Long-term results of transanal endoscopic microsurgery after endoscopic polypectomy of malignant rectal adenoma.

BACKGROUND: There is no consensus on the treatment and prognosis of malignant rectal polyps. The aim of the present study was to determine the role of transanal endoscopic microsurgery (TEM) after endoscopic complete polypectomy of malignant rectal adenomas with long-term follow-up. METHODS: Of 105 patients with pT1 rectal carcinoma in 32 patients TEM followed complete endoscopic polypectomy while 73 had primary TEM. Local recurrence (LR), distant metastasis, overall and cancer-specific survival were determined by the Kaplan-Meier method. RESULTS: Median follow-up was 9.1 years. In 32 patients with TEM following complete polypectomy no residual cancer was found. LR occurred in 3/28 (11%) patients with low-risk carcinoma (pT1 G1/2/X, L0/X, R0) and in 1/4 (25%) with high-risk carcinoma (pT1 G3/4 or L1). After primary TEM with complete resection (minimal distance >1 mm) LR occurred in 6/60 (10%) with low-risk carcinoma. After incomplete TEM resection (minimal distance ≤1 mm) LR occurred in 3/8 (38%) patients with low-risk and in 1/5 (20%) patients with high-risk carcinoma. Grading was the only significant risk factor for LR after endoscopic polypectomy followed by TEM (p = 0.002). At all outcomes did not differ between postpolypectomy TEM and primary TEM. CONCLUSIONS: Patients with malignant rectal polyps removed by endoscopic polypectomy have a substantial risk of LR even if TEM of polyp site is cancer free. Risk of LR depends on tumor characteristics. In low-risk carcinoma long-term follow-up is necessary. The high LR rate in patients with high-risk rectal carcinoma restricts the use of TEM alone.

[Single Centre Study: Results of Transanal Endoscopic Microsurgery of Rectal Tumors since 2003 vs. Results of Endoscopic Submucosal Dissection Reported in the Literature]. / Single-Center-Studie: Ergebnisse der transanalen endoskopischen Abtragung von Rektumtumoren seit 2003 vs. literaturbasierten Ergebnissen der endoskopischen Submukosaresektion.

BACKGROUND: Due to the variety of methods for local ablation of sessile rectal polyps and low-risk T1 rectal cancer, a retrospective study by transanal local excision, the endoscopic microsurgery (TEM) was performed. The results of the TEM were compared with literature-based results of endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: 174 patients who had received a TEM during the period from March 2003 to October 2011 for a removal of a rectal polyp or low risk cancer were included in the study. The evaluation included the en bloc and R0 resection rate, duration of surgery, the postoperative hospitalisation, postoperative complications and recurrence rate. RESULTS: The en bloc-resection rate was 87.5 % (152 of 174) and the R0 resection was achieved in 84.5 % (147 of 174) of the cases. The average surgery duration was 33 (5-121) min, with an average specimen size of 4 (1.2-13) cm. The average postoperative length of stay included 5 (1-15) d. The postoperative complication rate was 3 % (4 of 174) and the recurrence rate was 4 % (7 of 174) with an average follow-up of 36 (6-108) months. CONCLUSION: Compared to the Japanese results of ESD in the rectum based on literature results, we show equal or better results for the TEM. Compared to the European results of the ESD, the results of the TEM show advantages in terms of higher en bloc and R0 resection rates, shorter intervention times also with larger specimen sizes and a lower postoperative complication rate.

[The Ludwigshafen Osteoporosis Screening Questionnaire (LOS Questionnaire): result of the evaluation of anamnestic risk factors in osteoporosis diagnostics]. / Ludwigshafener Osteoporosescreeningbogen (LOS-Bogen) : Resultat aus der Evaluation anamnestischer Risikofaktoren in der Osteoporosediagnostik.

BACKGROUND: Osteoporosis is a major health problem worldwide and is included in the WHO list of the top ten major diseases. However, it is often undiagnosed until the first fracture occurs, due to inadequate patient education and lack of insurance coverage for screening tests. METHODS AND MATERIAL: In our study of 78 patients with metaphyseal long bone fractures, we searched for a correlation between anamnestic risk factors, bone-specific laboratory values, and the bone morphogenic density (BMD). Each indicator was examined as a possible diagnostic instrument for osteoporosis. The secondary aim of this study was to demonstrate the high prevalence of osteoporosis in patients with metaphyseal fractures. RESULTS: Of our fracture patients 76.9% had decreased bone density and 43.6% showed manifest osteoporosis in DXA (densitometry) measurements. Our modified LOS Questionnaire, identifying anamnestic risk factors, correlated highly significantly (p=0.01) with reduced BMD, whereas seven bone-specific laboratory values (p=0.046) correlated significantly. CONCLUSION: Anamnestic risk factors correlate with pathological BMD more than bone-specific laboratory values. The LOS Questionnaire used in this study would therefore function as a cost-effective primary diagnostic instrument for identification of osteoporosis patients.

