Superscan on 68Ga PSMA PET/CT in patients with metastatic prostate carcinoma: A case series.

Prostate cancer is the second most common malignancy in men worldwide, with a good prognosis when is detected and treated in early stages, but, when it presents progression to castration-resistant metastatic prostate cancer, most of the cases will have bone metastasis, decreasing the quality of life and life expectancy. For the evaluation of the disease in the routinary clinical practice, 68Ga-PSMA PET/CT, among others is a valuable tool for the evaluation of the disease extension. 68Ga-PSMA PET/CT detects the presence of PSMA receptor in the tumoral tissue, but also has physiologic uptake in certain organs, such as liver, spleen, intestine, kidneys, lacrimal and salivary glands. Total or partial absence of uptake in those organs is rare and may be due to a high metastatic tumor burden, a phenomenon originally described in bone scintigraphy as super scan. We describe a case series of seven patients with prostate cancer from the National Institute of Cancerology in Colombia, in which a super scan pattern was found in the evaluation with 68Ga-PSMA PET/CT, proposing the suppression of uptake in the intestine, liver, spleen, lacrimal and salivary glands as the main criteria for its definition, and showing that renal uptake persists in most cases, considering that, unlike the super scan in conventional bone scintigraphy, this is not a criterion necessary for its definition in the study with 68Ga-PSMA.

Metabolic syndrome is associated with aggressive prostate cancer regardless of race.

PURPOSE: Recent meta-analyses suggest the Metabolic Syndrome (MS) increases high-grade prostate cancer (PC), although studies are inconsistent and few black men were included. We investigated MS and PC diagnosis in black and white men undergoing prostate biopsy in an equal access healthcare system. We hypothesized MS would be linked with aggressive PC, regardless of race. METHODS: Among men undergoing prostate biopsy at the Durham Veterans Affairs Hospital, medical record data abstraction of diagnosis or treatment for hypertension (≥ 130/85 mmHg), dyslipidemia (HDL < 40 mg/dL), hypertriglyceridemia (≥ 150 mg/dL), diabetes, hyperglycemia (fasting glucose ≥ 100 ml/dL), and central obesity (waist circumference ≥ 40 inches) were done. Biopsy grade group (GG) was categorized as low (GG1) or high (GG2-5). Multinomial logistic regression was used to examine MS (3-5 components) vs. no MS (0-2 components) and diagnosis of high grade and low grade vs. no PC, adjusting for potential confounders. Interactions between race and MS were also tested. RESULTS: Of 1,051 men (57% black), 532 (51%) had MS. Men with MS were older, more likely to be non-black, and had a larger prostate volume (all p ≤ 0.011). On multivariable analysis, MS was associated with high-grade PC (OR = 1.73, 95% CI 1.21-2.48, p = 0.003), but not overall PC (OR = 1.17, 95% CI 0.88-1.57, p = 0.29) or low grade (OR = 0.87, 95% CI 0.62-1.21, p = 0.39). Results were similar in black and non-black men (all p-interactions > 0.25). CONCLUSION: Our data suggest that metabolic dysregulation advances an aggressive PC diagnosis in both black and non-black men. If confirmed, prevention of MS could reduce the risk of developing aggressive PC, including black men at higher risk of PC mortality.

Comparative Pathobiology of Canine and Human Prostate Cancer: State of the Art and Future Directions.

First described in 1817, prostate cancer is considered a complex neoplastic entity, and one of the main causes of death in men in the western world. In dogs, prostatic carcinoma (PC) exhibits undifferentiated morphology with different phenotypes, is hormonally independent of aggressive character, and has high rates of metastasis to different organs. Although in humans, the risk factors for tumor development are known, in dogs, this scenario is still unclear, especially regarding castration. Therefore, with the advent of molecular biology, studies were and are carried out with the aim of identifying the main molecular mechanisms and signaling pathways involved in the carcinogenesis and progression of canine PC, aiming to identify potential biomarkers for diagnosis, prognosis, and targeted treatment. However, there are extensive gaps to be filled, especially when considering the dog as experimental model for the study of this neoplasm in humans. Thus, due to the complexity of the subject, the objective of this review is to present the main pathobiological aspects of canine PC from a comparative point of view to the same neoplasm in the human species, addressing the historical context and current understanding in the scientific field.

