A non-comparative phase II study of dose intensive chemotherapy with doxorubicin and ifosfamide followed by high dose ICE consolidation with PBSCT in non-resectable, high grade, adult type soft tissue sarcomas.

The objective was to determine the role of dose intensive induction chemotherapy in patients with soft tissue sarcomas (STS) that were considered unresectable. Treatment consisted of 2-3 cycles of doxorubicin (Dox) and ifosfamide (Ifo) followed by high dose chemotherapy with ifosfamide, carboplatin, etoposide (HD-ICE) plus peripheral blood stem cell transplantation (PBSCT). 30 out of 631 consecutive patients, median age 46 years (21-62), with high grade STS were included. 29 patients completed at least 2 cycles of Dox/Ifo. HD-ICE was withheld because of progressive disease (PD) in 5 patients, neurotoxicity in 6 cases, insufficient peripheral blood stem cell (PBSC) mobilization, complete remission (CR) and refusal in 1 patient each. HD-ICE was associated with non-haematological grade III toxicity including emesis, mucositis, fever, neurotoxicity, and transaminase level elevation. Two additional patients attained a partial response after HD-ICE. Overall, 24 of 30 (80%) patients underwent surgery, with complete tumor resections in 19 patients (63% of all patients, 79% of the operated subgroup); however, 2 of these required amputation. After a median follow up period of 50 months in surviving patients (range, 26-120), 5-year PFS and OS rates were 39% and 48%, respectively. Induction chemotherapy plus consolidation HD-ICE is generally feasible, but is associated with significant neurotoxicity. The advantage of HD-ICE over conventional dose chemotherapy plus external beam radiation therapy (EBRT) in non-resectable disease remains unproven.

Relevance and methods of interventional breast sonography in preoperative axillary lymph node staging.

Reduction of therapy-induced morbidity is an important goal for the improvement of the quality of breast cancer treatment. The introduction of sentinel lymph node biopsy (SLNB) significantly contributed to the reduction of surgery-induced morbidity in the shoulder-arm region. However, a clinically positive nodal status is still considered a contra-indication for SLNB. The current data constellation clearly shows that the clinical and also the sonographic malignancy assessment is insufficient for the accurate identification of the nodal status. A merely clinical and/or image-based appraisal of the axillary lymph node status would lead to overtreatment due to unnecessary axillary dissection in approximately 40 % of patients. In order to reduce the rate of unnecessary axillary dissection (AD), pretreatment interventional clarification is necessary to provide more detailed information about the histological condition of the lymph node. Comparing the currently available methods, fine needle aspiration (FNA) is the best in terms of cost and time requirement, practicability and complication rate. However, considering the sensitivity, it is inferior to ultrasound-guided core needle biopsy (CNB). Thus, a negative FNA outcome requires further clarification, which possibly can be performed with CNB. With a specificity of nearly 100 % and therefore a low rate of false positive cases for FNA, complete AD can be indicated by a positive FNA result. In the context of the interventional procedure, it must be stressed that FNA requires a high level of expertise on the part of both the examiner and the cytologist. The prerequisite for optimal interventional diagnostics of lymph nodes is an adequate sonographic assessment on the basis of standardized sonomorphological criteria.

True adenomas of the cardia: a case series of 3 patients.

BACKGROUND/AIM: True adenomas of the cardia appear to be extremely rare lesions. There are no data on the natural history and histopathological background of these lesions. We report 3 patients with true adenomas of the cardia. METHODS AND RESULTS: Three patients with polypoid masses at the cardia below the Z-line were submitted to a tertiary referral center for further diagnosis and therapy. In 2 of the 3 cases Barrett's esophagus with low-grade intraepithelial neoplasia was assumed on the basis of histopathological examination of biopsy specimens taken from the surface of the lesions. Polypectomy was performed in all 3 cases. In 2 of the 3 cases the final histopathological diagnosis of low-grade adenoma of the cardia could only be established after complete removal of the polypoid masses. CONCLUSIONS: Adenomas of the cardia can be mistaken for dysplasia arising from Barrett's esophagus, if the diagnosis is based on endoscopic biopsies only. It is, therefore, reasonable to completely remove any suspicious lesions by endoscopy not only for therapeutic but also for diagnostic reasons.

An innovative, safe and sterile sigmoid access (ISSA) for NOTES.

