Endoclips as novel fiducial markers in trimodality bladder-preserving therapy of muscle-invasive bladder carcinoma: feasibility and patient outcomes

ABSTRACT Hypothesis: Endoclip can be used as fiducial marker in urology. Objective: To assess the feasibility, cost effectiveness and reliability of endoclips as novel fiducial markers in precision radiotherapy, as part of a trimodality bladder-preserving treatment (TBPT) of muscle-invasive bladder carcinoma. Materials and Methods: This retrospective study was performed at Weifang People's Hospital (Weifang, China) from January 2015 to June 2018. A total of 15 patients underwent TBPT. Endoclips were applied to healthy edges of the resected bladder wall as novel fiducial markers. Radio-sensitizing chemotherapy and routine precision radiotherapy were given. The number and position of the endoclips during radiotherapy sessions were monitored. Complications and tumor recurrence were analyzed. Results: The mean age (±standard deviation) of the patients was 67±10 years (range 46-79). There were 3 females and 12 males. Forty-nine endoclips were applied in all patients (3.3±0.8). The tumor was completely visibly resected in all patients. The number of endoclips remained the same through the planned last radiotherapy session (3.3±0.8), i.e., none were lost. All endoclips were removed after the last radiotherapy session. The average number of follow-up months was 38.9±13.2 (range 11-52). There were no procedure-related complications at discharge or follow-up. At one-year, overall recurrence-free survival was 93.3%. Two patients had recurrences at 18 months and 10 months after TBPT, respectively, and salvage radical cystectomy was performed with no further recurrences. Another patient died due to metastasis 9 months after the completion of therapy. Conclusions: Endoclips are reliable, safe and cost-effective as novel fiducial markers in precision-radiotherapy post-TBPT.

Right atrium tumor extension through the inferior vena cava. considerations about nine cases operated under cardiopulmonary bypass

Abstract Introduction: Adrenocortical and renal cell carcinomas rarely invade the right atrium (RA). These neoplasms need surgical treatment, are very aggressive and have poor prognostic and surgical outcomes. Case series: We present a retrospective cohort of nine cases of RA invasion through the inferior vena cava (four adrenocortical carcinomas and five renal cell carcinomas). Over 13 years (2002-2014), nine patients were operated in collaboration with the team of urologists. Surgery was possible in all patients with different degrees of technical difficulty. All patients were operated considering the imaging examinations with the aid of CPB. In all reported cases (renal or suprarenal), the decision to use CPB with deep hypothermic circulatory arrest (DHCA) on surgical strategy was decided by the team of urological and cardiac surgeons. Conclusion: Data retrospectively collected from patients of public hospitals reaffirm: 1) Low incidence with small published series; 2) The selected cases did not represent the whole historical casuistry of the hospital, since they were selected after the adoption of electronic documentation; 3) Demographic data and references reported in the literature were presented as tables to avoid wordiness; 4) The series highlights the propensity to invade the venous system; 5) Possible surgical treatment with the aid of CPB in collaboration with the urology team; 6) CPB with DHCA is a safe and reliable option; 7) Poor prognosis with disappointing late results, even considering the adverse effects of CPB on cancer prognosis are expected but not confirmed.

Relationship between serum MMP-9 level and prognosis after radical resection for Hilar cholangiocarcinoma patients

Abstract Purpose: To analyze the preoperative serum matrix metalloproteinase-9 (MMP-9) levels and prognosis of patients with hilar cholangiocarcinoma (HC) undergoing radical resection. Methods: Preoperative serum MMP-9 levels in patients with HC undergoing radical resection were detected by enzyme-linked immunosorbent assay (ELISA). The ROC curve assay was used to analyze the preoperative serum MMP-9 level to determine the most valuable cut-off point. The relationship between MMP-9 and clinicopathological features of HC patients was analyzed. Kaplan-Meier method was used to analyze the prognostic factors, and COX regression model was used to analyze the independent risk factors affecting prognosis. Results: Preoperative serum MMP-9 levels were significantly elevated in the death patients compared with the survival patients. The most valuable cut-off point for preoperative serum MMP-9 for prognosis was 201.93 ng/mL. Preoperative serum MMP-9 was associated with Bismuth-Corlette classification) and lymph node metastasis. Kaplan-Meier analysis showed that MMP-9, Bismuth-Corlette classification, Lymph node metastasis, Portal vein invasion, Hepatic artery invasion, Liver invasion, Incised margin, and Preoperative biliary drainage were related to prognosis. Cox regression model confirmed that hepatic artery invasion, liver invasion, incised margin, and MMP-9 have the potential to independence predicate prognosis in HC patients. Conclusion: Preoperative serum MMP-9 has high predictive value for prognosis and is an independent influencing factor for the prognosis of patients with hilar cholangiocarcinoma.

