L’inclusion récente de la profondeur d’invasion (PI) dans la classification des carcinomes épidermoïdes de la cavité orale de l’American Joint Committee on Cancer (AJCC) a des répercussions cliniques majeures. Plusieurs études ont récemment évalué la fiabilité de diverses modalités d’imagerie et techniques de biopsie pour mesurer la PI en préopératoire. L’objectif premier de ce mémoire est de réviser systématiquement la littérature et comparer les différentes méthodes décrites de mesure de PI en préopératoire pour les carcinomes épidermoïdes de la langue mobile. Le second objectif est d’étudier la précision et la fiabilité de la mesure de PI sur une biopsie au poinçon dans les carcinomes épidermoïdes de stade in situ (Tis)-T1-T2, N0 de la langue mobile. Une revue systématique a été effectuée en suivant le guide PRISMA[1]. Les études évaluant la fiabilité de la PI mesurée sur la biopsie ou l’imagerie médicale, en les comparant à la PI histopathologique finale, ont été inclues dans une méta-analyse afin d’obtenir des coefficients de corrélation combinés pour chaque modalité d’imagerie. L’imagerie par résonnance magnétique (IRM) s’est avérée être la modalité d’imagerie la mieux étudiée et présente une bonne fiabilité. Le computed tomography (CT) scan est peu étudié, mais semble moins fiable. L’échographie linguale ne peut être comparée à ces deux modalités d’imagerie car elle est plus fréquemment utilisée pour mesurer l’épaisseur tumorale que la PI. La seconde étude est une preuve de concept prospective. Un poinçon profond a été utilisé pour échantillonner la portion la plus profonde de carcinomes épidermoïdes de la langue mobile de stade Tis-T1-2, N0 chez 27 patients. Des coefficients de corrélation de Spearman ont été calculés entre la PI estimée à la palpation manuelle, mesurée à la biopsie, et à l’histopathologie. La sensibilité et la spécificité de la biopsie au poinçon pour distinguer le Tis du carcinome épidermoïde invasif ont été calculées. Bien que la PI mesurée à la biopsie ne corrèle pas fortement avec la PI histopathologique, cette preuve de concept est limitée par la taille d’échantillon. La biopsie au poinçon semble toutefois être un outil fiable pour distinguer le Tis de l’invasif. D’autres études sont nécessaires avant de pouvoir recommander l’utilisation systématique de la biopsie pour décider en préopératoire si un évidement cervical électif est nécessaire. / The inclusion of depth of invasion (DOI) in the American Joint Committee on Cancer’s staging system for oral cavity squamous cell carcinoma (SCC) has major clinical impacts. Recent studies have evaluated the reliability of imaging modalities and biopsy techniques to measure DOI preoperatively. The first objective of this master’s thesis is to systematically review and compare the preoperative DOI measurement methods that have been studied so far in oral tongue SCC (OTSCC). The second objective is to prospectively study the precision and reliability of punch biopsy to measure DOI preoperatively in early (in situ (Tis)-T1-T2, N0) OTSCC, and its ability to distinguish Tis from invasive carcinoma. A systematic review was conducted according to the PRISMA guidelines. Studies that evaluated the reliability of DOI measured on biopsy or imaging (rDOI) by comparing it to DOI on histopathology (pDOI) were included in a meta-analysis to obtain pooled correlation coefficients for each imaging modality. Overall, magnetic resonance imaging (MRI) is the better studied modality. It has a good reliability to measure preoperative rDOI in OTSCC. CT is less studied but appears to be less reliable. Ultrasound (US) cannot be compared to these imaging modality as it has been used more often to measure tumor thickness (TT) than DOI. The second study is a prospective proof-of-concept. A deep punch biopsy was used to sample tumors preoperatively in the deepest part of the tumor in 27 patients with early (Tis-T12, N0) oral tongue squamous cell carcinoma. Spearman’s correlations were calculated between DOI measured on digital palpation (cDOI), biopsy (bDOI) and final pDOI. The sensitivity and specificity of punch biopsy to distinguish Tis from invasive carcinoma was also calculated. Although bDOI does not seem to correlate strongly with pDOI, this proof-of-concept was limited by a small sample size. Punch biopsy appears to be a reliable tool to distinguish Tis from invasive carcinoma. Further studies on punch biopsy are needed to recommend its use to evaluate pDOI preoperatively and determine whether elective neck dissection is necessary in early OTSCC.

