Matrix metalloproteinase-2 polymorphism is associated with prognosis in prostate cancer

Objective: Prostate cancer (PCa) is the most frequent tumor in males in Brazil. Single nucleotide polymorphisms (SNP) have been demonstrated in the promoter region of matrix metalloproteinases (MMPs) genes and have been associated with development and progression of some cancers. In this study, our aim was to investigate a possible relation between polymorphism of the promoter region of the MMP2 gene and classical prognostic parameters in prostate cancer. Materials and methods: Genomic DNA was extracted using conventional protocols. The DNA sequence containing the polymorphic site was amplified by real-time polymerase chain reaction, using fluorescent probes (TaqMan). Results: In patients with tumors of a higher stage (pT3), a polymorphic allele in the MMP2 gene was more frequent (P = 0.026) than in patients with lower tumor stage. A polymorphic allele in the MMP2 gene was more frequent in Gleason >= 7 than in Gleason <= 6 (P = 0.042). Conclusions: We conclude that MMP2 polymorphism can be used together with pathological stage and Gleason score to identify patients with worse prognosis. Our results illustrate the potential use of MMP2 SNP as a molecular marker for prostate cancer. (C) 2010 Elsevier Inc. All rights reserved.

Complete Clinical Response after Neoadjuvant Chemoradiation for Distal Rectal Cancer

Multimodality treatment of rectal cancer, with the combination of radiation therapy, chemotherapy, and surgery has become the preferred approach to locally advanced rectal cancer The use of neoadjuvant chemoradiation therapy (CRT) has resulted in reduced toxicity rates, significant tumor down-sizing and downstaging, better chance of sphincter preservation, and improved functional results A proportion of patients treated with neoadjuvant CRT may ultimately develop complete clinical response Management of these patients with complete clinical response remains controversial and approaches including radical resection, transanal local excision, and observation alone without immediate surgery have been proposed The use of strict selection criteria of patients after neoadjuvant CRT has resulted in excellent long-term results with no oncological compromise after observation alone in patients with complete clinical response Recurrences are detectable by clinical assessment and frequently amenable to salvage procedures

Submucosal Injection of 0.4% Hydroxypropyl Methylcellulose Facilitates Endoscopic Mucosal Resection of Early Gastrointestinal Tumors

Background and Aims: Submucosal injection of a viscoelastic solution prolongs submucosal lift, thus, facilitating endoscopic mucosal resection. Our objective was to assess the safety and clinical effectiveness of 0.4% hydroxypropyl methylcellulose (HPMC) as a submucosal injectant for endoscopic mucosal resection. Patients and Methods: A prospective, open-label, multicenter, phase 2 study was conducted at 2 academic institutions in Brazil. Eligible participants included patients with early gastrointestinal tumors larger than 10 mm. Outcomes evaluated included complete resection rates, volume of HPMC injected, duration of the submucosal cushion as assessed visually, histology of the resected leisons, and complication rates. Results: Over a 12-month period, 36 eligible patients with superficial neoplastic lesions (stomach 14, colon 11, rectum 5, esophagus 3, duodenum 3) were prospectively enrolled in the study. The mean size of the resected specimen was 20.4 mm (10 to 60 mm). The mean volume of 0.4% HPMC injected was 10.7 mL (range 4 to 35 mL). The mean duration of the submucosal fluid cushion was 27 minutes (range 9 to 70 min). Complete resection was successfully completed in 89%. Five patients (14%) developed immediate bleeding requiring endoclip and APC application. Esophageal perforation occurred in 1 patient requiring surgical intervention. There were no local or systemic adverse events related to HPMC use over the follow-up period (mean 2.2 mo). Conclusion: HPMC solution (0.4%) provides an effective submucosal fluid cushion and is safe for endoscopic resection of early gastrointestinal neoplastic lesions.

