Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity.

Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.

An improved reprogrammable mouse model harbouring the reverse tetracycline-controlled transcriptional transactivator 3.

Reprogrammable mouse models engineered to conditionally express Oct-4, Klf-4, Sox-2 and c-Myc (OKSM) have been instrumental in dissecting molecular events underpinning the generation of induced pluripotent stem cells. However, until now these models have been reported in the context of the m2 reverse tetracycline-controlled transactivator, which results in low reprogramming efficiency and consequently limits the number of reprogramming intermediates that can be isolated for downstream profiling. Here, we describe an improved OKSM mouse model in the context of the reverse tetracycline-controlled transactivator 3 with enhanced reprogramming efficiency (>9-fold) and increased numbers of reprogramming intermediate cells albeit with similar kinetics, which we believe will facilitate mechanistic studies of the reprogramming process.

[Surgical complications in kidney transplantation and their influence on graft survival]. / Complicaciones quirúrgicas en el trasplante renal y su influencia en la supervivencia del injerto.

OBJECTIVES: To analyze surgical complications in kidney transplantation and their influence on graft survival. MATERIALS AND METHODS: A retrospective analysis was made of the early and late surgical complications occurring in 216 consecutive kidney transplants performed at our institution and their influence on graft survival. RESULTS: At least one surgical complication occurred in 82 (38%) of the 216 transplantations, and 68 (31%) required some type of repeat surgery, 23 in the early postoperative period and 45 more than 3 months after surgery. Mean follow-up was 48 months (SD +/-33.4), and median follow-up 48 months (range, 0-166 months). No recipient or donor factors predisposing to surgical complications were found. Graft survival was significantly shorter in patients with surgical complications [3- and 5-year survival rates of 86% (95% CI 83-89) and 78% (95% CI 73-82) as compared to 92% (95% CI 90-94) and 88% (95% CI 85-91), p=0.004]. Early repeat surgery, venous thrombosis, and wound infection were among the complications having an independent influence on graft survival. A multivariate analysis of graft survival in the whole group showed early repeat surgery to be a factor with an independent prognostic value (OR: 4.7; 95% CI 2.2-10, p<0.0001). Delayed function and donor age older than 60 years were the other independent influential factors. CONCLUSION Surgical complications have an influence on graft survival. The need for early repeat surgery, delayed function, and donor age older than 60 years are independent predictors of graft survival.

[Pelvic lymph node dissection (extended vs standard) and prostate cancer]. / Linfadenectomía (ampliada vs estándar) y cáncer de próstata.

The role and the potential benefit, if any, of pelvic lymphadenectomy in prostate cancer are still controversially discussed. It is generally accepted that PLND at time of radical prostatectomy is the only reliable diagnostic procedure to achieve as much individual histological staging information as possible to trigger postoperative adjuvant management. However, the extent of pelvic lymph node dissection (limited vs. extended) and the most suitable candidates for this procedure are still a matter of intense debate. The aim of this review is to critically evaluate the current status on lymph node dissection in prostate cancer.

[Gleason score 8-10 prostatic adenocarcinoma: prognostic influence in the biochemical progression free survival]. / Adenocarcinoma de próstata gleason clínico 8-10: influencia pronóstica en la supervivencia libre de progresión bioquímica.