BACKGROUND AND STUDY AIMS: The use of a transcolonic approach for natural orifice transluminal endoscopic surgery (NOTES) offers relevant advantages compared with a transgastric procedure. However both techniques are still limited by specific shortcomings that need to be resolved before the transluminal approach can be translated to human applications. In this article we describe an innovative method for a transcolonic procedure, which might represent the next step forward in NOTES. PATIENTS AND METHODS: In three acute and five survival porcine models we evaluated a specially designed guide tube, which is inserted via a transcolonic approach into the abdominal cavity after intraperitoneal instillation of a decontamination solution. After endoscopic evaluation of the abdomen the closure of the entry site was performed surgically. Main parameters obtained in the study were the feasibility and safety of the approach, the bacterial contamination due to the transcolonic procedure, and the safe closure of the entry site. Animals in the survival model were euthanized 10 days after the procedure. RESULTS: The transcolonic approach took place without complications. There was no bleeding or laceration of adjacent organs. The surgical closure guaranteed a leak-proof closure of the entry site. All pigs in the survival model showed an excellent postinterventional course. At necropsy, the colonic incision sites were completely closed and appeared well healed. No abscesses or any sign of inflammation could be identified. CONCLUSIONS: The transcolonic approach using an innovative guide tube is feasible and safe. The technique described offers mentionable advantages and therefore reduces the known shortcomings of NOTES. However, further studies are needed to approve our results of an initial evaluation.

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study.

AIMS: To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS: The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS: 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION: The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.

Myositis proliferans: diagnosis and therapy of a pseudosarcomatous soft tissue lesion.

Myositis proliferans is a soft tissue neoplasia with rare incidence. In the most cases, it is localized in the region of the neck, shoulder, pelvis and thigh. Due to its rapid growth and histological picture, the tumour may appear as a malignant neoplasia. We report the case of a 29-year-old woman suffering from an increasing painful swelling of the left proximal lower leg. Performed biopsies and histological examinations provided the diagnosis of myositis proliferans adjacent to the fibula, which responded to local resection and did not recur after 2 years. We show the importance of adequate diagnostic and therapeutic approach to avoid unnecessary and probably radical overtherapy of the patient.

Microcirculation of subepithelial gastric tumors using contrast-enhanced ultrasound.

OBJECTIVES: The evaluation of subepithelial tumors of the stomach is normally the domain of gastroscopy and endoscopic ultrasound. We investigated these rare tumors using transabdominal B-mode ultrasound and performed perfusion analysis of these tumors with contrast enhanced ultrasound. METHODS: Patients with gastrointestinal stromal tumors (GIST, n = 3), leiomyoma (n = 1) and schwannoma (n = 1) were routinely examined using conventional B-mode-ultrasound, colour Doppler ultrasound and contrast-enhanced ultrasound (contrast media: Sonovue; ultrasound device: Siemens Acuson Sequoia 512). Gastroscopy, endosonography with puncture of the subepithelial tumor and computed tomography were also performed in all patients. After surgery, the resected stomach tumors were correlated with the preoperative imaging findings. RESULTS: All calculated tumor sizes using any imaging modalities showed a good correlation with the macroscopic tumor sizes ex-vivo. Histologically increased tumor size of the GISTs was correlated with large, central avascular areas. The GISTs and the leiomyoma presented with mixed echogenicity in B-mode-ultrasound. Colour Doppler ultrasound was able to detect some vessels in the periphery of the tumor only. Using contrast-enhanced ultrasound the GISTs and the leiomyoma presented hypervascular. The contrast pattern of these lesions was from the periphery to the centre or diffuse or a progressive centrifugal fill in during the arterial phase. We also registered slowly progressive washout starting at the end of the arterial phase and increasing into the late phase. The contrast media behaviour in the schwannoma was different from that describt above within the GISTs: it was noted to have a diffuse intralesional pattern at the start of the arterial phase followed by an early, rapidly progressing washout-phenomenon. CONCLUSION: In our pilot study B-mode transabdominal ultrasound was able to visualise gastric subepithelial tumors larger than three centimetre. Contrast-enhanced ultrasound is a proven method in clinical practice for the perfusion analysis of gastric subepithelial tumors. It can also be used for the planning of ultrasound-guided biopsies to avoid punctures of necrotic tumor parts.

[Endothelial adrenal cyst mimicking cystic echinococcosis in a Turkish woman]. / Endotheliale Nebennierenzyste als Differenzialdiagnose zur zystischen Echinokokkose bei einer türkischen Patientin.

