Can Neutrophil-to-Lymphocyte ratio predict the response to BCG in high-risk non muscle invasive bladder cancer?

ABSTRACT Objectives: To evaluate the neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor for response of high risk non muscle invasive bladder cancer (HRNMIBC) treated with BCG therapy. Materials and Methods: Between March 2010 and February 2014 in a tertiary center 100 consecutive patients with newly diagnosed HRNMIBC were retrospectively analyzed. Patients were divided according to NLR value: 46 patients with NLR value less than 3 (NLR < 3 group), and 54 patients with NLR value more than 3 (NLR ≥ 3 group). At the end of follow-up 52 patients were high grade disease free (BCG-responder group) and 48 patients underwent radical cystectomy for high grade recurrence or progression to muscle invasive disease (BCG non-responder group). The average follow-up was 60 months. Intervention: analysis and correlation of preoperative NLR value with response to BCG in terms of recurrence and progression. Results: The optimal cut-off for NLR was ≥ 3 according to the receiver operating characteristics analysis (AUC 0.760, 95% CI, 0.669-0.850). Mean NLR value was 3.65 ± 1.16 in BCG non-responder group and 2.61 ± 0.77 in BCG responder group (p = 0.01). NLR correlated with recurrence (r = 0.55, p = 0.01) and progression risk scores (r = 0.49, p = 0.01). In multivariate analysis, NLR (p = 0.02) and EORTC recurrence risk groups (p = 0.01) were associated to the primary endpoint. The log-rank test showed statistically significant difference between NLR < 3 and NLR ≥ 3 curves (p < 0.05). Conclusions: NLR value preoperatively evaluated could be a useful tool to predict BCG response of HRNMIBC. These results could lead to the development of prospective studies to assess the real prognostic value of NLR in HRNMIBC.

Adjuvant chemotherapy for locally advanced upper tract urothelial carcinoma: updated results of the Seoul National university hospital experience

Objectives: The objective of this study was to update the long-term outcome in the treatment of locally advanced upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU) regarding the role of adjuvant chemotherapy. Materials and methods: Clinical data from 138 patients who underwent RNU for locally advanced UTUC (pT3/4 or pN+) were analyzed. Results: The adjuvant chemotherapy group comprised 66 patients, and other 72 patients did not receive adjuvant chemotherapy. Cisplatin-based chemotherapy was the most common regimen, depending on the patient's eligibility and renal function. The median follow-up period was 48.7 months (interquartile range: 29.2-96.9 months). The 3-and 5-year disease-specific survival (DSS) rates were 76.0% and 69.9% for the non-adjuvant chemotherapy group versus 74.6% and 54.5% for the adjuvant chemotherapy group (p=0.301, log-rank test). Overall survival (OS) rates for the same time period were 70.1% and 62.9% for the non-adjuvant chemotherapy group versus 73.8% and 53.2% for the adjuvant chemotherapy group (p=0.931, log-rank test). On multivariate analysis, adjuvant chemotherapy could not predict DSS and OS after surgery. When patients who received cisplatin-based adjuvant chemotherapy (n=59) were compared to those who did not receive adjuvant chemotherapy, similar results were found. Conclusions: There does not appear to be a significant DSS or OS benefit associated with adjuvant chemotherapy. Prospective randomized clinical trials are necessary to verify the effect of adjuvant chemotherapy on locally advanced UTUC.

Predictors of fluid intravasation during operative hysteroscopy: a preplanned prospective observational study with 200 cases / Preditores de intravasamento durante histeroscopia cirúrgica: um estudo observacional prospectivo com 200 casos

PURPOSE: To verify the predictors of intravasation rate during hysteroscopy. METHODS: Prospective observational study (Canadian Task Force classification II-1). All cases (n=200 women; 22 to 86 years old) were treated in an operating room setting. Considering respective bag overfill to calculate water balance, we tested two multiple linear regression models: one for total intravasation (mL) and the other for absorption rate (mL.min-1). The predictors tested (independent variables) were energy (mono/bipolar), tube patency (with/without tubal ligation), hysterometry (cm), age≤50 years, body surface area (m2), surgical complexity (with/without myomectomy) and duration (min). RESULTS: Mean intravasation was significantly higher when myomectomy was performed (442±616 versus 223±332 mL; p<0.01). In the proposed multiple linear regression models for total intravasation (adjusted R2=0.44; p<0.01), the only significant predictors were myomectomy and duration (p<0.01).In the proposed model for intravasation rate (R2=0.39; p<0.01), only myomectomy and hysterometry were significant predictors (p=0.02 and p<0.01, respectively). CONCLUSIONS: Not only myomectomy but also hysterometry were significant predictors of intravasation rate during operative hysteroscopy. .

