[Psammomatous melanotic schwannoma as indicator of a Carney complex]. / Psammomatöses melanotisches Schwannom als Indikator eines Carney-Komplexes.

Within a few months a 31-year-old female patient was diagnosed with a psammomatous melanotic schwannoma, an atrial myxoma and microfollicular adenomas in both thyroid lobes. Therefore, sufficient diagnostic criteria of a Carney complex were fulfilled. The Carney complex is an inherited autosomal dominant disorder with highly variable phenotypes, which was initially described by Carney in 1985 as a complex of myxomas, spotty skin pigmentation and endocrine overactivity. Pathologists should consider this differential diagnosis in reports when confronted with a psammomatous melanotic schwannoma.

Approaches targeting K(V)10.1 open a novel window for cancer diagnosis and therapy.

K(V)10.1 has recently become generally accepted as a promising cancer target, as it is ectopically expressed in the majority of solid tumors. Due to its cell-surface accessibility, K(V)10.1 has a strong potential for tumor treatment and diagnosis. Given that its mode of action is likely independent of conventional cancer pathways such as tyrosine kinases, K(V)10.1 opens a novel window for treating cancer. In this review we will give an overview of the current status of data linking K(V)10.1 to cancer, and propose techniques that could exploit K(V)10.1's properties for the management of cancer.

Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a ß-galactosidase-activatable prodrug seco-analog of duocarmycin SA.

Breast cancer is the most common cause of cancer-related death worldwide, thus remaining a crucial health problem among women despite advances in conventional therapy. Therefore, new alternative strategies are needed for effective diagnosis and treatment. One approach is the use of oncolytic viruses for gene-directed enzyme prodrug therapy. Here, the lacZ-carrying vaccinia virus (VACV) strain GLV-1h68 was used in combination with a ß-galactosidase-activatable prodrug derived from a seco-analog of the natural antibiotic duocarmycin SA. Tumor cell infection with the VACV strain GLV-1h68 led to production of ß-galactosidase, essential for the conversion of the prodrug to the toxic compound. Furthermore, drug-dependent cell kill and induction of the intrinsic apoptosis pathway in tumor cells was also observed on combination therapy using the prodrug and the GLV-1h68 strain, despite the fact that VACV strains encode antiapoptotic proteins. Moreover, GI-101A breast cancer xenografts were effectively treated by the combination therapy. In conclusion, the combination of a ß-galactosidase-activatable prodrug with a tumor-specific vaccinica virus strain encoding this enzyme, induced apoptosis in cultures of the human GI-101A breast cancer cells, in which a synergistic oncolytic effect was observed. Moreover, in vivo, additional prodrug treatment had beneficial effects on tumor regression in GLV-1h68-treated GI-101A-xenografted mice.

Synthesis of the deoxyaminosugar (+)-D-forosamine via a novel domino-Knoevenagel-hetero-Diels-Alder reaction.

A synthesis of (+)-D-forosamine was developed. The sugar-scaffold was constructed by a new domino-Knoevenagel-hetero-Diels-Alder reaction from easily available starting materials.

[Gastrointestinal stromal tumors: a broad clinical spectrum from incidental -discovery to acute gastrointestinal bleeding]. / Gastrointestinale Stromatumoren (GIST): variable klinische Manifestationen vom Zufallsbefund bis zur akuten gastrointestinalen Blutung.

Three cases of gastrointestinal stromal tumors (GIST) are reported as typical examples of the broad clinical spectrum in which these rare tumors can be detected. The first case describes an 82-year-old patient with a hemorrhagic shock due to upper gastrointestinal bleeding from a GIST of the stomach. GIST most frequently present with either gastrointestinal bleeding, abdominal pain or a detectable mass on physical examination or by ultrasound imaging. Clinically asymptomatic tumor growth also occurs as demonstrated by the second case of a 44-year-old -woman with an incidental finding of GIST during surgery of the esophagus. The cases are used to discuss the consequences for therapy and prognosis resulting from the heterogeneity of this tumor entity; the relevant immunohistochemical markers used to distinguish between various tumor subtypes of gastrointestinal mesenchymal tumors (GIMT) are listed. Since gastrointestinal stromal tumors (GIST) represent the most common subgroup of GIMT, we focus on the clinicopathological prognostic factors of GIST. The third case of a 40-year-old patient with a malignant GIST recurrence after surgery and exhibiting secondary resistance after one year of successful therapy with the receptor tyrosine kinase inhibitor imatinib (Gleevec), antagonizing pathogenetically relevant constitutive c-KIT activation, illustrates the potential and limitations of the only effective drug treatment for advanced GIST.