Synthesis and in vitro multidrug resistance modulating activity of a series of dihydrobenzopyrans and tetrahydroquinolines.

A series of dihydrobenzopyrans and tetrahydroquinolines was synthesized and pharmacologically tested for their ability to inhibit P-glycoprotein mediated daunomycin efflux in multidrug resistant CCRF-CEM vcr1000 cells. Several compounds exhibit activities in the range of the reference compounds verapamil and propafenone. Preliminary structure-activity relationship studies propose the importance of high molar refractivity values of the compounds and the presence of an additional basic nitrogen atom.

Structure-activity relationship studies on benzofuran analogs of propafenone-type modulators of tumor cell multidrug resistance.

A series of benzofurylethanolamine analogs of propafenone (1a) have been prepared and evaluated for multidrug resistance-reversing activity in two in vitro assay systems. As for propafenones, an excellent correlation of biological data with calculated lipophilicity values was found for benzofurans, whereby the latter generally had lower activity/lipophilicity ratios. Almost identical slopes of the regression lines were obtained for both propafenones and benzofurans. Multiple linear regression analysis of the complete data set yielded an equation with excellent predictive power (r2 cross-valid = 0.968). Interaction measurements with artificial membranes indicated that the differences in activity between these two series of compounds are not due to differences in the interaction pattern with biological membranes.

Substituted 4-acylpyrazoles and 4-acylpyrazolones: synthesis and multidrug resistance-modulating activity.

A series of 4-acyl-3-pyrazolone derivatives with a 3-substituted 2-hydroxy-3-aminopropyl chain attached to pyrazole N-1 (7-20) as well as isomeric 4-acyl-5-(3-substituted 3-amino-2-hydroxypropoxy)pyrazole derivatives (5, 6) were synthesized, and their multidrug resistance (MDR)-modulating activity was measured using the daunomycin efflux assay. Reaction of N1-substituted 4-acyl-3-pyrazolones (tautomer to 4-acyl-5-hydroxypyrazoles) with excessive epichlorohydrin and successive treatment with an appropriate amine resulted in N-alkylation and thus afforded the target pyrazolone derivatives 7-20. In contrast, O-alkylation occurred upon reaction with 1 equiv of epichlorohydrin and subsequent treatment with amine leading to the corresponding 4-acyl-5-pyrazolyl ethers 5 and 6. QSAR studies showed a good correlation of MDR-modulating activity with lipophilicity of the compounds. Inclusion of hydrogen bond acceptor strength and steric parameters as descriptors led to a QSAR equation with remarkably increased predictive power (r2cv = 0.92). Additionally, ortho substitution of the propanolamine side chain and the acyl moiety is favorable. Detailed NMR spectroscopic investigations were carried out with the title compounds.

Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements.

Propafenone analogs (PAs) were previously identified as potent inhibitors of P-glycoprotein (Pgp)-mediated toxin efflux. For this as well as other classes of Pgp inhibitors, lipophilicity as well as hydrogen bond acceptor strength are important determinants of biological activity. The question as to whether a direct interaction between PA-type modulators and Pgp takes place was addressed by means of Pgp ATPase measurements and transport studies. Propafenone-type modulators stimulated ATPase activity up to 2-fold over basal activity in a concentration-dependent biphasic manner. Within a series of structural homologs, Ka values of ATPase stimulation strongly correlated with lipophilicity. Analogs containing a quaternary nitrogen stimulated Pgp ATPase activity with lesser efficacy, while Ka values were somewhat higher when compared to corresponding tertiary analogs. Transport studies performed in inside-out plasma membrane (I/O) vesicles demonstrated that analogs containing a tertiary nitrogen rapidly associated with the biomembrane. Quaternary analogs, which are restricted by a permanent positive charge in transiting the plasma membrane by diffusion, accumulated in Pgp containing I/O vesicles in an ATP-dependent and cyclosporin A-inhibitable manner, which identified them as Pgp substrates. Identical structure-activity relationships were found in either Pgp ATPase stimulation experiments in I/O vesicles or in toxin efflux inhibition studies using intact cells. Therefore, differences in membrane transit are not responsible for the observed structure-activity relationships.

Characteristics of bone metabolism markers during the healing of osteoporotic versus nonosteoporotic metaphyseal long bone fractures: a matched pair analysis.