OBJETIVO: Testar preditores do ritmo de intravasamento durante histeroscopia cirúrgica. MÉTODOS: Estudo prospectivo observacional (classificação: Canadian Task Force II-1) incluindo casos conduzidos em centro cirúrgico (n=200 mulheres; 22 a 86 anos de idade). Considerando os erros de aferição nas embalagens de solução de irrigação para calcular o balanço hídrico, nós testamos dois modelos de regressão linear múltipla: um para intravasamento total (mL) e outro para ritmo de intravasamento (mL.min-1). Os preditores testados (variáveis independentes) foram energia (mono/bipolar), permeabilidade tubária (com/sem ligadura tubária), histerometria (cm), status ovariano (idade≤50 anos), área de superfície corporal (m2), complexidade de cirurgia (com/sem miomectomia) e tempo de ressecção (min). RESULTADOS: O intravasamento médio foi significativamente maior quando miomectomia foi realizada (442±616 versus 223±332 mL, p<0,01). No modelo proposto para intravasamento total (R2 ajustado=0,44; p<0,01), os únicos preditores significativos foram miomectomia e tempo de duração (p<0,01). No modelo proposto para a taxa de intravasamento (R2=0,39; p<0,01), somente miomectomia e histerometria foram preditores significativos (p=0,02 e p<0,01, respectivamente). CONCLUSÕES: Não só a miomectomia mas também a histerometria são preditores significativo da taxa de intravasamento durante histeroscopia cirúrgica. .

Impact of adjuvant chemotherapy in patients with upper tract urothelial carcinoma and lymphovascular invasion after radical nephroureterectomy

PURPOSE: To evaluate the impact of adjuvant chemotherapy (AC) in patients with upper tract urothelial carcinoma and lymphovascular invasion (LVI) after radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively analyzed the clinical records and clinicopatholgic outcomes of patients (n=552) treated with RNU between 1986 and 2013. Patients treated with neoadjuvant chemotherapy and those for whom LVI status was not recorded were excluded. Patients were divided into two groups according to LVI (n=86) or no LVI (n=256). RESULTS: The study included 344 patients (240 men and 104 women) with a median of 53.9 months of follow-up (range, 1-297 months) after RNU. Tumors were organ confined (T2/N0) in 211 (61.3%) and tumor grade high in 291 (84.6%). AC was administered in 64 patients (18.6%). A total of 280 patients (81.4%) were treated with surgery alone. Patients with LVI tended to be older (p=0.049), have a higher pT stage (pT3/T4, p<0.001), be pN+ (p<0.001), have a high tumor grade (p<0.001), and experience recurrence (p<0.001). In the multivariate analysis, LVI was an independent prognostic factor for cancer-specific survival and overall survival (p=0.002 and p<0.001, respectively). The multivariate analysis demonstrated that in the subgroup of patients with LVI, AC was a significant prognostic factor for cancer-specific survival and overall survival (hazard ratio, 0.51; p=0.027 and hazard ratio, 0.50; p=0.025, respectively). CONCLUSIONS: AC does not seem to reduce mortality in patients with advanced upper tract urothelial carcinoma after RNU. In the subgroup of patients with LVI, AC had a positive impact on cancer-specific survival and overall survival. LVI would be helpful for selecting patients who are appropriate for AC.