BACKGROUND: Cystic liver lesions include hepatic echinococcosis as an important differential diagnosis, especially in patients from endemic countries. Serology might be false negative in a relevant percentage of the patients. Thus, modern clinical imaging techniques are the most important non-invasive means for making or excluding the diagnosis of hepatic echinococcosis. CASE REPORT: A 37-year-old Turkish woman was admitted to hospital because of abdominal pressure, lack of appetite and weight loss. The suspected radiological diagnosis of hepatic echinococcosis was made based on a septated, cystic liver process with calcifications seen in an already performed computered tomography. The physical examination and laboratory findings did not show any specific pathology. The serological tests for echinococcosis were negative. The MRI scan of the liver showed a 10 x 7.5 cm large, multi-segmented, cystic lesion between the right kidney and the right liver lobe. The cyst was discussed as possibly having an origin from the right adrenal gland and very unlikely from the liver or kidney. Ultrasonography (Siemens-Acuson Sequoia 512, Mountain View) showed a cystic lesion with septated structures and calcifications between the right kidney and the liver without a typical capsule. Contrast-enhanced ultrasound after fractionated injection of 4.8 mL Sonovue (Bracco, Milano) showed an intensive perfusion of the septa in the cyst. We admitted the patient for surgery. Interoperatively a right adrenalectomy and cystectomy was performed. Histology showed an epithelial adrenal cyst. The patient was asymptomatic twelve months after surgery. CONCLUSION: High-end-ultrasonography with microbubble contrast media of the second generation is the primary diagnostic tool for the differential diagnosis of cystic lesions of the liver and adrenal glands. MRI or CT scans might be additionally indicated in the case of poor ultrasound conditions in a patient or before planned surgery, but can also fail to correct determine the origin of a cyst.

[Contrast media-enhanced and B-imaging ultrasound as a diagnostic and follow-up tool of hepatic echinococcosis in a 19-year-old Turkish woman]. / Kontrastmittel- und B-Bild-Ultraschall in der Diagnostik und Therapiekontrolle der hepatischen Echinokokkose bei einer türkischen Patientin.

HISTORY: A 19-year-old Turkish woman was admitted to the emergency room because of the worsening recurrent pain in the right abdomen radiating to the right shoulder and right flank. INVESTIGATIONS: Ultrasound examination showed a polycystic mass in the right lobe of the liver surrounded by a capsule. A contrast-enhanced ultrasound examination was done. It revealed, starting in the arterial phase, marginal enhancement near the capsule of the liver lesion. TREATMENT AND COURSE: The suspected diagnosis of a hydatid liver disease caused by Echinococcus granulosus was confirmed by serology. The patient was treated with oral albendazole (400 mg, twice daily) for eight weeks. Follow-up ultrasound examinations showed significantly reduced "collapsing" cyst membranes. A hydatid cyst weighing 130 g and 8 cm in diameter was resected by open laparatomy nine weeks after diagnosis. Albendazole treatment was continued for six months and well tolerated by the patient. One year after surgical treatment the serology was negative. CONCLUSIONS: Ultrasound examination is the method of choice for the initial diagnosis and follow-up of hepatic echinococcosis. Serology is not always reliable. The treatment depends on the WHO stage of the disease and individual factors.

[Molecular diagnosis of mycobacterial infections]. / Molekulare Mykobakterien-Diagnostik.

Tuberculosis remains a leading cause of morbidity and mortality worldwide. A rapid and reliable diagnosis and discrimination from infections with nontuberculous mycobacteria (NTM) is critical. Frequently, formalin-fixed, paraffin-embedded (FFPE) tissues remain the only source for detection of micro-organisms in suspected cases of mycobacterial infection. Recently, numerous methods, including PCR assays, in situ hybridization and immunohistochemistry have been developed for detection of mycobacteria in FFPE samples. PCR-based assays are directed either against M.tbc.-specific sequences, such as IS6110, or amplify regions common to many mycobacterial species, e.g. the 65 kDa antigen, and then require sequencing or restriction fragment length polymorphism for species identification. Whereas the detection of DNA of M.tbc. in the correct setting is always of clinical relevance, the presence of various NTM species has to be interpreted with great caution due to their ubiquitous nature. However, the routine application of molecular tests has demonstrated that NTM infections are more common than previously thought, even in non-immunosuppressed hosts. The introduction of real-time PCR technology allows precise quantification of mycobacterial DNA and can be used for species identification through melting point analysis or appropriate DNA probes. Application of these assays originally developed for clinical microbiology offer a great opportunity for diagnostic improvement in molecular pathology as compared to qualitative PCR, mainly due to an increased specificity and a lower risk of contamination. Given the clinical impact of a positive molecular result for M. tbc., future efforts have to be aimed at standardization and quality control.

The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma.

The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy+/-surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value.