O adenocarcinoma prostático (ACP) é um tumor freqüente, que ocupa a segunda posição tanto em mortalidade quanto em incidência dentre as neoplasias malignas masculinas. O estadiamento local do ACP, que consiste na avaliação de extensão extracapsular (EEC) e invasão das vesículas seminais, tem importância fundamental na escolha do tratamento adequado e no prognóstico da doença, destacando-se que a prostatectomia radical é geralmente considerada o tratamento de escolha em tumores confinados à próstata. Os exames clínico-laboratoriais, e a graduação histológica de Gleason pré-operatória, não apresentam eficácia adequada no estadiamento local destes tumores, com elevadas taxas de subestadiamento. O objetivo deste trabalho foi comparar as eficácias da ultra-sonografia endorretal com power-Doppler (USD) e da ressonância magnética com bobina endorretal (RM) no estadiamento local do ACP. Quarenta e dois pacientes com diagnóstico de ACP confirmado por biópsia prostática foram prospectivamente estudados por RM, e 36 destes foram estudados também por USD, sendo os achados obtidos por estes métodos comparados com aqueles observados no estudo anátomo-patológico (AP) pós-prostatectomia radical. Na avaliação de extensão extracapsular por sextantes contíguos, os resultados de sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e acurácia para EEC foram persistentemente superiores para a RM em relação ao USD, devendo-se salientar que tanto a RM quanto o USD apresentaram altos valores de especificidade ( > 85%), considerado o critério mais importante no sentido de se evitar diagnósticos falso-positivos. Tanto o USD quanto a RM apresentaram acurácia adequada na avaliação de invasão das vesículas seminais. No USD, foi observada associação estatisticamente significante entre abaulamento irregular do contorno prostático e presença de EEC, enquanto na RM, os critérios de abaulamento irregular do contorno prostático e principalmente presença de tecido sólido na gordura periprostática apresentaram associação estatisticamente significante com EEC. Os resultados obtidos mostraram que o emprego dos métodos de imagem no estadiamento local pode reduzir as taxas de subestadiamento clínico. Observou-se também que ambos os métodos apresentam baixa especificidade na localização tumoral, e que não houve diferença significativa na avaliação do volume prostático pelo USD, RM e AP. / Prostatic adenocarcinoma is a common tumor, corresponding to the second most common type of cancer and the second most common cause of cancer deaths among men. Local staging of prostatic cancer, which consists in the evaluation of extracapsular extension and seminal vesicle invasion, is an important factor for the prognosis and treatment of the disease, being radical prostatectomy one of the gold-standard treatment modalities for localized cancers. Rectal exam, PSA levels and pre-surgical Gleason stage are not reliable exams for local staging, with high understaging scores. The purpose of this study was the evaluation of endorectal power-Doppler ultrasound (US) and endorectal magnetic resonance imaging (MRI) for local staging of prostate cancer. Forty-two patients with biopsy-proven prostatic cancer were prospectively studied with endorectal MRI, and 36 of them were also studied with endorectal Doppler US, with the imaging results compared to the post-surgical hystopathological results.Sensitivity, specificity, positive predictive value, negative predictive value and accuracy results for extracapsular spread of disease were better for MRI than for US, however both methods obtained high ( > 85%) specificity results, which is considered the most important criteria for local staging. Accuracy for seminal vesicle invasion was adequate for both USD and MRI. At US, statistically significant correlation was observed between extracapsular extension of tumor and irregular bulging of the prostatic contour, while at MRI, statistically significant correlation was observed for irregular bulging and extraprostatic solid tissue. Our results showed that the use of imaging methods for local staging of prostatic tumors could reduce the rates of clinical understaging. Additional findings were the low specificity of both imaging methods for tumor localization, and the absence of differences between US, MRI and pathology for prostatic volume measurement.

O adenocarcinoma prostático (ACP) é um tumor freqüente, que ocupa a segunda posição tanto em mortalidade quanto em incidência dentre as neoplasias malignas masculinas. O estadiamento local do ACP, que consiste na avaliação de extensão extracapsular (EEC) e invasão das vesículas seminais, tem importância fundamental na escolha do tratamento adequado e no prognóstico da doença, destacando-se que a prostatectomia radical é geralmente considerada o tratamento de escolha em tumores confinados à próstata. Os exames clínico-laboratoriais, e a graduação histológica de Gleason pré-operatória, não apresentam eficácia adequada no estadiamento local destes tumores, com elevadas taxas de subestadiamento. O objetivo deste trabalho foi comparar as eficácias da ultra-sonografia endorretal com power-Doppler (USD) e da ressonância magnética com bobina endorretal (RM) no estadiamento local do ACP. Quarenta e dois pacientes com diagnóstico de ACP confirmado por biópsia prostática foram prospectivamente estudados por RM, e 36 destes foram estudados também por USD, sendo os achados obtidos por estes métodos comparados com aqueles observados no estudo anátomo-patológico (AP) pós-prostatectomia radical. Na avaliação de extensão extracapsular por sextantes contíguos, os resultados de sensibilidade, especificidade, valor preditivo positivo, valor preditivo negativo e acurácia para EEC foram persistentemente superiores para a RM em relação ao USD, devendo-se salientar que tanto a RM quanto o USD apresentaram altos valores de especificidade ( > 85%), considerado o critério mais importante no sentido de se evitar diagnósticos falso-positivos. Tanto o USD quanto a RM apresentaram acurácia adequada na avaliação de invasão das vesículas seminais. No USD, foi observada associação estatisticamente significante entre abaulamento irregular do contorno prostático e presença de EEC, enquanto na RM, os critérios de abaulamento irregular do contorno prostático e principalmente presença de tecido sólido na gordura periprostática apresentaram associação estatisticamente significante com EEC. Os resultados obtidos mostraram que o emprego dos métodos de imagem no estadiamento local pode reduzir as taxas de subestadiamento clínico. Observou-se também que ambos os métodos apresentam baixa especificidade na localização tumoral, e que não houve diferença significativa na avaliação do volume prostático pelo USD, RM e AP. / Prostatic adenocarcinoma is a common tumor, corresponding to the second most common type of cancer and the second most common cause of cancer deaths among men. Local staging of prostatic cancer, which consists in the evaluation of extracapsular extension and seminal vesicle invasion, is an important factor for the prognosis and treatment of the disease, being radical prostatectomy one of the gold-standard treatment modalities for localized cancers. Rectal exam, PSA levels and pre-surgical Gleason stage are not reliable exams for local staging, with high understaging scores. The purpose of this study was the evaluation of endorectal power-Doppler ultrasound (US) and endorectal magnetic resonance imaging (MRI) for local staging of prostate cancer. Forty-two patients with biopsy-proven prostatic cancer were prospectively studied with endorectal MRI, and 36 of them were also studied with endorectal Doppler US, with the imaging results compared to the post-surgical hystopathological results.Sensitivity, specificity, positive predictive value, negative predictive value and accuracy results for extracapsular spread of disease were better for MRI than for US, however both methods obtained high ( > 85%) specificity results, which is considered the most important criteria for local staging. Accuracy for seminal vesicle invasion was adequate for both USD and MRI. At US, statistically significant correlation was observed between extracapsular extension of tumor and irregular bulging of the prostatic contour, while at MRI, statistically significant correlation was observed for irregular bulging and extraprostatic solid tissue. Our results showed that the use of imaging methods for local staging of prostatic tumors could reduce the rates of clinical understaging. Additional findings were the low specificity of both imaging methods for tumor localization, and the absence of differences between US, MRI and pathology for prostatic volume measurement.