Combination of gemcitabine and carboplatin in urothelial cancer patients unfit for cisplatin due to impaired renal or cardiac function

PURPOSE: Combination of gemcitabine and carboplatin is the accepted treatment for metastatic urothelial cancer patients unfit for cisplatin-based chemotherapy. MATERIALS AND METHODS: Gemcitabine 1000 mg/m² (days 1, 8) and carboplatin AUC-4.5 (day 1) were given every 21 days to 23 patients with creatinine clearance < 60 mL/min, cardiac ejection fraction < 45% or active ischemia. Patient characteristics included: median age 73 (56-86) years; primary site: bladder 17 (73%), upper tract 6 (27%) patients; Bajorin's prognostic groups: good 6 (26%), intermediate 11 (48%) and poor 6 (26%) patients. Data was retrospectively documented. Patients were followed until they expired. RESULTS: We obtained objective responses in 8 (34.7%) patients, (95% CI, 16.3-57.2%), including one patient with complete response. The median progression-free survival was 4 (0.2-16.5+) months and the overall survival 8.6 (0.2-45.3+) months. At time of analysis, 4 patients (17%) remained disease free; 3 of them underwent resection of residual disease. Toxicity included: infection in 9 (39%) patients; among them, one died from pneumonia; bleeding > grade 2 in 3 (13%) patients and fatigue grade 3 in 2 (9%) patients. Hematologic toxicity included grade 4 thrombocytopenia in 2 (9%) patients and grade 4 neutropenia in 3 (13%) patients. Five (22%) patients discontinued therapy due to toxicity. CONCLUSIONS: Combination of gemcitabine and carboplatin demonstrated clinical activity in patients with advanced urothelial cancer unfit for cisplatin. It was associated with considerable toxicity. Resection of residual disease is feasible in this population.

Phase II trial of neoadjuvant gemcitabine and cisplatin in patients with resectable bladder carcinoma

OBJECTIVES: Gemcitabine and cisplatin (GC) is an active combination in the treatment of metastatic bladder cancer. We have prospectively analyzed the efficacy and tolerability of GC as neoadjuvant treatment of invasive bladder cancer MATERIALS AND METHODS: In this single-institution phase II trial, patients with muscle-invasive transitional cell carcinoma received three cycles of gemcitabine 1200 mg/m² on days 1 and 8 with cisplatin 75 mg/m² on day 1 prior to surgery. Radiologic response was evaluated by computed tomography and magnetic resonance imaging. All patients were referred to surgery after chemotherapy completion RESULTS: Between June 2002 and March 2005, 22 patients (19 males) were enrolled. Median age was 63 years. Initial stage was II (T2) in 11 and III (T3-4) in 11 patients. Median follow-up is 26 months (4-43). Partial or complete radiologic response rate was documented in 13 out of 20 assessable patients (70 percent). One patient was excluded due to sarcomatoid carcinoma at definitive pathologic examination. Cystectomy was performed in 15 patients and pelvic radiotherapy in four patients. Nine out of 21 patients (43 percent) relapsed and four (19 percent) died due to disease progression. Complete pathologic response was observed in four patients (26.7 percent of 15). Median progression-free survival was 27 months (CI 95 percent not reached) with median overall survival of 36 months (CI 95 percent: 28.7 - 43.3). Grade III/IV toxicity was infrequent, with no deaths due to chemotherapy CONCLUSIONS: The combination of GC is effective and well-tolerated when used as neoadjuvant therapy in muscle-invasive bladder cancer. Longer follow-up is necessary to evaluate its impact on the overall survival of these patients.

El bacilo de Calmette-Guérin como inmunomodulador en el cáncer de vejiga / The bacillus Calmette-Guérin as immunomodulator in bladder cancer

The bacillus Calmette-Guérin (BCG) is regarded as the most successful immunotherapy against superficial bladder carcinoma recurrences to date. BCG intravesical therapy for superficial bladder cancer has shown its efficacy and advantage over classical therapeutic strategies. This efficacy is based on complex and long lasting immune activation. The initial step is the binding of mycobacteria to the urothelial lining, which depends on the interaction of a fibronectin attachment protein on the bacteria surface with fibronectin in the bladder wall. Granulocytes and other immunocompetent mononuclear cells became attracted to the bladder wall and a cascade of proinflammatory cytokines sustains the immune response. In the bladder wall a largely TH1 based cytokine milieu and granuloma-like cellular foci are established. Within this scenario, the most important effector mechanisms might be the direct antitumor activity of interferons and the cytotoxic activity of NK cells. Current treatment consists of an induction phase of 6 weeks and a maintenance dose schedule of 3 weeks every three months up to 36. The majority of patients present adverse events related to dose administration due to bladder inflammatory response and on only a few ocassions, there are mayor complications like granulomatous prostatitis. Among all the neoplasms only in superficial bladder cancer the BCG is proved to be effective.