Enzyme and proton-activated prodrugs for a selective cancer therapy.

This review is a survey of two approaches for a selective anticancer therapy that are based on a specific cleavage of specially designed non-toxic prodrugs with the liberation of a cytotoxic compound either by antibody-enzyme conjugates targeted to tumor-associated antigens or by acid-catalyzed hydrolysis of the prodrugs due to the increased concentration of hydronium ions in malignant tissue under hyperglycemic conditions. Herein, the design, synthesis and the biological testing of prodrugs are described.

Effects of intra-abdominal drainages on adhesion formation and prevention by phospholipids in a rat model. Drainages and adhesion formation.

BACKGROUND AND AIMS: The study was designed to asses the adhesiogenic capacity of silicone drainages and the protective effect of phospholipids (PL). MATERIALS AND METHODS: A total of 75 Wistar rats were randomly assigned to the different groups. In a preliminary trial (pt; n = 15), all rats underwent midline laparotomy. The control group (C(pt); n = 5) received no further treatment. In the other animals, either an 'easy flow' drainage (EF(pt); n = 5) or an 'Aachen' drainage (AC(pt); n = 5) was placed into the abdominal cavity. In the final study (fs; n = 60), rats underwent laparotomy and colonic anastomosis. The control groups (C(fs)) received no drainages. In the other groups either one of the two types of drainages (EF(fs), AC(fs)) were introduced. In 50% of the rats, 75 mg/kg of PL were administered intraperitoneally (C(fs)+PL, EF(fs)+PL, AC(fs)+PL). The other rats received no additional treatment (C(fs)ØPL, EF(fs)ØPL, AC(fs)ØPL). All animals were sacrificed 10 days after surgery. Areas of adhesions and anastomotic bursting pressures were measured (mean +/- SD). RESULTS: In the preliminary trial, analysis of variance (ANOVA) revealed no differences between the groups after application of drainages (values are given in mean +/- SD): C(pt) mean 23.3 +/- 29.4 mm(2), EF(pt) 829.7 +/- 679.3 mm(2), AC(pt) 609.9 +/- 219.4 mm(2). In the final study, 2-factorial ANOVA showed a significant effect (p < 0.001) for the use of drainages but not for the application of PL (C(fs)ØPL 140.6 +/- 124.2 mm(2), C(fs)+PL 67.7 +/- 60.4 mm(2), EF(fs)ØPL 1,217.0 +/- 458.3 mm(2), EF(fs)+PL 1,266.8 +/- 368.3 mm(2), AC(fs)ØPL 861.7 +/- 274.8 mm(2), AC(fs)+PL 544.2 +/- 193.8 mm(2)). Post hoc test for pairwise comparisons adjusted to Bonferroni showed significant differences (p < 0.001) between all of the three pairs (C(fs) 104.1 +/- 92.3 mm(2) vs. EF(fs) 1,241.9 mm(2) +/- 413.3 mm(2); C(fs) vs. AC(fs) 702.9 mm +/- 234.3 mm(2); EF(fs) vs. AC(fs)). DISCUSSION: The final study demonstrates the adhesiogenic capacity of silicone drainage tubes in combination with anastomoses. Any protective effect of PL alone or in combination with drainages could not be shown. CONCLUSIONS: Indication for the use of drainages in standard surgical procedures should be reconsidered within the scope of their potential to cause adhesions and subsequent complications.

[Relevance of colour-duplex echography for detection and therapy of recurrences in the follow-up of head and neck cancer]. / Relevanz farbduplexsonographischer Untersuchungen für Rezidivdetektion und -behandlung in der Tumornachsorge von Kopf-Hals-Karzinomen.