Meningeal carcinomatosis in breast cancer: prognostic factors and outcome

Meningeal carcinomatosis (MC) occurs in up to 5% of breast cancer patients. Few studies have evaluated prognostic markers in breast cancer patients with MC. Our aim was to describe the treatment of breast cancer patients with MC, and identify prognostic factors related to survival. Sixty breast cancer patients that had a diagnosis of MC between January 2003 and December 2009 were included. The median age was 46 years (range 27-76). Most patients had invasive ductal carcinoma (78.3%) and high histological/nuclear grade (61.7/53.3%). Estrogen and progesterone receptors were positive in 51.7 and 43.3% of patients, respectively, and 15% were HER-2-positive. Symptoms at presentation were headache, cranial nerve dysfunction, seizures, and intracranial hypertension signals. Diagnosis was made by CSF cytology in 66.7% of cases and by MRI in 71.7%. Intrathecal (IT) chemotherapy was used in 68.3% of patients, and 21.6% received a new systemic treatment (chemo- or hormone therapy). Median survival was 3.3 months (range 0.03-90.4). There was no survival difference according to age, nuclear grade, hormonal and HER-2 status, CSF features, sites of metastasis, systemic and IT chemotherapy, or radiotherapy. However, histological grade and performance status had a significant impact on survival in the multivariate analysis. Only four papers have addressed prognostic factors in breast cancer patients with MC in the last two decades. The results of those reports are discussed here. High histological grade and poor performance status seem to impact survival of breast cancer patients with MC. Prospective studies are necessary to clarify the role of IT and systemic treatment in the treatment of those patients.

Association Between Integrin Expression and Prognosis in Localized Prostate Cancer

BACKGROUND. Integrins and other adhesion molecules are essential for maintaining the epithelial phenotype. Some studies have reported correlations between abnormalities in their expression and carcinogenesis, but their role in prostate cancer is unclear. Our aim was to study the expression profile of integrins in surgical specimens of prostate cancer and associate their expression patterns with patient outcomes. METHODS. We selected 111 patients with localized prostate cancer who had undergone radical prostatectomy. Of these patients, 60 had no tumor recurrence after a median follow-up of 123 months. Integrin expression was evaluated by immunohistochemistry in a tissue microarray containing two tumor samples per patient. A semiquantitative analysis was employed. We measured the association between the expression of eight integrins and tumor recurrence. RESULTS. Multivariate analysis showed that expression of alpha 3 and alpha 3 beta 1 was related to worse outcome. When alpha 3 expression was strong and alpha 3 beta 1 expression was positive, the odds of recurrence were 3.0- and 2.5-fold higher, respectively. Only 19% and 28% of patients were recurrence-free in a mean period of 123 months of follow up when their tumors showed strong alpha 3 or positive alpha 3 beta 1 immuno-expression, respectively. CONCLUSIONS. We have shown that the expression of integrin alpha 3 beta 1 was independently associated with tumor recurrence after radical prostatectomy, suggesting that this integrin is a potential prognostic marker. Prostate 70: 1189-1195, 2010. (C) 2010 Wiley-Liss, Inc.

Systemic chemotherapy-induced microsatellite instability in the mononuclear cell fraction of women with breast cancer can be reproduced in vitro and abrogated by amifostine

Objectives Microsatellite instability (MSI) induction by alkylating agent-based chemotherapy (ACHT) may underlie both tumor resistance to chemotherapy and secondary leukaemias in cancer patients. We investigated if ACHT could induce MSI in tumor-derived plasma-circulating DNA (pfDNA) and in normal peripheral blood mononuclear (PBMN) cells. We also evaluated if amifostine could interfere with this process in an in-vitro model. Methods MSI was determined in pfDNA, PBMN cells and urine cell-free DNA (ufDNA) of 33 breast cancer patients before and after ACHT. MCF-7 cells and PBMN from normal donors were exposed in vitro to melphalan, with or without amifostine. Results We observed at least one MSI event in PBMN cells, pfDNA or ufDNA of 87, 80 and 80% of patients, respectively. In vitro, melphalan induced MSI in both MCF-7 and normal PBMN cells. In PBMN cells, ACHT-induced MSI occurred together with a significant decrease in the expression of the DNA mismatch repair gene hMSH2. Amifostine decreased hMSH2 expression and also prevented MSI induction only in normal PBMN cells. Conclusions ACHT induced MSI in PBMN cells and in tumour-derived pfDNA. Because of its protective effect against ACHT induction of MSI in normal PBMN cells in vitro, amifostine may be a potential agent for preventing secondary leukaemias in patients exposed to ACHT.