El bacilo de Calmette-Guérin (BCG) es considerado como la inmunoterapia más exitosa en contra del carcinoma de vejiga superficial recidivante hasta la fecha. La terapia intravesical con el BCG para el cáncer superficial de vejiga ha mostrado su eficacia y ventaja sobre otras estrategias terapéuticas; esta eficacia está basada en una compleja y larga duración de la activación inmunológica. El paso inicial es la unión de la micobacteria al urotelio, la cual depende de la interacción con la fibronectina de la bacteria con la fibronectina del urotelio. Los granulocitos y otras células mononucleares inmunocompetentes son atraídos hacia la pared vesical, así activando una cascada inmunológica a través de secreción de diversas citocinas, quienes estimulan a las células asesinas naturales (NK) activadas por el BCG, las cuales son capaces de diferenciar células neoplásicas y del epitelio urinario normal. En la pared vesical se encuentra un medio ambiente de citocinas principalmente del tipo TH1 y se forman focos celulares similares a granulomas. Dentro de este escenario los mecanismos efectores más importantes parecen ser la actividad antitumoral directa de los interferones y la actividad citotóxicas de las células NK. El tratamiento actual consiste en la administración intravesical del bacilo en una primera fase de inducción de seis semanas y posteriormente dosis de mantenimiento cada tres meses hasta los 36 meses. La mayoría de los pacientes presentan efectos adversos locales secundarios a la reacción inflamatoria y en un porcentaje muy pequeño se presentan complicaciones mayores como prostatitis y orquiepididimitis granulomatosa. De entre todas estas neoplasias sólo en el cáncer superficial de vejiga se han demostrado resultados satisfactorios con el empleo del BCG.

Sarcomatoid carcinoma with osseous differentiation in the bladder

INTRODUCTION: Bladder sarcomatoid carcinoma is a very rare variant of transitional cell carcinoma. With disputed nomenclature, the tumor has been described previously under a variety of names such as sarcomatoid carcinoma, pseudosarcoma, malignant mixed mesodermal/Müllerian tumor, metaplastic carcinoma and spindle cell carcinoma. This malignancy represents 0.3 percent of all bladder tumors and has an aggressive behavior yielding a poor prognosis despite radio and chemotherapy. CASE REPORT: An 81 y/o man presented with a transitional cell carcinoma and underwent a transurethral resection. Adjuvant onco-BCG was introduced. After 9 months of follow-up, a local tumoral recurrence occurred and a new transurethral resection revealed sarcomatoid carcinoma with osseous elements. A radical cystoprostatectomy was then carried out.

Granulomatous hepatitis after intravesical BCG treatment for bladder cancer.

Intravesical bacillus Calmette-Guerin (BCG) is used in patients with urinary bladder carcinoma. Although it is generally well tolerated, granulomatous hepatitis is a rare but serious complication. We report a 42-year-old man and a 56-year-old man who developed granulomatous hepatitis following intravesical BCG. One of them was treated successfully with antitubercular therapy; the other died because of BCG sepsis and multi-organ failure.

Intravesical adjuvant therapy using mitomycin C.

Bladder cancer is mostly superficial at first diagnosis. High incidence of recurrence is the major problem after initial management with transurethral resection (TUR) of bladder tumor. Adjuvant chemotherapy has been advocated to reduce the incidence of recurrence. A study was carried out to observe the efficacy of intravesical adjuvant therapy with single immediate versus delayed multi-dose regimen of Mitomycin C (MMC) in preventing recurrence of superficial bladder cancer. One hundred Patients having intermediate risk superficial bladder cancer were randomized into two equal groups. All patients were followed carefully. Total duration of follow-up was minimum 12 months, maximum 36 months, mean 29 months. No recurrence was seen on 3(rd), 6(th) and 9(th) month of intravesical therapy. As much as 94% and 96% of recurrence free rate was observed in immediate single and delayed multi-dose group respectively on 12(th) month; 86% and 84% on 18(th) month; 74% and 72% on 24(th) month; 70% and 68% on 36(th) month of follow-up cystoscopy respectively. Efficacy of post transurethral resection of bladder tumour (TURBT) MMC single immediate dose was found similar to that of MMC delayed multi-dose regimen in preventing the recurrence of intermediate risk superficial bladder transitional cell carcinoma (TCC) in the study. The difference between the two groups insignificant (p>0.05).

