Apparent diffusion coefficient measurements of the pancreas, pancreas carcinoma, and mass-forming focal pancreatitis.

BACKGROUND: Mass-forming focal pancreatitis (FP) may mimic pancreatic cancer (PC) on magnetic resonance (MR) imaging, and the preoperative differential diagnosis is often difficult. Recently, the usefulness of diffusion-weighted imaging (DWI) in the diagnosis of pancreatic cancer has been reported in several studies. PURPOSE: To investigate if apparent diffusion coefficient (ADC) measurements based on diffusion-weighted echo-planar imaging (DW-EPI) may distinguish between normal pancreas parenchyma, mass-forming focal pancreatitis, and pancreas carcinoma. MATERIAL AND METHODS: MRI was performed on 64 patients: 24 with pancreas carcinoma (PC), 20 with mass-forming focal pancreatitis (FP), three patients with other focal pancreatic disease as well as 17 controls without any known pancreatic disease. Diffusion-weighted sequence with ADC maps and T2-weighted sequence for anatomical information was performed. Apparent diffusion coefficient (ADC) maps were automatically created and analyzed using a dedicated user interface. In the group with pancreas disease the abnormal parenchyma was detected by using T1- and T2-weighted images and the region of interest (ROI) was transferred exactly to the ADC map and the coefficients were registered. In the control group the ROI was set to the head of the pancreas followed by a similar registration of the ADCs. RESULTS: ADC values for mass-forming FP and PC differed significantly from ADC values for normal pancreas parenchyma (P = 0.001/P = 0.002). Mean ADC values for mass-forming FP were 0.69 ± 0.18 × 10(-3) mm(2)/s. ADC values for PC were 0.78 ± 0.11 × 10(-3) mm(2)/s, compared to ADC values of 0.17 ± 0.06 × 10(-3) mm(2)/s in the control group. However there was no significant difference in ADCs between PC and mass-forming FP (P = 0.15). CONCLUSION: ADC measurements clearly differentiated between normal pancreatic tissue and abnormal pancreas parenchyma (PC and mass-forming FP). However there is an overlap in values of PC and mass-forming FP, with the consequent problem of their correct identification.

Mutational status of KIT and PDGFRA and expression of PDGFRA are not associated with prognosis after curative resection of primary gastrointestinal stromal tumors (GISTs).

BACKGROUND: The aim of this study was to investigate if immunohistochemical expression and mutational status of KIT and PDGFRA in GISTs are associated with the clinical course and disease-free survival after curative resection of the primary tumor without adjuvant systemic therapy. METHODS: Paraffin-embedded tumor sections of 95 GISTs were analyzed for KIT and PDGFRA expression by immunohistochemistry. PDGFRA expression was judged using a scoring system subdividing tumors in negative/weak and strong immunoreactivity groups. For mutation analysis, exons 9, 10, 11, 13, and 17 of KIT and exons 10, 12, 14, and 18 of PDGFRA were sequenced. RESULTS: Of 95 R0-resected GISTs, 69% showed strong PDGFRA immunoreactivity. Gastric GISTs revealed a significantly higher rate of strong PDGFRA immunoreactivity (P = 0.01) and longer DFS (P = 0.015) than GISTs of the small intestine. KIT mutations were detected in 43 of 63 (68.3%) completely sequenced cases while PDGFRA mutations were identified in 6 cases (10%). In multivariate analysis, neither KIT/PDGFRA expression nor mutational status of KIT or PDGFRA were independent prognostic factors. Only mitotic rate predicted recurrence independently. CONCLUSION: Our data do not support the notion that expression of PDGFRA or mutations in KIT or PDGFRA are independent prognostic factors after curative resection of primary GIST.

Who profits from neoadjuvant radiochemotherapy for locally advanced esophageal carcinoma?

BACKGROUND: Patients suffering from locally advanced esophageal carcinoma are generally treated using multimodal therapies. This prospective, non-randomized trial was performed to evaluate the survival benefit of neoadjuvant radiochemotherapy prior to surgery in comparison with surgery only. PATIENTS & METHODS: Histopathological outcomes and survival were compared between 61 patients who underwent neoadjuvant radiochemotherapy and 64 comparable control patients who had been under-staged. After neoadjuvant therapy, tumor regression was assessed using the method described by Mandard in 1994. Survival curves for the two groups were estimated using the Kaplan-Meier method, and compared with the log-rank test. RESULTS: Median and 3-year recurrence-free survival for the entire group were 26 months and 39.7%, respectively. The median and 3-year overall survival reached 34 months and 48.1%. Patients who showed complete response to neoadjuvant therapy had significantly improved survival (35 months) compared to patients with residual tumor cells (28 months), patients with tumors unresponsive to radiochemotherapy (22 months), or patients who received surgery only (control group, 29 months). Patients with nodal-negative carcinomas showed significantly longer survival after surgery only and after neoadjuvant therapy compared to patients with lymph node-positive cancers. CONCLUSIONS: Complete response after neoadjuvant radiochemotherapy is associated with significantly improved survival. Negative nodal status is a major determinant of outcomes following primary operation or neoadjuvant treatment.

