A Combination of Positive Tumor HLA-I and Negative PD-L1 Expression Provides an Immune Rejection Mechanism in Bladder Cancer.

BACKGROUND: Tumor human leukocyte antigen class I (HLA-I) expression plays an important role in T cell-mediated tumor rejection. Loss of HLA-I is associated with cancer progression and resistance to immunotherapy, including antibodies blocking programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling. Our objective was to analyze a correlation between HLA-I, tumor immune infiltration, and PD-L1/PD-1 axis in bladder cancer in association with the clinicopathologic features of patients. METHODS: We analyzed 85 cryopreserved bladder tumors by immunohistochemistry to investigate the expression of HLA-I, PD-L1, PD-1, CD3, CD8, and CXC chemokine receptor 4 (CXCR4). The results were correlated with tumor stage and other clinicopathologic variables of patients. RESULTS: We found a strong positive correlation between tumor HLA-I expression and infiltration with CD3+ and CD8 + T cells. PD-L1 expression was positive in 15.5% of tumors and heterogeneous in 40.5%, and was linked to a more advanced tumor stage. The majority of HLA-I-positive/heterogeneous tumors also expressed PD-L1 and PD-1, which were significantly correlated with each other and with lymphocyte infiltration. Interestingly, the analysis of the simultaneous expression of both markers revealed that 85.2% of tumors with a positive/heterogeneous HLA-I phenotype and negative for PD-L1 were mostly non-invasive, representing a 'tumor rejection' immune phenotype. CONCLUSIONS: High tumor HLA-I expression with absence of PD-L1 provides bladder cancer with an immune rejection mechanism. Evaluation of PD-L1 and HLA-I together should be considered in bladder cancer and may provide a new predictive biomarker of tumor invasiveness and of the response to 'immune checkpoint' therapy.

[New therapeutic schedules of Sunitinib: Current evidence regarding the 2:1 scheme.] / Nuevos esquemas terapéuticos con Sunitinib: evidencia actual en torno a la pauta 2:1.

INTRODUCTION: In 2006, sunitinib approval by the FDA was a real revolution for the treatment of metastatic renal cell carcinoma (mRCC). However, considerable rates of dose reductions and therapeutic suppressions with the standard regimen (4:2) have forced the search for new schedule proposals in order to optimize the balance between side effects and oncologic efficacy. Among these new proposals, the 2:1 scheme is the one that has generated more expectations. OBJECTIVE: The objective of this paper is to make a review and critical discussion of current evidence about the new schedules of treatment with sunitinib. METHODS: Unstructured review of the literature on the various therapeutic regimens with sunitinib, making a comparison in terms of progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: We summarize the data from all relevant studies published to date comparing the standard 4:2 schedule versus the new 2:1. Most patients treated with 2:1 scheme are grouped in three retrospective observational studies and mostly correspond to patients who were initially treated with a 4:2 scheme and then moved to 2:1. A phase II randomized clinical trial comparing 4:2 and 2:1 schemes from the beginning has also been conducted. None of these studies found significant differences between the two regimens in terms of PFS or OS. Regarding the toxicity profile, the 2:1 scheme has proved to be more advantageous than the 4:2. CONCLUSIONS: Despite the still limited amount of data, current evidence supports the use of a 2:1 schedule, as it provides patients substantial advantages because of its better tolerability profile, without a loss in oncological efficacy. Currently, the 2:1 scheme is an appropriate alternative therapeutic strategy, especially in patients with poor tolerance to the standard 4:2 regimen.

Nuevos esquemas terapéuticos con Sunitinib: evidencia actual en torno a la pauta 2:1 / New therapeutic schedules of Sunitinib: current evidence regarding the 2:1 scheme