BACKGROUND: Head and neck malignancies have a high rate of recurrences. Since the prognosis is often limited an early detection and therapy onset is essential for survival. This study surveys the relevance of regular colour-duplex echography examinations in the follow-up for detection and therapy of recurrent head and neck carcinomas. PATIENTS AND METHODS: In a prospective non-randomized study 43 patients were surveyed over a mean observation period of 28 (8-44) months. In addition to clinical and colour-duplex echography (CDS) examinations, computed tomography (CT) and positron-emission-tomography using 18fluorodeoxyglucose (PET) were performed. RESULTS: A recurrence was detected in 17/43 (39.5 %) patients. The median survival was 42 months. CDS was the most reliable procedure for the diagnosis of regional recurrences with an accuracy of 94.2 %. Sensitivity and specificity of CDS for the diagnosis of all recurrences was found to be 80 % and 78,6 % respectively. CT yielded identical results. In PET sensitivity was 82.4 % and specificity was found to be 88.4 %. In clinical examinations including panendoscopy sensitivity was 64.7 % only. In 7/17 recurrences a therapy was performed with curative intention. In 4 cases an early diagnosis by CDS contributed to a successful therapy. CONCLUSION: CDS is the imaging procedure of choice for the routine follow-up of head and neck cancer patients. In order to perform a comprehensive assessment of the head and neck region, for re-staging and to exclude second primary tumours additional (pan)endoscopy is necessary. CDS supports due to a high resolution and reliability an early therapy onset and a minimal invasive therapy. Thus, this procedure can significantly contribute to the successful treatment of recurrences in head and neck cancer.

[Diagnosis and differential diagnosis of extraskeletal, para-articular chondroma of the knee]. / Diagnose und Differenzialdiagnose des extraskeletalen, paraartikulären Chondroms des Kniegelenkes.

AIM: Extraskeletal chondromas in the region of the knee joint are very rare tumors which may cause diagnostic problems and have concomitant therapeutic consequences. METHOD: In a case report we present the clinical, radiological and histological features of an a extraskeletal chondroma. RESULTS: A 47-year-old female patient presented with an infrapatellar, painless tumor of the knee joint. The clinical features were unspecific. On plain X-ray images, calcifications were visabled within Hoffa's fat pad. An important preoperative imaging procedure was MRI, which showed a well defined mass of 2.5 cm in diameter with a hyperintense signal on fat suppressed images. Subsequent operative therapy involved marginal resection of the tumor. CONCLUSION: The differentiation of this entity especially from myxoid chondrosacroma and synovial chondroamatosis was crucial with respect to an adequate therapy. Further differential diagnoses included heterotopic ossifications, synovial sarcoma, mesenchymoma and soft-tissue osteosarcoma.

Influence of intraperitoneal phospholipid dosage on adhesion formation and wound healing at different intervals after surgery.

BACKGROUND: Adjuvant therapy is needed to prevent adhesion formation as a major cause of postoperative morbidity and mortality. The efficacy of phospholipids (PLs) has been proven; however, information on dosage and drug safety are still outstanding. MATERIALS AND METHODS: Forty-eight Chinchilla rabbits underwent median laparotomy, abrasion of the peritoneum, jejunal anastomosis, and an electrocautery incision of the liver. The operation was completed by intraperitoneal administration of PLs in two different concentrations (30 mg/kg and 70 mg/kg body weight). In the control group, the abdomen was closed without additional treatment. Adhesion area, anastomotic bursting pressure, tensile strength of the midline incision, and healing of the liver wound were assessed on days 3, 5, 7, and 10, respectively. RESULTS: The mean areas of adhesions in the control group were slightly larger than in the PL groups after 3 days and 5 days. On day 7 and day 10, both PL groups presented with significantly smaller adhesion areas (P<0.05). In all groups, we measured equal anastomotic bursting pressures on the 3rd, 5th, and 10th postoperative days. After 7 days, the mean value of the PL 70-mg group (17.2 kPa) was significantly lower than in the other groups (control 22.1 kPa, PL 30 mg 20.7 kPa; P<0.05). The tensile strengths of the laparotomy wound measured after intervals of 5 days and 7 days were not statistically different. On day 3, it was reduced after 30 mg PL but enhanced after 70 mg PL, whereas 10 days after surgery the strength increased with the PL dosage. The inflammatory reparative response to hepatic injury, jejunal anastomosis, and midline incision was not affected by PLs as assessed by histological analysis. CONCLUSION: These results prove the efficacy of PLs in adhesion prevention in two concentrations. The findings reveal an unimpeded healing of anastomoses, laparotomy wounds, and liver incisions at different periods after surgery.

