High-definition endoscopy with iScan and Lugol's solution for the detection of inflammation in patients with nonerosive reflux disease: histologic evaluation in comparison with a control group.

Nonerosive reflux disease (NERD) is commonly diagnosed in patients with symptoms of reflux. The aim of the present study was to determine whether high-definition endoscopy (HD) plus equipped with the iScan function or chromoendoscopy with Lugol's solution might permit the differentiation of NERD patients from those without reflux symptoms, proven by targeted biopsies of endoscopic lesions. A total of 100 patients without regular intake of proton pump inhibitors and with a normal conventional upper endoscopy were prospectively divided into NERD patients and controls. A second upper endoscopy was performed using HD+ with additional iScan function and then Lugol's solution was applied. Biopsy specimens were taken from the gastroesophageal junction in all patients. A total of 65 patients with reflux symptoms and 27 controls were included. HD(+) endoscopy with iScan revealed subtle mucosal breaks in 52 patients; the subsequent biopsies confirmed esophagitis in all cases. After Lugol's solution, 58 patients showed mucosal breaks. Sensitivity for the iScan procedure was 82.5%, whereas that for Lugol's solution was 92.06%. Excellent positive predictive values of 100% and 98.3%, respectively, were noted. The present study suggests that the majority of patients with NERD and typical symptoms of reflux disease can be identified by iScan or Lugol's chromoendoscopy as minimal erosive reflux disease (ERD) patients.

[How should cytopathology be taught?]. / Wie soll Zytopathologie gelehrt werden?

Cytopathology is not excessively employed in the whole faculty of pathology in Germany, in contrast to some neighboring countries. Cytopathology also suffers from a lack of next generation cytologists, because experienced and interested specialists as well as assistants actively engaged in cytology (ZTA, cytological technical assistant and MTLA medical laboratory technical assistant) are only available in limited numbers. However, cytopathological expertise is urgently needed, not only in the diagnostics of gynecological cancer screening but also for assessment of many non-gynecological preparations, which have nowadays become more demanding and more complex particularly due to the technical developments in internal medicine. In addition, adjuvant methods have become incorporated into cytopathology, the interpretation of which must be carried out within this specialty.This article gives a review of the status quo of cytopathology in Germany and sketches how training and advanced education opportunities are organized and if necessary could be improved. The course of specialist medical training as well as the ZTA and MTLA training are described, also as a teaching concept (e.g. microscopy of current cases, microscopy of case collections and online microscopy). In order to provide cytopathology in Germany with a wider perspective, a paradigm shift in the internal approach to cytology is suggested so that the next generation can perceive this specialty not as a burden but as a chance.

[Documentation quality of histopathology reports of prostate needle biopsies: a snapshot]. / Dokumentationsqualität histopathologischer Befundberichte von Prostatastanzbiopsien : Eine Momentaufnahme.