INTRODUCCIÓN: En 2006, la aprobación de Sunitinib por la FDA supuso una auténtica revolución en el tratamiento del carcinoma de células renales metastásico (CCRm). No obstante, las considerables tasas de reducciones de dosis y supresiones terapéuticas con el esquema terapéutico estándar (pauta 4:2), han forzado la búsqueda de nuevas propuestas posológicas con el objetivo de optimizar el equilibrio entre los efectos adversos y la eficacia terapéutica. Entre estas nuevas propuestas, la pauta 2:1 es la que más expectativas ha generado. OBJETIVO: El objetivo de este trabajo es realizar una síntesis y discusión crítica de la evidencia actual acerca de los nuevos esquemas de tratamiento con Sunitinib. MÉTODOS: Revisión no estructurada de la literatura sobre los distintos esquemas terapéuticos con Sunitinib, realizando una comparativa en términos de supervivencia libre de progresión (SLP), supervivencia global (SG) y toxicidad. RESULTADOS: Se exponen los datos de todos los estudios de relevancia publicados hasta la fecha en los que se compara la pauta 4:2 frente a la pauta 2:1. La mayoría de los pacientes tratados con el esquema 2:1 se aglutinan en tres estudios observacionales retrospectivos y, en su mayoría, corresponden a pacientes que inicialmente estuvieron tratados con un esquema 4:2 y luego pasaron al 2:1. Además se ha realizado un ensayo clínico aleatorizado fase II que compara el esquema 4:2 con el esquema 2:1 desde el inicio. Ninguno de estos estudios ha encontrado diferencias significativas entre ambas pautas en términos de SLP o SG, llegando a ser éstas incluso superiores a las de los esquemas 4:2. En cuanto al perfil de toxicidad, el esquema 2:1 ha mostrado ser más ventajoso que el 4:2. CONCLUSIONES: A pesar de la todavía escasa cantidad de datos, la evidencia actual sustenta la utilización del esquema 2:1 pues ofrece ventajas sustanciales a los pacientes con CCRm debido a su mejor perfil de tolerabilidad, sin que ello implique una pérdida de eficacia oncológica. Actualmente, la pauta 2:1 constituye una estrategia terapéutica alternativa adecuada, especialmente en aquellos pacientes con mala tolerancia al régimen 4:2

INTRODUCTION: In 2006, Sunitinib approval by the FDA was a real revolution for the treatment of metastatic renal cell carcinoma (mRCC). However, considerable rates of dose reductions and therapeutic suppressions with the standard regimen (4:2) have forced the search for new schedule proposals in order to optimize the balance between side effects and oncologic efficacy. Among these new proposals, the 2:1 scheme is the one that has generated more expectations. OBJECTIVE: The objective of this paper is to make a review and critical discussion of current evidence about the new schedules of treatment with Sunitinib. METHODS: Unstructured review of the literature on the various therapeutic regimens with Sunitinib, making a comparison in terms of progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: We summarize the data from all relevant studies published to date comparing the standard 4:2 schedule versus the new 2:1. Most patients treated with 2:1 scheme are grouped in three retrospective observational studies and mostly correspond to patients who were initially treated with a 4:2 scheme and then moved to 2:1. A phase II randomized clinical trial comparing 4:2 and 2:1 schemes from the beginning has also been conducted. None of these studies found significant differences between the two regimens in terms of PFS or OS. Regarding the toxicity profile, the 2:1 scheme has proved to be more advantageous than the 4:2. CONCLUSIONS: Despite the still limited amount of data, current evidence supports the use of a 2:1 schedule, as it provides patients substantial advantages because of its better tolerability profile, without a loss in oncological efficacy. Currently, the 2:1 scheme is an appropriate alternative therapeutic strategy, especially in patients with poor tolerance to the standard 4:2 regimen

[Evolution of urinary lithiasis composition in a Spanish health care area over the last four decades]. / Evolución de la composición de las litiasis urinarias en un área sanitaria española en las últimas cuatro décadas.

OBJECTIVE: To provide an updated epidemiological description of urinary lithiasis in a health area in the Western hemisphere over the past four decades. METHODS: 2704 urinary lithiases analysed in our institution between 1980 and 2015 were retrospectively reviewed. They were analyzed using polarized light microscopy, and in the case this method had questionable results we used X-ray diffraction. The variables collected were the lithiasis chemical composition (oxalates, phosphates, uric acid, infectious, cystine, mixed, other). Regarding the date of the analysis, the series of cases was grouped into four periods (1980-1989, 1990- 1999, 2000-2009, and 2010-2015), and also by sex and age of the patient. RESULTS: The mean age at diagnosis was 48.32 years (49.37 in men vs 46.53 in women, p=0.005). A male predominance was found (58.7%). Throughout the four decades, the involvement of women has progressively diminished compared to men. Of all the lithiases, the most frequent were those composed of oxalates (43.3%), followed by uric acid (16.9%) and infectious types (10.7%). The uric acid and oxalate lithiases were more common in men than in women (67.4% vs. 32.6% and 59.1% vs. 40.9%, respectively, p<0.001), while the lithiasis of infectious origin was more frequent in women than in men (56.3% vs. 43.7%, p<0.001). Throughout the time period, a trend of increasing oxalic lithiases and decreasing uric acid and phosphate lithiases was observed, as well as an increase of infectious lithiases over the past five years. CONCLUSIONS: In our setting, urinary lithiases appear more frequently in males at the end of the fourth decade of life. The most common lithiases are composed of oxalates, and their frequency has increased over time, while uric acid and phosphates lithiases have decreased.