PURPOSE: The activity and metabolism of fracture healing can be monitored quantitatively by measuring bone turnover markers (BTMs) in serum or urine. However, in osteoporotic bone, the exact metabolism processes during the healing of metaphyseal fractures remain unknown. There is no diagnostic approach which currently allows dynamic insight into the fracture healing processes in order to monitor the progression of healing and to assist in therapeutic decision making. METHODS: Between March 2007 and February 2009, 30 patients over 50 years of age who suffered a metaphyseal fracture were included in our study. The levels of the osteoanabolic marker BAP (bone-specific alkaline phosphatase) and osteocatabolic marker ß-CTX [crosslinked C-(CTX)-telopeptide-of-type-I-collagen] were monitored during the fracture healing of osteoporotic and nonosteoporotic fractures for a duration of 8 weeks. RESULTS: After an initial decrease of BAP in the first week, the BAP level steadily increased through the fourth week in both groups. The levels of BAP in the osteoporotic group surpassed the healthy group. ß-CTX steadily increased in healthy bone up to the fourth week; in osteoporotic bone, ß-CTX first increased and, thereafter, decreased from the first week onwards. CONCLUSIONS: In this work, the first molecular biological aspects of osteoporotic fracture healing have been uncovered, helping to explain the mechanisms of delayed fracture healing in osteoporotic bone. The early decrease of reduced ß-CTX as well as elevated BAP during the healing process may be the first aspects within the delayed healing of osteoporotic bone. Further studies are necessary in order to achieve more detailed insight to fracture healing and to ascertain the progression of fracture healing as being essential (criteria) for therapeutic decision making.

Molecular epidemiology of the nasal colonization by methicillin-susceptible Staphylococcus aureus in Swiss children.

Nasal carriage of Staphylococcus aureus contributes to an increased risk of developing an infection with the same bacterial strain. Genetic regulatory elements and toxin-expressing genes are virulence factors associated with the pathogenic potential of S. aureus. We undertook an extensive molecular characterization of methicillin-susceptible S. aureus (MSSA) carried by children. MSSA were recovered from the nostrils of children. The presence of Panton-Valentine leukocidin (PVL), exfoliatins A and B (exfoA and exfoB), and the toxic-shock staphylococcal toxin (TSST-1) and agr group typing were determined by quantitative PCR. A multiple-locus variable-number of tandem repeat analysis (MLVA) assay was also performed for genotyping. Five hundred and seventy-two strains of MSSA were analysed. Overall, 30% were positive for toxin-expressing genes: 29% contained one toxin and 1.6% two toxins. The most commonly detected toxin gene was tst, which was present in 145 (25%) strains. The TSST-1 gene was significantly associated with the agr group 3 (OR 56.8, 95% CI 32.0-100.8). MLVA analysis revealed a large diversity of genetic content and no clonal relationship was demonstrated among the analysed MSSA strains. Multilocus sequence typing confirmed this observation of diversity and identified ST45 as a frequent colonizer. This broad diversity in MSSA carriage strains suggests a limited selection pressure in our geographical area.

Synthesis and pharmacological activity of the stereoisomers of GP-88, a propafenone-type modulator of multidrug resistance.

All four stereoisomers of the propafenone-type MDR-modulator GP-88 (1) were synthesized using a combined approach with chiral pool building blocks and an acetalic protective group, which allows not only diastereoseparation but also assignment of absolute configuration via NMR spectroscopy. Those isomers with different configuration on the center of chirality in the propanolamine side chain showed statistically different PGP-inhibitory activity. Generally, the (R)-configured isomers were by a factor of nearby two higher active than the (S)-isomers. No differences in activity were observed for isomers with different configuration on the benzylic center of chirality.

Studies on propafenone-type modulators of multidrug-resistance IV1): synthesis and pharmacological activity of 5-hydroxy and 5-benzyloxy derivatives.

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3. Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a-d. Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a-d. Structure activity relationship studies showed, that the 5-hydroxy derivates 6a-d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a-d showed almost identical EC50 values, independent of their log P value.

A combined Hansch/Free-Wilson approach as predictive tool in QSAR studies on propafenone-type modulators of multidrug resistance.

A series of 48 propafenone-type modulators of multidrug resistance was synthesized and their P-glycoprotein inhibitory activity was measured using the daunomycin efflux assay. Both a Free-Wilson and a combined Hansch/Free-Wilson analysis were performed using log P, partial log P and molar refraction values as Hansch descriptors. The results of the Free-Wilson analysis show that modifications on the central aromatic ring generally influence pharmacological activity, whereby in almost all cases a decrease in MDR-modulating potency is observed (Q2cv = 0.66). The combined approach results in equations with remarkably higher predictive power (Q2cv = 0.83), specifically molar refractivity shows high significance in all equations derived. This indicates that polar interactions also contribute to protein binding.