BACKGROUND: A standardized assessment of findings from prostate needle biopsies in pathology is of great importance for the individual recommendations for therapy of patients with prostate cancer. To this end criteria were developed which are formulated as recommendations in the S3 guidelines for prostate cancer and in joint instructions of the Bundesverband Deutscher Pathologen (BDP, "National Association of German Pathologists") and the Deutsche Gesellschaft für Pathologie (DGP, "German Society of Pathology"). In this article the findings from tumor positive prostate needle biopsies taken from various institutes in Germany, were investigated exclusively to determine to what extent the recommended parameters were followed. MATERIAL AND METHODS: The study encompassed the findings from 91 patients with a mean age of 65.3 years from whom an average of 9.3 biopsy samples from different regions of the prostate were submitted. All diagnosed tumors corresponded to a standard type adenocarcinoma according to the classification of the World Health Organization (WHO) which was detected in an average of 2.5 biopsy regions per patient. The assessment was made from H & E stained serial sections which was supplemented in 11 (12.1%) cases by special staining methods and in 40 (44%) cases by immunohistochemical staining techniques. The length of the needle biopsy was documented in 88 (96.7%) cases and the tumor spread also in 88 cases. The tumor stage was reported in 16 cases (17.6%). RESULTS: The Gleason grading score (GS) was reported in all 91 cases whereby the old GS was explicitly used in 1 case and the modified GS in all other cases. The allocated GS ranged from 4 to 10 whereby 8 cases were graded as ≤5, 46 as GS grade 6, 27 as GS grade 7 and 10 as GS >7. Out of 45 cases with several positive biopsy samples, 38 were uniformly graded (84.4%), 6 out of the 7 samples which were not uniformly graded were allocated a GS of 6 or 7 and 1 sample was graded as GS 6-9. In 64 cases (70.3%) the conventional 3-stage WHO grading (n=42) and the Helpap grading (n=22) were additionally used. The WHO and Helpap grading scores were found to be highly correlated with the GS grading scores and the Union for International Cancer Control (UICC) grading scores derived from it (χ²-test, p<0.001), although surprising allocations were selected in isolated cases. CONCLUSION: In total, the only serious deficits were that in three cases (3.3%) no information was supplied on the estimated spread of the tumor in the tumor positive biopsies because this information can be decisive for therapy decisions, particularly for the selection of an active surveillance strategy. Also a relatively large number of cases were assigned a GS score ≤ 5 which is not recommended in the modified Gleason grading. Furthermore, translation of the GS into the other grading forms used revealed that the biological assessment of the GS showed clear differences between the various participating institutes. In conclusion, the findings of the pathologists as a rule incorporated all the parameters necessary for a therapy decision in accordance with the guidelines so that they can be considered comprehensive and completely valid apart from a few exceptions.

Chest CT findings in EBUS-TBNA-proven anthracosis in enlarged mediastinal lymph nodes.

PURPOSE: We demonstrate the multislice computed tomography (MSCT) findings of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)-proven hilar and mediastinal lymph node enlargement with signs of anthracosis. MATERIALS AND METHODS: 53 enlarged lymph nodes in 39 patients (28 male, 11 female) with EBUS-TBNA-confirmed anthracosis were analyzed retrospectively. RESULTS: The mean short axis diameter of the enlarged lymph nodes with signs of anthracosis was 13.7  mm. Lymph nodes most often showed an oval shape (84  %) and were well defined in 66  % of cases. Lymph node confluence was observed in 32  % of cases. Calcifications were documented in 24.5  % of cases. Contrast enhancement and fatty involution were seen seldom (3.8  %). Lymph node necrosis was not seen. CONCLUSION: Lymph node anthracosis may be found most often in enlarged, well defined lymph nodes with an oval shape, frequently associated with confluence and calcifications.

[Pleural effusion cytology of asbestos-associated malignant mesothelioma and lung carcinoma in the diagnosis of occupational diseases by the statutory accident insurance funds]. / Zytopathologische Ergussdiagnostik in der berufsgenossenschaftlichen Begutachtung von Asbest-assoziierten malignen Mesotheliomen und Lungenkarzinomen.

Pleural effusion often represents the first clinical symptom of lung carcinoma and malignant mesothelioma. As pleural punctation is performed quite early in the diagnostic procedure, effusion cytology frequently gives the first evidence about the presence of tumour cells and tumor histogenesis. In this study, we report on seven cases which were evaluated in our institution for the Employers' Liability Insurance Association, based solely on cytology findings.The mean age of the seven patients with a given long-term asbestos exposure during their working life was 81.7 years. On average eight smears per patient were investigated. In addition to routine cytology, immunocytochemistry, DNA image cytometry, AgNOR-analysis and fluorescence in situ hybridization were applied in a case-specific way. The results were interpreted against the clinical and occupational history of the respective patient.Definitive diagnosis could be made in six cases. In three of them, the diagnosis of malignant mesothelioma was made. Two cases were diagnosed as malignant effusion due to metastatic lung cancer. In one case, cells of high-grade Non-Hodgkin's lymphoma (NHL) were diagnosed and a malignant mesothelioma was excluded. In the last case, malignant mesothelioma could not be diagnosed unequivocally by cytology. In all seven cases, our interpretation was accepted by Employers' Liability Insurance Association. The five mesothelioma or lung cancer cases were accepted as asbestos-associated occupational disease, while the NHL case was rejected. In the last case, malignant mesothelioma was diagnosed later by autopsy, and the case was retroactively accepted as occupational disease.Cytology-based tumor diagnosis including adjuvant methods is a useful and reliable approach in cases of asbestos-associated tumours. Acceptance of occupational disease on the basis of cytological diagnoses even by the Employers' Liability Insurance Association helps avoid invasive pleural or lung biopsies in cases with an unequivocally positive effusion cytology of lung cancer or malignant mesothelioma.

