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Purpose: Androgens stimulate the production of hypoxia-inducible factor (HIF1α) and ultimately vascular endothelial growth factor (VEGF-A). Additionally, epithelial growth factor (EGF) mediates HIF1α production. Carbonic anhydrase IX (CAIX) expression is associated with tumor cell hypoxia in a variety of malignancies. This study assesses the prognostic relation between HIF1α, VEGF-A, EGF Receptor and CAIX expression by immunochemistry in diagnostic samples of patients with intermediate- and high-risk localized prostate cancer treated with radiation therapy, with or without androgen deprivation therapy (ADT)., Materials and Methods: Between 1994 and 2004, 103 prostate cancer patients (mean age, 68.7 ± 6.2), with prostate cancer (mean PSA, 13.3 ± 3.7), were treated with radiation therapy (RT, median dose, 74 Gy). Fifty seven (55.3%) patients received ADT (median duration, 6 months; range, 0 - 24). Median follow-up was 97.6 months (range, 5.9 - 206.8)., Results: Higher EGFR expression was significantly (p = 0.04) correlated with higher Gleason scores. On univariate analysis, HIF1α nuclear expression was a significant (p = 0.02) prognostic factor for biological progression-free survival (bPFS). A trend towards significance (p = 0.05) was observed with EGFR expression and bPFS. On multivariate analysis, low HIF1α nuclear (p = 0.01) and high EGFR (p = 0.04) expression remained significant adverse prognostic factors., Conclusions: Our study suggests that high nuclear expression of HIF1α and low EGFR expression in diagnostic biopsies of prostate cancer patients treated with RT ± ADT is associated with a good prognosis.

Epstein-Barr virus (EBV) is associated with several types of cancers including Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC). EBV-encoded latent membrane protein 1 (LMP1), a multifunctional oncoprotein, is a powerful activator of the transcription factor NF-κB, a property that is essential for EBV-transformed lymphoblastoid cell survival. Previous studies reported LMP1 sequence variations and induction of higher NF-κB activation levels compared to the prototype B95-8 LMP1 by some variants. Here we used biopsies of EBV-associated cancers and blood of individuals included in the Swiss HIV Cohort Study (SHCS) to analyze LMP1 genetic diversity and impact of sequence variations on LMP1-mediated NF-κB activation potential. We found that a number of variants mediate higher NF-κB activation levels when compared to B95-8 LMP1 and mapped three single polymorphisms responsible for this phenotype: F106Y, I124V and F144I. F106Y was present in all LMP1 isolated in this study and its effect was variant dependent, suggesting that it was modulated by other polymorphisms. The two polymorphisms I124V and F144I were present in distinct phylogenetic groups and were linked with other specific polymorphisms nearby, I152L and D150A/L151I, respectively. The two sets of polymorphisms, I124V/I152L and F144I/D150A/L151I, which were markers of increased NF-κB activation in vitro, were not associated with EBV-associated HL in the SHCS. Taken together these results highlighted the importance of single polymorphisms for the modulation of LMP1 signaling activity and demonstrated that several groups of LMP1 variants, through distinct mutational paths, mediated enhanced NF-κB activation levels compared to B95-8 LMP1.

Recent findings have attested the protective effects of erythropoietin (EPO) in ischemically challenged organs. We therefore aimed at elaborating the underlying mechanism of EPO-mediated protection in musculocutaneous tissue undergoing persistent ischemia after acute injury. Mice were assigned to five experimental groups equipped with a randomly perfused flap fixed in a dorsal skinfold chamber, whereas the sixth group did not undergo flap preparation: EPO, L-Name, EPO and L-Name, EPO and bevacizumab, untreated flap, and nonischemic chamber (control). Intravital fluorescence microscopic analysis of microhemodynamics, apoptotic cell death, macromolecular leakage and angiogenesis was carried out over a 10-day period. Further, immunohistochemical analysis was used to study the protein expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF). Increased expression of eNOS in EPO-administered mice correlated with significant arteriolar dilation and thus increased blood flow resulting in a maintained functional capillary density (FCD) at day 10. In addition, EPO induced a VEGF upregulation, which was associated with newly formed capillaries. In addition, EPO was able to reduce ischemia-induced apoptotic cell death and finally to significantly reduce flap necrosis. In contrast, coadministration of L-Name abolished EPO-mediated tissue protection by abrogating the dilatory effect resulting in reduced FCD and tissue survival, without counteracting angiogenesis and apoptotic cell death, whereas additional administration of bevacizumab did not influence the beneficial effect of EPO on flap survival despite abrogating angiogenesis. Macromolecular leakage was found to be increased in all treatment groups. This study shows that EPO administration prevents musculocutaneous tissue from ischemic necrosis as a consequence of an eNOS-dependent arteriolar hyperperfusion maintaining capillary perfusion, thus representing a promising approach to pharmacologically protect ischemically challenged tissue.