OBJECTIVE: Hereby, we analyze the characteristics of the clinical Gleason 8-10 group of patients with in our series diagnosed of Prostate Cancer and treated by means of radical prostatectomy, and we try to ascertain which are the influence factors within this group upon progression and progression free survival. MATERIAL AND METHODS: From the global series of 781 patients with T1-T2 prostate cancer treated by means of radical prostatectomy between 1990 and 2004, we study 108 with a Gleason score on the biopsy of 8-10. Median PSA was 12 ng/ml and 50% were T2. Variables related to biochemical progression and progression free survival have been studied, comparing the group of Gleason 8-10 with the rest and analyzing, within the Gleason 8-10 group which are the related variables with progression and progression free survival, trying to find a predictive model. Contingency tables and logistic regression have been employed. For the survival analysis, Kaplan Meyer curves, log-rank and Cox models. RESULTS: Actual State: 62.7% (490/781) are alive and free of biochemical progression, 24.8% (194/781) are alive with biochemical progression, 2.9% (23/781) are dead by cancer and 1.9% (15/781) are dead by other cause and 7.6% (59/781) are lost. Biochemical progression study of the whole series (781 patients) Clinical Gleason score 8-10 is a influence factor on the univariate study (OR2,61 IC 95%: 1.7-4). In the progression free survival study (PFS) of the whole series (781 patients) the PFS in Clinical Gleason 8-10 at 3 and 5 years is 56 +/- 5% y 35 +/- 7%, significantly worse than the rest of the group (p < 0.0001). In the multivariate study of the influence factors on the PFS includes Clinical Gleason Score 8-10 as an independent prognostic factor (OR: 2.6 IC 95%: 1.6-4.12) p = 0.003, together with the clinical stage (OR: 1.,81 IC 95%: 1.18-2.78) p < 0.006, the PSA (OR: 1.03 IC 95%: 1.025-1.046) p < 0.0001 and the side of tumor on the biopsy (OR: 1.5 IC 95%: 1.01-2.24) p = 0.045. In the clinical Gleason score 8-10 group the influent factors on the PFS are. PSA (OR: 1.02 IC 95%: 1.003-1.04) and pathological stage (OR: 3.84 IC 95%: 1.77-8.27). Patients with a pT2 have a significantly better survival than those pT3 at 3 and 5 years (80 +/- 6%; 54 +/- 13% y 40 +/- 7%; 27 +/- 7%) (p < 0.0001). The best cut point for the PSA is 11 ng/ml. Patients with a PSA < 11 ng/ml have a 3 and 5 years survival better than those with >11 ng/ml PSA (74 +/- 7%, 30 +/- 22% y 40 +/- 7%, 26 +/- 7%) (p < 0.0001). CONCLUSIONS: Clinical Gleason Score 8-10 is a negative independent prognostic factor on the progression free survival, but its prognosis is better if they present a PSA prior surgery lower than 11 ng/ml and the pathological stage is a pT2.

[Extracorporeal circulation and hypothermy surgery in tumors with vena cava extension: 20 years experience at the University Clinic of Navarra]. / Cirugía con circulación extracorpórea e hipotermia en tumores con extensión a vena cava: 20 años de experiencia de la clínica Universitaria de Navarra.

OBJECTIVE: We present our 20 years experience treating patients with vena cava extension in whom an extracorporeal circulation, hypothermia, cardio circulatory arrest (ECC-H-CCA) in order to perform, together with a tumoral resection, a thrombus resection. MATERIAL AND METHODS: From 1985 to 2005 a total of 28 retroperitoneal tumor were treated: 25 renal cancers, a Wilms tumor, a paratesticular rabdomiosarcoma, and a pheocromocitoma. All of them had an extension by means of thrombus above the suprahepatics veins. All of them were treated by means of ECC-H-CCA for thrombus extraction. A descriptive study of the serie is performed as well as a Kaplan Meyer survival study. RESULTS: Surgical complications were present within 10 patients (35%), with a surgical mortality of two patients (7%): one intra-operatively because a massive embolism of the lungs and the other because of a lung embolism on the 4th post-operative day. Global actuarial survival was 29.1+/-10% at three years and 17.5+/-8% at five years. Analyzing only who do not have metastatic lesions, nor lymph nodes at diagnosis their three year survival was 50.9+/-16.3% and 32.2+/-16% at five years. Mean while those who have any metastatic lesion at diagnosis their three and five years survival was 20.8+/-12% and 10.4+/-9% respectively. CONCLUSIONS: The employ of surgical techniques with ECC-H-CCA with in oncological pathology associated with vena cava thrombus is justified and its employment does not worsen the survival; it is indicated because its results, allowing a complete tumoral resection in a safe and reproducible fashion.

[Steroid and xenobiotic receptor (SXR), multidrug resistance gene (MDR1) and GSTs, SULTs and CYP polymorphism expression in invasive bladder cancer, analysis of their expression and correlation with other prognostic factors]. / Expresion del receptor de esteroides y xenobioticos (SXR) y del gen de multirresistencia drogas (MDR1) y de los polimorfismos de las enzimas Gsts, SULTs y CYP en tumores vesicales profundos, analisis de su expresion y correlación con otros factores pronósticos.

