Should Lutetium-prostate specific membrane antigen radioligand therapy for metastatic prostate cancer be used earlier in men with lymph node only metastatic prostate cancer?

PURPOSE: Lutetium labelled prostate-specific membrane antigen radioligand therapy (Lu-PSMA RLT) has shown pleasing early results in management of high-volume metastatic castration resistant prostate cancer (mCRPC), but its role in the early treatment of men with only lymph node metastasis (LNM) is unknown. The aim was to assess the outcome of Lu-PSMA RLT earlier in the treatment of men with only LNM. MATERIALS AND METHODS: Single institution retrospective review of men with only LNM on staging Ga-PSMA PET PSMA who proceeded with Lu-PSMA RLT. RESULTS: There were 17 men with only LNM, including 13 with mCRPC and 3 who were both hormone and chemotherapy naïve. The median PSA was 3.7 (0.46-120 ng/mL). A PSA decline of ≥50% occurred in 10/17 (58.8%), decreasing to <0.2 ng/mL in 35.3% (6/17). The PSA continues to decline or remain stable in 10/17 (58.8%) with a median follow-up of 13 months, and 8/17 (47.1%) have not reached their pre-treatment levels. There were no significant side effects. There was a better PSA response in men without prior chemotherapy (p=0.05). The prostate cancer specific and overall survival is 82.4% (14/17). CONCLUSIONS: Our results identify improved PSA response to Lu-PSMA RLT in men with only LNM, especially in the chemotherapy naïve cohort, compared to previous series with more advanced mCRPC. These findings provide important proof of principle to aid with planning of future prospective randomized trials evaluating the role of Lu-PSMA RLT earlier in the management of node metastatic prostate cancer, including men naïve of ADT and chemotherapy.

ENZA-p trial protocol: a randomized phase II trial using prostate-specific membrane antigen as a therapeutic target and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901).

OBJECTIVES: To determine the activity and safety of lutetium-177 (177 Lu)-prostate-specific membrane antigen (PSMA)-617 in men with metastatic castration-resistant prostate cancer (mCRPC) commencing enzalutamide, who are at high risk of early progression, and to identify potential prognostic and predictive biomarkers from imaging, blood and tissue. PARTICIPANTS AND METHODS: ENZA-p (ANZUP 1901) is an open-label, randomized, two-arm, multicentre, phase 2 trial. Participants are randomly assigned (1:1) to treatment with enzalutamide 160 mg daily alone or enzalutamide plus 177 Lu-PSMA-617 7.5 GBq on Days 15 and 57. Two additional 177 Lu-PSMA-617 doses are allowed, informed by Day-92 Gallium-68 (68 Ga)-PSMA positron emission tomography (PET; up to four doses in total). The primary endpoint is prostate-specific antigen (PSA) progression-free survival (PFS). Other major endpoints include radiological PFS, PSA response rate, overall survival, health-related quality of life, adverse events and cost-effectiveness. Key eligibility criteria include: biochemical and/or clinical progression; 68 Ga-PSMA PET-avid disease; no prior androgen signalling inhibitor, excepting abiraterone; no prior chemotherapy for mCRPC; and ≥2 high-risk features for early enzalutamide failure. Assessments are 4 weekly during study treatment, then 6 weekly until radiographic progression. Response Evaluation Criteria in Solid Tumours (RECIST) are used to assess imaging conducted every 12 weeks, 68 Ga-PSMA PET at baseline, Days 15 and 92, and at progression, and 18 F-fluorine deoxyglucose (18 F-FDG) PET at baseline and progression. Translational samples include blood (and optional biopsies) at baseline, Day 92, and first progression. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga-PSMA and 18 F-FDG PET/CT, circulating tumour cells and circulating tumour DNA. The trial will enrol 160 participants, providing 80% power with a two-sided type-1 error rate of 5% to detect a hazard ratio of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. RESULTS AND CONCLUSION: The combination of 177 Lu-PSMA-617 and enzalutamide may be synergistic. ENZA-p will determine the safety and efficacy of the combination in addition to developing predictive and prognostic biomarkers to better guide treatment decisions.

UpFrontPSMA: a randomized phase 2 study of sequential 177 Lu-PSMA-617 and docetaxel vs docetaxel in metastatic hormone-naïve prostate cancer (clinical trial protocol).