Clinicopathologic factors associated with recurrence in parotid carcinoma / Clinicopathologic factors associated with recurrence in parotid carcinoma

Abstract Introduction: Parotid carcinomas have varying histological types and diverse biologic behaviors. Establishing an adequate treatment plan and predicting recurrence is important. Objective: To analyze the risk factors associated with recurrence in our 5 year experience with 30 cases of primary parotid carcinoma undergoing surgery at a single institute. Methods: From January 2009 to December 2013, 30 patients with surgical treatment of parotid carcinoma were identified based on their medical records. Results: The 30 patients were comprised of 17 males and 13 females. Among 11 patients with T4 tumors, seven patients had recurrence. Among seven patients with cervical nodal metastasis, all patient except one had recurrence. Clinically late stages (stage III and IV) showed more common recurrence than early stage (stage I and II) lesions. Lymphovascular invasion was seen in 5 patients, and all patients had recurrence. Among 11 patients with extracapsular spread, 7 patients had recurrence. In 17 patients with high grade carcinomas, ten patients had recurrence. In 13 patients with low grade carcinomas, no patients experienced recurrence. Conclusion: T- and N-stage, clinical stage, lymphovascular invasion, extracapsular spread, and histopathologic grade correlate significantly with recurrence in parotid carcinoma.

Resumo: Introdução: Os carcinomas da parótida têm diferentes tipos histológicos e comportamentos biológicos diversos. O estabelecimento de um plano de tratamento adequado e a previsão de recorrência são muito importantes. Objetivo: Analisar os fatores de risco associados à recorrência em nossa experiência de cinco anos com 30 casos de carcinoma parotídeo primário submetidos a cirurgia em uma única instituição. Método: De janeiro de 2009 a dezembro de 2013, 30 pacientes com tratamento cirúrgico de carcinoma parotídeo foram identificados com base nos prontuários. Resultados: Entre os 30 pacientes, 17 eram homens e 13, mulheres. Dos 11 pacientes com tumores T4, sete apresentaram recorrência. Entre sete pacientes com metástase em linfonodo cervical, todos, exceto um, apresentaram recorrência. Lesões em estágios clínicos tardios (III e IV) apresentaram recorrência mais comumente do que as dos estágios iniciais (I e II). A invasão linfovascular foi observada em cinco pacientes e todos os cinco apresentaram recorrência. Entre 11 pacientes com disseminação extracapsular, sete apresentaram recorrência. Dos 17 pacientes com carcinomas de alto grau, dez apresentaram recorrência. Em 13 pacientes com carcinomas de baixo grau, nenhum apresentou recorrência. Conclusão: Estágios T e N, estágio clínico, invasão linfovascular, disseminação extracapsular e grau histopatológico correlacionam-se de maneira significante com recorrência do carcinoma de parótida.

Gastric neobladders: surgical outcomes of 91 cases using different techniques

ABSTRACT Introduction: We report on the surgical results of a series of 91 patients who received gastric neobladders as urinary diversion after radical cystectomies performed for the treatment of muscle-invasive bladder cancers. Materials and Methods: We report on a retrospective case series of 91 patients who received gastric neobladders as urinary diversion after radical cystectomies performed for the treatment of muscle-invasive bladder cancers. Different techniques of gastric neobladders were employed from 1988 to 2013 at a university hospital in the South of Brazil. Results: Initial outcomes utilizing Leong (Antral) and Nguyen-Mitchell (Wedge) technique were unsatisfactory, yielding high pressure, low capacity reservoirs. Further developments of these techniques, with the detubularized gastric neobladder and the "spherical" gastric neobladders resulted in low pressure, high capacity reservoirs, with better surgical and urodynamic outcomes. Complication and perioperative mortality rates of our series of gastric neobladders were significantly higher than historical results of techniques using ileum or colon. Conclusions: Stomach is an exceptional option for the creation of neobladders after radical cystectomies, but due to the increased complication rates it should be reserved for specific situations (e.g., renal insufficiency, previous pelvic/abdominal radiotherapy, short bowel syndromes).

Diagnostic accuracy of multiparametric magnetic resonance imaging in detecting extracapsular extension in intermediate and high - risk prostate cancer

ABSTRACT Objectives: To evaluate the diagnostic performance of preoperative multiparametric magnetic resonance imaging (mp-MRI) as a predictor of extracapsular extension (ECE) and unfavorable Gleason score (GS) in patients with intermediate and high-risk prostate cancer (PCa). Materials and Methods: Patients with clinically localized PCa who underwent radical prostatectomy (RP) and had preoperative mp-MRI between May-2011 and December-2013. Mp-MRI was evaluated according to the European Society of Urogenital Radiology MRI prostate guidelines by two different readers. Histopathological RP results were the standard reference. Results: 79 patients were included; mean age was 61 and median preoperative prostate-specific antigen (PSA) 7.0. On MRI, 28% patients had ECE evidenced in the mp-MRI, 5% seminal vesicle invasion (SVI) and 4% lymph node involvement (LNI). At RP, 39.2% had ECE, 26.6% SVI and 12.8% LNI. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of mp-MRI for ECE were 54.9%, 90.9%, 76%, 81% and 74.1% respectively; for SVI values were 19.1%, 100%, 77.3%, 100% and 76.1% respectively and for LNI 20%, 98.4%, 86.7%, 66.7% and 88.7%. Conclusions: Major surgical decisions are made with digital rectal exam (DRE) and ultrasound studies before the use of Mp-MRI. This imaging study contributes to rule out gross extraprostatic extension (ECE, SVI, LNI) without competing with pathological studies. The specificity and NPV are reasonable to decide surgical approach. A highly experienced radiology team is needed to provide accurate estimations of tumor extension and aggressiveness.