17-year follow-up of a randomized prospective controlled trial of adjuvant intravesical doxorubicin in the treatment of superficial bladder cancer

PURPOSE: To evaluate the efficacy of adjuvant intravesical doxorubicin in superficial transitional cell carcinoma of the urinary bladder on long-term follow-up. MATERIALS AND METHODS: Between July 1986 and November 1991, all patients harboring superficial bladder cancers (Ta or T1) with one or more of these criteria (stage > a, grade > 1, size > 1 cm, multiple or recurrent tumors) were randomized to receive either 50 mg doxorubicin or no adjuvant therapy. Patients with recurrences were allowed to receive doxorubicin or other intravesical agents. Recurrence, progression and survival were analyzed. RESULTS: There were 82 patients included (64 males and 18 females). The mean age was 64 years. Forty-six patients were randomized to the doxorubicin group and 36 to the control group. Final analysis was made at median follow-up of 45, 128 and 131.5 months for recurrence, progression and survival, respectively. Recurrence free, progression free and disease specific survival did not differ significantly between groups. The 10-year Kaplan-Meier estimates for recurrence free, progression free and disease specific survival were 67 percent, 84 percent and 92 percent, respectively for the doxorubicin group, and were 50 percent, 89 percent and 97 percent, respectively for the control group. Tumor size predicted recurrence (p = 0.013) and grade predicted progression (p = 0.004) with multivariate analysis. CONCLUSIONS: Adjuvant intravesical doxorubicin could not be shown to improve recurrence, progression and survival of superficial bladder cancer, compared with control on long-term follow-up. Tumor size and grade were shown to be prognostic factors for recurrence and progression, respectively.

Carcinoma de células transicionales del tracto urinario superior: factores pronósticos / Transitional cell carcinoma of the upper urinary tract: prognostic factors

El carcinoma de células transicionales del tracto urinario superior representa aproximadamente el 5 por ciento de todos los tumores de urotelio. El tratamiento estándar es la nefroureterectomía, aunque en años recientes se ha producido un mayor desarrollo de técnicas conservadoras para tumores superficiales y de bajo grado. El objetivo de este trabajo es presentar una descripción de los pacientes operados por esta enfermedad tumoral durante los últimos 10 años en nuestra institución, evaluando la importancia de los probables factores pronósticos de recurrencia y sobrevida después del tratamiento quirúrgico. Los datos fueron obtenidos mediante revisión de fichas clínicas, informes de anatomía patológica y certificados de defunción, además de seguimiento telefónico, de los pacientes operados un nuestro centro entre 1992 y 2001. Fueron registradas las características de los pacientes y de los tumores, la forma de presentación, el estudio diagnóstico, el tratamiento recibido, las recurrencias y las muertes, señalando la causa de éstas. Para el análisis estadístico se compararon curvas de Kaplan-Meier mediante log-rank test. Se obtuvieron datos de 25 pacientes, 16 hombres y 9 mujeres. El seguimiento fue de 100 por ciento, con una mediana de seguimiento de 13,8 meses (1-56 meses). La edad promedio fue de 69±13 años. El tumor primario se localizó en pelvis, uréter y unión pieloureteral en 76 por ciento, 16 por ciento y 8 por ciento de los casos respectivamente. El factor de riesgo más importante fue el tabaquismo (40 por ciento de los pacientes). El 88 por ciento de los pacientes tuvo hematuria macroscópica como forma de presentación. En el 90 por ciento de los casos fue necesario realizar dos o más estudios de imágenes para el diagnóstico. El tratamiento inicial de todos los pacientes fue quirúrgico: nefrectomía en 18 pacientes (72 por ciento), nefrectomía en 4, nefrectomía parcial en 1 y nefroureterectomía distal en 1. El tumor fue superficial (Ta/T1) en 20 por ciento e invasor (T2-T4) en el 80 por ciento de los casos. El 70 por ciento de los tumores tuvo grado III o IV de Broders. La linfadenectomía fue positiva en 2 de 6 pacientes. Se empleo quimioterapia y/o radioterapia adyuvante en 4 pacientes. La tasa de sobrevida actuarial cáncer-específica a 5 años fue de 100 por ciento para los tumores superficiales (Ta/T1) y de 40 por ciento para los tumores invasores (t2-t4)...