Background: Sentinel lymph node (SLN) biopsy plays a major role in the surgical management of primary breast cancer. The aim of this study was to assess the diagnostic accuracy of the assessment of axillary frozen sections of SLNs for micrometastasis diagnosis., Patients and Methods: This study focused on 278 SLNs from 149 patients. Each lymph node was fully analyzed by frozen section. After fixation, serial sections were cut and stained by hematoxylin and eosin (HE) and for pan-cytokeratins by immunohistochemistry (IHC)., Results: Tumor cells were detected in 63 SLNs, 41 on frozen sections and 22 on controls. Of these 63 positive SLNs, 42 contained metastases, 10 contained micrometastases and 11 contained isolated tumor cells. The specificity and positive predictive value of SLN frozen sections for micrometastasis was 100%. The sensitivity was 83.3% for metastasis, 40% for micrometastasis; the false-negative rate was 16.7% for metastasis and 60% for micrometastasis., Conclusion: Analysis of frozen section of SLNs is an accurate method for metastasis detection, allowing concurrent axillary dissection when positive. The protocol for SLN analyses described herein shows good sensitivity for micrometastasis detection.

Background: The category "atypical glandular cells" (AGC) in The Bethesda System (TBS) 2001 represents equivocal glandular atypia. The objective was to determine the clinical significance of diagnosing AGC using new TBS 2001 on Thin-Prep. There is scant information on the diagnosis of AGC and its outcome on ThinPrep using TBS 2001., Methods: 174 "ThinPrep" Pap tests reported as atypical glandular cells of unknown significance (AGUS) using TBS 1991 during the period (2001-2004) were reclassified using AGC subcategories of TBS 2001. Follow-up histology was correlated with AGC subcategories of TBS 2001 and in women <40 and >or=40 years of age., Results: The mean AGC rate significantly decreased from 0.7% to 0.3%. (p <0.02). The frequency of clinically significant lesions on followup was higher with AGC diagnosis (51%, 21/41) than AGUS diagnosis (36%, 37/103). It was significantly higher for atypical endocervical cells favouring neoplasia (AEC-FN) (67%, 4/6) and AGC with concurrent squamous intraepithelial lesions (SIL) (67%, 8/12) than for the atypical endocervical cells, not otherwise specified (AECNOS) subcategory (12.5%, 2/16). All clinically significant lesions were high grade squamous intraepithelial lesions (HSIL) in women <40 years but in women >or=40 years, the majority (70%) were glandular. In categories atypical glandular cells favouring neoplasia (AGC-FN) and atypical endometrial cells (AEMC) all women had clinically significant glandular lesions., Conclusions: AEC-FN, AGC-FN, AEMC and AGC with concurrent SIL subcategories represented high risk diagnoses. The sequence of further investigations may vary by age and presence of postmenopausal bleeding.

The rupture of an intra-abdominal testicular neoplasm is a rare cause of acute abdomen and massive intra-abdominal haemorrhage. We report the case of a 70-year-old male presenting a massive intra-abdominal bleeding caused by a Leydig cell tumour in an undescended testis. The clinical details and pathology of this rare testicular tumour are discussed.

Background: A low yield of lymph nodes (LN) in abdominoperineal resection (APR) specimen has been associated with preoperative radiation therapy (XRT) in population-based studies, which may preclude adequate staging of anorectal carcinomas. We hypothesized that the number of LN retrieved in APR specimen was correlated with the dose and the timing of pelvic irradiation., Patients and Methods: We performed a retrospective study of 102 patients who underwent APR in a single institution between 1980 and 2004. Pathological reports were reviewed and the number of lymph nodes retrieved in APR specimens was correlated with: 1) Preoperative radiation; 2) Dose of pelvic irradiation; and 3) Time interval between the end of XRT and surgery., Results: There were 61 men and 41 women, with a median age of 66 (range 25-89) years. There were 12 patients operated for squamous cell carcinoma of the anal canal (SCCA) and 90 for rectal cancer. 83% and 46% of patients with anal and rectal cancer respectively underwent radical/neoadjuvant radiotherapy. The mean +/- SD number of LN in APR specimen was 9.2 +/- 5.9. The mean number of LN in APR specimen was significantly lower in patients who underwent preoperative XRT (8 +/- 5.5 vs. 10.5 +/- 6.1, Mann-Whitney U test, p = 0.02). The mean number of LN was not significantly different after XRT in patients with SCCA than in patients with rectal cancer (6.2 +/- 5.3 vs. 7.8 +/- 5.3, p = 0.33). Finally, there was an inverse correlation between the yield of LN and the time elapsed between XRT and surgery (linear regression coefficient r = -0.32, p = 0.03)., Conclusion: Our data indicate that: 1) radiation therapy affects the yield of LN retrieval in APR specimen; 2) this impact is time-dependent. These findings have important implications with regard to anatomic-pathological staging of anal and rectal cancers and subsequent decision-making regarding adjuvant chemotherapy.