INTRODUCTION: Steroid and Xenobiotic Receptor (SXR) has demonstrated its activation by numerous drugs, including cytochrome P450 potent inducers like rifampicina or cotrimazol. The role of SXR is well known, and lies regulating in a positive manner cytochrome P450 3A4 (CYP3A4) transcription and the multidrug resistance gene (MDR1), it's considered a key in the xenobiotic detoxification mechanism, being involved in all phases of the detoxification process. Enzymes involved in Policyclic Aromatic hidrocarbures (PAH) metabolism and degradation are polymorphic in humans, including glutation S-transferases (GSTs), N-acetiltransferases (NATs), sulfotransferases (SULTs)1A1 and cytochrome p450 (CYP)1B1. OBJECTIVES: The objectives we've planned are: 1. Analyze the expression of the transcription factor SXR and MDR1 in bladder by means of RT-PCR real time, both in normal bladder and in tumoral bladder. 2. Analyze the relation between clinical and pathological factors with the expression of SXR and MDR1. 3. Analyze the expression of the polymorphims CYP1B1, GSTM1 GSTT1 and SULT1A1 and their correlation with different clinic-pathological and molecular factors. MATERIAL AND METHODS: In a prospective way the size of the sample was estimated. In 67 patients from two institutions (Hospital Universitario Miguel Servet (49 HUMS) and Clinica Universitaria de Navarra (18 CUN)), diagnosed of invasive bladder cancer and treated by means of radical cystectomy, were determined the expression of both SXR and MDR1 by means of real time PCR, as well as the polymorphisms CYP1B1, GSTM1 GSTT1 y SULT1A1 by means of RFLP (Restriction fragment length polymorphism). Correlations with other prognostic factors by contingency tables were performed. RESULTS: Average follow up was 23.7 months with a median of 28.26 months. Of the 67 patients studied, 31 patients (46.3) presented disease progression, in form of local recurrence or in distant metastasis or both. With a average time to progression of 12.4 months and a median of 10 months, with a range of 1.1 month to 31.9 month. 36 patients (53.7%) did not have any evidence of disease progression during follow up. The Steroid and Xenobiotic Receptor as well as the Multidrug Resistance Gene (MDR1) are expressed in both normal bladder (0.94DeltaCt y 0.94DeltaCt) and tumoral bladder in the cystectomy specimen (1.09 DeltaCt y 0.45 DeltaCt). We've analyzed their expression in a quantitative manner and in a qualitative manner. The expression of SXR correlates with the presence of ca. in situ (p=0.024), vasculo-lymphatic invasion (p=0.05) mean while MDR1 correlates with presence of vasculo-lymphatic invasion (p=0.05) Both factors are correlate between each others (p=0.011). Polymorphisms: CYP1B1, GSTM1, GSTT1 and SULT1A1, are expressed in these patients but their expression doesn't correlates with any prognostic factor CONCLUSIONS: Both SXR and MDR1 are expressed in normal bladder as well as in tumoral bladder. And their expression correlates with different prognostic factors with influence in the survival described in the literature.

Sindbis virus replicon particles encoding calreticulin linked to a tumor antigen generate long-term tumor-specific immunity.

Alphavirus vectors have emerged as a promising strategy for the development of cancer vaccines and gene therapy applications. In this study, we used the replication-defective vaccine vector SIN replicon particles from a new packaging cell line (PCL) to develop SIN replicon particles encoding calreticulin (CRT) linked to a model tumor antigen, human papillomavirus type 16 (HPV16) E7 protein. The linkage of CRT to E7 in SIN replicon particles resulted in a significant increase in E7-specific CD8(+) T-cell precursors and a strong antitumor effect against E7-expressing tumors in vaccinated mice. SINrep5-CRT/E7 replicon particles enhanced presentation of E7 through the major histocompatibility complex (MHC) class I pathway by infecting dendritic cells (DCs) directly and pulsing DCs with lysates of cells infected by SINrep5-CRT/E7 replicons. Vaccination of immunocompromised (BALB/c nu/nu) mice with SINrep5-CRT/E7 replicon particles also generated significant reduction of lung tumor nodules, suggesting that antiangiogenesis may contribute to the antitumor effect of SINrep5-CRT/E7 replicon particles. Furthermore, SINrep5-CRT/E7 replicon particles generated long-term in vivo tumor protection effects and antigen-specific memory immunities. We concluded that the CRT strategy used in the context of SIN replicon particles facilitated the generation of a highly effective vaccine for cancer prophylaxis and immunotherapy.