Curative resection of a primarily unresectable acinar cell carcinoma of the pancreas after chemotherapy.

BACKGROUND: Acinar cell carcinoma (ACC) represents only 1-2% of pancreatic cancers and is a very rare malignancy. At the time of diagnosis only 50% of the tumors appear to be resectable. Reliable data for an effective adjuvant or neoadjuvant treatment are not available. CASE PRESENTATION: A 65-year old male presented with obstructive jaundice and non-specific upper abdominal pain. MRI-imaging showed a tumor within the head of the pancreas concomitant with Serum-Lipase and CA19-9. During ERCP, a stent was placed. Endosonographic fine needle biopsy confirmed an acinar cell carcinoma. Laparotomy presented an locally advanced tumor with venous infiltration that was consequently deemed unresectable. The patient was treated with five cycles of 5-FU monotherapy with palliative intention. Chemotherapy was well tolerated, and no severe complications were observed. Twelve months later, the patient was in stable condition, and CT-scanning showed an obvious reduction in the size of the tumor. During further operative exploration, a PPPD with resection of the portal vein was performed. Histopathological examination gave evidence of a diffuse necrotic ACC-tumor, all resection margins were found to be negative. Eighteen months later, the patient showed no signs of recurrent disease. CONCLUSION: ACC responded well to 5-FU monochemotherapy. Therefore, neoadjuvant chemotherapy could be an option to reduce a primarily unresectable ACC to a point where curative resection can be achieved.

Color Doppler imaging predicts portal invasion by pancreatic adenocarcinoma.

BACKGROUND: Tumor infiltration of the intima of the portal vein (PV) and superior mesenteric vein (SMV) by pancreatic adenocarcinoma is classically considered a criterion for unsuitability for resection and poor prognosis. This study was performed to evaluate modern color duplex imaging (CDI) for the assessment of PV/SMV infiltration by pancreatic adenocarcinomas. METHOD: From 1994 to 2005, Whipple's procedure or pylorus-preserving pancreato-duodenectomy (PPPD) was performed in 303 patients with pancreatic adenocarcinoma; 35 of these underwent partial PV/SMV resection. Applying a previously reported CDI score, we evaluated the integrity of the echogenic border layer between the vein and tumor (mural demarcation) and maximum blood flow velocity (V (max)) in the PV segment in contact with the tumor. The results were compared to the final histological findings in the resected venous walls. RESULTS: CDI findings correlated well with the histological invasion grades. By measuring V (max )and evaluating mural demarcation, we observed a sensitivity of 66.7% and 100% and a specificity of 98.3% and 93.9%, respectively, in predicting full thickness vein invasion, including the intima. V (max) above 80 cm/s and lack of mural demarcation were predictors of PV/SMV invasion. The postoperative survival rates depended on the depth of tumor infiltration into the PV/SMV. CONCLUSIONS: Modern CDI is a reliable and valid technique for evaluation of morphological and hemodynamic parameters in the portal vein segment adjacent to pancreatic adenocarcinoma. Maximal blood-flow velocity in the portal segment in contact with the tumor and absence of the echogenic vessel-parenchymal sonographic interface are parameters predictive of tumor infiltration of the portal intima.

Wound healing in the rabbit cornea after corneal collagen cross-linking with riboflavin and UVA.