Vaginal cuff recurrence after radical cystectomy: an under - studied site of bladder cancer relapse

ABSTRACT Introduction: Vaginal cuff recurrence of tumor following radical cystectomy is a rare site of disease recurrence, however it has never been specifically studied. The aim of the study is to evaluate incidence, risk factors, and long-term oncologic outcomes of vaginal cuff recur- rence in a cohort of female patients treated with radical cystectomy for invasive urothelial carcinoma of the bladder. Materials and Methods: From 1985 to 2012, a prospectively maintained institutional blad- der cancer registry was queried for vaginal cuff recurrence post radical cystectomy. Over- all mortality and cancer-specific mortality were reported using the Kaplan-Meier method for patients with vaginal cuff recurrence, recurrence at another local or distant site, and those without evidence of recurrence. Comparisons were performed using the log-rank test. Cox proportional hazards regression model was performed to assess predictors of vaginal cuff recurrence. Results: From 469 women treated with radical cystectomy for bladder cancer, 34 patients (7.3%) developed vaginal cuff recurrence, 130 patients (27.7%) had recurrence involving ei- ther a local or distant site, and 305 patients (65%) had no evidence of recurrence. The 5-year overall mortality-free survival rate was 32.4% for vaginal cuff recurrence, but 25.0% for other sites of recurrence. Cancer-specific mortality-free survival rate was 32.4% for vaginal cuff recurrence, and 30.3% for the other sites of recurrence. Multivariate Cox proportional hazards regression analysis demonstrated that the presence of tumor in posterior location at radical cystectomy (Hazard Ratio [HR], 0.353 [95% CI, 0.159-0.783]) and anterior vaginec- tomy, compared to no vaginectomy (HR, 2.595 [95% CI, 1.077-6.249]) were independently associated with vaginal cuff recurrence. Conclusion: Anterior vaginectomy, despite our best attempts, is perhaps not sufficient to prevent vaginal cuff recurrence. Therefore, follow-up evaluation is essential, and further studies are necessary to address the optimal approach for initial management. Patient Summary: Although vaginal cuff recurrence is an unusual site of recurrence, careful evaluation is needed before cystectomy and during follow-up to identify patients at risk.

Impact of historic histopathologic sample review on the risk of recurrence in patients with differentiated thyroid cancer

ABSTRACT Objective To compare the historic risk of recurrence (RR) and response to therapy to risk stratification estimated with historical pathology reports (HPRs) and contemporary re-review of the pathological slides in patients with differentiated thyroid cancer (DTC). Subjects and methods Out of 210 DTC patients with low and intermediate RR who underwent total thyroidectomy and remnant ablation in our hospital, 63 available historic pathologic samples (HPS) were reviewed. The RR and the response to therapy were evaluated considering historical histological features (histological type, tumor size, capsular invasion, number of lymph node metastases) and then, reassessed after observing additional histological features (vascular invasion, extrathyroidal extension, size of lymph node metastases, presence of extranodal extension, and/or status of the resection margins). Results A change in the RR category was observed in 16 of 63 cases (25.4%). Out of 46 patients initially classified as low RR, 2 patients were reclassified as intermediate RR, 4 as high RR, and 1 as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Out of 17 patients initially classified as intermediate RR, 3 were reassigned to the low RR group, 5 as high RR, and 1 as NIFTP. The percentages of structural incomplete response at final follow-up changed from 2.2 to 0% (p = 1) in patients with low RR and from 6.3 to 20% (p = 0.53) in patients with intermediate RR. Conclusion A detailed report of specific features in the HPR of patients with DTC might give a more accurate RR classification and a better estimation of the response to treatment.

Survival and prognosis of young adults with gastric cancer

OBJECTIVES: Survival data for young adults (YA) with gastric cancer is conflicting and scarce in Brazil. The aim of this study was to compare the clinicopathological factors and survival rates of younger and older patients with gastric cancer. METHODS: Hospital registries for 294 gastric cancer patients from a reference cancer hospital in São Paulo, Brazil, were consulted for the retrieval of clinicopathological information and follow-up time. Patients were placed into the following groups: YA (≤40 years; N=71), older adult (OA: 41 to 65 years; N=129) and elderly (E: ≥66 years; N=94). Differences were assessed through Pearson's χ2 test, Kaplan-Meier analysis, Log rank test and Cox regression. RESULTS: More YA were diagnosed with advanced disease (clinical stage III/IV: 86.7% YA, 69.9% OA, and 67% E); however, fewer E patients underwent surgery (64.3% YA, 72.7% OA, and 52.4% E). The median overall survival among all patients was 16 months, and the overall survival rate was not significantly different among the age groups (p=0.129). There were no significant differences in the disease-free survival rate. Metastatic disease at diagnosis (HR=4.84; p<0.01) was associated with an increased hazard of death for YA. CONCLUSION: Overall survival was similar among age groups. Metastatic disease at diagnosis was the only factor associated with a poorer prognosis in YA. These results suggest that younger patients deserve special attention regarding the detection of early stage disease.