Evolución de la composición de las litiasis urinarias en un área sanitaria española en las últimas cuatro décadas / Evolution of urinary lithiasis composition in a Spanish health care area over the last four decades

OBJETIVO: Obtener una descripción actualizada de las características epidemiológicas de las litiasis urinarias de un área sanitaria occidental durante las últimas cuatro décadas. MÉTODOS: Revisamos retrospectivamente 2704 litiasis analizadas en un área sanitaria española entre 1980 y 2015. El análisis se realizó mediante microscopía de luz polarizada, y si dicho método presentaba resultados dudosos se recurrió a la difracción con rayos X. Las variables recogidas fueron: la composición química de las litiasis (oxalatos, fosfatos, ácido úrico, infecciosas, cistina, mixtas, otras), la fecha del análisis agrupada en cuatro periodos (1980-1989, 1990-1999, 2000- 2009, 2010-2015), el sexo y la edad del paciente. RESULTADOS: La edad media al diagnóstico fue de 48,32 años (49,37 en varones vs 46,53 en mujeres, p = 0,005). Se encontró un predominio masculino (58,7%), y a lo largo de las cuatro décadas, la afectación en mujeres disminuyó. Las litiasis más frecuentes fueron las compuestas por oxalatos (43,3%), seguidas de las de ácido úrico (16,9%) y las infecciosas (10,7%). Las litiasis úricas y oxálicas fueron más frecuentes en varones que en mujeres (67,4% vs 32,6% y 59,1% vs 40,9%, respectivamente, p < 0,001); sin embargo, las de origen infeccioso fueron más frecuentes en mujeres que en varones (56,3% vs 43,7%, p < 0,001). Se apreció una tendencia al aumento de las litiasis oxálicas y a la disminución de las úricas y por fosfatos. Además, observamos un incremento de las litiasis infecciosas en los últimos 5 años. CONCLUSIONES: En nuestro medio, las litiasis aparecen con más frecuencia en varones en la cuarta década de la vida. Las más frecuentes son las oxálicas, cuya proporción ha aumentado a lo largo de las últimas décadas, mientras que las de ácido úrico y fosfato han disminuido

OBJECTIVE: To provide an updated epidemiological description of urinary lithiasis in a health area in the Western hemisphere over the past four decades. METHODS: 2704 urinary lithiases analysed in our institution between 1980 and 2015 were retrospectively reviewed. They were analyzed using polarized light microscopy, and in the case this method had questionable results we used X-ray diffraction. The variables collected were the lithiasis chemical composition (oxalates, phosphates, uric acid, infectious, cystine, mixed, other). Regarding the date of the analysis, the series of cases was grouped into four periods (1980-1989, 1990- 1999, 2000-2009, and 2010-2015), and also by sex and age of the patient. RESULTS: The mean age at diagnosis was 48.32 years (49.37 in men vs 46.53 in women, p = 0.005). A male predominance was found (58.7%). Throughout the four decades, the involvement of women has progressively diminished compared to men. Of all the lithiases, the most frequent were those composed of oxalates (43.3%), followed by uric acid (16.9%) and infectious types (10.7%). The uric acid and oxalate lithiases were more common in men than in women (67.4% vs. 32.6% and 59.1% vs. 40.9%, respectively, p p < 0.001), while the lithiasis of infectious origin was more frequent in women than in men (56.3% vs. 43.7%, p < 0.001). Throughout the time period, a trend of increasing oxalic lithiases and decreasing uric acid and phosphate lithiases was observed, as well as an increase of infectious lithiases over the past five years. CONCLUSIONS: In our setting, urinary lithiases appear more frequently in males at the end of the fourth decade of life. The most common lithiases are composed of oxalates, and their frequency has increased over time, while uric acid and phosphates lithiases have decreased

[Cold ischemia and renal graft survival: A paired analysis comparing first and second grafts from the same donor]. / Isquemia fría y supervivencia del injerto. Diferencias entre el primer y segundo injerto de un mismo donante.