Down-regulation of the candidate tumor suppressor gene PAR-4 is associated with poor prognosis in breast cancer

Substantial experimental evidence indicates that PAWR gene (PKC apoptosis WT1 regulator; also named PAR-4, prostate apoptosis response-4) is a central player in cancer cell survival and a potential target for cancer-selective targeted therapeutics. However, little is known about the role of PAR-4 in breast cancer. We investigated the possible role of PAR-4 expression in breast cancer. IHC results on tissue microarrays containing 1,161 primary breast tumor samples showed that 57% (571/995) of analyzable cases were negative for PAR-4 nuclear staining. Down-regulation of nuclear PAR-4 protein expression predicted a poor prognosis for breast cancer patients (OS; P=0.041, log-rank test). PAR-4 down-regulation also correlates with poor survival in the group of patients with luminal A subtype breast cancer (P=0.028). Additionally, in this large series of breast cancer patients, we show that ERBB2/HER2, EGFR and pAKT protein expression are significantly associated with shorter disease-free survival and overall survival, but the prognosis was even worse for HER2-positive, EGFR-positive or pAKT-positive breast cancer patients with tumors negative for nuclear PAR-4 expression. Furthermore, using three-dimensional (3D) cell culture we provide preliminary results showing that PAR-4 is highly expressed in the MCF10A cells inside the acini structure, suggesting that PAR-4 might have a role in the lumen acini formation. Taken together, our results provide, for the first time, evidence that PAR-4 may have a role in the process of the mammary eland morphogenesis and its functional inactivation is associated with tumor aggressive phenotype and might represent an additional prognostic and predictive marker for breast cancer.

Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer: A Multi-institutional Collaboration

Background: Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined. Objective: To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP. Design, setting, and participants: This is a retrospective, international, multi-institutional cohort analysis. There was amedian follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers. Intervention: Open SRP. Measurements: BCR after SRP was defined as a serum prostate-specific antigen (PSA) >= 0.1 or >= 0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancerspecific death. Results and limitations: Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31-43), 77% (95% CI, 71-82), and 83% (95% CI, 76-88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period. Conclusions: In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in > 75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Short- and long-term survival of patients with metastatic solid cancer admitted to the intensive care unit: prognostic factors

Decisions for intensive care unit (ICU) admissions in patients with advanced cancer are complex, and the knowledge of survival rates and prognostic factors are essential to these decisions. Ours objectives were to describe the short- and long-term survival of patients with metastatic solid cancer admitted to an ICU due to emergencies and to study the prognostic factors presented at ICU admission that could be associated with hospital mortality. We retrospectively analysed the charts of all patients with metastatic solid cancer admitted over a 1-year period. This gave a study sample of 83 patients. The ICU, hospital, 1-year and 2-year survival rates were 55.4%, 28.9%, 12.0% and 2.4% respectively. Thrombocytopenia (odds ratio 26.2; P = 0.006) and simplified acute physiology score (SAPS II) (odds ratio 1.09; P = 0.026) were independent factors associated with higher hospital mortality. In conclusion, the survival rates of patients with metastatic solid cancer admitted to the ICU due to emergencies were low, but of the same magnitude as other groups of cancer patients admitted to the ICU. The SAPS II score and thrombocytopenia on admission were associated with higher hospital mortality. The characteristics of the metastatic disease, such as number of organs with metastasis and central nervous system metastasis were not associated with the hospital mortality.