Ortho-carboranyl glycosides for the treatment of cancer by boron neutron capture therapy.

Distinct biological properties of the ortho-carboranyl (1,2-dicarba-closo-dodecaboranyl) glycosides 1, 2 and 3 were evaluated to estimate the suitability of these compounds for cancer treatment by boron neutron capture therapy. The boron uptake into B16-Melanoma cells was significantly higher by incubating the cells with aqueous solutions of carboranyl glucoside 1 (11.2 ppm after 3h), lactoside 2 (13.2 ppm after 12h) and maltoside 3 (20.0 ppm after 24h) compared with solutions of clinically used p-boronophenylalanine (BPA) 5 (3.1 ppm after 24h). Carboranyl maltoside 3 was more effective than boron-10 enriched 5 in killing C-6 rat glioma cells by incubating the cells with the compound and subsequent treatment with thermal neutrons. 3 was also administrated iv, in concentrations of 25 mg boron/kg body weight to rats bearing brain tumors. After a period of 4h after administration the concentration of boron in the tumor tissue was 3.0 ppm.

A strategy for tumor-selective chemotherapy by enzymatic liberation of seco-duocarmycin SA-derivatives from nontoxic prodrugs.

Immuno-conjugates obtained by linking enzymes with appropriate monoclonal antibodies, which bind to tumor-associated antigens, can be employed in a tumor-selective antibody directed enzyme prodrug therapy (ADEPT). For this strategy the glycosides 17a--c were prepared as prodrugs of CI-TMI 14 which is a structurally simplified analogue of the highly potent antitumor agent duocarmycin SA 2. Exposure of 17a--c to cultured carcinoma cells of line A549 displayed a very low toxicity; however, after addition of the corresponding enzymes and exposure for 24 h at prodrug concentrations of <0.1 microM the proliferation of the carcinoma cells was inhibited almost completely with ED(50prodrug)/ED(50drug) of up to 270 in the presence and in the absence of the enzyme. The synthesis of 17a--c was achieved by transformation of nitroanisidine 6 into 12 which was glycosidated to give 16a--c. Removal of the silyl groups, introduction of a chlorine atom and solvolysis of the acetal groups led to 17a-c, of which 17a and 17c are promising candidates for further elaboration.

[Benign metastasizing leiomyoma of the lung--a rare differential diagnosis of pulmonary space-occupying lesions]. / Das benigne metastasierende Leiomyom der Lunge--eine seltene Differentialdiagnose pulmonaler Raumforderungen.

HISTORY AND ADMISSION FINDINGS: A 45-year-old woman was refferred for diagnosis of an accidentally found symptomless space-occupying lesions in the central part of the right lung. She had undergone a hysterectomy 4 years before and reported smoking 15 cigarettes daily since the age of 17 years. Physical examination was normal. INVESTIGATIONS: As primary bronchial carcinoma or metastasis to the lung was suspected she underwent a series of diagnostic tests: sonography, computed tomography (CT), gastroscopy, coloscopy, bronchoscopy, skeletal scintigraphy, gynaecological examination and various laboratory tests, none of which indicated a primary extrapulmonary tumour. CT-guided fine-needle biopsy then suggested benign metastasizing pulmonary leiomyoma (BMPL). TREATMENT AND COURSE: The largest of the tumours were surgically removed, confirming BMPL. Hormone receptors (for oestrogen, progesterone) having been demonstrated, progesterone treatment was initiated as prophylaxis against recurrences. CT 6 months later revealed new intrapulmonary foci. Administration of luteinizing hormone-releasing hormone analog to stop completely any oestrogen effect, and CT of the thorax 6 months later showed that both tumour numbers and their size had been reduced. The patient remained asymptomatic and the findings had not changed in the subsequent 12 months. CONCLUSION: BMPL is a rare cause of a space-occupying pulmonary lesion, predominantly affecting middle-aged women after hysterectomy for uterine myoma. The pathogenesis remains unclear, hormone-dependent tumour growth being discussed as a possible mechanism. Anti-oestrogen administration is the treatment of choice to achieve remission and effective prevention of recurrences.