[Prostate carcinoma and syndrome of inappropriate antidiuretic hormone secretion]. / Carcinoma de próstata y síndrome de secreción inadecuada de hormona antidiurética.

Prostate cancer is an extremely rare cause of syndrome of inappropriate antidiuretic hormone (SIADH) secretion. These tend to be aggressive tumors and SIADH can carry serious clinical consequences. A 64 years old patient was diagnosed with Gleason 4+3: 7 prostate adenocarcinoma in December 2014 and received hormonal blockade therapy. By March 2015 he was admitted for symptomatic hyponatremia and SIADH secretion was diagnosed, with no other probable cause than prostate cancer. He suffered a rapid progression of his oncologic disease, surprisingly with PSA in normal range, and died in the short term. There is great clinical and histopathological variability in the cases reported in the literature of association of prostate carcinoma and SIADH. However, they all agree on the aggressiveness of these tumors. This characteristic is present in tumors that have neuroendocrine features. They are frequently resistant to hormonal treatment and may present with paraneoplastic syndromes such as SIADH. The profile of its molecular alterations is under study for the development of target therapies. The association of prostate adenocarcinoma and SIADH is very uncommon and could involve neuroendocrine differentiation. For this reason, it is essential to perform a new biopsy of the tumor or its metastases at the progressive disease in order to conduct an appropriate treatment according to its morphological, immunohistochemical and, in the future, molecular characteristics.

Carcinoma de próstata y síndrome de secreción inadecuada de hormona antidiurética / Prostate carcinoma and syndrome of inappropriate antidiuretic hormone secretio

El cáncer de próstata es una causa extremadamente rara de síndrome de secreción inadecuada de hormona antidiurética (SIADH). Se trata de tumores agresivos asociados a un síndrome que puede aparejar consecuencias graves. Un paciente de 64 años fue diagnosticado de adenocarcinoma de próstata Gleason 4+3: 7 en 2014 y recibió terapia de bloqueo hormonal. En 2015 debió ser ingresado por hiponatremia sintomática y se le diagnosticó un SIADH, sin otra causa probable más que el cáncer de próstata. Sufrió rápida progresión de su enfermedad oncológica, llamativamente cuando su PSA se encontraba en valores normales, y falleció al corto plazo. Existe gran variabilidad clínica e histopatológica de los casos informados en la literatura de asociación de carcinoma de próstata y SIADH, sin embargo, todos coinciden en la agresividad de estos tumores. Estas características se presentan en tumores con diferenciación neuroendocrina, frecuentemente resistentes al tratamiento hormonal y que pueden presentar síndromes paraneoplásicos como el SIADH. El perfil de sus alteraciones moleculares se encuentra en estudio para el desarrollo de terapias target. La asociación de adenocarcinoma de próstata y SIADH es muy infrecuente y podría implicar diferenciación neuroendocrina. Por tal motivo es esencial una nueva biopsia del tumor o de sus metástasis a la progresión de la enfermedad para poder conducir un tratamiento adecuado de acuerdo a sus características morfológicas, inmunohistoquímicas y, en un futuro, moleculares.

Prostate cancer is an extremely rare cause of syndrome of inappropriate antidiuretic hormone (SIADH) secretion. These tend to be aggressive tumors and SIADH can carry serious clinical consequences. A 64 years old patient was diagnosed with Gleason 4+3: 7 prostate adenocarcinoma in December 2014 and received hormonal blockade therapy. By March 2015 he was admitted for symptomatic hyponatremia and SIADH secretion was diagnosed, with no other probable cause than prostate cancer. He suffered a rapid progression of his oncologic disease, surprisingly with PSA in normal range, and died in the short term. There is great clinical and histopathological variability in the cases reported in the literature of association of prostate carcinoma and SIADH. However, they all agree on the aggressiveness of these tumors. This characteristic is present in tumors that have neuroendocrine features. They are frequently resistant to hormonal treatment and may present with paraneoplastic syndromes such as SIADH. The profile of its molecular alterations is under study for the development of target therapies. The association of prostate adenocarcinoma and SIADH is very uncommon and could involve neuroendocrine differentiation. For this reason, it is essential to perform a new biopsy of the tumor or its metastases at the progressive disease in order to conduct an appropriate treatment according to its morphological, immunohistochemical and, in the future, molecular characteristics.