Ureteral orifice involvement by urothelial carcinoma: long term oncologic and functional outcomes

ABSTRACT Purpose: Bladder cancer (BC) may involve the ureteral orifice, and the resection of the orifice has oncological and functional consequences such as development of upper tract urothelial carcinoma (UTUC), vesicoureteral reflux or ureteral stenosis. The aim of this study was to investigate the oncological and functional outcomes of the ureteral orifice resection in BC patients and determine the predictive factors for UTUC development. Materials and Methods: A total of 1359 patients diagnosed with BC, between 1992 and 2012, were reviewed retrospectively. Patients were grouped with respect to orifice resection and compared for development of UTUC, survival and functional outcomes. Kaplan-Meier method was used to compare survival outcomes. Logistic regression analysis was performed to determine predictors of UTUC development. Results: Ureteral orifice involvement was detected in 138 (10.2%) patients. The rate of synchronous (10.1% vs. 0.7%, p=0.0001) and metachronous (5.3% vs. 0.9%, p=0.0001) UTUC development was found to be higher in patients with ureteral orifice involvement. Orifice involvement and tumor stage were found to be associated with development of UTUC in the regression analysis. Overall (p=0.963) and cancer specific survival rates (p=0.629) were found to be similar. Hydronephrosis was also significantly higher in patients with orifice involved BC, due to the orifice obstruction caused by the tumor (33.3% vs. 13.9%, p<0.05). Conclusions: BC with ureteral orifice involvement has significantly increased the risk of having synchronous or metachronous UTUC. However, orifice involvement was not found to be associated with survival outcomes. Development of stricture due to resection is a very rare complication.

Prognostic factors affecting outcomes in multivisceral en bloc resection for colorectal cancer

OBJECTIVES: This study sought to determine the clinical and pathological factors associated with perioperative morbidity, mortality and oncological outcomes after multivisceral en bloc resection in patients with colorectal cancer. METHODS: Between January 2009 and February 2014, 105 patients with primary colorectal cancer selected for multivisceral resection were identified from a prospective database. Clinical and pathological factors, perioperative morbidity and mortality and outcomes were obtained from medical records. Estimated local recurrence and overall survival were compared using the log-rank method, and Cox regression analysis was used to determine the independence of the studied parameters. ClinicalTrials.gov: NCT02859155. RESULTS: The median age of the patients was 60 (range 23-86) years, 66.7% were female, 80% of tumors were located in the rectum, 11.4% had stage-IV disease, and 54.3% received neoadjuvant chemoradiotherapy. The organs most frequently resected were ovaries and annexes (37%). Additionally, 30.5% of patients received abdominoperineal resection. Invasion of other organs was confirmed histologically in 53.5% of patients, and R0 resection was obtained in 72% of patients. The overall morbidity rate of patients in this study was 37.1%. Ureter resection and intraoperative blood transfusion were independently associated with an increased number of complications. The 30-day postoperative mortality rate was 1.9%. After 27 (range 5-57) months of follow-up, the mortality and local recurrence rates were 23% and 15%, respectively. Positive margins were associated with a higher recurrence rate. Positive margins, lymph node involvement, stage III/IV disease, and stage IV disease alone were associated with lower overall survival rates. On multivariate analysis, the only factor associated with reduced survival was lymph node involvement. CONCLUSIONS: Multivisceral en bloc resection for primary colorectal cancer can be performed with acceptable rates of morbidity and mortality and may lead to favorable oncological outcomes.

A novel model to estimate lymph node metastasis in endometrial cancer patients

OBJECTIVES: To evaluate the postoperative pathological characteristics of hysterectomy specimens, preoperative cancer antigen (CA)-125 levels and imaging modalities in patients with endometrial cancer and to build a risk matrix model to identify and recruit patients for retroperitoneal lymphadenectomy. METHODS: A total of 405 patients undergoing surgical treatment for endometrial cancer were retrospectively reviewed and analyzed. Clinical (age and body mass index), laboratory (CA-125), radiological (lymph node evaluation), and pathological (tumour size, grade, lymphovascular space invasion, lymph node metastasis, and myometrial invasion) parameters were used to test the ability to predict lymph node metastasis. Four parameters were selected by logistic regression to create a risk matrix for nodal metastasis. RESULTS: Of the 405 patients, 236 (58.3%) underwent complete pelvic and para-aortic lymphadenectomy, 96 (23.7%) underwent nodal sampling, and 73 (18%) had no surgical lymph node assessment. The parameters predicting nodal involvement obtained through logistic regression were myometrial infiltration >50%, lymphovascular space involvement, pelvic lymph node involvement by imaging, and a CA-125 value >21.5 U/mL. According to our risk matrix, the absence of these four parameters implied a risk of lymph node metastasis of 2.7%, whereas in the presence of all four parameters the risk was 82.3%. CONCLUSION: Patients without deep myometrial invasion and lymphovascular space involvement on the final pathological examination and with normal CA-125 values and lymph node radiological examinations have a relatively low risk of lymph node involvement. This risk assessment matrix may be able to refer patients with high-risk parameters necessitating lymphadenectomy and to decide the risks and benefits of lymphadenectomy.