INTRODUÇÃO: O tratamento e o seguimento do carcinoma papilífero de tireoide (CPT) são individualizados pelos riscos de recorrência e mortalidade. A indicação do iodo radioativo (iodo-131) para ablação de remanescente tireóideo captante é controversa em casos classificados como de baixo risco. Por diminuir a massa tireóidea remanescente, a dose ablativa com iodo-131 (DAIR) facilita o seguimento pós-operatório, mas tem riscos e onera o tratamento. Não se encontrou na literatura estudo demonstrando a evolução da captação cervical do iodo-131 e da concentração sérica de tireoglobulina (TG) em pacientes submetidos à tireoidectomia total por CPT de riscos muito baixo e baixo, sem DAIR. OBJETIVO: Avaliar a evolução da captação cervical do iodo-131 e da concentração sérica de TG em pacientes com CPT de baixo e muito baixo risco, após tireoidectomia total e não submetidos a DAIR. MÉTODOS: Foi realizado estudo prospectivo não randomizado em pacientes com CPT de baixo e muito baixo risco submetidos a tireoidectomia total, atendidos no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período setembro de 2008 novembro de 2011. Após a tireoidectomia foi ministrada levotiroxina na dose necessária para manter a concentração de hormônio tireo-estimulante (TSH) entre 0,5 e 1,0 U/ml. Dosagem sérica de TG, pesquisa de corpo inteiro com iodo-131 (PCI) e dosagem de iodo urinário foram realizadas sob estímulo de TSH endógeno elevado por interrupção da reposição hormonal com levotiroxina, por 30 dias, e dieta pobre em iodo por 15 dias. Foram realizadas ultrassonografias cervicais três e 12 meses após a tireoidectomia. As concentrações séricas de TSH e tiroxina livre sem supressão do TSH foram realizadas seis, nove e 12 meses após a tireoidectomia. RESULTADOS: Dos 26 pacientes incluídos, 22 eram do sexo feminino (84,6%), e quatro, do masculino (15,4%), com idade variando de 27 a 45 anos (média de 38,5 anos e mediana de 39,5 anos). Onze pacientes (42,3%) foram estratificados como de muito baixo risco, e 15 (57,7%), como de baixo risco. Todos os pacientes estavam em hipotireoidismo, no momento da avaliação inicial e final (TSH > 30?U/ml), e os exames realizados seis, nove e 12 meses após a operação, com ingestão de levotiroxina, mostraram as medianas da concentração de TSH de 3,4 ?U/mL, 0,3 ?U/mL e 1,5 ?U/mL, respectivamente. A média da captação de iodo-131 caiu de 1,9% na avaliação inicial para 0,5% na final, e a média da concentração sérica de TG estimulada caiu de 3,1 ng/mL para 1,9 ng/ml. CONCLUSÃO: Houve diminuição estatisticamente significativa da captação cervical do iodo-131 e da concentração sérica de TG sem DAIR nos pacientes submetidos a tireoidectomia total por CPT de baixo e muito baixo risco, sem supressão do TSH / INTRODUCTION: The treatment and follow-up of papillary thyroid carcinoma (PTC) are individualized according to the risk of recurrence and mortality. Radioiodine ablation of thyroid remnant is controversial in low-risk patients. By reducing the thyroid remnant, ablation with radioiodine facilitates the follow-up, but it adds risks and increases the cost of the treatment. We found no published study showing the outcome of cervical uptake of radioactive iodine and the serum concentration of thyroglobulin (TG) in patients undergoing total thyroidectomy for PTC classified as very low risk and low risk who did not undertake ablative dose of radioactive iodine. OBJECTIVE: The aim of this study was to document changes in the cervical uptake of radioiodine and changes in TG concentrations in low-risk and very low-risk PTC patients not submitted to radioiodine remnant ablation (RRA). METHODS: We conducted a prospective non-randomized study in patients with PTC classified as low risk and very low risk undergoing total thyroidectomy at the General Hospital of the University of Sao Paulo, School of Medicine, from September 2008 to November 2011. Levothyroxine was administered after thyroidectomy at a dose required to maintain the concentration of thyroid stimulating hormone (TSH) between 0.5 and 1.0 ?U/ml. Serum thyroglobulin, whole body scan with iodine-131 and urinary iodine were evaluated under high endogenous TSH stimulation after 30 days levothyroxine withdrawal and iodine-poor diet for 15 days. Neck ultrasounds were performed three and 12 months after thyroidectomy. The concentration of serum TSH and free thyroxine without TSH suppression were measured six, nine and 12 months after thyroidectomy. RESULTS: Of the 26 patients included, 22 were female (84.6%) and four were male (15.4%), aged ranged from 27 to 45 years (mean 38.5 years, median 39.5 years). Eleven patients (42.3%) were classified as very low risk and 15 (57.7%) as low risk. All subjects were hypothyroidism at the time of the initial and final evaluations (TSH> 30 ?U/ml). Tests performed six, nine and 12 months after the operation with levothyroxine showed the median concentration of TSH 3.4 ?U/ml, 0.3 U/ml and 1.5 ?U/ml, respectively. The average uptake of iodine-131 dropped 1.9% at baseline to the end of 1.5% and higher mean serum thyroglobulin fell from 3.1 ng/mL to 1.9 ng/ml. CONCLUSION: There was a statistically significant reduction in cervical radioiodine uptake and in stimulated TG level over one year\'s observation of low-risk and very low-risk papillary thyroid carcinoma patients who were not treated with RRA, even in the absence of TSH suppression