E-cadherin and beta-catenin Loss of Expression Related to Bone Metastasis in Prostate Cancer

Objectives: E-cadherin and beta-catenin are adhesion molecules responsible for the maintenance of normal epithelial cell phenotype. A disturbance in epithelial cell adhesion, which leads to a more invasive and metastatic phenotype, is a hallmark of tumor progression. Several immunohistochemical studies have reported a strong correlation between loss of their expression to higher stage and grade in prostate carcinoma, but their influence in metastatic process is not yet known. The aim of this study is to verify the role of adhesion molecules in the progression of prostate cancer (PC), assessing the expression of E-cadherin and beta-catenin in bone metastasis. Materials and Methods: Twenty-eight bone metastases of prostate carcinoma were submitted to immunohistochemistry analysis for E-cadherin and beta-catenin expression. In 6 patients, we were able to assess the expression of the adhesion molecules in the primary tumors and their respective metastases. The definition of normal expression for both antibodies was strong and diffuse expression in more than 70% of tumor cells. Results: In bone metastases, there was loss of expression of E-cadherin and beta-catenin in 86% and 82%, respectively. Among the primary tumors, E-cadherin and beta-catenin expression was normal in 83% and 50% cases, respectively. Considering the 6 patients with paired primary and bone metastasis, we found loss of expression for both E-cadherin and beta-catenin in most of the cases. Conclusions: Comparing primary PC and its metastasis, we showed persistent loss of E-cadherin and beta-catenin expression. This phenomenon may be related to metastatic potential in PC, because we have shown underexpression for E-cadherin and beta-catenin in 86% and 82% of bone metastases.

Establishment and characterization of human bladder cancer cell lines BexBra1, BexBra2, and BexBra4

Bladder cancer (BC) is the fourth most common cancer in the USA. In Brazil, BC represents 3% of the total existing carcinomas in the population and represents the second highest incidence among urological tumors. The majority of bladder cancer cell lines available were derived from Caucasians and established in the seventies or eighties. Thus, neoplasia development in these cells likely occurred in environment conditions vastly different than today. In the present study, we report the establishment and characterization of three Brazilian bladder cancer cell lines (BexBra1, BexBra2, and BexBra4). These cell lines may be helpful for dissecting the genetic and epigenetic aspects that trigger the progression of BC. Moreover, the development of a Brazilian representative of the disease will allow us to investigate the potential inter-racial differences of malignancy-associated phenotypes in bladder cancer.

Combination of Multiple Molecular Markers Can Improve Prognostication in Patients With Locally Advanced and Lymph Node Positive Bladder Cancer

Purpose: We tested whether the combination of 4 established cell cycle regulators (p53, pRB, p21 and p27) could improve the ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder. We also assessed whether the combination of molecular markers is superior to any individual biomarker. Materials and Methods: The study comprised 692 patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder treated with radical cystectomy and bilateral lymphadenectomy (median followup 5.3 years). Scoring was performed using advanced cell imaging and color detection software. The base model incorporated patient age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of positive lymph nodes, concomitant carcinoma in situ and adjuvant chemotherapy. Results: Individual molecular markers did not improve the predictive accuracy for disease recurrence and cancer specific mortality. Combination of all 4 molecular markers into number of altered molecular markers resulted in significantly 1 higher predictive accuracy than any single biomarker (p < 0.001.). Moreover addition of number of altered molecular markers to the base model significantly improved the predictive accuracy for disease recurrence (3.9%, p < 0.001) and cancer specific mortality (4.3%, p < 0.001). Addition of number of altered molecular markers retained statistical significance for improving the prediction of clinical outcomes in the subgroup of patients with pT3N0 (280), pT4N0 (83) and pTany Npositive (329) disease (p < 0.001). Conclusions: While the status of individual molecular markers does not add sufficient value to outcome prediction in patients with advanced urothelial carcinoma of the bladder, combinations of molecular markers may improve molecular staging, prognostication and possibly prediction of response to therapy.