Laparoscopic Radical Cystectomy in the Elderly - Results of a Single Center LRC only Series

ABSTRACT Objective: To compare outcome of laparoscopic radical cystectomy (LRC) with ileal conduit in 22 elderly ( (≥75 years) versus 51 younger (<75 years) patients. patients. Materials and Methods: Analysis of prospectively gathered data of a single institution LRC only series was performed. Selection bias for LRC versus non-surgical treatments was assessed with data retrieved from the Netherlands Cancer Registry. Results: Median age difference between LRC groups was 9.0 years. (77.0 versus 68.0 years). Both groups had similar surgical indications, body mass index and gender distribution. Charlson Comorbidity Index score was 3 versus 4 in ≥50% of younger and elderly patients. Median operative time (340 versus 341 min) and estimated blood loss (<500 versus >500mL) did not differ between groups. Median total hospital stay was 12.0 versus 14.0 days for younger and elderly patients. Grade I-II 90-d complication rate was higher for elderly patients (68 versus 43%, p=0.05). Grade III-V 90-d complication rate was equal for both groups (23 versus 29%, p=0.557). 90-d mortality rate was higher for elderly patients (14 versus 4%, p=0.157). Median follow-up was 40.0 months for younger and 57.0 months for elderly patients. Estimated overall and cancer-specific survival at 5years. was 46% versus 35% and 64% versus 64% for younger and elderly patients respectively. Conclusions: Our results suggest that LRC is feasible in elderly patients, where a non-surgical treatment is usually favoured.

External validation of EORTC risk scores to predict recurrence after transurethral resection of brazilian patients with non-muscle invasive bladder cancer stages Ta and T1

ABSTRACT Validate the EORTC risk tables in Brazilian patients with NMIBC. Methods: 205 patients were analyzed. The 6 parameters analyzed were: histologic grading, pathologic stage, size and number of tumors, previous recurrence rate and concomitant CIS. The time for first recurrence (TFR), risk score and probability of recurrence were calculated and compared to the probabilities obtained from EORTC risk tables. C-index was calculated and accuracy of EORTC tables was analyzed. Results: pTa was presented in 91 (44.4%) patients and pT1 in 114 (55.6%). Ninety-seven (47.3%) patients had solitary tumor, and 108 (52.7%) multiple tumors. One hundred and three (50.2%) patients had tumors smaller than 3 cm and 102 (40.8%) had bigger than 3 cm. Concomitant CIS was observed in 21 (10.2%) patients. Low grade was presented in 95 (46.3%) patients, and high grade in 110 (53.7%). Intravesical therapy was utilized in 105 (56.1%) patients. Recurrence was observed in 117 (57.1%) patients and the mean TFR was 14,2 ± 7,3 months. C-index was 0,72 for 1 year and 0,7 for 5 years. The recurrence risk was 28,8% in 1 year and 57,1% in 5 years, independently of the scoring risk. In our population, the EORTC risk tables overestimated the risk of recurrence in 1 year and underestimated in 5 years. Conclusion: The validation of the EORTC risk tables in Brazilian patients with NMIBC was satisfactory and should be stimulated to predict recurrence, although these may overestimated the risk of recurrence in 1 year and underestimated in 5 years.

Marcadores e mecanismos de resistência à terapia neoadjuvante e o papel das vesículas extracelulares secretadas pelas células tumorais no câncer de reto / Biomarkers and mechanisms of resistance to neoadjuvnat therapy and the role of extracelular vesicles secreted by tumor cells in rectal cancer

