Interplay Between Immune and Cancer-Associated Fibroblasts: A Path to Target Metalloproteinases in Penile Cancer

Extracellular matrix (ECM) remodeling and inflammation have been reported in penile carcinomas (PeCa). However, the cell types and cellular crosstalk involved in PeCa are unexplored. We aimed to characterize the complexity of cells and pathways involved in the tumor microenvironment (TME) in PeCa and propose target molecules associated with the TME. We first investigated the prognostic impact of cell types with a secretory profile to identify drug targets that modulate TME-enriched cells. The secretome analysis using the PeCa transcriptome revealed the enrichment of inflammation and extracellular matrix pathways. Twenty-three secreted factors were upregulated, mainly collagens and matrix metalloproteinases (MMPs). The deregulation of collagens and MMPs was confirmed by Quantitative reverse transcription - polymerase chain reaction (RT-qPCR). Further, the deconvolution method (digital cytometry) of the bulk samples revealed a high proportion of macrophages and dendritic cells (DCs) and B cells. Increased DCs and B cells were associated with better survival. A high proportion of cancer-associated fibroblasts (CAFs) was observed in low-survival patients. Patients with increased CAFs had decreased immune cell proportions. The treatment with the MMP inhibitor GM6001 in CAF cells derived from PeCa resulted in altered cell viability. We reported a crosstalk between immune cells and CAFs, and the proportion of these cell populations was associated with prognosis. We demonstrate that a drug targeting MMPs modulates CAFs, expanding the therapeutic options of PeCa

The study of the screening impact on clinical staging of patients with prostate cancer

INTRODUÇÃO: O câncer de próstata (CAP) é a neoplasia mais comum em homens (excluindo câncer de pele não-melanoma) com mais de 190.000 casos novos esperados em 2010 nos Estados Unidos sendo que mais de 27.000 morrerão em desta doença. No Brasil, segundo o Instituto Nacional do Câncer, a estimativa é em torno de 50 mil casos novos de CAP para 2010. OBJETIVOS: Avaliar a experiência do rastreamento para CAP realizado pelo Hospital de Câncer de Barretos através de uma Unidade Móvel de Prevenção de Câncer (UMPC), e verificar qual o impacto deste rastreamento no estádio clínico em comparação com pacientes diagnosticados e/ou encaminhados ao HCB. MATERIAL E MÉTODO: De janeiro de 2004 a dezembro de 2007, realizou-se rastreamento de CAP em voluntários acima de 45 anos através da UMPC em localidades com difícil acesso à saúde. Foram convocados homens com pelo menos um destes três critérios a seguir: a) PSA sérico = 4,0 ng/ml, b) toque retal suspeito, ou c) PSA entre 2,5 e 4,0 ng/ml com relação PSA livre/total (rPSAl/t) = 15%. Para se avaliar o impacto do rastreamento no estádio clínico ao diagnóstico dos pacientes portadores de CAP, analisaram-se os dois grupos. O grupo I inclui casos de CAP diagnosticados de janeiro de 2005 a dezembro de 2007, através da UMPC. O grupo II inclui pacientes com CAP atendidos pelo HCB no mesmo período, que não haviam feito diagnóstico pela UMPC; e foram encaminhados ao HCB por médicos de especialidades diversas, devido a PSA elevado e/ou TR suspeito realizado na xvii localidade de origem ou a diagnóstico histológico confirmado de CAP. A revisão de prontuários para os grupos realizou-se no serviço de arquivo médico (SAME) e utilizou-se a mesma ficha de coleta de dados, priorizando TNM, PSA e escore de Gleason. Os grupos I e II foram comparados com relação a estadiamento (TNM), PSA e escore de Gleason e feita análise estatística destes dados. RESULTADOS: De janeiro de 2004 a dezembro de 2007, foram rastreados 17.571 homens de 231 cidades brasileiras. Destes, 71,4% nunca tinham feito toque retal e 70,9% nunca fizeram PSA anteriormente. Foram biopsiados 1.647, 904 devido a PSA = 4,0 ng/ml (54,9%), 324 devido a TR suspeito (19,7%), 117 devido a alteração simultânea de ambos os anteriores (7,1%) e 302 quando a relação foi = 15% com PSA entre 2,5 e 3,9 ng/ml (18,3%). Foram diagnosticados 652 casos de CAP (3,7%). Destes, 609 (93,4%) clinicamente localizados (T1-2) e 43 (6,6%) foram T3-4. Na avaliação radiológica e cintilográfica, 26 (4%) eram N1 e 18 (2,8%) eram M1. Comparando-se os grupos, observou-se valores de PSA mais baixos (p<0.001), estadiamento clínico mais favorável (p<0,001), e escore de Gleason com menor grau para o grupo I (p<0.001). CONCLUSÕES: A UMPC mostrou ser uma ferramenta importante para se rastrear populações com acesso médico precário em um país com grande extensão territorial e desigualdades socioeconômicas como o Brasil. O rastreamento mostrou melhoria estatisticamente significativa do estadiamento clínico ao diagnóstico em relação aos pacientes diagnosticados na rotina do Hospital de Câncer de BarretosBACKGROUND: Prostate cancer (PC) is as the most common neoplasm in men (excluding skin cancer non-melanoma) with more than 190,000 new cases expected in 2009 in the United States and more than 27,000 will die from the disease. In Brazil, according to the Brazilian National Cancer Institute, the estimate is almost 50.000 new cases for 2009. OBJECTIVES: To assess the experience of PC screening conducted by the Barretos Cancer Hospital (BCH) through a mobile cancer prevention unit (MCPU), and to verify the impact of screening on clinical stage compared with patients diagnosed and/or referred to the HCB. MATERIAL AND METHODS: From January 2004 to December 2007, a PC screening was applied to volunteers over 45 years old through a MCPU which reached Brazilian locations with difficult access to health. Men with at least one of the following three criteria were called for further evaluation: a) serum PSA level = 4.0 ng/ml, b) suspicious digital rectal examination (DRE), or c) PSA level of 2.5-4.0 ng/mL and a percent-free PSA (%fPSA) level =15%. To assess the impact of screening on clinical stage at diagnosis of patients screened and non-screened, the men were analyzed in two groups. The PC cases screened from January 2005 to December 2007 through the MCPU constituted Group I. Comprising group II, there was patients with PC treated by BCH in the same period, who hadnt been diagnosed by the MCPU. These patients in group II were referred to hospital by xix physicians of several specialties, mainly due to elevated serum PSA and/either suspicion DRE or histological diagnosis of PC. The data for both groups was held in the medical records and used the same form, prioritizing the data for the TNM staging, PSA and Gleason score. Groups I and II were compared with concern to staging (TNM), PSA and Gleason score and the statistical analysis of these data was performed. RESULTS: From January 2004 to December 2007, 17,571 men from 231 Brazilian cities were screened. Among them 71.4% had never been submitted to DRE examination and 70.9% never had a PSA test. 1,647 men were submitted to biopsy, 904 due to PSA = 4.0 ng/ml (54.9%), 324 due to suspicion DRE (19.7%), 117 due the simultaneous of both earlier (7.1%) and 302 with %fPSA level =15% and PSA between 2.5-3.9 ng/ml (18.3%). It were diagnosed 652 cases of PC (3.7%). Among them, 609 (93.4%) were clinically localized (T1- 2) and 43 (6.6%) were T3-4. In the image exams, 26 (4%) were N1 and 18 (2.8%) were M1. The comparison between both groups showed lower serum PSA values (p <0.001), more favorable clinical stage (p <0.001) and Gleason score in group I (p <0.001). CONCLUSIONS: The MCPU has proved to be an important tool in screening populations with poor medical access in a country with large territory and socioeconomic inequalities such as Brazil. The screening showed statistically significant improvement of clinical staging at diagnosis compared to patients diagnosed in the routine of the BC