<p>Napredak na polju molekularne biologije omogućio je identifikaciju molekularnih markera za karcinom bronha sa vrednim prognostičkim i prediktivnim značajem i njihova uloga kod uznapredovalog, metastatskog oblika bolesti je u velikoj meri istražena, dok kod ranih stadijuma bolesti jo&scaron; uvek nije sasvim jasna. Cilj ovog istraživnja bio je da se utvrdi učestalost najče&scaron;ćih genskih alteracija u tumorskim ćelijama bolesnika sa ranim stadijumom adenokarcinoma bronha, da se utvrdi pojedinačna zavisnost ispitivanih genskih alteracija u tumorskim ćelijama sa određenim kliničko-patolo&scaron;kim karakteristikama i da se utvrdi potencijalni prognostički značaj pojedinačne genske alteracije u tumorskim ćelijama na vreme preživljavanja bez povratka bolesti i ukupno vreme preživljavanja. Istraživanje je obuhvatilo 161 bolesnika sa adenokarcinomom bronha, stadijuma bolesti od I do IIIA, kod kojih je sprovedena radikalna hirur&scaron;ka resekcija u Institutu za plućne bolesti Vojvodine u periodu izmedju 2007 i 2014 godine. U tumorskim uzorcima fiksiranim u parafinu odredjivane su mutacije EGFR, KRAS i PIK3CA gena, ALK i ROS1 rearanžman i PD1 i PD-L1 ekspresija. Kliničkopatolo&scaron;ke karakteristike su preuzete iz registra za karcinom bronha Instituta za plućne bolesti Vojvodine. Ukupno preživljavanje je računato od dana operacije do dana smrti, a preživljavanje bez povratka bolesti je računato od dana operacije do momenta ponovne pojave bolesti. Od 161 testiranog tumorskog uzorka, prisustvo mutacija detektovano je kod 96 uzoraka (59.6%). Prisustvo mutacije KRAS gena detektovano je kod 69 (42.9%), mutacije EGFR gena kod 10 (6.2%), a mutacije PIK3CA gena kod 7 (4.3%) tumorskih uzoraka. ALK rearanžman je detektovan kod 3 (1.9%), a ROS1 rearanžman kod 7 (4.3%) tumorskih uzoraka. PD-1 ekspresija detektovana je u 71 tumorskom uzorku (45%), dok je PD-L1 ekspresija detektovana u 59 tumorskih uzoraka (36.6%). PD-1 ekspresija nije bila značajno povezana ni sa jednim od klinčko-patolo&scaron;kih karakteristika (uključujući KRAS, EGFR, ALK, ROS1 i PI3KCA status). PD-L1 ekspresija je bila značajno povezana sa tipom hirurgije (P = 0.01) i sa prisustvom KRAS mutacije (P = 0.02). Mutacioni status u domenu KRAS gena je bio značajno povezan sa godinama starosti (P = 0.004), polom (P = 0.006) i pu&scaron;ačkim statusom (P = 0.004). Mutacioni status u domenu EGFR gena je bio značajno povezan sa pu&scaron;enjem (P &lt; 0.001) i sa godinama starosti (P = 0.013). Mutacioni statusi u domenu gena za ALK, ROS1 i PI3KCA nisu bili značajno povezani ni sa jednom od ispitivanih kliničko-patolo&scaron;kih karakteristika. Prisustvo PD-1 ekspresije je bilo značajno povezano sa preživljavanjem bez povratka bolesti (P = 0.03) i ukupnim preživljavanjem (P = 0.01). PD-L1 ekspresija, KRAS, EGFR, ALK, ROS1 i PIK3CA mutacioni status nisu bili značajno opvezani sa preživljavanjem bez povratka bolesti i ukupnim preživljavanjem. Najče&scaron;će detektovane genske alteracije su mutacije u domenu KRAS i EGFR gena. Prisustvo KRAS mutacije je značajno povezano sa godinama starosti ispitanika, polom i pu&scaron;ačkim statusom dok je prisustvo EGFR mutacije značajno povezano sa godinama starosti ispitanika i pu&scaron;ačkim statusom. Prisustvo PD-L1 ekspresije je značajno povezano sa vrstom hirur&scaron;kog lečenja i sa prisustvom KRAS mutacija. Jedino prisustvo PD-1 ekspresije u tumorskim ćelijama predstavlja nezavistan prognostički faktor za preživljavanje bez povratka bolesti i ukupno preživljavanje bolesnika sa ranim stadijumom adenokarcinoma bronha.</p> / <p>Advances in the field of molecular biology gave us insight into biomarkers for lung cancer with great prognostic and predictive value and their role in advanced stage disease is well known while in early stage disease is yet to be proven. The aim of this study was to determine the frequencies of the most common gene alterations in patients with early stage lung adenocarcinoma, to determine the relationship between gene alterations in tumor cells and clinicopathologial characteristics and to determine prognostic value of each gene alteration regarding overall survival and disease free survival. One hundred sixty-one patients diagnosed with lung adenocarcinoma clinical stage I-IIIA who underwent radical surgical resection at the Institute for Pulmonary Diseases of Vojvodina between 2007 and 2014 were included in this study. Mutations in EGFR, KRAS and PIK3CA gene, ALK and ROS1 rearrangement and PD-1 and PD-L1 expression were determined in representative formalin-fixed, paraffin-embedded (FFPE) tumor block from each patient. Clinical data were extracted from the institutional lung cancer registry of the Institute for Pulmonary Diseases. Overall survival was calculated as time from the day of surgery to the day of death. Disease free survival was calculated as time from the day of surgery to the day of disease relapse. Among 161 tested tumor tissue, presence of mutation was found in 96 (59.6%) of them. There were 69 (42.9%) mutations in KRAS gene, 10 (6.2%) in EGFR gene and 7 (4.3%) in PIK3CA gene. ALK and ROS1 rearrangement were present in 3 (1.9%) and 7 (4.3%), respectively. PD-1 expression was determined in 71 (45.0%) tumor sample while PD-L1 expression was determined in 59 (36.6%). PD-1 expression was not correlated with any of the clinicopathologial characteristics (including KRAS, EGFR, ALK, ROS1 and PIK3CA mutational status). PD-L1 expression correlated with type of surgery (P = 0.01) and KRAS positivity (P = 0.02). KRAS mutation status correlated with age (P = 0.004), sex (P = 0.006) and smoking status (P = 0.004). EGFR status correlated with smoking status (P &lt; 0.001) and age (P = 0.013). ALK, ROS1 and PIK3CA status were not correlated with any of the clinicopathologial characteristics. PD-1expression was significantly associated with disease free survival (P = 0.03) and overall survival (P = 0.01). PD-L1 expression, KRAS, EGFR, ALK, ROS1 and PIK3CA status were not associated with disease free survival and overall survival. The most frequent gene alteration are mutations in KRAS and EGFR gene. Presence of KRAS mutation is in correlation with patients age, sex and smoking status while presence of EGFR mutation is in correlation with patients age and smoking status. PD-L1 expression is in correlation with type of surgery and KRAS mutational status. Only presence of PD-1 expression represent an independent prognostic factor for disease free survival and overall survival.</p>