PURPOSE: This study was undertaken to investigate the wound healing process of the first 6 weeks after photodynamic cross-linking treatment in the rabbit cornea, using the photosensitizer riboflavin and UVA. METHODS: After removal of the central epithelium, the right corneas of 8 Chinchilla rabbits were cross-linked with a photosensitizing 0.1% riboflavin solution and UVA light (370 nm; irradiance, 3 mW/cm(2); dose, 5.4 J/cm(2)) for 30 minutes. Two animals were euthanized 3 days, 7 days, 4 weeks, and 6 weeks postoperatively. The corneas of the enucleated eyes were evaluated using 4-microm light microscopic sections with routine stains and avidin-biotin complex immunostaining with anti-alpha-smooth muscle actin. RESULTS: By day 3 after treatment, complete apoptotic damage and loss of the endothelial cells and the stromal keratocytes were found in the irradiated area through the entire thickness of the stroma. There was marked stromal edema (850 +/- 66 vs. 332 +/- 43 microm in the untreated controls; P < 0.01). The epithelium was already closed again. At the margins of the lesion, there was a mild inflammatory reaction with scattered macrophages, lymphocytes, and neutrophils. By day 7, the endothelium was already intact again, and keratocyte repopulation of the posterior stroma was noted. By week 4, the keratocyte repopulation of the anterior stroma was observed with some acellular areas between. By week 6, the cytoarchitecture of the cornea seemed normal again. By weeks 4 and 6, alpha-actin-positive keratocytes were identified, especially in the periphery of the irradiated area. CONCLUSIONS: After riboflavin/UVA cross-linking of rabbit cornea, a complete cell loss occurs in the irradiation area with an irradiance of 3 mW/cm(2). The cytotoxic damage is repaired by repopulation after approximately 4-6 weeks. A combination of cross-linking with other procedures such as the implantation of intracorneal rings should be performed only after a sufficient time interval of approximately 2 months, allowing cellular regeneration.

Lack of efficacy of imatinib in a patient with metastatic Leydig cell tumor.

Imatinib is a tyrosine kinase inhibitor with activity in gastrointestinal stromal tumor and a variety of other solid and hematological malignancies. Studies in vitro and in a mouse model suggested that the imatinib might also be active in malignant Leydig cell tumor. We report on the--to our knowledge--first treatment experiment with imatinib in a patient with metastatic Leydig cell tumor. Unfortunately, the tumor progressed during treatment.

Analysis of the pancreatic tumor progression by a quantitative proteomic approach and immunhistochemical validation.

To increase the knowledge about the development of pancreatic ductal adenocarcinoma, (PDAC) detailed analysis of the tumor progression is required. To identify proteins differentially expressed in the pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of PDAC, we conducted a quantitative proteome study on microdissected PanIN cells. Proteins from 1000 microdissected cells were subjected to a procedure combining fluorescence dye saturation labeling with high resolution two-dimensional gel electrophoresis (2-DE). Differentially regulated protein spots were identified using protein lysates from PDAC tissues as a reference proteome followed by nanoLC-ESI-MS/MS. Thirty-seven single lesions of different PanIN grade (PanIN 1A/B, PanIN 2, PanIN 3) from nine patients were analyzed. Their protein expression was compared with each other, with PDAC cells and with normal ductal cells. The differential expression of differentially regulated protein spots was validated by means of immunohistochemistry using tissue microarrays. Of 2500 protein spots, 86 were found to be significantly regulated (p < 0.05, ratio > 1.6) during PanIN progression. Thirty-one nonredundant proteins were identified by mass spectrometry. Immunohistochemistry revealed that the differential expression of the selected candidate proteins major vault protein (MVP), anterior gradient 2 (AGR 2) and 14-3-3 sigma, annexin A4, and S100A10 could be successfully validated in PanIN lesions. The highly sensitive and robust proteome analysis revealed differentially regulated proteins involved in pancreatic tumor progression. The analysis of normal preneoplastic and neoplastic pancreatic tissue establishes a basis for identification of candidate biomarkers in PanIN progression that can be detected in pancreatic juice and in serum or are candidates for in vivo imaging approaches.

Outcome of invasive and noninvasive intraductal papillary-mucinous neoplasms of the pancreas (IPMN): a 10-year experience.

BACKGROUND: Intraductal papillary-mucinous neoplasms (IPMN) were officially introduced into the TNM classification in 1996. Based on a two-center database, we reevaluated histopathological findings, clinicopathological pattern, predictive markers for malignancy, and outcome. METHODS: Between 1996 and 2006, a total of 1424 pancreatic resections were performed in the University Hospitals Dresden and Mannheim. Pathologists of both institutions reviewed the IPMN diagnoses and other with cystic or solid tumor diagnoses. All possible markers, such as diabetes, jaundice, etc., were analyzed for prediction of malignancy. We performed a survival analysis based on the morphologic classification to determine the prognosis of IPMN. RESULTS: There were 43 patients of primarily diagnosed IPMN along with 1174 patients with diagnoses, such as ductal adenocarcinoma. In 207 patients, the diagnoses revealed other cystic or small solid tumors. A histopathological review of the latter patients revealed 54 IPMNs, resulting in a total of 97 IPMN patients (29 noninvasive, 68 invasive). All IPMN patients had a median survival of 36 months. Recurrence occurred more frequently in invasive IPMN. Predictive markers of malignancy were pain, preoperative weight loss, jaundice, and elevated CA 19.9. The strongest independent prognostic factor was invasive growth. The survival analysis revealed excellent prognosis for noninvasive IPMN. CONCLUSIONS: Since the introduction of IPMN in 1996, even specialized centers have had to deal with a learning curve. By reevaluating all cystic or small solid tumors, centers can improve and their patients' treatment can be optimized. Because the preoperative diagnostic methods are not sensitive enough to differentiate between benign and malignant lesions, surgery is advocated for all main duct IPMN, because they have a high malignant potential. For branch duct IPMN, surgery is advocated if the lesion is symptomatic, >3 cm, or has enlarged nodules.