Prospective, blinded comparison of cytology and DNA-image cytometry of brush biopsies for early detection of oral malignancy.

OBJECTIVES: Adjunctive techniques like DNA image cytometry (DNA-ICM) have been attributed to enhance the diagnostic performance of oral brush biopsies. The aim of the study was an evaluation of brush biopsies, analysed according to morphological criteria and by DNA-ICM vs. histological findings in a blinded prospective trial. MATERIALS AND METHODS: Eighty eight brush biopsies of 70 patients were sampled. Only clinical suspicious but not evident malignant oral lesions were included. Clinical diagnosis was leukoplakia (n = 36), lichen planus (n = 18), verruciform erythroplakia (n = 12), erythroleukoplakia (n = 9), erosion (n = 7) and induration (n = 6). Evaluation was conducted via histology, cytology and DNA-ICM. RESULTS: Histological diagnosis revealed eight cases of squamous intraepithelial dysplasia (SIN 1 n = 6, SIN 2 n = 2), four cases of carcinoma-in situ and 25 cases of oral T1-cancer. Remaining cases were leukoplakia (n = 28), lichen planus (n = 15) and local inflammation (n = 8). Brush biopsy detected malignant lesions including SIN>1 with a sensitivity of 55% and a specificity of 100%. DNA-ICM had a sensitivity of 70% and a specificity of 100%. The combination of both methods showed a sensitivity of 76% and a specificity of 100%. The predominant reason for false negative results were sampling errors with insufficient cells (86% in brush biopsy and 100% in DNA-ICM). CONCLUSION: DNA-ICM has the potential to substantially improve the sensitivity of a pure morphological interpretation of oral brush biopsies. Method inherent sampling errors may be accountable for a lower sensitivity compared to conventional histological diagnosis. Therefore, DNA-ICM should not be used to rule out malignancy, when lesions are already clinically suspicious for oral cancer.

SDF1ß expression in renal cell carcinoma correlates with grading and infiltration by CD8+ T-cells.

For several tumor entities, a significant correlation between the chemokine stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), metastasis and tumor proliferation, as well as prognosis, has been described. In this study, a series of 105 renal cell carcinoma patients were analyzed in terms of expression of SDF1α and SDF1ß and infiltration by CD4+ and CD8+ T-cells and the data correlated with TNM category, grading and survival. While the splice variant SDF1α had no impact on tumor grading, T-cell invasion or overall survival, expression of SDF1ß showed a significant correlation with tumor grading and also suggested a correlation with metastasis, as well as CD8+ T-cell invasion. These results indicate a potential T-cell-mediated antitumor response induced by SDF1ß up-regulation. Therefore targeting the SDF1ß-CXCR4 signaling pathway may be a promising means for new therapeutic strategies in advanced tumor stages.

An open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer.

BACKGROUND: Sunitinib monotherapy in pretreated patients with advanced gastric cancer (AGC) was investigated. Preplanned analyses of tumour biomarkers on treatment outcome were performed. PATIENTS AND METHODS: Patients received sunitinib 50mg/day for 4 weeks with 2 weeks rest until disease progression or unacceptable toxicity. The primary end-point was objective response rate (ORR). Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Fifty-two patients were enrolled and treated (safety population, SP). In the intention to treat population (n=51); the ORR was 3.9%, median PFS was 1.28 months [95% CI, 1.18-1.90], median OS was 5.81 months [95% CI, 3.48-12.32], the estimated one-year survival rate was 23.7% [95%CI: 12.8-36.5]. In subgroup analyses, tumour VEGF-C expression compared with no expression was associated with significantly shorter median PFS (1.23 versus 2.86 months, logrank p=0.0119) but there was no difference in tumour control rate (p=0.142). In the SP, serious adverse events occurred in 26 patients, leading to 13 deaths, all sunitinib unrelated. Thirty-eight patients died from progressive disease, nine died <60 days after treatment start. CONCLUSION: Sunitinib monotherapy was associated with limited tumour response and good/moderate tolerability in this setting.

[Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) as primary diagnostic tool for unclear lesions in the upper gastrointestinal tract]. / Endosonographie mit Feinnadelpunktion in der Primärdiagnostik unklarer Raumforderungen im oberen Gastrointestinaltrakt.

BACKGROUND: Endoscopic Ultrasound (EUS) and the EUS guided fine-needle Aspiration (EUS-FNA) increasingly plays an important role in the diagnostic evaluation of lesions or lymph nodes in the mediastinum and upper gastrointestinal tract of unknown origin. The objective of this study was to assess safety and accuracy of EUS-FNA in two secondary and tertiary health care providers. METHODS: Prospectively, from Mai 2003 to June 2007, all patients underwent EUS with devices from Pentax (FG38UX, EC3830UT) with EUS-FNA (Cook or Mediglobe) at Johannes Gutenberg University and Catholic Hospital in Mainz. In all cases, cytology and extracted cells were histological examined by the same pathologists. In case of negative EUS results, patients were observed for at least 12 months after initial diagnosis later by reanalysis, CT-scan and follow-up clinical data to confirm the diagnosis. RESULTS: In total, 776 patients with EUS and 167 EUS-FNA (21.5 %) could be evaluated. Median age was 62 years, 68 % of patients were male. Patients underwent EUS-FNA in the mediastinum (n = 54), pancreas (73), stomach (13), liver, adrenal glands and rectum (n = 6). The complication rate of EUS-FNA was very low with only 0.6 %, mainly consistent of one minor haemorrhage at the aspiration site. A clear histological diagnosis could not be achieved in 12.5 % (21/167). Statistical analyses of all EUS-FNA revealed a sensitivity of 77.8 % (95 %CI 67,2 - 86,3) and a specificity of 98.5 % (95 % CI 92,2 - 100), with a positive and negative predictive value of 98.4 % and of 78.1 %, respectively. The overall accuracy was 87 % (95 %CI 80,4 - 92,0). CONCLUSION: EUS combined with FNA is a safe tool for first histological evaluation of unidentified lesions or lymph nodes in the mediastinum and upper gastrointestinal tract, indicative for gastrointestinal cancers.

High definition colonoscopy combined with i-Scan is superior in the detection of colorectal neoplasias compared with standard video colonoscopy: a prospective randomized controlled trial.

INTRODUCTION: Colonoscopy is the accepted gold standard for the detection of colorectal cancer. The aim of the current study was to prospectively compare high definition plus (HD+) colonoscopy with I-Scan functionality (electronic staining) vs. standard video colonoscopy. The primary endpoint was the detection of patients having colon cancer or at least one adenoma. METHODS: A total of 220 patients due to undergo screening colonoscopy, postpolypectomy surveillance or with a positive occult blood test were randomized in a 1 : 1 ratio to undergo HD+ colonoscopy in conjunction with I-Scan surface enhancement (90i series, Pentax, Tokyo, Japan) or standard video colonoscopy (EC-3870FZK, Pentax). Detected colorectal lesions were judged according to type, location, and size. Lesions were characterized in the HD+ group by using further I-Scan functionality (p- and v-modes) to analyze pattern and vessel architecture. Histology was predicted and biopsies or resections were performed on all identified lesions. RESULTS: HD+ colonoscopy with I-Scan functionality detected significantly more patients with colorectal neoplasia (38 %) compared with standard resolution endoscopy (13 %) (200 patients finally analyzed; 100 per arm). Significantly more neoplastic (adenomatous and cancerous) lesions and more flat adenomas could be detected using high definition endoscopy with surface enhancement. Final histology could be predicted with high accuracy (98.6 %) within the HD+ group. CONCLUSIONS: HD+ colonoscopy with I-Scan is superior to standard video colonoscopy in detecting patients with colorectal neoplasia based on this prospective, randomized, controlled trial.