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Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--><b><span style="font-size:11.0pt;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;color:black;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Uvod: </span></b><span style="font-size:11.0pt;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;color:black;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Karcinom dojke je heterogena bolest koju karakteri&scaron;u različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodolo&scaron;ko određivanje i analiza jo&scaron; uvek nisu standardizovani. <b>Cilj: </b>Utvrditi graničnu (&ldquo;cut-off&rdquo;) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao &scaron;to su životna dob bolesnica, veličina tumora, histolo&scaron;ki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodi&scaron;njeg perioda praćenja pacijentkinja. <b>Metode: </b>Retrospektivno je analizirano 120 patohistolo&scaron;kih izve&scaron;taja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. <b>Rezultati: </b>Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42&plusmn;10,17 godina; prosečna veličina tumora 17,98&plusmn;6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49&plusmn;20,23 meseci. Vrednost &ldquo;cut off&rdquo; indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92&plusmn;8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histolo&scaron;ki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p &gt; 0,05). <b>Zaključak: </b>Zbog heterogene prirode oboljenja, kori&scaron;ćenjem standardnih histopatolo&scaron;kih faktora i biomarkera te&scaron;ko je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima lo&scaron;e prognoze.</span></p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Tanja Lakic</o:Author> <o:Version>12.00</o:Version> </o:DocumentProperties></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> <w:DontGrowAutofit/> <w:SplitPgBreakAndParaMark/> <w:DontVertAlignCellWithSp/> <w:DontBreakConstrainedForcedTables/> 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Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--></p><p class="Default"><b><span style="font-size:11.0pt">Introduction: </span></b><span style="font-size:11.0pt">Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. <b>Objective: </b>Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient&#39;s age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. <b>Methods: </b>Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. </span><b><span style="font-size:11.0pt">Results: </span></b><span style="font-size:11.0pt">The average patient&rsquo;s age was 57.42&plusmn;10.17 years; average tumor size 17.98&plusmn;6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49&plusmn;20.23 months. &quot;Cut off&quot; Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn&rsquo;t show significant relationship between Ki-67 and patient&rsquo;s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor&rsquo;s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92&plusmn;8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p&gt; 0.05). </span><b><span style="font-size:11.0pt">Conclusion: </span></b><span style="font-size:11.0pt">Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis. </span></p>

<p>Receptor humanog epidermalnog faktora rasta 2 (HER2) pripada porodici receptora protein-tirozin kinaze čija je aktivacija povezana sa proliferacijom malignih ćelija, inhibicijom apoptoze, tumorskom angiogenezom i sposobnosti invazije i metastaziranja. Povećana proteinska ekspresija HER2 receptora može nastati kao posledica amplifikacije gena i/ili transkripcijskih promena. Ekspresija HER2 receptora u humanim tumorima povezuje se sa agresivnijim pona&scaron;anjem i lo&scaron;ijom prognozom. Učestalost povećane proteinske ekspresije HER2 receptora u nesitnoćelijskim karcinomima pluća (NSCLC) je najvi&scaron;e zastupljena u adenokarcinomu u odnosu na druge histolo&scaron;ke tipove. Identifikacija HER2 pozitivnih NSCLC omogućava određivanje grupe pacijenata koji bi bili kandidati za specifičnu terapiju. Problem predstavlja izbor metode detekcije HER2 receptora i nepostojanje utvrđenog protokola za očitavanje rezultata kao &scaron;to postoji kod karcinoma dojke i želuca. Osnovni ciljevi ove doktorske disertacije su bili: da se odredi učestalost povećane proteinske ekspresije HER2 receptora u adenokarcinomu pluća; da se uporede rezultati povećane proteinske ekspresije HER2 receptora dobijene kori&scaron;ćenjem HER2 antitela &bdquo;Hercep Test Dako&ldquo; i &bdquo;Ventana anti-HER2/neu (4B5)&ldquo; antitela; da se uporedi prisustvo amplifikacije HER2 gena pomoću in situ hibridizacije (ISH) (Dual IHC HER2 kit;Ventana Medical Systems) retestiranjem uzoraka kod kojih je povećana proteinska ekspresija HER2 receptora ocenjena sa 2+ i 3+ dobijena &bdquo;Hercep Test Dako&ldquo; sa prisustnom amplifikacijom HER2 gena na uzorcima koji su pomoću &bdquo;Ventana anti-HER2/neu (4B5)&ldquo; ocenjeni sa 2+ i 3+; da se uporedi učestalost povećane proteinske ekspresije HER2 receptora i prisustva HER2 genske amplifikacije kod različitih histolo&scaron;kih podtipova adenokarcinoma pluća; da se utvrdi da li je povećana proteinska ekspresija HER2 receptora u adenokarcinomu pluća i/ili prisustvo genske amplifikacije povezano sa demografskim (starost i pol pacijenta) parametrima, pu&scaron;ačkim statusom, pojavom metastaza u regionalnim limfnim čvorovima i udaljenim organima, infiltracijom pleure i okolnih struktura, odnosno stadijumom bolesti. Povećana proteinska ekspresija HER2 receptora u adenokarcinomu pluća iznosi 7,4% za Hercep Test Dako i 2,7% za Ventana anti-HER2/neu (4B5) antitelo. Kod pozitivne ekspresije slažu se u 2%, dok se kod negativne ekspresije slažu u 91,9% slučajeva, &scaron;to je ukupno 93,9%. Učestalost amplifikacije HER2 gena kod adenokarcinoma pluća je 17,6%, od toga je kod 2,7% slučajeva prisutna high grade amplifikacija. Postoji statistički značajna povezanost između povećane proteinske ekspresije HER2 receptora dobijene upotrebom HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela i amplifikacije HER2 gena. Amplifikacija HER2 gena prisutna je kod 90,9% pacijenata sa povećanom proteinskom ekspresijom HER2 receptora koja se dobije upotrebom HercepTest Dako i kod 75% upotrebom Ventana anti-HER2/neu (4B5) antitela. Povećana proteinska ekspresija HER2 receptora dobijena pomoću HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela je najče&scaron;ća kod solidnog predominantnog tipa adenokarcinoma u patolo&scaron;kom T2a deskriptoru i IB stadijumu i acinarnog predominantnog tipa adenokarcinoma u patolo&scaron;kom T1b deskriptoru i IA stadijumu. Amplifikacija HER2 gena je najče&scaron;ća kod solidnog a zatim kod acinarnog i papilarnog predominantnog tipa adenokarcinoma. Povećana proteinska ekspresija HER2 receptora dobijena pomoću HercepTest Dako i Ventana anti-HER2/neu (4B5) antitela i amplifikacija HER2 gena se najče&scaron;će javljaju kod mu&scaron;karaca, pu&scaron;ača, u starosnoj dobi od 61-70 godina, tumora veličine 31-50 mm, N0 i M0 statusu bolesti, bez prisustva tumorske infiltracije pleure i okolnih struktura.