[Pheochromocytoma with thrombus in cava]. / Feocromocitoma con trombo en cava.

Pheochromocytoma, a paraganglioma of suprarenal location, is a catecholamine-secreting chromaffin cell tumour. Spread of these tumours to the vena cava is rare and the thrombus only reaches the right atrium in exceptional cases. We present the case of a patient who, without previous symptomatology, presented with a clinical picture of multiorganic dysfunction with primary manifestation of a suprarenal tumour with vascular spread to the right atrium affecting the right suprahepatic vein.

[Incidentally detected renal cancer. Prognostic factors]. / Tumores renales incidentales. Factores pronósticos.

OBJECTIVE: To study the clinical and pathological characteristics of incidental renal tumors treated in our center. MATERIAL AND METHODS: A retrospective review is conducted of 318 nephrectomies comparing the clinico-pathological variables of renal tumors diagnosed incidentally with those of symptomatic renal tumors. The factors influencing disease-free survival are analyzed in both groups. RESULTS: In our experience, although incidental renal tumors presented better survival than symptomatic ones owing to their better pathological state and tumor grade, incidental diagnosis was not an independent influencing factor in the multivariate study. Only when patients were studied who did not present metastases on diagnosis did incidental diagnosis become an influencing factor very close to statistical significance. CONCLUSIONS: Incidental diagnosis is not an independent prognostic factor.

[Follicular carcinoma of the thyroid manifested initially as asymptomatic primary renal neoplasm]. / Masa renal asintomática como primera manifestación de carcinoma folicular de tiroides.

Metastases in the kidney are rare, evenmore if primary source is thyroid. We report the tenth case of metastases in the kidney from thyroid, and it is the first to be follicular type and absolutely asymptom. Sonography and computerized tomography with suspicion of renal tumour are showed in a asymtom female 75 years old. Left partial nephrectomy was perfomed, initially it has been pathologically diagnosed as renal clear cells tumour, however the definitive pathologic report showed follicular tumour of thyroid. Local and systemic stage was discovered with complementary techniques. Sources of metastases in kidney and diagnoses techniques are discussed.

[Mutations of the androgen receptor gene in patients with clinically localized adenocarcinoma of the prostate]. / Mutaciones del gen del receptor de andrógenos en pacientes con adenocarcinoma de próstata clínicamente localizado.

UNLABELLED: The aim of this study was to detect mutations in the human androgen receptor gene in radical prostatectomy specimens. MATERIAL AND METHODS: The genomic sequence was realized in 67 radical prostatectomy specimens. The mean age was 64 years old. The PSA median was 15 ng/ml. TNM 1997: 34.3% were T1 and 65.7% T2. Genomic sequence: 1. Radical prostatectomy specimens desparaffitation. 2. Extraction of the DNA 3. DNA amplification. 4. Automatic genome sequence. 5. Comparison with Gene-Bank. RESULTS: 16.7% of the specimens were mutated. The most frequent mutation was the punctual mutation. The exon most frequent mutated was exon 1.

[Urinary incontinence: new pharmacologic therapies]. / Nuevos fármacos en el tratamiento de la incontinencia urinaria.

Several classes of drugs have been investigated for their efficacy in treating overactive bladder syndrome (OAB) and stress urinary incontinence (SUI). Surgery and behavioral therapies are currently the mainstay of treating SUI. However, results are also being made available about a new oral medication, Duloxetine, which appears to be clinically safe and effective for the treatment of SUI. On the other hand, a new muscarinic receptor antagonist, Solifenacin, has been shown in clinical trials to be clinically effective, safe and well tolerated for treating OAB.

[Solitary lung metastasis after radical prostatectomy]. / Metástasis pulmonar solitaria tras prostatectomía radical.

Prostate carcinoma is diagnosed in earlier phases of its evolution, but this carcinoma may have an unpredictible evolution. Radical treatment (surgery and radiotherapy) is the best treatment in clinically localized tumors. The biochemical failure over 5 years from the surgery is 20-50% of the patients; the biochemical failure over 10 years from the surgery is less frequent because of prognostic factors from the biologic nature of the tumor. We report a case with biochemical and clinical failure over 10 years from the surgery.

[Prognosis factors in pT3 renal carcinoma]. / Factores pronóstico en carcinoma renal pT3.