Proceso carcinogenico de las próstatas caninas: via WNT canónica y su estudio comparado / Carcinogenic process of canine prostate: WNT canonical pathway and its comparative study / Processo carcinogênico das próstatas caninas: via WNT canônica e seu estudo comparado

La especie canina presenta semejanza con la especie humana con relación a las lesiones prostáticas. Es la única especie en presentar tumores espontáneos con frecuencia, de esta manera representa un importante modelo para estudio comparativo de afecciones de la glándula. El desarrollo de las neoplasia prostáticas es una enfermedad con causas multifactoriales, entre estas, alteraciones genéticas y epigenéticas están involucradas. Por lo tanto, el perro puede ser un modelo natural y espontaneo para el estudio de lesiones preneoplásicas e neoplásicas de próstata canina. En el futuro, podrá ser utilizado como modelo en pruebas pre-clínicas de medicamentos, como ya fue realizado para osteosarcoma, por ejemplo. Una de las vías importantes para el desarrollo de los carcinomas prostáticos es la WNT canónica dependiente de la proteína Beta-catenina. En esta revisión abordaremos el papel de esta vía y su participación en la carcinogénesis prostática, importante en humanos y perros, además de algunas proteínas involucradas en la regulación de la misma.

Prostate of dogs have similar lesions to that observed in human and is the only species other than man which frequently displays spontaneous prostatic tumors. In this way, the dog represent an important model of studying different prostatic affections. The prostate cancer development is multifactorial and among them, genetic and epigenetic alterations are involved. The dog can be a natural and spontaneous model to study preneoplastic and neoplastic lesions, with potential future studies as models for pre-clinical tests. One of important pathway to prostate carcinogenesis is beta catenin dependent canonical WNT pathway. In this paper, we review the role of this pathway in prostate carcinogenesis, important in humans and dogs, besides some regulatory proteins involved in this pathway.

A espécie canina apresenta semelhanças com a espécie humana com relação às lesões prostáticas, sendo a única espécie a apresentar tumores espontâneos e com frequência, desse modo representa um importante modelo para estudo comparativo de afecções desta glândula. O desenvolvimento das neoplasias prostáticas é multifatorial e dentre eles, alterações genéticas e epigenéticas estão envolvidas, portanto o cão pode ser um modelo natural e espontâneo para o estudo das lesões pré neoplásicas e neoplásicas da próstata, com futuro alto potencial de ser utilizado como modelo em testes pré-clínicos de medicamentos. Uma das vias importantes para o desenvolvimento dos carcinomas prostáticos é a WNT canônica, dependente da proteína Beta-catenina. Nesta revisão, abordaremos o papel desta via e sua participação na carcinogênese prostática, importante em humanos e cães, além de algumas proteínas envolvidas na regulação da mesma.

Proceso carcinogenico de las próstatas caninas: via WNT canónica y su estudio comparado / Carcinogenic process of canine prostate: WNT canonical pathway and its comparative study / Processo carcinogênico das próstatas caninas: via WNT canônica e seu estudo comparado