Lymphadenectomy in Colorectal Cancer Liver Metastases Resection: Incidence of Hilar Limph Nodes Micrometastasis

Background: Liver resection is considered the best treatment for metastatic colorectal cancer. Several prognostic factors have been investigated, and many studies have shown that hepatic hilum lymph nodes involvement has a negative impact on prognosis. The present study evaluated the frequency of microscopic involvement of hilar lymph nodes, through systematic lymphadenectomy and analysis of micrometastases in patients undergoing hepatectomy due to colorectal metastasis. Methods: A total of 28 patients underwent hepatic resection with hilar lymphadenectomy. Lymph nodes considered negative by conventional hematoxylin and eosin (H&E) staining were analyzed by serial sectioning with 100-mu m intervals and immunohistochemistry (IHC) with antihuman pancytokeratin antibody AE1/AE3. Results: In average, 6.18 lymph nodes were dissected per patient. No morbidity or mortality was associated to lymphadenectomy. In two patients, conventional H&E analysis showed presence of microscopic lymph node metastasis. H&E analysis allowed the identification of three other patients with lymph node micrometastases. The overall frequency of microscopic metastases, including micrometastasis, was 18%. Conclusions: Systematic lymphadenectomy allowed the detection of microscopic lymph node metastases, resulting in more accurate staging of extrahepatic disease. The inclusion of IHC increased the detection of lymph node micrometastasis. J. Surg. Oncol. 2009;100:534-537. (C) 2009 Wiley-Liss, Inc.

Predictive models for diagnosis of pleural effusions secondary to tuberculosis or cancer

Background and objective: Tuberculosis (TB) and cancer are two of the main causes of pleural effusions which frequently share similar clinical features and pleural fluid profiles. This study aimed to identify diagnostic models based on clinical and laboratory variables to differentiate tuberculous from malignant pleural effusions. Methods: A retrospective study of 403 patients (200 with TB; 203 with cancer) was undertaken. Univariate analysis was used to select the clinical variables relevant to the models composition. Variables beta coefficients were used to define a numerical score which presented a practical use. The performances of the most efficient models were tested in a sample of pleural exudates (64 new cases). Results: Two models are proposed for the diagnosis of effusions associated with each disease. For TB: (i) adenosine deaminase (ADA), globulins and the absence of malignant cells in the pleural fluid; and (ii) ADA, globulins and fluid appearance. For cancer: (i) patient age, fluid appearance, macrophage percentage and presence of atypical cells in the pleural fluid; and (ii) as for (i) excluding atypical cells. Application of the models to the 64 pleural effusions showed accuracy higher than 85% for all models. Conclusions: The proposed models were effective in suggesting pleural tuberculosis or cancer.

Iliac-hepatic arterial bypass for compromised collateral flow during modified Appleby operation for advanced pancreatic cancer

Involvement of the celiac trunk and common hepatic artery are two of the most common forms of vascular invasion by tumours of the distal pancreas, and until recently this finding was considered a contra-indication to resection. We described a modified Appleby operation for locally advanced distal pancreatic cancer with compromised hepatic collateral flow that needed hepatic arterial revascularization, successfully accomplished by left external iliac-hepatic arterial bypass with Dacron prosthesis. Patient recovery was uneventful and he was discharged on the 10th postoperative day. Postoperative angio-CT disclosed a patent arterial bypass. Patient is well and asymptomatic 13 months after operation. At the time of this writing, postoperative CT scan showed no evidence of disease and CA 19-9 level is normal. There is a well established rationale to perform extended resection of pancreatic carcinomas that compromise vascular structures. Modified Appleby procedure can safely be performed, has oncological advantages to palliative procedures and provides relief of pain but is reserved for selected patients. Preservation of hepatic arterial flow has utmost importance to avoid hepatobiliary complications as liver necrosis, liver abscess, gallbladder necrosis or cholecystitis. In this case, hepatic revascularization was particularly challenging, but was successfully accomplished by left external iliac-hepatic arterial bypass. To our knowledge this type of arterial bypass has never been described so far in the English literature and its description may be important for surgeons dealing with advanced pancreatic cancer. (C) 2009 Elsevier Ltd. All rights reserved.