OBJECTIVES: To identify independent predictors of progression and global survival in patients affected by pT3 renal cell carcinoma. To make risk groups by risk factors. MATERIAL AND METHODS: We evaluated 117 patients with pT3 renal cell carcinoma. 88 was M0 and 29 M1. Most frequent clinical feature: asintomatic patients. 80 males (69%) and 37 females (31%). Mean age 59 (24-82). Median follow up 34 months (mean 44 +/- 39 months). RESULTS: Pathological stage (TNM 1997) was pT3a in 52 patients (43.6%), pT3b 63 patients (53.6%) and pT3c 2 patients. HISTOLOGY: clear cell carcinoma 106 patients (90.6%), papillary 5 patients (4.3%) an dchromophobe 4 patients (3.4%). Nuclear grading according Fuhrman's classification: G1 13 patients, G2 45 patients, G3 32 and G4 12 patients. Size > 4 cm (p = 0.005/p = 0.0019), grade 3-4 (p = 0.006/p = 0.0007), N+ (p = 0.034/p = 0.009) and M+ (p = 0.035/p = 0.042) were independent prognosis factors for progression and global survival of the pT3 renal cell carcinoma. Patients M0 with 0 or 1 risk factor have better global survival tanh patients M0 with 3 or 4 risk factors and patients M1. CONCLUSIONS: Size, grade, N+ and M+ were independent prognosis factors for progression and global survival of the pT3 renal cell carcinoma. Tera are no differencies in global survival between patients M0 with 2 or 3 risk factors and patients M1.

[Usefulness of PET in the diagnosis and response to treatment of extragonadal germinal tumor with atypical presentation]. / Utilidad del PET en el diagnóstico y respuesta al tratamiento en un tumor germinal extragonadal de presentación atípica.

Primary tumors of extragonadal origin are rare, with fewer than 1000 cases described in the literature. Although the exact incidence of EGTs is unknown, clinical data suggest that roughly 3% to 5% of all germ cell tumors. We expose a case report of EGT with unusually clinic presentation. We present our diagnostic and therapeutic experience in this injuries.

[Clinical features, diagnosis, and prognosis of renal carcinoma]. / Clínica, diagnóstico y pronóstico del carcinoma renal.

Significant conceptual changes have taken place in renal tumoral diseases over the last few years. As a result of the authors' broad institutional experience, this overall revision describes the most up-to-date clinical and diagnostic aspects of this condition. Emphasis is made on molecular staging and two variables that guide the prognosis of the disease, a decisive feature to establish treatment and to contribute to change current survival rates.

[Treatment of renal carcinoma]. / Tratamiento del carcinoma renal.

The standard therapy for renal carcinoma is radical surgery. When dealing with single, under 4 cm tumors and in the case of renal tumors in single-kidney patients, the choice therapy is nephrectomy or partial nephrectomy. Response rates in metastatic renal carcinoma using the various immune therapy approaches available range from 15 to 35%, responses being short-lasting.

[Prognostic value of P53, Ki67, and Rb protein in infiltrating bladder tumors]. / Valor pronóstico de la p53, Ki67 y la proteína Rb en los tumores vesicales infiltrantes.

OBJECTIVES: To determinate whether increased expression of the p53 and Ki67 and the of the tumour suppressor gene retinoblastoma (prot Rb), in an immunohistochemistry study, were associated with relapse in invasive bladder cancer. MATERIALS AND METHODS: 47 patients with invasive bladder cancer. 42 men and 5 women. Mean age 63 years old. Relapse in 19 patients (40%). Mean time until recurrence 8.5 months. p53 and Ki67 were study in 47 patients and prot Rb in 40 patients. RESULTS: p53: Mean expression 41%. There were significant differences in the increased expression of p53 between patients with and without relapse (p = 0.03). A statistically significant association was then observed between patients with p53 > 20% (vs p53 < 20%) and adverse outcome of the disease (p = 0.04). Ki67 and prot Rb: There were no significant differences in relapse and progression free survival between Ki67 > 40% (vs Ki67 < 40%) and prot Rb < 10% (vs prot Rb > 10%). p53 expression showed a statistically significant correlation with Ki67 and prot Rb. CONCLUSION: p53 is a good prognostic marker for the relapse and progression free survival in invasive bladder cancer.