Osseointegration of one-piece zirconia implants compared with a titanium implant of identical design: a histomorphometric study in the dog.

OBJECTIVE: The aim of this study was to evaluate osseointegration of one-piece zirconia vs. titanium implants depending on their insertion depth by histomorphometry. MATERIAL AND METHODS: Four one-piece implants of identical geometry were inserted on each side of six mongrel dogs: (1) an uncoated zirconia implant, (2) a zirconia implant coated with a calcium-liberating titanium oxide coating, (3) a titanium implant and (4) an experimental implant made of a synthetic material (polyetheretherketone). In a split-mouth manner they were inserted in submerged and non-submerged gingival healing modes. After 4 months, dissected blocks were stained with toluidine blue in order to histologically assess the bone-to-implant contact (BIC) rates and the bone levels (BL) of the implants. RESULTS: All 48 implants were osseointegrated clinically and histologically. Histomorphometrically, BL in the crestal implant part did not differ significantly with regard to material type or healing modality. The submerged coated zirconia implants tended to offer the most stable crestal BL. The histometric results reflected the different healing modes by establishing different BL. The median BIC of the apical implant part of the zirconia and titanium group amounted to 59.2% for uncoated zirconia, 58.3% for coated zirconia, 26.8% for the synthetic material and 41.2% for titanium implants. CONCLUSIONS: Within the limits of this animal study, it is concluded that zirconia implants are capable of establishing close BIC rates similar to what is known from the osseointegration behaviour of titanium implants with the same surface modification and roughness.

Recognition and characterization of small colonic neoplasia with high-definition colonoscopy using i-Scan is as precise as chromoendoscopy.

BACKGROUND: The EPKi system (Pentax, Japan) enables resolution above HDTV. Aim of the study was to test the efficacy of HD+ alone and with the new post-processing digital filter i-Scan or chromoendoscopy (Methylene blue 0.1%) in screening for colorectal cancer. We focused on lesions less than 5 mm as a surrogate marker for the optical possibilities of the EPKi system. METHODS: The last 30 cm of the colon in a screening population were inspected with HD+ alone, in combination with i-Scan (2:1 randomisation) and subsequently with chromoendoscopy. All lesions were characterized and targeted biopsies were performed. RESULTS: i-Scan augmented in 69 patients the identification of lesions from 176 to 335 (p<0.001) and chromoendoscopy to 646 (p<0.001). The additional lesions were mainly flat (type IIb, 74%), which were only recognized using i-Scan or chromoendoscopy. The amount of neoplasias was not significantly different (HD+: 5, i-Scan: 11, Chromoendoscopy: 11), but all could correctly be predicted using i-Scan or chromoendoscopy. CONCLUSIONS: HD+ colonoscopy with and without i-Scan unmask a plethora of small lesions but chromoendoscopy can even advance the number. However, i-Scan was able to predict neoplasia as precisely as chromoendoscopy and might shortly replace chromoendoscopy as a more time efficient tool.

Risk factors in patients with rapid recurrent hepatitis C virus-related cirrhosis within 1 year after liver transplantation.

BACKGROUND: Recurrent cirrhosis (RC) due to pretransplant underlying disease leads to organ failure and subsequent death after orthotopic liver transplantation (OLT). RC occurs in up to 30% of patients with recurrent hepatitis C (HCV) within 5 years after OLT. We sought to identify early risk factors for rapid RC within the first year after OLT in HCV-positive patients. METHODS: Among 404 liver transplanted patients at the University of Mainz between 1998 and 2008, 90 were HCV-RNA positive. To identify predictive factors for rapid RC, we compared HCV-positive patients with advanced fibrosis stages within 1 year after OLT (n = 13) with these without RC at 5 years after OLT (n = 23). RESULTS: Overall, poorer patient survival was associated with advanced fibrosis scores in the 1-year protocol biopsy and nonresponse to interferon treatment before OLT. The strongest predictive factors for rapid RC were persistently high levels of alkaline phosphatase, bilirubin, viral load at 6 months after OLT, and multiple steroid pulse therapies. The CCR2-V64I polymorphism was not associated with rapid RC. CONCLUSION: We presented a group of patients with HCV-related rapid RC within the first year after OLT to identify predictive factors for rapid fibrosis progression.