Prognostic significance of immunohistochemical RhoA expression on survival in pancreatic ductal adenocarcinoma: a high-throughput analysis.

Among all human carcinomas, pancreatic cancer has one of the worst survival rates. Most patients will die of this cancer shortly after diagnosis, and currently, surgery is the only potential cure. Ductal adenocarcinoma is the most common histologic type. The search for prognostic parameters has progressed from mere physical or histomorphological tumor properties to molecular parameters. These, in turn, might point toward new therapeutic strategies. The K-ras oncogene is known to play a role in early stages of ductal adenocarcinoma carcinogenesis, and ras homologues are differentially expressed in cancerous versus normal ductal cells. RhoA belongs to a family of ras homologues comprising RhoA, RhoB, and RhoC. It is a guanosine triphosphatase associated with the cytoskeleton that seems to be involved in epithelial mesenchymal transition, a process of dedifferentiation. Immunohistologic RhoA expression was studied in a tissue microarray of 94 pancreatic ductal adenocarcinomas and correlated with clinicopathologic parameters and follow-up. RhoA protein expression, measured as labeling intensity or evaluated as percentage of reactive tumor cells, correlated with overall survival. A multivariate analysis demonstrated that RhoA protein expression is independent from other known prognostic parameters such as tumor size or grade. Moreover, a score combining RhoA expression with tumor size and grade resulted in a highly significant increase in the prognostic value for the overall survival of patients with pancreatic ductal adenocarcinoma.

The rare case of a symptomatic atherosclerotic aneurysm of the superior epigastric artery mimicking an acute cholecystitis.

True aneurysms of the epigastric artery are rare. We report a case of a 65-year-old female who was admitted for increasing upper abdominal pain. A leukocytosis, pyrexia, breathing stop on inspiration, and a palpable mass next to the right costal arch with severe local pain were suspicious for acute cholecystitis. Surprisingly, sonography and CT scan revealed a 5 x 4 cm structure limited to the abdominal wall directly above the gallbladder, which showed an arterial flow in the duplex scan. After resection and an uneventful postoperative course, the histological findings confirmed the diagnosis of a symptomatic true atherosclerotic aneurysm.

Cross-linking of scleral collagen in the rabbit using riboflavin and UVA.

PURPOSE: Scleral biomechanical weakness and thinning is known to be one of the main factors in the pathogenesis of progressive myopia. We tried to strengthen rabbit sclera by cross-linking scleral collagen using ultraviolet A (UVA) and the photosensitizer riboflavin. METHODS: Circumscribed 10 x10 mm sectors of the posterior--equatorial sclera of six chinchilla rabbit eyes were treated in vivo using a UVA double diode with 4.2 mW/cm(2) UVA at 370 nm and applying 0.1% riboflavin-5-phosphate drops as photosensitizer for 30 min. 1 day postoperatively biomechanical stress--strain measurements of three treated scleral strips were performed using a microcomputer-controlled biomaterial testing device and compared to non-treated contralateral control sclera. In addition, three treated eyes were examined histologically by light microscopy, TUNEL staining and electron microscopy to evaluate side-effects. RESULTS: Following the cross-linking treatment, the ultimate stress was 11.87+/-1.8 MPa versus 3.63+/-0.40 in the controls (increase of 227.9%, p=0.014), Young's modulus 27.67+/-4.16 MPa versus 4.9+/-.15 MPa in the controls (increase of 464.7%, p=0.021) and ultimate strain 92.2+/-7.43% versus 165.63+/-19.09% in the controls (decrease of 54.52%, p=0.012). Histologically, serious side-effects were found in the entire posterior globe with almost complete loss of the photoreceptors, the outer nuclear layer and the retinal pigment epithelium (RPE). CONCLUSIONS: Our new method of scleral collagen cross-linking proved very effective in increasing the scleral mechanical strength; the new treatment may represent an option for strengthening scleral tissue in progressive myopia. However, serious side-effects were observed in the outer retina. In future studies these side-effects could be avoided by reducing the irradiation dose below the cytotoxic level of the retina. Before its clinical application, the new method should be tested in a myopia animal model.