OBJECTIVE: To assess the activity and safety of sequential lutetium-177 (177 Lu)-PSMA-617 and docetaxel vs docetaxel on a background of androgen deprivation therapy (ADT) in men with de novo metastatic hormone-naïve prostate cancer (mHNPC). PATIENTS AND METHODS: UpFrontPSMA (NCT04343885) is an open-label, randomized, multicentre, phase 2 trial, recruiting 140 patients at 12 Australian centres. Key eligibility criteria include: prostate cancer with a histological diagnosis within 12 weeks of screening commencement; prostate-specific antigen (PSA) >10 ng/mL at diagnosis; ≤4 weeks on ADT; evidence of metastatic disease on computed tomography (CT) and/or bone scan; high-volume prostate-specific membrane antigen (PSMA)-avid disease with a maximum standardized uptake value >15; and absence of extensive discordant fluorodeoxyglcuose (FDG)-positive, PSMA-negative disease. 68 Ga-PSMA-11 and 18 F-FDG positron-emission tomography (PET)/CT undergo central review to determine eligibility. Patients are randomized 1:1 to experimental treatment, Arm A (177 Lu-PSMA-617 7.5GBq q6w × 2 cycles followed by docetaxel 75 mg/m2 q3w × 6 cycles), or standard-of-care treatment, Arm B (docetaxel 75 mg/m2 q3w × 6 cycles). All patients receive continuous ADT. Patients are stratified based on disease volume on conventional imaging and duration of ADT at time of registration. The primary endpoint is the proportion of patients with undetectable PSA (≤0.2 ng/L) at 12 months after study treatment commencement. Secondary endpoints include safety, time to castration resistance, overall survival, PSA and radiographic progression-free survival, objective tumour response rate, early PSMA PET response, health-related quality of life, and frequency and severity of adverse events. Enrolment commenced in April 2020. RESULTS AND CONCLUSIONS: The results of this trial will generate data on the activity and safety of 177 Lu-PSMA-617 in men with de novo mHNPC in a randomized phase 2 design.

Examining Absorbed Doses of Indigenously Developed 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer Patients at Baseline and During Course of Peptide Receptor Radioligand Therapy.

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed 177Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with 177Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic 68Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of 177Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of 177Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of 177Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window.

MicroRNA-155 deficiency attenuates inflammation and oxidative stress in experimental autoimmune prostatitis in a TLR4-dependent manner.

To explore the mechanism of microRNA-155 (miR-155) deficiency, protecting against experimental autoimmune prostatitis (EAP) in a toll-like receptor 4 (TLR4)-dependent manner. After wild-type (WT) and miR-155-/- mice were injected with complete Freund's adjuvant and prostate antigen to establish EAP model, half were randomly selected for injection with lipopolysaccharide (LPS, a TLR4 ligand). The following experiments were then performed: von Frey filaments, hematoxylin-eosin (HE) staining, real time quantitative polymerase chain reaction (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). And the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the level of Malondialdehyde (MDA) were detected by corresponding kits.miR-155-/- mice with prostatitis exhibited the attenuated pelvic tactile allodynia/hyperalgesia and the suppressed TLR4/nuclear factor-kappa B (NF-κB) pathway as compared with the WT mice with prostatitis. In addition, LPS enhanced the upregulation of miR-155 and the activation of the TLR4/NF-κB pathway in the prostatic tissues of WT mice with EAP. Furthermore, prostatitis mice had aggravated inflammation scores accompanying the increased interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, interferon-γ, IL-12, and MDA in prostatic tissues with the decreased IL-10, SOD and GSH-Px, and the unaltered IL-4. Compared with the mice from the WT + EAP group and the miR-155-/- + EAP + LPS group, mice from the miR-155-/- + EAP group had decreased inflammation and oxidative stress. miR-155 deficiency ameliorated pelvic tactile allodynia/hyperalgesia in EAP mice and improved inflammation and oxidative stress in prostatic tissues in a TLR4-dependent manner involving NF-κB activation, thereby exerting a therapeutic effect in chronic prostatitis treatment.

Evaluation of the preventive and therapeutic effects of a recombinant vector co-expressing prostate-specific stem cell antigen and Clostridium perfringens enterotoxin on prostate cancer in rats.