La especie canina presenta semejanza con la especie humana con relación a las lesiones prostáticas. Es la única especie en presentar tumores espontáneos con frecuencia, de esta manera representa un importante modelo para estudio comparativo de afecciones de la glándula. El desarrollo de las neoplasia prostáticas es una enfermedad con causas multifactoriales, entre estas, alteraciones genéticas y epigenéticas están involucradas. Por lo tanto, el perro puede ser un modelo natural y espontaneo para el estudio de lesiones preneoplásicas e neoplásicas de próstata canina. En el futuro, podrá ser utilizado como modelo en pruebas pre-clínicas de medicamentos, como ya fue realizado para osteosarcoma, por ejemplo. Una de las vías importantes para el desarrollo de los carcinomas prostáticos es la WNT canónica dependiente de la proteína Beta-catenina. En esta revisión abordaremos el papel de esta vía y su participación en la carcinogénesis prostática, importante en humanos y perros, además de algunas proteínas involucradas en la regulación de la misma.(AU)

Prostate of dogs have similar lesions to that observed in human and is the only species other than man which frequently displays spontaneous prostatic tumors. In this way, the dog represent an important model of studying different prostatic affections. The prostate cancer development is multifactorial and among them, genetic and epigenetic alterations are involved. The dog can be a natural and spontaneous model to study preneoplastic and neoplastic lesions, with potential future studies as models for pre-clinical tests. One of important pathway to prostate carcinogenesis is beta catenin dependent canonical WNT pathway. In this paper, we review the role of this pathway in prostate carcinogenesis, important in humans and dogs, besides some regulatory proteins involved in this pathway.(AU)

A espécie canina apresenta semelhanças com a espécie humana com relação às lesões prostáticas, sendo a única espécie a apresentar tumores espontâneos e com frequência, desse modo representa um importante modelo para estudo comparativo de afecções desta glândula. O desenvolvimento das neoplasias prostáticas é multifatorial e dentre eles, alterações genéticas e epigenéticas estão envolvidas, portanto o cão pode ser um modelo natural e espontâneo para o estudo das lesões pré neoplásicas e neoplásicas da próstata, com futuro alto potencial de ser utilizado como modelo em testes pré-clínicos de medicamentos. Uma das vias importantes para o desenvolvimento dos carcinomas prostáticos é a WNT canônica, dependente da proteína Beta-catenina. Nesta revisão, abordaremos o papel desta via e sua participação na carcinogênese prostática, importante em humanos e cães, além de algumas proteínas envolvidas na regulação da mesma.(AU)

Induction of Oxidants Distinguishes Susceptibility of Prostate Carcinoma Cell Lines to p53 Gene Transfer Mediated by an Improved Adenoviral Vector.

Previously, the authors developed an adenoviral vector, Ad-PG, where transgene expression is regulated by a p53-responsive promoter. When used to transfer the p53 cDNA, a positive feedback mechanism is established. In the present study, a critical comparison is performed between Ad-PGp53 and AdRGD-PGp53, where the RGD motif was incorporated in the adenoviral fiber protein. AdRGD-PGp53 provided superior transgene expression levels and resulted in the killing of prostate carcinoma cell lines DU145 and PC3. In vitro, this effect was associated with increased production of cytoplasmic and mitochondrial oxidants, DNA damage as revealed by detection of phosphorylated H2AX, as well as cell death consistent with apoptosis. Differential gene expression of key mediators of reactive oxygen species pathways was also observed. Specifically, it was noted that induction of known p53-target genes Sestrin2 and PIG3, as well as a novel target, NOX1, occurred in PC3 cells only when transduced with the improved vector, AdRGD-PGp53. The participation of NOX1 was confirmed upon its inhibition using a specific peptide, resulting in reduced cell death. In situ gene therapy also resulted in significantly improved inhibition of tumor progression consistent with oxidant-induced DNA damage only when treated with the novel AdRGD-PGp53 vector. The study shows that the improved adenovirus overcomes limitations associated with other p53-expressing vectors and induces oxidant-mediating killing, thus supporting its further development for cancer gene therapy.

EpCAM Expression in Lymph Node and Bone Metastases of Prostate Carcinoma: A Pilot Study.