Trisomy 8 as sole karyotypic aberration in an ovarian metastasizing Sertoli-Leydig cell tumor.

Sertoli-Leydig cell tumors (SLCTs) represent a rare group of sex-cord stromal tumors of the ovary of unknown pathogenesis. We report a SLCT of intermediate differentiation with peritoneal recurrence and lymph node metastasis 12 months after removal, including cytogenetic analysis by comparative genomic hybridization and fluorescence in situ hybridization, which showed trisomy 8 as sole unbalanced karyotypic aberration. Our results provide evidence that a simple numeric chromosomal abnormality in SLCT may be associated with a malignant phenotype and suggest that the molecular pathogenesis of SLCT may be different from ovarian granulosa-stromal cell tumors.

Facial-selective allylation of methyl ketones for the asymmetric synthesis of alpha-substituted tertiary homoallylic ethers.

The asymmetric synthesis of enantiomerically pure a-substituted tertiary homoallylic ethers 4a, 11 and 12a-c by the allylation of ethyl methyl ketone (la) with gamma-substituted allylsilanes 9a-h is described. The allylsilanes were obtained by a nickel-catalysed Grignard cross-coupling reaction of (E)- and (Z)-(3-iodoallyl)trimethylsilane with various Grignard reagents. The reaction of the allylsilanes with la in the presence of the trimethylsilyl ether of N-trifluoroacetylnorpseudoephedrine (3), and catalytic amounts of a mixture of trimethylsilyl triflate and trifluoromethanesulfonic acid led to the homoallylic ethers 4a, 11 and 12a-c with two new stereogenic centres, with a selectivity of 1:9 to >20:1 for the homoallylic and of 1:99 to >60:1 for the allylic centre. The facial selectivity does not depend on the configuration of the allylsilane, and in all reactions the anti product is preferentially formed. Interestingly, a pronounced switch of facial selectivity takes place with increasing length of the alkyl group of the allylsilane.

Highly efficient synthesis of linear pyrrole oligomers by twofold Heck reactions.

The twofold Heck reaction of the vinylpyrroles 3a and 3b with the iodobenzenes 4a-c led to the linear pyrrole oligomers 5, 6, and 7. The synthesis of both symmetrical and unsymmetrical oligomers, such as 10a and 10b, was also accomplished by a Heck reaction of 8 and 9 and by a Heck reaction of 3a and 11 followed by a Wittig reaction and a second Heck reaction with 8. The pentacyclic oligomers 14 and 19 were prepared by a twofold Heck reaction of 13 with 4 and by a twofold Heck reaction of 15 with 16 followed by a Wittig reaction and a twofold Heck reaction with 8.

Inhibitory effect of a matrix metalloproteinase inhibitor on growth and spread of human pancreatic ductal adenocarcinoma evaluated in an orthotopic severe combined immunodeficient (SCID) mouse model.

The present study was aimed at evaluating the effect of the matrix metalloproteinase (MMP) inhibitor prinomastat (AG3340) on tumor progression using an orthotopic pancreatic carcinoma model in severe combined immunodeficient mice. In controls, receiving vehicle only, the poorly differentiated ductal adenocarcinoma invaded into adjacent organs and metastasized to different sites in the abdomen and to the lungs. Treatment with prinomastat, intraperitoneally twice daily for 21 days, reduced primary tumor volume significantly to 19.0 (+/-7.7)% of control, with induction of necrosis, differentiation, and fibrotic tissue in the pancreatic tumors. Invasion was not observed in 63% of prinomastat-treated mice, and metastases were reduced markedly. Surprisingly, prinomastat-treated tumors had on average higher microvessel densities as a consequence of an increased angiogenesis in perinecrotic tumor areas. We conclude that prinomastat is highly effective in inhibiting pancreatic carcinoma growth and progression in an orthotopic cancer model. This model appears to be a valuable tool to investigate the potency of novel antimetastatic strategies in pancreatic ductal adenocarcinoma by specifically targeting certain MMPs.