The effects of Clostridium perfringens enterotoxin (CPE) and prostate stem cell antigen (PSCA) on cancer prevention or treatment have been previously studied separately. For the first time, here we have elaborated a recombinant vector to co-express and study the cumulative effects of both of these factors on prostate cancer (PCa) in an animal model. The recombinant pBudCE4.1-cpe-PSCA vector was constructed in large scale. Rats were vaccinated by vector or vector plus chitosan nanoparticles before or after induction of PCa (preventive or therapeutic studies) by N-methyl N-nitrosurea and testosterone. Prostate tumors were weighed and histologically examined. Tumors and infusion site tissues as well as blood samples of all rats were collected and assessed by serological and molecular tests. We showed that vaccination with vector (along with or without nanoparticles) led to lower PCa incidence and tumor weight. The L-1ß, IL6, and TNF-α serum levels and their gene expression accompanied by C-CAM1 gene expression in vaccinated groups were significantly higher than controls while no difference was seen in CK20 expression among all groups. Our findings showed that vector could effectively stimulate the immune system of rats to either prevent or suppress the PCa tumors. Adding chitosan nanoparticles did not affect the results significantly.

Molecular allergy diagnostics refine characterization of children sensitized to dog dander.

BACKGROUND: Sensitization to dog dander is an important risk factor for rhinoconjunctivitis and asthma but is not sufficient for diagnosing dog allergy. Molecular allergy diagnostics offer new opportunities for refined characterization. OBJECTIVES: We sought to study the association between sensitization to all presently known dog allergen components and clinical symptoms of dog allergy in children evaluated by using nasal provocation tests (NPTs). METHODS: Sixty children (age, 10-18 years) sensitized to dog dander extract underwent NPTs with dog dander extract. Measurement of IgE levels to dog dander and to Can f 1, Can f 2, Can f 3, and Can f 5 was performed with ImmunoCAP, and measurement of IgE levels to Can f 4 and Can f 6 was performed with streptavidin ImmunoCAP. An IgE level of 0.1 kUA/L or greater was considered positive. RESULTS: There was an association between sensitization to an increasing number of dog allergen components and a positive nasal challenge result (P = .01). Sensitization to lipocalins (odds ratio [OR], 6.0; 95% CI, 1.04-34.5), in particular Can f 4 (OR, 6.80; 95% CI 1.84-25.2) and Can f 6 (OR, 5.69; 95% CI, 1.59-20.8), was associated with a positive NPT result. Monosensitization to Can f 5 was related to a negative NPT result (OR, 5.78; 95% CI, 1.01-33.0). CONCLUSION: Sensitization to an increasing number of dog allergen components and to lipocalins is associated with dog allergy. Monosensitization to Can f 5 should not be regarded primarily as a marker for dog allergy.

Cuantificación de la determinación del antígeno prostático específico en la práctica clínica habitual / Quantification of Prostate-Specific Antigen determination in usual clinical practice

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64Cu-PSMA uptake in meningioma: A potential pitfall of a promising radiotracer / Captación de 64Cu-PSMA en un meningioma: falso positivo de un radiofármaco prometedor

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PCA3 como biomarcador de segunda línea en un programa de screening oportunista prospectivo, aleatorizado y controlado / PCA3 as a second-line biomarker in a prospective controlled randomized opportunistic prostate cancer screening programme