O câncer de reto é o segundo tumor mais comum no intestino grosso correspondendo a um terço do total de casos de câncer colorretal (CCR). Pacientes com câncer de reto em estádios II e III são tratados com radioquimioterapia neoadjuvante seguida de ressecção cirúrgica do tumor. Análises das peças cirúrgicas ressecadas mostraram que apenas 10-45% dos pacientes obtém resposta patológica completa (RCp) à terapia neoadjuvante, estando essa associada com uma diminuição da recorrência local, melhora da sobrevida livre de doença e aumento na preservação esfincteriana. Apesar da melhora na sobrevida nas últimas décadas, a resposta à terapia neoadjuvante continua variável e imprevisível e não é possível identificar e separar clinicamente os grupos de pacientes que terão ou não resposta completa ao tratamento neoadjuvante. Além disso, os mecanismos de resistência à radioquimioterapia nos tumores de reto são pouco compreendidos. Dessa forma, o objetivo principal deste estudo foi identificar marcadores e mecanismos celulares relacionados à resistência à terapia neoadjuvante em adenocarcinoma de reto e o papel das vesículas extracelulares (VEs) nesse processo. O estudo proteômico comparativo entre biópsias obtidas de tumores pré-tratamento com o tumor residual removido cirurgicamente pós-tratamento radioquimioterápico mostrou uma importante alteração no perfil de expressão proteica. Entre as proteínas que aumentam a expressão após a neoadjuvância estão as proteínas de reparo de dano de DNA, Ku70 e Ku80, e a proteína de tráfego intracelular Rab5C. Em um modelo in vitro, foi demonstrado que Rab5C orquestra um mecanismo de resistência à radioterapia nos tumores de reto através da modulação da internalização de EGFR promovida por radiação ionizante (RI). O EGRF intracelular por sua vez é essencial para regular a expressão de Ku70 e Ku80 e a resistência celular à RI. Estes dados apontam Rab5C e EGFR como potenciais alvos terapêuticos para sensibilizar células de câncer de reto resistentes ao tratamento neoadjuvante. Também foi observado que a RI promove alterações epigenéticas predominantemente de hipometilação, e entre os genes alterados estão SPG20 e TBC1D16, sendo o primeiro importante para a internalização de EGFR e o segundo para a regulação de Rab5C e modulação de EGFR. O perfil de expressão proteica foi ainda comparado entre biópsias pré-tratamento de pacientes com RCp e sem resposta patológica, e o resultado mostrou que esses dois grupos de pacientes apresentam um diferente perfil de expressão proteica. Nos pacientes com RCp as proteínas com aumento da expressão estão atuando em vias que favorecem a resposta à terapia, como a detoxificação de glutationa e degradação de glicogênio, enquanto as proteínas com aumento da expressão em pacientes sem RCp estão envolvidas em vias do metabolismo energético do tumor as quais contribuem para a resistência tumoral à terapia. As diferenças observadas nestes grupos devem ser amplamente exploradas uma vez que podem ser marcadores preditivos de resposta ao tratamento radioquimioterápico. A realização de estudos funcionais foi viabilizada pela geração de um modelo celular de tumor de reto resistente à radioterapia. Ao analisar as VEs secretadas por estas células foi observado que a RI não altera a quantidade e o tamanho médio das VEs secretadas, porém é capaz de alterar o carregamento proteico das mesmas. De fato, as VEs de células irradiadas apresentam um perfil proteico diferente quando comparadas as VEs de células não irradiadas, onde encontramos aumento da expressão de Ku70, Ku80 e Rab5C, além das metiltransferases NSUN2 e GLYM nas VEs de células pós RI. Interessantemente, as VEs secretadas por células irradiadas são capazes de transmitir a resistência à RI às células não irradiadas. Além disso os resultados mostraram que o tratamento com VEs de células irradiadas promove metilação em 98% do DNA avaliado em células SW837 em comparação ao tratamento com VEs de células não irradiadas. Os genes hipermetilados estão envolvidos em vias relacionadas ao sistema imune, como a apresentação de antígeno, sinalização de imunodeficiência primária e maturação de células dendríticas. Por fim, foi identificado que a expressão da proteína A33 está relacionada ao grau de diferenciação dos tumores colorretais, e que essa proteína está presente em VEs secretadas por células de adenocarcinoma de reto, indicando que a mesma pode ser usada para isolar VEs específicas do tecido colorretal. Os dados obtidos neste trabalho apontam mecanismos relacionados à resistência à terapia neoadjuvante no adenocarcinoma de reto e que em conjunto permitirão identificar novos alvos terapêuticos com potencial de melhorar a resposta à radioquimioterapia, além de identificar marcadores de resposta à terapia neoadjuvante antes do tratamento e dessa forma, poupar os pacientes não respondedores de terapias tóxicas e melhorar a sustentabilidade na saúde poupando os custos com drogas não eficientes para um grupo de pacientes.