Recurrencia del cáncer vesical superficial con el uso de BCG / Recurrence in superficial bladder cancer with the use of BCG

La recurrencia del cáncer vesical superficial puede llegar a un 10-80 por ciento, la cual puede ser disminuida significativa con el uso de quimioterápicos o BCG post cirugía. El objetivo de este trabajo es analizar los resultados con el uso de BCG intravesical post cirugía, de acuerdo a nuestro protocolo de tratamiento. Se revisan retrospectivamente, las fichas clínicas de 108 pacientes, con diagnóstico de cáncer vesical, tratados en el Hospital Dr. Sótero del Río y en Clínica Integramédica. Sesenta y nueve pacientes con tumor vesical superficial (Tis, Ta, T1), (55 H y 14 M) fueron sometidos a resección transuretral. Un 55,1 por ciento (n=39) recibió BCG adyuvante y un 44,9 por ciento (n=31) fueron observados. El esquema de tratamiento fue de 25-27 mg de BCG/semana por 3 veces (esquema 1: n=4), 25-27 mg/semana por 6 veces (esquema 2: n=11) y 25-27 mg/semana por 6 veces más refuerzos (esquema 3: n=20). El control consistió en cistoscopia, con o sin citología urinaria, más estudio por imágenes del tórax y la vía urinaria superior. El seguimiento promedio fue de 36,2 meses, con una mediana de 16 meses (rango: 1-250 meses), en el 83,3 por ciento de los pacientes. La recurrencia global de los pacientes tratados y no tratados con BCG fue de 28,9 por ciento y 41,9 por ciento, respectivamente. En estadío 0is, 0a y I, la recurrencia con y sin BCG fue de un 25 por ciento y 100 por ciento, 25 por ciento y 37,5 por ciento, y de 35,7 por ciento y 38,5 por ciento, respectivamente. La recidiva de los tumores superficiales varió según el esquema de BCG empleado, siendo de un 50 por ciento con el esquema 1, 36,4 por ciento con el esquema 2 y 15,0 por ciento con el 3. En un subgrupo de 42 pacientes con tumores vesicales superficiales, todos seguidos por más de 12 meses, la recurrencia en los estadíos 0is y 0a y I, con y sin BCG, fue de 33,3 por ciento y 100 por ciento; 23,5 por ciento y 80 por ciento; y de 55,6 por ciento y 66,7 por ciento, respectivamente. En este subgrupo, la recidiva también resultó claramente dependiente del esquema de BCG utilizado, siendo de un 50 por ciento para el esquema 1, 44,4 por ciento para el esquema 2 y 20 por ciento para el 3. Estos resultados confirman la utilidad de un esquema de BCG con dosis de 25 o 27 mg por instilación. Para establecer fracaso o éxito en el tratamiento con BCG, el seguimiento debiera ser al menos de 12 meses, ya que una observación menor puede dar índices de recurrencia falsamente bajos...

Transitional cell carcinoma of the ureter and struvite calculi

Context: The association of primary carcinoma of the ureter and lithiasis is extremely rare. We report a rare case of a primary carcinoma of the ureter with corariform calculus. Case Report: 60-year-old phaeodermal female, reported a history of right-side nephritic colic, hyperthermia and pyuria during the past 20 years andhad received treatment for urinary infections a number of times. The first clinical presentation was related to lithiasis and the tumor had not been shown up by excretory urography, cystoscopy or ultrasonography. Two months after the calculus had been eliminated, the patient began to have serious symptoms and a grade III transitional cell carcinoma of the ureter was discovered. Total nephroureterectomy and M.V.A.C. (Metrotrexate + Vinblastina + Doxo Rubicina + Cisplatina) chemotherapy were tried unsuccessfully. In this report we emphasize the diagnostic difficulty caused by the concomitant presence of the two pathologies. In our opinion, the rapid evolution in this case is directly related to the high grade of the tumor.