Objetivos: Determinar el comportamiento del PCA3 como un marcador de segunda línea en un programa de cribado oportunista de cáncer de próstata (CaP) y su comparación con la calculadora de riesgo 3 del cribado aleatorizado europeo en cáncer de próstata (ERSPC RC-3). Material y métodos: En total de 5.199 hombres de 40-75 años se hicieron la prueba del antígeno prostático específico (PSA) y un tacto rectal (TR). Aquellos con TR normal y PSA ≥ 3ng/ml se realizaron un PCA3. Todos los hombres con PCA3 ≥ 35 se hicieron biopsia inicial (BxI) -12 cilindros-. Aquellos con PCA3 < 35 se aleatorizaron 1:1 a BxI u observación. Los resultados se comparan con los obtenidos con la aplicación de la calculadora ERSPC RC-3. Resultados: PCA3 se testó en 838 hombres (16,1%). En los grupos PCA3(+) y PCA3(-), las tasas de detección global de CaP fueron del 40,9 y del 14,7% a una mediana de seguimiento de 21,7 meses (p < 0,001. En el grupo PCA3(+) (n = 301, 35,9%), se identificó CaP en 115 hombres en BxI (38,2%). En el brazo aleatorizado, 256 se hicieron BxI y se objetivó CaP en 46 (18,0%) (p < 0,001). La potencial tasa de ahorro de biopsias siguiendo el corte PCA3 = 35 hubiera sido de 64,1% frente a la de 76,6% si hubiéramos usado ERSPC RC-3. Sin embargo, la tasa estimada de falsos negativos de CaP de alto grado (CaPAG = Gleason ≥ 7) se hubiera reducido un 37,1% (de 89 a 56 pacientes) al usar el PCA3. Si hubiéramos usado el corte 35 de PCA3 para no realizar BxI, hubiésemos dejado de diagnosticar un 14,7% de CaP y un 9,1% de CaP clínicamente significativo, a un seguimiento medio aproximado de 2 años. Conclusiones: Cuando se usa PCA3-35 como biomarcador de segunda línea en hombres con PSA ≥ 3ng/ml y TR normal, se puede obviar la BxI un 12,5% menos que usando la ERSPC RC-3, pero reduciendo los falsos negativos un 36,2%. A un seguimiento de 21,7 meses, este protocolo dual no hubiera detectado un 9,1% de CaP clínicamente significativo, por lo que el seguimiento con estrictos criterios de biopsia basados en PSA y TR es obligatorio en casos con PCA3 < 35

Objectives: PCA3 performance as a single second line biomarker is compared to the European Randomised Study of Screening for Prostate Cancer risk calculator model 3 (ERSPC RC-3) in an opportunistic screening in prostate cancer (PCa). Material and methods: 5,199 men, aged 40-75y, underwent prostate-specific antigen (PSA) screening and digital rectal examination (DRE). Men with a normal DRE and PSA ≥3ng/ml had a PCA3 test done. All men with PCA3 ≥ 35 underwent an initial biopsy (IBx) -12 cores-. Men with PCA3 < 35 were randomized 1:1 to either IBx or observation. We compared them to those obtained with ERSPC RC-3. Results: PCA3 test was performed on 838 men (16.1%). In PCA3(+) and PCA3(-) groups, global PCa detection rates were 40.9% and 14.7% with a median follow-up (FU) of 21.7 months (P <.001). In the PCA3(+) arm (n = 301, 35.9%), PCa was identified in 115 men at IBx (38.2%). In the randomized arm, 256 underwent IBx and PCa was found in 46 (18.0%) (P < .001). The biopsy-sparing potential would have been 64.1% as opposed to 76.6% if we had used ERSPC RC-3. However, the estimated false negative cases for HGPCa would have been reduced by 37.1% (89 to 56 patients). Moreover, if we had applied PCA3-35 to avoid IBx, 14.7% PCa and 9.1% of clinical significant PCa patients would not have been diagnosed during this FU. Conclusions: When PCA3-35 is used as a second-line biomarker when PSA ≥ 3ng/ml and DRE is normal, IBx could be avoided in 12.5% less than if ERSPC RC-3 is used and would reduce the false negative cases by 36.2%. At a FU of 21.7 months, this dual protocol would miss 9.1% of clinically significant PCa, so strict FU is mandatory with established biopsy criteria based on PSA and DRE in cases with PCA3 < 35

¿Detección precoz o cribado en la prevención del cáncer de próstata? / Early detection or screening in the prevention of prostate cancer?

El cáncer de próstata (CP) es la neoplasia primaria más frecuente en varones del mundo desarrollado, y la segunda causa de muerte por cáncer en varones de los Estados Unidos, por detrás del cáncer broncopulmonar. En Europa supone la tercera causa de muerte por cáncer en varones (tras los cánceres broncopulmonar y colorrectal). En la actualidad el papel del screening del CP está cuestionado. En el siguiente artículo se resumen los aspectos epidemiológicos más relevantes del CP, así como los principales ensayos clínicos sobre cribado de CP, y las recomendaciones de las diferentes asociaciones científicas médicas sobre la realización o no del cribado del CP (AU)