</p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Tanja Lakic</o:Author> <o:Version>12.00</o:Version> </o:DocumentProperties></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> 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Name="Bibliography"/> <w:LsdException Locked="false" Priority="39" QFormat="true" Name="TOC Heading"/> </w:LatentStyles></xml><![endif]--><!--[if gte mso 10]><style> /* Style Definitions */ table.MsoNormalTable{mso-style-name:"Table Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--></p><p class="Default"><span style="font-size:11.5pt">Human epidermal growth factor 2 (HER2) is a member of the epidermal growth factor family having tyrosine kinase activity, which is directly linked to malignant cells proliferation, apoptosis inhibition, tumor angiogenesis and ability for invasion and metastasis. Increased protein expression of HER2 receptors can be the consequence of gene amplification and/or transcription changes. Expression of HER2 receptors in human tumors is associated with more aggressive behavior and worse prognosis. Incidence of increased protein expression of HER2 receptors in non-small-cell lung carcinoma (NSCLS) is mainly represented in adenocarcinoma, in comparison with other histological types. Identification of HER2 positive NSCLC enables determination of a group of patients who would be candidates for specific therapy. The problem occurs in choosing the method of detection of HER2 receptors and non-existence of determined protocol for reading the results, as the one ones which exist for breast and gastric carcinoma. The main objectives of this PhD dissertation were: to determine the incidence of increased protein expression of HER2 receptors in lung adenocarcinoma; to compare the results of the increased protein expression of HER2 receptors obtained by using HER2 antibodies &quot;HercepTest Dako&quot; and &quot;Ventana anti-HER2/neu (4B5)&quot; antibodies; to compare the presence of HER2 gene amplification by in situ hybridization (ISH) (Dual IHC HER2 kit: Ventana Medical Systems) by retesting the samples in which the increased protein expression of HER2 receptors was graded with 2+ and 3+, obtained by &quot;HercepTest Dako&quot; with present gene HER2 amplification on samples obtained by &quot;Ventana anti-HER2/neu (4B5) and graded with 2+ and 3+; to compare the incidence of increased protein expression of HER2 receptors and presence of HER2 gene amplification in different histological subtypes of lung adenocarcinoma; to determine if the increased protein expression of HER2 receptors in lung adenocarcinoma and/or presence of gene amplification is related to demographic (age and sex of the patient) parameters, smoking status, appearance of metastases in regional lymphatic nodes, distant organs, infiltration of pleura and surrounding structures, and stage of the disease. Increased protein expression of HER2 in lung adenocarcinoma is 7.4% for HercepTest Dako and 2.7% for Ventana anti-HER2/neu (4B5) antibody. In positive expression they are correlated in 2%, while in negative expression they are correlated in 91.9% cases, which is overall 93.9%. The incidence of HER2 gene amplification in lung adenocarcinoma is 17.6%, from that in 2.7% of the cases high grade amplification is present. There is a statistically significant correlation between increased protein expression of HER2 receptors obtained by use of HercepTest Dako and Ventana anti-HER2 /neu (4B5) antibody and amplification of HER2 genes. Amplification of HER2 genes is present in 90.9% of patients with increased protein expression of HER2 receptors, which is obtained by using HercepTest Dako and in 75% patients by using Ventana anti-HER2/neu (4B5) antibody. Increased protein expression of HER2 receptors obtained by HercepTest Dako and Ventana anti-Her2/neu (4B5) antibody is most common in solid predominant type of adenocarcinoma in pathological T2a descriptor and IB stadium and acinar predominant type of adenocarcinoma in pathological T1b descriptor and IA stadium. Amplification of HER2 genes is most common in solid, and then in acinar and papillary predominant type of adenocarcinoma. Increased protein expression of HER2 receptors obtained by HercepTest Dako and Ventana anti-HER2/neu (4B5) antibody and amplification of HER2 genes most commonly occurs in men, smokers, at the age of 61-70 years, tumor size 31-50 mm, NO and MO disease status, without presence of tumor infiltration of pleura and surrounding structures. </span></p>

INTRODUÇÃO: O tratamento e o seguimento do carcinoma papilífero de tireoide (CPT) são individualizados pelos riscos de recorrência e mortalidade. A indicação do iodo radioativo (iodo-131) para ablação de remanescente tireóideo captante é controversa em casos classificados como de baixo risco. Por diminuir a massa tireóidea remanescente, a dose ablativa com iodo-131 (DAIR) facilita o seguimento pós-operatório, mas tem riscos e onera o tratamento. Não se encontrou na literatura estudo demonstrando a evolução da captação cervical do iodo-131 e da concentração sérica de tireoglobulina (TG) em pacientes submetidos à tireoidectomia total por CPT de riscos muito baixo e baixo, sem DAIR. OBJETIVO: Avaliar a evolução da captação cervical do iodo-131 e da concentração sérica de TG em pacientes com CPT de baixo e muito baixo risco, após tireoidectomia total e não submetidos a DAIR. MÉTODOS: Foi realizado estudo prospectivo não randomizado em pacientes com CPT de baixo e muito baixo risco submetidos a tireoidectomia total, atendidos no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período setembro de 2008 novembro de 2011. Após a tireoidectomia foi ministrada levotiroxina na dose necessária para manter a concentração de hormônio tireo-estimulante (TSH) entre 0,5 e 1,0 U/ml. Dosagem sérica de TG, pesquisa de corpo inteiro com iodo-131 (PCI) e dosagem de iodo urinário foram realizadas sob estímulo de TSH endógeno