Rectal cancer is the second most common cancer in large intestine, corresponding to one third of total cases of colorectal cancer (CRC). Patients with rectal cancer in stage II and III are treated with neoadjuvant chemoradiation followed by surgical resection. Analyzes of the resected tumor demonstrated that only 10-45% of the patients achieve pathological complete response (pCR) after neoadjuvant therapy, which is associated with a decrease in local recurrence, improvement of disease free survival and increase in sphincter preservation. Despite the improvement in survival in the last decades, the response to neoadjuvant therapy is still variable and unpredictable, and before the surgery it is not possible to identify and separate clinically the group of patients that will or will not have complete response to neoadjuvant treatment. Moreover, the mechanisms of resistance of rectal tumors to chemoradiation are poorly understood. Thus, the main objective of this work was to identify biomarkers and cellular mechanisms related to the resistance to neoadjuvant therapy in rectal adenocarcinomas and the role of extracellular vesicles (EVs) in this process. The comparative proteomic study between biopsy obtained from tumors pretreatment with residual tumor, post chemoradiation treatment, removed by surgery showed an important alteration in the protein expression profile. Among the proteins with increased expression after neoadjuvant therapy are the DNA repair proteins Ku70 and Ku80, and the protein involved in the intracellular trafficking, Rab5C. It was demonstrated in vitro that Rab5C orchestrates a mechanism of radioresistance in rectal tumors by modulating the EGFR internalization promoted by ionizing radiation (IR). The intracellular EGFR is essential to regulate Ku70 and Ku80 expression and the cell resistance to IR. These data pointed Rab5C and EGFR as potential therapeutic targets to sensitize rectal cancer cells resistant to neoadjuvant treatment. It was also observed that IR promotes epigenetic alterations, predominantly hypomethylation, and between the altered genes are SPG20 and TBC1D16, the first is important to EGFR internalization, while the second regulates Rab5C and modulates EGFR. The protein expression profile was further compared between biopsy pretreatment of patients with and without pCR, and the results showed that these two groups of patients present a different protein expression profile. In patients with pCR the proteins with increased expression are involved in pathways favoring the response to therapy, as glutathione-mediated detoxification and glycogen degradation, while the proteins with increased expression in patients without pCR are involved in tumor energetic metabolism pathways that contribute to tumor resistance to therapy. The observed differences in these groups should be widely explored since they may be predictive markers of response to chemoradiation treatment. The performance of functional studies was possible by generation of a cellular model of rectal tumor resistant to radiotherapy. The analysis of the EVs secreted by these cells showed that IR does not alter the amount and the medium size of secreted EVs, but is able to change their protein content. EVs from irradiated cells presented a different protein profile when compared to EVs from non-irradiated cells, where it was found the increased expression of Ku70, Ku80 and Rab5C, besides the methyltransferases NSUN2 and GLYM in EVs after irradiation. Interestingly, the EVs secreted by irradiated cells are capable of transfering resistance to IR to non-irradiated cells. Moreover, the results showed that the treatment of SW837 cells with EVs from irradiated cells promoted methylation in 98% of the analyzed DNA in comparison with the treatment with EVs from non-irradiated cells. The hypermethylated genes are involved in pathways related to immune system, as antigen presentation, primary immunodeficiency signaling and dendritic cells maturation. Lastly, it was identified that the A33 expression is related to the colorectal tumors differentiation degree, and this protein is present in EVs secreted by rectal adenocarcinoma, indicating that it may be used to isolate EVs specific from colorectal tissues. The data obtained in this work pointed to mechanisms related to resistance to neoadjuvant therapy in rectal adenocarcinoma that together will allow to identify new therapeutic targets with the potential to improve the response to chemoradiation, as well as to identify markers of response to neoadjuvant therapy before the treatment, and, in this way, avoid the non-responder patients to receive toxic therapies and improve health sustainability, sparing cost with non-efficient drugs for a group of patients.

Blood flow velocity in monocular retinoblastoma assessed by color doppler

OBJECTIVE: To analyze the flow of retrobulbar vessels in retinoblastoma by color Doppler imaging. METHODS: A prospective study of monocular retinoblastoma treated by enucleation between 2010 and 2014. The examination comprised fundoscopy, magnetic resonance imaging, ultrasonography and color Doppler imaging. The peak blood velocities in the central retinal artery and central retinal vein of tumor-containing eyes (tuCRAv and tuCRVv, respectively) were assessed. The velocities were compared with those for normal eyes (nlCRAv and nlCRVv) and correlated with clinical and pathological findings. Tumor dimensions in the pathological sections were compared with those in magnetic resonance imaging and ultrasonography and were correlated with tuCRAv and tuCRVv. In tumor-containing eyes, the resistivity index in the central retinal artery and the pulse index in the central retinal vein were studied in relation to all variables. RESULTS: Eighteen patients were included. Comparisons between tuCRAv and nlCRAv and between tuCRVv and nlCRVv revealed higher velocities in tumor-containing eyes (p <0.001 for both), with a greater effect in the central retinal artery than in the central retinal vein (p =0.024). Magnetic resonance imaging and ultrasonography measurements were as reliable as pathology assessments (p =0.675 and p =0.375, respectively). A positive relationship was found between tuCRAv and the tumor volume (p =0.027). The pulse index in the central retinal vein was lower in male patients (p =0.017) and in eyes with optic nerve invasion (p =0.0088). CONCLUSIONS: TuCRAv and tuCRVv are higher in tumor-containing eyes than in normal eyes. Magnetic resonance imaging and ultrasonography measurements are reliable. The tumor volume is correlated with a higher tuCRAv and a reduced pulse in the central retinal vein is correlated with male sex and optic nerve invasion.