There is an urgent need for new imaging modalities in prostate carcinoma staging. A non-invasive modality that can assess lymph node and bone metastases simultaneously is preferred. Epithelial cell adhesion molecule (EpCAM) is a membranous protein of interest as an imaging target since it is overexpressed in prostatic carcinoma compared with benign prostate epithelium and compared with stroma. However, EpCAM expression in lymph node metastases is sparsely available in the literature and EpCAM expression in bone metastases is yet unknown. The current study evaluates the expression of EpCAM in prostate carcinoma lymph nodes, in matched normal lymph nodes, in prostate carcinoma bone metastases, and in normal bone by immunohistochemistry. EpCAM was expressed in 100% of lymph node metastases (21 out of 21), in 0% of normal lymph nodes (0 out of 21), in 95% of bone metastases (19 out of 20), and in 0% of normal bone (0 out of 14). Based on these results, EpCAM may be a feasible imaging target in prostate carcinoma lymph node and bone metastases. Prospective clinical trials are needed to confirm current results. Preoperative visualization of prostate carcinoma metastases will improve disease staging and will prevent unnecessary invasive surgery.

Prostate-specific membrane antigen can promote in vivo osseous metastasis of prostate cancer cells in mice

Reports remain insufficient on whether and how prostate-specific membrane antigen (PSMA) can influence in vivo osseous metastasis of prostate cancer (PCa). In the present study, the authors induced stable expression of PSMA in mouse PCa cell line RM-1. In vivo osseous metastasis was induced in 37 6-week-old female C57BL/6 mice weighing 22.45 ± 0.456 g. RM-1 cells were actively injected into the femoral bone cavity, leading to bilateral dissymmetry of bone density in the femoral bone. Tumor cells were also detected in bone tissue by pathological examination. The impact on bone density was demonstrated by the significant difference between animals injected with RM-PSMA cells (0.0738 ± 0.0185 g/cm²) and animals injected with RM-empty plasmid cells (0.0895 ± 0.0241 g/cm²). The lytic bone lesion of the RM-PSMA group (68.4%) was higher than that of the control group (27.8%). Immunohistochemistry showed that the expression of both vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) was distinctly higher in the RM-PSMA group than in the control group, while ELISA and Western blot assay indicated that VEGF and MMP-9 were higher in the RM-PSMA group compared to the control group (in vitro). Thus, the present study proposed and then confirmed for the first time that PSMA can promote in vivo osseous metastasis of PCa by increasing sclerotic destruction of PCa cells. Further analyses also suggested that PSMA functions positively on the invasive ability of RM-1 by increasing the expression of MMP-9 and VEGF by osseous metastases in vivo.

Adenocarcinoma incidental de próstata en resección transuretral por causa benigna: Hospital de San José, julio 2006 a marzo 2008 / Incidental prostatic adenocarcinoma during transurethral resection for a bening cause: San Jose Hospital, july 2006 - march 2008

La resección transuretral de próstata es un procedimiento común para tratar patologías urinarias obstructivas benignas. Al material obtenido se le practica estudio histológico para confirmar la naturaleza benigna, pero en algunos casos se ha encontrado como hallazgo incidental un adenocarcinoma en estadios tempranos. No se sabe con claridad cuánto material debe procesarse o si la cantidad de tejido examinado aumenta la posibilidad de encontrar cáncer. El objetivo de este trabajo es determinar la frecuencia de adenocarcinoma incidental de próstata en pacientes sometidos a RTU por causa benigna. Reune 196 casos de RTU en los que se procesó en una segunda fase todo el tejido restante obtenido, describiendo las variables edad, peso del espécimen, número de láminas procesadas, niveles de PSA y categoría diagnóstica, la cual fue clasificada como negativa para maglinidad, PIN alto de grado y adenocarcinoma de próstata estadios T1a y T1b. Se encontró que la frecuencia de cáncer próstata en pacientes a quienes se les realizó RTU por hiperplasia prostática benigna en el Hospital de San José fue muy baja, dos pacientes de 71 y 80 años, además de otro que corresponde a una neoplasia intraepitelial de alto grado (PIN de AG) con niveles normales de PSA, lo que evidencia que la frecuencia es menor que la reportada en la literatura internacional.