Evaluation of renal defect healing, hemostasis, and urinary fistula after Laparoscopic partial nephrectomy with oxidized cellulose

Background and Purpose: Laparoscopic partial nephrectomy (LPN) has been performed at several institutions using oxidized cellulose ( OC) as a means of bleeding and urinary fistula (UF) prevention. However, a foreign-body reaction mimicking either abscess or tumor recurrence has been associated with the use of OC. We evaluated renal-defect healing after LPN with and without OC.Materials and Methods: Sixteen female Landrace pigs underwent lower-pole excision; all the collecting systems were entered and then closed with absorbable running suture. in group 1, hemostatic U-shaped stitches were the only method of hemostasis. in group 2, a bolster of OC was added to the renal defect. the pigs were sacrificed at 1, 4, 7, or 21 days, and gross findings such as perirenal collection were observed. A catheter was advanced up to the kidney, and methylene blue was injected with collecting system pressure observation; burst pressure was defined as the appearance of extravasation. High risk for UF was defined as burst pressure <10 mm Hg.Results: Neither hemorrhage nor urinoma was observed during sacrifice. One pig from group 2 had a burst pressure of 4 mm Hg at 7 days ( high risk for UF). At 21 days in group 2, the tissue was grossly solid, apparently a granuloma. Suppuration tended to be greater in group 2. the foreign-body reaction was more intense in group 2 and was strongly present at 4, 7, and 21 days.Conclusions: the use of OC is associated with higher scores of suppuration and foreign-body reaction. After LPN with OC, postoperative day 7 might be a critical time for the development of urinary leakage.Universidade Federal de São Paulo, Div Urol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Expt Surg, São Paulo, BrazilUniversidade Federal de São Paulo, Div Urol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Expt Surg, São Paulo, BrazilWeb of Scienc