elevado por interrupção da reposição hormonal com levotiroxina, por 30 dias, e dieta pobre em iodo por 15 dias. Foram realizadas ultrassonografias cervicais três e 12 meses após a tireoidectomia. As concentrações séricas de TSH e tiroxina livre sem supressão do TSH foram realizadas seis, nove e 12 meses após a tireoidectomia. RESULTADOS: Dos 26 pacientes incluídos, 22 eram do sexo feminino (84,6%), e quatro, do masculino (15,4%), com idade variando de 27 a 45 anos (média de 38,5 anos e mediana de 39,5 anos). Onze pacientes (42,3%) foram estratificados como de muito baixo risco, e 15 (57,7%), como de baixo risco. Todos os pacientes estavam em hipotireoidismo, no momento da avaliação inicial e final (TSH > 30?U/ml), e os exames realizados seis, nove e 12 meses após a operação, com ingestão de levotiroxina, mostraram as medianas da concentração de TSH de 3,4 ?U/mL, 0,3 ?U/mL e 1,5 ?U/mL, respectivamente. A média da captação de iodo-131 caiu de 1,9% na avaliação inicial para 0,5% na final, e a média da concentração sérica de TG estimulada caiu de 3,1 ng/mL para 1,9 ng/ml. CONCLUSÃO: Houve diminuição estatisticamente significativa da captação cervical do iodo-131 e da concentração sérica de TG sem DAIR nos pacientes submetidos a tireoidectomia total por CPT de baixo e muito baixo risco, sem supressão do TSH / INTRODUCTION: The treatment and follow-up of papillary thyroid carcinoma (PTC) are individualized according to the risk of recurrence and mortality. Radioiodine ablation of thyroid remnant is controversial in low-risk patients. By reducing the thyroid remnant, ablation with radioiodine facilitates the follow-up, but it adds risks and increases the cost of the treatment. We found no published study showing the outcome of cervical uptake of radioactive iodine and the serum concentration of thyroglobulin (TG) in patients undergoing total thyroidectomy for PTC classified as very low risk and low risk who did not undertake ablative dose of radioactive iodine. OBJECTIVE: The aim of this study was to document changes in the cervical uptake of radioiodine and changes in TG concentrations in low-risk and very low-risk PTC patients not submitted to radioiodine remnant ablation (RRA). METHODS: We conducted a prospective non-randomized study in patients with PTC classified as low risk and very low risk undergoing total thyroidectomy at the General Hospital of the University of Sao Paulo, School of Medicine, from September 2008 to November 2011. Levothyroxine was administered after thyroidectomy at a dose required to maintain the concentration of thyroid stimulating hormone (TSH) between 0.5 and 1.0 ?U/ml. Serum thyroglobulin, whole body scan with iodine-131 and urinary iodine were evaluated under high endogenous TSH stimulation after 30 days levothyroxine withdrawal and iodine-poor diet for 15 days. Neck ultrasounds were performed three and 12 months after thyroidectomy. The concentration of serum TSH and free thyroxine without TSH suppression were measured six, nine and 12 months after thyroidectomy. RESULTS: Of the 26 patients included, 22 were female (84.6%) and four were male (15.4%), aged ranged from 27 to 45 years (mean 38.5 years, median 39.5 years). Eleven patients (42.3%) were classified as very low risk and 15 (57.7%) as low risk. All subjects were hypothyroidism at the time of the initial and final evaluations (TSH> 30 ?U/ml). Tests performed six, nine and 12 months after the operation with levothyroxine showed the median concentration of TSH 3.4 ?U/ml, 0.3 U/ml and 1.5 ?U/ml, respectively. The average uptake of iodine-131 dropped 1.9% at baseline to the end of 1.5% and higher mean serum thyroglobulin fell from 3.1 ng/mL to 1.9 ng/ml. CONCLUSION: There was a statistically significant reduction in cervical radioiodine uptake and in stimulated TG level over one year\'s observation of low-risk and very low-risk papillary thyroid carcinoma patients who were not treated with RRA, even in the absence of TSH suppression

Introdução: Apesar dos avanços nas técnicas de diagnóstico e tratamento, o câncer de próstata avançado ainda é uma condição letal. Terapêuticas mais eficazes são necessárias para reduzir as taxas de morbi-mortalidade associadas à doença. A Proteína-78 regulada pela glicose (GRP78), uma proteína de choque térmico envolvida na apresentação de antígenos, foi recentemente descrita como sendo um possível marcador molecular para o câncer de próstata. Ainda mais, a resposta imune a essa proteína mostrou correlação com o desenvolvimento de doença hormônio-independente e com pior sobrevida para a doença. Objetivos: Neste estudo, avaliou-se a hipótese de que a GRP78 poderia ser usada como marcador molecular em câncer de próstata no desenvolvimento de um sistema de receptor-ligante, através do uso da tecnologia de apresentação de fagos. Casuística e métodos: Inicialmente, foram clonados dois peptídeos que apresentam afinidade à proteína regulada pela GRP78 (os peptídeos WIFPWIQL e WDLAWMFRLPVG) no vetor fUSE5, criando-se fagos com capacidade teórica de ligação à mesma proteína. Posteriormente foi testada a capacidade de ligação desses fagos à GRP78 na membrana de células prostáticas malignas em solução, em xeno-tumores in vivo e em metástases ósseas de câncer de próstata humano. Resultados: Demonstrou-se que ambos os fagos se ligam especificamente à GRP78 in vitro, em comparação à proteínas com seqüência semelhante (proteínas de choque térmico 70 e 90) e não semelhante (albumina sérica bovina). Em seguida, mostrou-se que esses fagos se ligam com afinidade pelo menos 30 vezes maior à células de câncer de próstata que o fago controle, e que os fagos são internalizados por essas células. Posteriormente, mostrou-se que os fagos rastrearam xeno-tumores prostáticos quando injetados in vivo num modelo animal de câncer de próstata. Finalmente, mostrou-se que os fagos ligam-se especificamente à GRP78 expressa em metástases ósseas de adenocarcinoma prostático humano. Conclusões: Os fagos criados apresentam capacidade de ligação específica à GRP78 in vitro, em células em suspensão e in vivo. A estratégia e o sistema de receptor-ligante definidos no presente estudo podem ter implicacões relevantes no desenvolvimento de terapias dirigidas para o tratamento do câncer