Histological variants and prognostic factors of papillary thyroid carcinoma at the Colombian Instituto Nacional de Cancerología, 2006-2012 / Variantes histológicas y factores pronósticos del carcinoma papilar de tiroides en el Instituto Nacional de Cancerología de Colombia, 2006-2012

Introduction: Thyroid cancer is the most common endocrine neoplasia and the papillary subtype is the most frequent; there are histological and clinical factors associated with a higher risk of recurrence and metastasis. Objective: The aim of this study was to examine the histological, prognostic and clinical characteristics of papillary thyroid carcinomas diagnosed at the National Cancer Institute of Colombia. Materials and methods: A retrospective cohort study was carried out on 619 patients with papillary thyroid carcinoma between 2006 and 2012; we analyzed the sociodemographic, histological, prognostic and clinical characteristics. Results: 87.7% of cases were women. The presence of two or more variants in the same case was considered a particular variant, which we called combined pattern. Combined pattern was then the most frequent (50.9%), followed by the follicular variant (23.4%) including subtypes encapsulated and unencapsulated, and the classic variant (22.1%). Mean tumor size was 20.8 mm. More than half of the cases had capsular invasion, extrathyroidal invasion and lymph node involvement. When compared with the other variants, the combined pattern carcinomas had a higher risk of invasion of the thyroid capsule, extraganglionar invasion and metastasis. Conclusions: Our results are in many aspects similar to those already reported. However, the presence of the combined pattern implied a higher risk for capsular invasion, nodal involvement, extranodal involvement and metastasis in comparison with those which had just one variant. Further studies are necessary to confirm these results.

Introducción. El cáncer de tiroides es la neoplasia más común y el subtipo papilar es el más frecuente; hay factores histológicos y clínicos asociados con un mayor riesgo de recidiva y metástasis. Objetivo. Examinar las características histológicas, clínicas y de pronóstico de los carcinomas papilares de tiroides diagnosticados en el Instituto Nacional de Cancerología de Colombia. Materiales y métodos. Se llevó a cabo un estudio de cohorte retrospectiva que incluyó a 619 pacientes con carcinoma papilar de tiroides entre 2006 y 2012; se analizaron las características sociodemográficas, histológicas, de pronóstico y clínicas. Resultados. El 87,7% de casos correspondió a mujeres. La presencia de dos o más variantes histológicas en un mismo caso se consideró como una variante a la cual se denominó patrón combinado; esta fue la más frecuente (50,9 %), seguida de la variante folicular (23,4 %), incluidos los subtipos encapsulados o no encapsulado y la variante clásica (22,1 %). El promedio del tamaño tumoral fue de 20,8 mm. En más de la mitad de los casos se evidenció invasión capsular, invasión extratiroidea y metástasis en ganglios linfáticos. Comparados con otras variantes histológicas, los carcinomas con patrón combinado presentaron mayor riesgo de invasión de la cápsula tiroidea, de invasión extraganglionar y de metástasis. Conclusión. En muchos aspectos los resultados fueron similares a los reportados previamente; sin embargo, se encontró que la presencia del patrón combinado aumentaba el riesgo de invasión capsular, metástasis en nódulos linfoides y extensión extratiroidea en comparación con los que tenían una sola variante. Sería necesario hacer estudios acerca del mecanismo biológico de la diferenciación en células cancerosas con el fin de ahondar sobre este fenómeno.

Probability of Extraprostatic Disease According to the Percentage of Positive Biopsy Cores in Clinically Localized Prostate Cancer

Prediction of extraprostatic disease in clinically localized prostate cancer is relevant for treatment planning of the disease. The purpose of this study was to explore the usefulness of the percentage of positive biopsy cores to predict the chance of extraprostatic cancer.

Fiocruz as an actor in Brazilian foreign relations in the context of the Community of Portuguese-Speaking Countries: an untold story / A Fiocruz como ator da política externa brasileira no contexto da Comunidade dos Países de Língua Portuguesa: uma história revelada

Brazilian foreign policy paradigms and changes in the global scenario since the Cold War created conditions for stronger ties between Brazil and Portuguese-speaking African countries. Recently, Brazil took the lead in regional integration processes and in South-South cooperation initiatives. These strategies and Fiocruz's acknowledged technical expertise resulted in its direct involvement in Brazilian foreign public health policy in the Community of Portuguese-Speaking Countries. Fiocruz developed cooperation projects in various areas, sharing its know-how and best practices in the most critical fields in partner countries, consolidating "public health framework cooperation" and contributing to diversifying Brazil's partners and promoting Brazil as a global actor.

Os paradigmas da política externa brasileira e as mudanças no cenário global desde a Guerra Fria criaram as condições para aproximação do Brasil com os países africanos de língua portuguesa. Recentemente, o Brasil tomou a liderança nos processos de integração regional e nas iniciativas de cooperação Sul-Sul. Essas estratégias e a reconhecida expertise técnica da Fiocruz abriram espaço para o envolvimento direto da instituição na política externa do Brasil com a Comunidade de Países de Língua Portuguesa na área da saúde. A Fiocruz desenvolveu projetos de cooperação em áreas diversas, compartilhando seu know-how e melhores práticas em áreas prioritárias dos países parceiros, consolidando a "cooperação estruturante em saúde" e contribuindo para a diversificação de parceiros do país e promovendo o Brasil como ator global.