroscopy at 2.0 T. The purpose of the study was to assess local disposition kinetics in intact tissue following subcutaneous injection of a platinum-containing drug. Serial 195Pt NMR measurements have been carried out in four animals after administration of carboplatin solutions with doses ranging from 37.1 to 59.4 mg per kg body weight. A surface coil of 2 cm diameter tuned to 18.3 MHz was placed over the injection site (back of the neck of the animals). To optimize measurement parameters of the single-pulse-acquire sequence and to determine chemical shifts and the detection threshold, in vitro 195Pt NMR experiments have been performed on model solutions of potassium tetrachloroplatinate(II), carboplatin, and cisplatin with different solvents such as H2O, DMSO, and DMF. Resonances of PtCl2-4, carboplatin, cisplatin, and cis-[Pt(NH2)Cl(DMSO)]+ were observed at chemical shift positions delta = -1623 ppm, -1705 ppm, -2060 ppm (cisplatin in DMSO), and -3120 ppm, respectively, relative to the reference signal of Na2PtCl6 at delta = 0 ppm. A spin-lattice relaxation time of carboplatin of T1 = (0.103 +/- 0.02) s was measured. The threshold for NMR detection of platinum-containing compounds estimated from the in vitro experiments was 10 micromol (corresponding to approximately 4.8 mM). In vivo 195Pt NMR spectra obtained in four rats after administration of carboplatin showed a broad resonance at delta = -(1715 +/- 8) ppm. The signal-to-noise ratio of this peak (starting 2 min after the injection) was approximately 9:1 for a measurement time of 6 min (TR= 13 ms, 28672 transients). The elimination rate constant of local disposition of carboplatin was kel = 0.017 (0.008-0.025) min-1 (median and range).
Cross-sectional imaging with CT and MRI plays an indispensable complementary role to endoscopy in the pretherapeutic workup and staging of laryngeal neoplasms. Adequate interpretation of the CT and MR images requires a thorough knowledge of the patterns of submucosal spread and familiarity with the diagnostic signs of neoplastic invasion as seen with each modality. In addition, the radiologist should be aware of the implications of imaging for staging and treatment. Both CT and MR imaging are highly sensitive for the detection of neoplastic invasion of the pre-epiglottic space, paraglottic space, subglottic region and cartilage. The high negative predictive value of both CT and MRI allows exclusion of neoplastic cartilage invasion quite reliably. The specificity of both CT and MRI is, however, limited and both methods may therefore overestimate the extent of tumor spread. Nevertheless, both cross-sectional imaging methods significantly improve the pretherapeutic staging accuracy of laryngeal tumors if used in addition to clinical examination and endoscopic biopsy. In the presence of a submucosal mass, CT and MRI play a key role for the diagnosis, as they may characterize the lesion, reliably depict its submucosal extent, and guide the endoscopist of perform deep biopsies that allow a definitive histological diagnosis.
The objective of this study was to analyze the radiologic features of atypical forms of squamous cell cancer and correlate them with clinical, endoscopic, and histopathologic findings. The CT and MRI images of 31 patients with atypical forms of squamous cell carcinoma were reviewed retrospectively and the radiologic findings were correlated with clinical, endoscopic, and histopathologic findings. Histopathologic diagnoses included undifferentiated carcinoma of nasopharyngeal type (n = 8), verrucous carcinoma (n = 18), spindle cell carcinoma (n = 3), and basaloid cell carcinoma (n = 2). Undifferentiated carcinoma of nasopharyngeal type was located in the supraglottis or piriform sinus beneath an intact mucosa and initial endoscopic biopsy was most often negative. The discrepancy between an intact mucosa at endoscopy and a solid mass with homogenous enhancement at CT or MRI was characteristic for these tumors and warranted further investigations to obtain the definitive histologic diagnosis. Verrucous carcinoma displayed characteristic clinical, radiologic, and pathologic features, namely, an exophytic tumor arising from the glottic level displaying a rugged surface with finger-like projections but with only minor submucosal infiltration. Spindle cell carcinoma appeared as a polypoid mass with a thin stalk arising from the supraglottis. Basaloid cell carcinoma displayed a distinct lobulated enhancement pattern which was observed on contrast-enhanced T1-weighted SE images. Although the MR and CT features of atypical forms of squamous cell carcinoma cannot be considered pathognomonic they should raise the differential diagnosis even if endoscopic biopsy has been negative. The radiologist's awareness of the appearance of these unusual tumors on CT and MR images may greatly facilitate the diagnostic work-up and helps to guide the endoscopist to the adequate biopsy site in order to establish the correct diagnosis.
UNLABELLED: Idiopathic macular holes are today treated surgically with good results. The prognostic value of factors predictive for the anatomical and functional outcome has not been completely evaluated. PATIENTS AND METHODS: One hundred and thirty-five eyes with penetrating macular holes (stage II-IV) were investigated prospectively. The mean follow-up was 19.5 months (6-50 months). RESULTS: In 86% of cases the hole was closed postoperatively. The age of the macular hole proved to be a significantly predictive factor for the outcome; the age of the patient did not. The diameter of the hole showed no influence on the results. Application of autologous serum in front of the hole did not significantly improve the anatomical, but the functional results. The strongest improvement of visual acuity was seen in eyes with poor preoperative function. In 118 eyes a prefoveal membrane could be peeled off. Seventeen eyes without detectable membrane showed identical results. CONCLUSION: Some predictive factors in macular hole surgery are proven, others remain uncertain. Identical results in eyes with and without prefoveal membranes support the assumption of different pathomechanisms in macular hole formation.