Transurethral resection of the prostate (TURP) is a common procedure performed to treat benign urinary obstruction conditions. The specimen obtained undergoes hystologic work-up to confirm benign nature, but in some cases, an early-stage adenocarcinoma is found incidentally. It is not clearly known how much material must be processed or if the amount of tissue examined increases likelihood of finding cancer. The purpose of this work is to determine the frequency rate of incidental prostatic adenocarcinoma in patients who undergo TURP for a benign cause. It gathers 196 cases of TURP in which all the remaining tissue obtained underwent a second phase work-out, considering variables as age, weight of specimen, number of slides processed, PSA levels and diagnostic category, which was classified as negative for malignancy, high-grade prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma in stages T1a and T1b. It was evidenced that the frequency of prostate cancer in patients who underwent TURP for benign prostatic hyperplasia at the San José Hospital was very low, consisting of two patients 71 and 80 years old, as well as one that corresponds to a high-grade prostatic intraepithelial neoplasia (PIN of AG) with normal PSA levels, which evidences that our frequency rate is smaller than that reported in international literature.

Performance of PSA and of PSA density in the diagnosis of prostate carcinoma

OBJECTIVE: The aim of the study was to investigate the influence of the prostate volume and PSA density on the performance of total PSA to diagnosis of prostate carcinoma. METHODS: We analyzed 217 patients (PSA 0-10ng/ml) submitted to transrectal sextant prostate biopsy. Criteria for biopsy indication was PSA >2ng/ml and/or digital rectal exam suspicious of prostate cancer. RESULTS: Fifty five patients had prostate neoplasia (25.3%) and in 8/55 (25.3%) the serum PSA was under 4ng/ml. The sensitivity and specificity of the test were respectively 98.2% / 16.6% at a cut-off point of 2.5ng/ml and 85.4% / 38.8% at cut-off of 4ng/ml. The corresponding values for prostates >40ml or 40ml were: 96.2% / 8.1% and 100% / 27.2% at the cut-off point of 2.5ng/ml, and 92.5% / 20% and 78.5% / 62.3% at a cut-off level of 4ng/ml. For prostates 40ml a PSA cut-off point of 4ng/ml leads to a misdiagnosis in 21.4% of the malignant tumors. The median PSAD of benign prostates are different according to prostate volume (.40ml or 40ml). PSAD at cut-off of 0.08 increases the PSA specificity at both PSA cut-off points. CONCLUSIONS: Prostate volume affects the sensitivity and specificity of PSA and the median values of PSAD. PSAD of 0.08 increases the PSA specificity specially at a cut-off point of 2.5ng/ml in prostates smaller than 40ml.

Performance of PSA and of PSA density in the diagnosis of prostate carcinoma

OBJECTIVE: The aim of the study was to investigate the influence of the prostate volume and PSA density on the performance of total PSA to diagnosis of prostate carcinoma. METHODS: We analyzed 217 patients (PSA 0-10ng/ml) submitted to transrectal sextant prostate biopsy. Criteria for biopsy indication was PSA >2ng/ml and/or digital rectal exam suspicious of prostate cancer. RESULTS: Fifty five patients had prostate neoplasia (25.3%) and in 8/55 (25.3%) the serum PSA was under 4ng/ml. The sensitivity and specificity of the test were respectively 98.2% / 16.6% at a cut-off point of 2.5ng/ml and 85.4% / 38.8% at cut-off of 4ng/ml. The corresponding values for prostates >40ml or 40ml were: 96.2% / 8.1% and 100% / 27.2% at the cut-off point of 2.5ng/ml, and 92.5% / 20% and 78.5% / 62.3% at a cut-off level of 4ng/ml. For prostates 40ml a PSA cut-off point of 4ng/ml leads to a misdiagnosis in 21.4% of the malignant tumors. The median PSAD of benign prostates are different according to prostate volume (.40ml or 40ml). PSAD at cut-off of 0.08 increases the PSA specificity at both PSA cut-off points. CONCLUSIONS: Prostate volume affects the sensitivity and specificity of PSA and the median values of PSAD. PSAD of 0.08 increases the PSA specificity specially at a cut-off point of 2.5ng/ml in prostates smaller than 40ml.