OBJECTIVE: To compare the characteristics, clinical course, and survival of pairs of renal grafts from the same donor, with special interest in cold ischemia times (CIT) as a risk factor for graft survival. METHODS: We retrospectively reviewed paired grafts originating from the same cadaver donor from our prospectively recorded database of kidney transplants, from 1987 to 2015. We selected and divided them into two groups depending on whether they corresponded to the first or second graft. RESULTS: We studied a total of 860 paired kidneys. Mean CIT for the first and second groups were 15.12 and 19.16 hours, respectively. In the second group we observed higher incidences of acute tubular necrosis and initial delayed graft function (59.9% vs. 69.4% and 54.9% vs. 63.5%, respectively; p<0.001). No significant differences in either creatinine clearance rate or the rate of dialysis were observed between the two groups. No difference was found between the first and second groups in terms of graft survival (18.4 vs. 18.1 years, respectively; log-rank, p=0.667), and no differences were found by dividing the grafts into different categories according to their CIT (<14, 14-17, 17-20, >20 hours). For the set of grafts studied, CIT did not act as a risk factor for graft survival (hazard ratio [HR]=1.014; p=0.312). CONCLUSIONS: The proportion of ATN and DGF were greater in second transplants. However, there were no differences in long-term graft survival. Furthermore, we found no evidence that a CIT for less than 24 hours acted as a risk factor to graft survival.

Isquemia fría y supervivencia del injerto. Diferencias entre el primer y segundo injerto de un mismo donante / Cold ischemia and renal graft survival: A paired analysis comparing first and second grafts from the same donor

OBJETIVO: Comparar las características, evolución y supervivencia de las parejas renales procedentes de un mismo donante, con especial interés en el tiempo de isquemia fría (TIF) como factor de riesgo de supervivencia del injerto. MÉTODOS: A partir de nuestra base de datos de trasplantados renales, realizada de forma prospectiva desde 1987 hasta 2015, seleccionamos aquellos injertos emparejados procedentes de un mismo donante cadáver y los dividimos en dos grupos según correspondieran al primer o al segundo injerto. RESULTADOS: Estudiamos un total de 860 riñones emparejados. El TIF medio del primer y segundo grupo fue de 15,12 y 19,16 horas respectivamente. En el segundo grupo se observó una mayor incidencia de necrosis tubular aguda (NTA) y función inicial retrasada del injerto (FRI) (59,9% vs 69,4%; y 54,9% vs 63,5%, respectivamente p < 0,001). No se observaron diferencias significativas entre ambos grupos en las cifras de aclaramiento de creatinina o en la tasa de paso a diálisis. En términos de supervivencia del injerto, no se encontraron diferencias entre el primer y el segundo grupo (18,4 vs 18,1 años respectivamente, Log-rank p = 0,667). Adicionalmente se estudio la isquemia fría del conjunto de injertos, sin apreciar diferencias según su TIF (<14, 14-17, 17-20, >20 horas), el cual no se comportó como un factor de riesgo de supervivencia del injerto (HR=1.014 (p = 0,312)). CONCLUSIONES: La proporción de NTA y FRI es mayor en los segundos trasplantados. Sin embargo, no existen diferencias en términos de supervivencia del injerto a largo plazo. No encontramos evidencia de que un TIF por debajo de 24h se comporte como un factor de riesgo de supervivencia del injerto

OBJECTIVE: To compare the characteristics, clinical course, and survival of pairs of renal grafts from the same donor, with special interest in cold ischemia times (CIT) as a risk factor for graft survival. METHODS: We retrospectively reviewed paired grafts originating from the same cadaver donor from our prospectively recorded database of kidney transplants, from 1987 to 2015. We selected and divided them into two groups depending on whether they corresponded to the first or second graft. RESULTS: We studied a total of 860 paired kidneys. Mean CIT for the first and second groups were 15.12 and 19.16 hours, respectively. In the second group we observed higher incidences of acute tubular necrosis and initial delayed graft function (59.9% vs. 69.4% and 54.9% vs. 63.5%, respectively; p20 hours). For the set of grafts studied, CIT did not act as a risk factor for graft survival (hazard ratio [HR]=1.014; p = 0.312). CONCLUSIONS: The proportion of ATN and DGF were greater in second transplants. However, there were no differences in long-term graft survival. Furthermore, we found no evidence that a CIT for less than 24 hours acted as a risk factor to graft survival

Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance.

Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss of HLA-I expression found in 50 % of tumors showed an association with increased incidence of tumor relapse, perineural invasion, and high D'Amico risk. The remaining HLA-I-positive tumors demonstrated locus and allelic losses detected in 26 and 12 % of samples, respectively. Loss of heterozygosity at chromosome 6 was detected in 32 % of the studied tumors. Molecular analysis revealed a reduced expression of B2M, TAP2, tapasin and NLRC5 mRNA in microdissected HLA-I-negative tumors. Analysis of twelve previously unreported cell lines derived from neoplastic and normal epithelium of cancerous prostate revealed different types of HLA-I aberration, ranging from locus and/or allelic downregulation to a total absence of HLA-I expression. The high incidence of HLA-I loss observed in PC, caused by both regulatory and structural defects, is associated with more aggressive disease development and may pose a real threat to patient health by increasing cancer progression and resistance to T-cell-based immunotherapy.

Right renal vein extension with cryopreserved external iliac artery allografts in living-donor kidney transplantations.

INTRODUCTION: A short right renal vein remains a challenge for renal transplant surgery, especially in the living donor. Our objective was to report on a new technique to solve this problem. TECHNICAL CONSIDERATIONS: We describe our experience with the use of cryopreserved iliac artery grafts for right renal vein extension. Two renal grafts from living donors with a short right renal vein were subjected to an extension with a cryopreserved external iliac artery allograft. There were no perioperative or postoperative complications. There were also no changes in ischemia times. The renal implantation was performed easily and conveniently using our standard technique. For the first and second procedures, at 3 and 3.5 years after surgery, respectively, both vascular grafts maintain good patency, and the renal function of both recipients is optimal. CONCLUSION: Tissue-banked cryopreserved cadaveric vessels can be a useful tool in renal transplant surgery. The use of a cryopreserved iliac artery for renal vein extension is a simple and effective new technique that can be added to the pool of surgical solutions for a short renal vein in living-donor kidney transplantation. To our knowledge, this is the first time that the use of such grafts for this purpose has been described.

Nephron-sparing surgery for adenocarcinoma in a renal allograft.

The incidence of malignant tumors in recipients of renal allografts is higher than in the general population. Renal cell carcinoma (RCC) accounts for 4.6% of the tumors in transplanted patients; of them, only 10% are found in transplanted kidneys. Transplantectomy has always been the usual treatment. However, during the last years, nephron-sparing surgery of the allograft is more frequently done in well-selected cases, and therefore dialysis can be avoided. We report the case of a 37-year-old female patient with renal transplant, diagnosed with a 4.5 cm tumor in the lower pole of the renal allograft. The patient underwent partial nephrectomy successfully. Six years after surgery, there is no evidence of recurrence of the disease and the patient maintains an adequate renal function.

Gouty tophi in the penis: a case report and review of the literature.

Gout is a metabolic disease characterized by hyperuricemia and the deposition of monosodium urate crystals in different anatomical locations. We report the case of a 61-year-old man who received consultation for gouty tophi in the penis, which is an unusual location for this type of pathology, that was resolved with the surgical removal of the tophi. We provide a review on gout and its treatment as well as other locations where atypical gouty tophi have been described.

Conservative management of unusual keratinising squamous metaplasia of the bladder in a 28-year-old female and overview of the literature.

Keratinizing squamous metaplasia of the bladder is rare and is usually associated with urinary tract infections and chronic irritation. It is considered a precancerous condition of squamous cell carcinoma, especially when more than 50% of the bladder surface is affected. Medical treatment cannot eradicate this lesion. When it is limited to a small area of the bladder, transurethral resection is possible. Annual cystoscopy with multiple biopsies as well as annual upper tract imaging is proposed in the follow up of these patients. We present a preliminary 2-year followup report of a keratinizing squamous metaplasia of the bladder in a 28-year-old female patient with no previous risk factors.