de próstata. / Introduction: Despite the advances in diagnosis and treatment, advanced prostate cancer remains a lethal condition. Improved methods of therapy are needed to reduce the morbidity and mortality rates associated with this disease. The Glucose-regulated protein-78 (GRP78), a stress-responsive heat-shock protein involved in antigen presentation, was recently described as a possible molecular marker for prostate cancer. Moreover, immune response against this protein was shown to have correlation with the development of androgen-independent prostate cancer and shorter overall survival. Objectives: We hipothesized that GRP78 could be used as a molecular marker for prostate cancer in the development of a receptor-ligand system, by using phage display technology. Patients and methods: We initially cloned two GRP78-targeting peptides (WIFPWIQL and WDLAWMFRLPVG) into a fUSE5-based phage. We then tested binding capacity of the phage to GRP78 in vitro, to GRP78 expressed in intact prostate cancer cell membranes, to a prostate cancer xenograft and to human bone metastases. Results: We showed that both phage created bound specifically to GRP78 in vitro, in comparison to related (Heat-shock proteins 70 and 90) and unrelated control proteins (bovine serum albumin). Next, we showed that these phage bound at least 30 times more to prostate cancer cells than the control phage, and were also internalized into these cells. Both GRP78-binding phage showed a strong homing in vivo to a human prostate cancer xenograft in a mouse model. Finally, we showed that both phage bound specifically to GRP78 expressed in human prostate cancer bone metastases. Conclusions: Both phage are capable of binding specifically to GRP78 in vitro, in the context of intact prostate cancer cells and in vivo. The strategy and the ligand-receptor system we have defined in this study may have relevant implications in the development of targeted therapies for the treatment of prostate cancer.

Introdução: Apesar dos avanços nas técnicas de diagnóstico e tratamento, o câncer de próstata avançado ainda é uma condição letal. Terapêuticas mais eficazes são necessárias para reduzir as taxas de morbi-mortalidade associadas à doença. A Proteína-78 regulada pela glicose (GRP78), uma proteína de choque térmico envolvida na apresentação de antígenos, foi recentemente descrita como sendo um possível marcador molecular para o câncer de próstata. Ainda mais, a resposta imune a essa proteína mostrou correlação com o desenvolvimento de doença hormônio-independente e com pior sobrevida para a doença. Objetivos: Neste estudo, avaliou-se a hipótese de que a GRP78 poderia ser usada como marcador molecular em câncer de próstata no desenvolvimento de um sistema de receptor-ligante, através do uso da tecnologia de apresentação de fagos. Casuística e métodos: Inicialmente, foram clonados dois peptídeos que apresentam afinidade à proteína regulada pela GRP78 (os peptídeos WIFPWIQL e WDLAWMFRLPVG) no vetor fUSE5, criando-se fagos com capacidade teórica de ligação à mesma proteína. Posteriormente foi testada a capacidade de ligação desses fagos à GRP78 na membrana de células prostáticas malignas em solução, em xeno-tumores in vivo e em metástases ósseas de câncer de próstata humano. Resultados: Demonstrou-se que ambos os fagos se ligam especificamente à GRP78 in vitro, em comparação à proteínas com seqüência semelhante (proteínas de choque térmico 70 e 90) e não semelhante (albumina sérica bovina). Em seguida, mostrou-se que esses fagos se ligam com afinidade pelo menos 30 vezes maior à células de câncer de próstata que o fago controle, e que os fagos são internalizados por essas células. Posteriormente, mostrou-se que os fagos rastrearam xeno-tumores prostáticos quando injetados in vivo num modelo animal de câncer de próstata. Finalmente, mostrou-se que os fagos ligam-se especificamente à GRP78 expressa em metástases ósseas de adenocarcinoma prostático humano. Conclusões: Os fagos criados apresentam capacidade de ligação específica à GRP78 in vitro, em células em suspensão e in vivo. A estratégia e o sistema de receptor-ligante definidos no presente estudo podem ter implicacões relevantes no desenvolvimento de terapias dirigidas para o tratamento do câncer de próstata. / Introduction: Despite the advances in diagnosis and treatment, advanced prostate cancer remains a lethal condition. Improved methods of therapy are needed to reduce the morbidity and mortality rates associated with this disease. The Glucose-regulated protein-78 (GRP78), a stress-responsive heat-shock protein involved in antigen presentation, was recently described as a possible molecular marker for prostate cancer. Moreover, immune response against this protein was shown to have correlation with the development of androgen-independent prostate cancer and shorter overall survival. Objectives: We hipothesized that GRP78 could be used as a molecular marker for prostate cancer in the development of a receptor-ligand system, by using phage display technology. Patients and methods: We initially cloned two GRP78-targeting peptides (WIFPWIQL and WDLAWMFRLPVG) into a fUSE5-based phage. We then tested binding capacity of the phage to GRP78 in vitro, to GRP78 expressed in intact prostate cancer cell membranes, to a prostate cancer xenograft and to human bone metastases. Results: We showed that both phage created bound specifically to GRP78 in vitro, in comparison to related (Heat-shock proteins 70 and 90) and unrelated control proteins (bovine serum albumin). Next, we showed that these phage bound at least 30 times more to prostate cancer cells than the control phage, and were also internalized into these cells. Both GRP78-binding phage showed a strong homing in vivo to a human prostate cancer xenograft in a mouse model. Finally, we showed that both phage bound specifically to GRP78 expressed in human prostate cancer bone metastases. Conclusions: Both phage are capable of binding specifically to GRP78 in vitro, in the context of intact prostate cancer cells and in vivo. The strategy and the ligand-receptor system we have defined in this study may have relevant implications in the development of targeted therapies for the treatment of prostate cancer.