High-definition endoscopy with i-Scan and Lugol's solution for more precise detection of mucosal breaks in patients with reflux symptoms.

BACKGROUND AND STUDY AIMS: Patients with gastroesophageal reflux disease are subdivided into non-erosive (NERD) and erosive reflux disease (ERD). The newly available EPKi processor enables high-definition resolution above HDTV standard (HD+). The aim of the study was to test the efficacy of HD+ esophagogastroduodenoscopy alone and in conjunction with i-Scan (newly developed postprocessing digital filter) and chromoendoscopy (Lugol's solution) for differentiation of reflux patients. METHODS: The distal esophagus of patients with heartburn was inspected with three imaging modalities. HD+ was followed by i-Scan and 15-mL Lugol's solution (1.5 %). The esophagus was evaluated for mucosal breaks (Los Angeles Classification [LA]). Small visible changes were also characterized, and targeted biopsies were performed. End points of the study were the presence and grade of esophagitis and the number of circumscribed changes. RESULTS: A total of 50 patients were included (female 29; mean age 54.7 years). HD+ identified nine patients with mucosal breaks (LA 7A; 2C), i-Scan was able to detect 12 patients (LA 8A; 2B; 2C; 0D) ( P = n. s.) and chromoendoscopy identified 25 patients (LA 16A; 7B; 1C, 1D) ( P < 0.01). Furthermore, a higher grade of esophagitis was recognized by using i-Scan and Lugol's solution in 19 patients. The number of circumscribed lesions could be increased from 21 (HD+) to 58 (i-Scan) ( P < 0.01), and up to 85 after Lugol spraying ( P < 0.01). CONCLUSIONS: Lugol's solution in conjunction with HD+ endoscopy significantly improves the identification of patients with esophagitis and reduces misclassification. The i-Scan filter and chromoendoscopy help to identify reflux-associated lesions.

Maxillary sinus grafting with a nano-structured biomaterial: preliminary clinical and histological results.

BACKGROUND: In this study the potential of a new and entirely synthetic, nano-structured hydroxyapatite-based biomaterial for sinus floor augmentation is evaluated. METHODS: 20 sinus floor elevations were carried out in a total of 20 patients. After a healing period of 6 months, in 10 cases cylinder-shaped bone biopsies were taken from the augmented maxillary region using trephine burs. RESULTS: The healing period progressed without any complications. General and specific histological analysis of the bone biopsies showed a high osteoclast activity at the margin of the biomaterial which was well integrated into the newly formed bone. CONCLUSION: This study demonstrates that new trabecular bone is formed after grafting with the nanocrystalline bone substitute after 6 months. Ongoing histomorphological studies are necessary to quantify the biomaterial-bone ratio and the exact amount of newly built bone in the augmented cavity after 6 months.

Correlation of multislice CT and histomorphology in HCC following TACE: predictors of outcome.