Expression of Ki-67 in squamous cell carcinoma of the penis.

OBJECTIVE: To investigate the Ki-67 labelling index (LI) as a prognostic factor for the outcome of penile carcinoma, as in squamous cell carcinoma (SCC) of the larynx the expression of this marker correlates with histological features indicative of prognosis. PATIENTS AND METHODS: We retrospectively analysed the records of 44 patients in whom primary SCC of the penis was treated with amputation and bilateral lymphadenectomy (pT1, in 24, pT2 in 20, pN+ in 10; G1 in 12, G2 in 28 and G3 in four). During a mean follow-up of 35.6 months, four patients had disease progression. Tumour tissue was stained immunohistochemically using the streptavidin-biotin method. The mean Ki-67 LI was defined as the percentage of total tumour cells that were Ki-67-positive. The results were compared with pathological tumour stage, grade, nodal status and clinical disease progression. RESULTS: The mean (range) Ki-67 LI was 40.5 (6.4-93.0)%; a high mean Ki-67 LI was significantly inversely correlated with tumour differentiation (P < 0.005) and there was a tendency for a high Ki-67 LI to be associated with advanced local tumour stage, nodal metastasis and clinical disease progression, but these correlations were not statistically significant (P = 0.07, 0.07 and 0.06, respectively). CONCLUSIONS: The Ki-67 LI is correlated with tumour grade in penile cancer, and may indicate a greater risk of nodal metastasis.

Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. METHODS: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. RESULTS: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change >3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin beta-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. CONCLUSION: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development.

Thermomechanical behavior of collagen-cross-linked porcine cornea.

PURPOSE: Collagen cross-linking using combined riboflavin/UVA treatment has been shown to increase the biomechanical rigidity of the cornea and has been used successfully for the treatment of progressive keratoconus. From morphological and biochemical investigations, a different degree of cross-linking for the anterior and posterior stroma by the treatment is suggested. The present study was undertaken to better evaluate this effect by testing the thermomechanical behavior. METHODS: Ten 10 x 5 mm corneal strips from porcine cadaver eyes enucleated within 5 h post mortem were cross-linked using the photosensitizer riboflavin and UVA irradiation (370 nm, irradiance = 3 mW/cm(2)) for 30 min and compared to ten untreated corneal strips and ten corneal strips cross-linked with 0.1% glutaraldehyde. The temperature in a water bath was raised from 60 to 95 degrees C with temperature increments of 1 degrees C per minute. The hydrothermal shrinkage of the corneal strips was measured in 2.5 degrees C steps using a micrometer. In addition, six 10-mm whole corneal buttons were cross-linked with riboflavin/UVA and immersed into water at 70 or 75 degrees C. RESULTS: The maximal hydrothermal shrinkage for the untreated control specimens and the posterior portion of the riboflavin/UVA-treated corneas was at 70 degrees C, for the anterior portion of the cornea cross-linked by riboflavin/UVA at 75 degrees C and for glutaraldehyde-cross-linked cornea at 90 degrees C. In the cross-linked corneal buttons, a typical mushroom-like shape was observed at 70 degrees C and a cylinder shape at 75 degrees C. CONCLUSIONS: The different degree of collagen cross-linking in the corneal stroma after riboflavin/UVA treatment is reflected by the differences in the maximal shrinkage temperature of the anterior and posterior portion. Therefore, in the corneas cross-linked with riboflavin/UVA a higher shrinkage temperature was observed for the anterior portion of the cornea (75 degrees C) compared to the posterior stroma (70 degrees C) due to the higher degree of cross-linking of the anterior stroma. The anterior localization of the cross-linking effect is advantageous for the endothelium and for the preservation of the anterior corneal curvature.

Large solitary fibrous tumor of the seminal vesicle.

Solitary fibrous tumors show a classic morphologic pattern ("patternless pattern") consisting mainly of a proliferation of bland spindle cells with varying amounts of thick, often hyalinized or keloid-like, intercellular collagen bundles. Immunohistochemistry shows a strong reactivity for CD34 antigen, vimentin, and, in a variable percentage, bcl-2 antigen. We report the case of a 50-year-old man with a large solitary fibrous tumor located in the pelvic cavity with a rare nonspecific histologic pattern of pseudovascular formations. The patient underwent pelvic exenteration with orthotopic continent urinary diversion and sigmoid-J-pouch bowel reconstruction. No signs of tumor recurrence were noted within 24 months of surgery.