Purpose: This study was undertaken to assess which ultrasound-derived parameter was superior for measuring venous reflux quantitatively and to evaluate the importance of popliteal vein valve reflux., Patients and Methods: A retrospective analysis was performed of 244 refluxive limbs in 182 patients who underwent ultrasound scanning, venous pressure measurement, air plethysmography, and clinical classification of severity according to the CEAP score. Reflux time (RT, s), peak reflux velocity (PRV, m/s), time of average rate of reflux (TAF, mL/min), absolute displaced volume retrogradely (ADV, mL) were compared to clinical class, ambulatory venous pressure (% drop), venous filling time (s), and venous filling index (mL/s) using nonparametric statistical tests. A P value of <.05 was considered significant. Limbs were divided into 3 groups: (A) axial great saphenous vein reflux only (n = 68); (B) axial deep reflux including popliteal vein incompetence with or without concomitant gastrocnemius or great or small saphenous vein reflux (all ultrasound reflux parameters of each refluxive vein added at the knee level) (n = 79); and (C) all limbs with popliteal vein reflux (the ultrasound data of the refluxive popliteal vein exclusively was used in comparison regardless of concomitant associated reflux) (n = 103). Limbs were also stratified into limbs with skin changes and ulcer (C-class 4-6) and those without (C-class 1-3) and subsequently compared., Results: No meaningful significant correlation was found between RT and the clinical and hemodynamic results in groups A and B. The PRV and TAF correlated significantly with the hemodynamic parameters. The PRV and TAF and clinical severity trended towards correlation in group A (P =.0554 and P =.0998, respectively), but was significantly correlated in group B. The poor hemodynamic condition in the subset of C-class 4-6 limbs in groups A and B was reflected in a greater PRV, TAF, and ADV in this subset as compared with the limbs in C-class 1-3. RT was not significantly different in the subsets of limbs, further suggesting that RT is not related to hemodynamic or clinical state of the limbs. No meaningful correlations were found in group C. Although the hemodynamic data were significantly poorer in the subset of limbs with C-class 4-6 than in C-class 1-3, the ultrasound-derived parameters were not significantly different., Conclusion: The duration of valve reflux time (or valve closure time) cannot be used to quantify severity of reflux and is purely a qualitative measurement. The PRV and the rate of reflux appeared to better reflect the magnitude of venous incompetence. In the presence of axial reflux, it appeared logical and physiologically correct to sum up these reflux parameters for each venous segment crossing the knee. The popliteal valve reflux (the "gatekeeper" function) was not in itself an important determinant of venous hemodynamics and clinical severity. Additional reflux in other venous segments must be taken into account.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the digestive tract. Most gastrointestinal soft tissue neoplasms, previously classified as leiomyomas, schwannomas, leiomyoblastomas or leiomyosarcomas, are today classified as GIST on the basis of molecular and immunohistological features. They originate from gastrointestinal pacemaker cells and are characterised by over-expression of the tyrosine kinase receptor KIT. Overall 5-year survival after surgical resection of GIST is approximately 60%. However, these tumours span a wide clinical spectrum from benign to highly malignant. Prognostic factors have recently been identified for GIST and include tumour size, mitotic rate and other minor factors. At present, surgery is the standard treatment for primary resectable GIST. Benign GIST have an excellent prognosis after primary surgical treatment, with over 90% 5-year survival. While recurrent or malignant GIST, which are resistant to radiotherapy and chemotherapy, had until recently an extremely poor prognosis even after surgical resection, with median survival of 12 months. The development of a tyrosine kinase inhibitor has changed the management of unresectable malignant cases. This new tyrosine kinase inhibitor, imatinib mesylate, which inhibits the c-kit receptor, has proved highly effective against GIST and has improved survival in metastatic GIST. This paper reviews the literature and our experience of GIST, including: diagnosis, pathology, treatment and prognosis.

Development of a soft-tissue sarcoma is an infrequent but well-known long-term complication of radiotherapy. Malignant fibrous histiocytomas, extraskeletal osteosarcomas, fibrosarcomas, malignant peripheral nerve sheath tumors, and angiosarcomas are most frequently encountered. Radiation-associated synovial sarcomas are exceptional. We report the clinicopathologic, immunohistochemical, and molecular features of two radiation-associated synovial sarcomas. One tumor developed in a 42-year-old female 17 years after external irradiation was given for breast carcinoma; the other occurred in a 34-year-old female who was irradiated at the age of 7 years for a nonneoplastic condition of the left hand. Both lesions showed morphologic features of monophasic spindle cell synovial sarcoma, were immunoreactive for cytokeratins, epithelial membrane antigen, CD99, CD117 (c-kit), and bcl-2 and bore the t(X;18) (SYT-SSX1) translocation. We conclude that synovial sarcoma has to be added to the list of radiation-associated soft-tissue sarcomas.