The purpose of this study was to correlate histopathological with CT findings in patients suffering from hepatocellular carcinoma (HCC) eligible for orthotopic liver transplantation (OLT), with a special focus on the antitumoral effect of transarterial chemoembolization (TACE) therapy. A total of 42 consecutive patients suffering from HCC had been treated prior to OLT by means of TACE. TACE was carried out with a mixture of Lipiodol (10-20 ml) and mitomycin C (max. dosage, 10 mg). TACE was performed at 6- to 8-week intervals. Follow-up investigation included contrast-enhanced multislice CT controls and laboratory control. Liver explants were evaluated macroscopically and microscopically to determine the number and size of the tumor lesions as well as the degree of tumor necrosis. Necrosis was investigated in H&E-stained sections. The degree of necrosis was classified as follows: 0-25%, 26-50%, 51-75%, 75-99%, and complete necrosis. Two hundred thirty-one TACE procedures (5.5 +/- 2.9; range, 1-14) were performed. Mean tumor size in CT before and after TACE was 4.1 +/- 2.4 (range, 1.0-12.0 cm) and 2.7 +/- 1.2 (range, 1.0-6.0 cm; p < 0.001). Mean tumor number before and after TACE in CT was 2.5 +/- 1.5 (n = 105; range, 1-8) and 2.4 +/- 2.0 (n = 103; range, 1-6; p = 0.99). In the surgical specimen tumor size and tumor number were 2.8 +/- 1.6 (range, 1.0-7.0 cm; p = 0.78) and 1.9 +/- 1.2 (range, 1-7; p = 0.003). Mean tumor necrosis was 67.8% +/- 28.1%. Tumor necrosis was subtotal or complete in 17 of 42 (40.5%) patients. Tumor necrosis correlated significantly with the degree of arterial devascularization in CT (p = 0.001), the amount of Lipiodol washout (p = 0.002), and the number of tumor lesions (i.e., unifocal vs. multifocal). Furthermore, elevated serum levels of bilirubin (p = 0.005) and decreased albumin (p = 0.004) affected the local antitumoral effect. A poor necrosis rate (< 25%) significantly correlated with the number of TACE procedures accomplished (p = 0.023). In conclusion, TACE provided an acceptable local antitumoral effect in patients scheduled for liver transplantation. Tumor necrosis depended significantly on the degree of arterial devascularization and the accumulation of Lipiodol within the HCC lesions. Unifocal tumors and preserved liver function were positive predictors for a more favorable local antitumoral effect. Poor necrosis rates were found in patients with significant Lipiodol washout and who received a limited number of TACE procedures.

pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer.

During malignant transformation, cancer cells have to evade cell-intrinsic tumor suppressor mechanisms including apoptosis, thus acquiring a phenotype that is relatively resistant to clinically applied anticancer therapies. Molecular characterization of apoptotic signal transduction defects may help to identify prognostic markers and to develop novel therapeutic strategies. To this end we have undertaken functional analyses of drug-induced apoptosis in human non-small cell-lung cancer (NSCLC) cells. We found that primary drug resistance correlated with defects in apoptosome-dependent caspase activation in vitro. While cytochrome c-induced apoptosome formation was maintained, the subsequent activation of caspase-9 and -3 was abolished in resistant NSCLC. The addition of recombinant pp32/putative human HLA class II-associated protein (pp32/PHAPI), described as a putative tumor suppressor in prostate cancer, successfully restored defective cytochrome c-induced caspase activation in vitro. Conditional expression of pp32/PHAPI sensitized NSCLC cells to apoptosis in vitro and in a murine tumor model in vivo. Immunohistochemical analyses of tumor samples from NSCLC patients revealed that the expression of pp32/PHAPI correlated with an improved outcome following chemotherapy. These results identify pp32/PHAPI as regulator of the apoptosis response of cancer cells in vitro and in vivo, and as a predictor of survival following chemotherapy for advanced NSCLC.

Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4.

In different tumour entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumour dissemination and poor prognosis. Therefore, we evaluated, if the expression of CXCR4 exerts similar effects in human hepatocellular carcinoma (HCC). Expression analysis and functional assays were performed in vitro to elucidate the impact of CXCL12 on human hepatoma cells lines. In addition, expression of CXCR4 was evaluated in 39 patients with HCC semiquantitatively and correlated with both, tumour and patients characteristics. Human HCC and hepatoma cell lines displayed variable intensities of CXCR4 expression. Loss of p53 function did not impact on CXCR4 expression. Exposure to CXCL12 mediated a perinuclear translocation of CXCR4 in Huh7/Hep3B cells and increased the invasive potential of Huh7 cells. In HCC patients, CXCR4 expression significantly correlated with progressed local tumours (T-status; P=0.006), lymphatic metastasis (N-status; P=0.005) and distant dissemination (M-status; P=0.009), as well as with a decreased 3-year-survival rate (P=0.01). In summary, strong expression of CXCR4 is significantly associated with progressed hepatocellular cancer.