Utilization of bone-anchored hearing aids in children.

OBJECTIVE: Bone-anchored hearing aids (BAHAs) are indicated for use in children with bilateral microtia or chronic suppurative otitis media, which precludes the use of conventional hearing aids. METHODS: Nineteen consecutive children using BAHAs were reviewed retrospectively. Outcome measures included the long-term stability of BAHAs, frequency of adverse dermatological reactions at the implant site, and audiologic thresholds. RESULTS: Osseointegration was achieved in 95% of patients. One patient lost the implant fixture secondary to direct head trauma. Site revisions were required for only two patients secondary to soft-tissue overgrowth at the abutment site. There were no differences between pre-implantation and post-implantation bone or air conduction thresholds, but there was a statistical improvement in the post-implantation aided thresholds. CONCLUSIONS: Utilization of paediatric BAHAs, in a distinct population, is a reliable and successful method for audiologic rehabilitation.

Efficacy of adhesion prevention and impact on wound healing of intraperitoneal phospholipids.

BACKGROUND: Postoperative peritoneal adhesions are a major complication of abdominal surgery. Adjuvant therapy is needed to prevent adhesion formation and subsequent sequelae. Previously published data proved the efficacy of phospholipids (PL) for this indication; however, additional information on drug safety was still outstanding. The underlying study was designed to investigate the influence of phospholipids on three different types of healing tissue. MATERIALS AND METHODS: A total of 48 Chinchilla rabbits underwent median laparotomy, standardized abrasion of the visceral and parietal peritoneum, jejunal anastomosis, and an electrocautery incision of the liver. The operation was completed by intraperitoneal administration of 10 ml/kg of either normal saline (NaCl) or phospholipids (12%). RESULTS: After 5 (NaCl 691 mm(2) vs PL 192 mm(2)) and 10 days (NaCl 625 mm(2) vs PL 88 mm(2)) the control group presented with significantly larger adhesion areas (P < 0.05). The bursting pressure of the anastomosis on the 5th (NaCl 16.1 kPa vs PL 18.2 kPa) and 10th (NaCl 19.7 kPa vs PL 18.6 kPa) postoperative days showed no statistically significant difference. The tensile strength of the laparotomy wound measured after intervals of 5 (NaCl 8.5 N cm(-1) vs PL 6.8 N cm(-1)) and 10 days (NaCl 23.0 N cm(-1) vs PL 20.2 N cm(-1)) was not statistically different either. The collagen protein ratio of anastomoses, laparotomy wounds, and liver incisions as well as the inflammatory-reparative response of the different tissues was not affected by PL. CONCLUSIONS: These results confirm the efficacy of phospholipids in adhesion prevention. The findings of uncompromised healing of anastomoses, laparotomy wounds, and liver incisions demonstrate the safety of this agent. Further data may qualify phospholipids for a clinical trial.

Synthesis of enantiopure homoallylic ethers by reagent controlled facial selective allylation of chiral ketones.

The stereoselective allylation of chiral methyl ketones to give tertiary homoallylic ethers, which can easily be transformed into homoallylic alcohols, is described. Reaction of the enantiopure ketones 8a-d and the racemic ketones 26a-d with the norpseudoephedrine derivative 2 or ent-2 and allylsilane in the presence of a catalytic amount of trifluoromethanesulfonic acid, led to a series of homoallylic ethers with good to excellent diastereoselectivity (85:15 to > 97:3). The allylation is reagent controlled and nearly independent from the stereogenic centers in the substrates. A partial kinetic resolution was observed using the racemic ketones 26a-d. In the reaction of the chiral ketones 8a-d with the achiral reagents ethoxytrimethylsilane and allylsilane only a low diastereoselectivity was observed.