Prostate cancer (PC) is the most common malignancy in men in the developed world and the second leading cause of cancer death in men in the USA, behind lung cancer. In Europe, it is the third leading cause of cancer death in men (after lung and colorectal cancers). The role of PC screening is currently being questioned. The following article summarises the most relevant epidemiological aspects of PC, as well as major clinical trials of PC screening, and recommendations of the various medical scientific associations on whether or not to screen for PC (AU)

Rentabilidad de la biopsia prostática y determinación de valores del PSA. Incidencia de cáncer prostático y complicaciones postbiopsia / Profitability of prostate biopsy and PSA values determination. Impact of prostate cancer and post-biopsy complications

OBJETIVO: Determinar la tasa diagnostica de cáncer prostático (CaP) de nuestro hospital mediante biopsia prostática (Bp), así como analizar si existen diferencias significativas entre las diferentes variables PSA y el resultado anatomo-patológico. De forma secundaria, analizar nuestra tasa de complicaciones postbiopsia. Material y MÉTODOS: Estudio retrospectivo descriptivo y analítico de los pacientes biopsiados en el año 2014, analizando las variables cuantitativas edad, PSA libre, PSA Total, Cociente PSA Libre/ Total y número de cilindros y analizando las variables cualitativas resultado de anatomía patológica y complicaciones. RESULTADOS: Incluimos en el estudio a 86 pacientes con una media de edad de 67,5 años [49-84]. La media del PSA total fue de 7,67 ng/dl [2,83- 29], PSA libre de 1,05 ng/dl [0,32-2,45] y cociente de 0,16 [0,05-0,31]. La media de cilindros extraídos por Bp fue de 10,5 cilindros [4-18]. La tasa de resultados positivos en Bp fue del 30,2% (26 pacientes). Al comparar los pacientes que tuvieron biopsia positiva vs biopsia negativas hallamos diferencias estadísticamente significativas entre valores de PSA libre (p = 0,039) y los del cociente de PSA (p = 0,015). Tras Bp precisaron ingreso por complicación 4 pacientes. CONCLUSIONES: Nuestra tasa diagnostica de CaP mediante Bp es similar a la de otras series descritas. El valor del cociente PSA libre/total es una herramienta fiable para indicar una biopsia. Nuestra tasa de complicaciones postbiopsia es similar a la de las guías Europeas, por lo que consideramos óptimo nuestro protocolo de profilaxis para la biopsia prostática

AIM: To determinate the diagnosis rate of prostate cancer (CaP) of our hospital through prostate biopsy (Pb) and to analyse whether there are significant differences between the diverse variables of PSA and the anatomic-pathology results. In addition an to a lesser extent, to study our rates of post-biopsy complications. Material and METHODOLOGY: retrospective research, both descriptive and analytical, of the patients who underwent biopsy in 2014, analysing the quantitative values of age, free PSA, total PSA, free/ total PSA quotient and number of cylinders, and analysis of the qualitative variables resulting from anatomic-pathology and further complications. RESULTS: The research includes 86 patients of 67.5 years old average [49-84]. The average total PSA was 7,67 ng/dl [2,83-29, free PSA 1,05 ng/dl [0,32-2,45] and PSA quotient of 0,16 [0,05-0,31]. The average cylinders obtained with Pb was 10.5 cylinders [4-18]. The rate of positive results in Bp was 30.2% (26 patients). When comparing patients with positive and negative Pbs, significant differences were found between free PSA values (p = 0,039) and those of PSA quotient (p = 0,015). Four patients required hospitalisation after Pb due to unforeseen complications. CONCLUSIONS: Our diagnosis rate of CaP through Pb is similar to the one of other described series. The PSA free/ total quotient is a reliable tool to indicate a biopsy. Our rate of post-biopsy complications is similar to the ones described in European guidelines which implies our prophylaxis protocol for prostate biopsy is optimum

Antígeno prostático específico. Desde sus inicios hasta su reconocimiento como biomarcador de cáncer de próstata / Prostatic specific antigen. From its early days until becoming a prostate cancer biomarker

El antígeno prostático específico (PSA por sus siglas en inglés) es desde mediados de 1980 el biomarcador más utilizado para medir riesgo presente y futuro de desarrollar cáncer de próstata, para su detección temprana y para medir respuesta a tratamientos y detectar recidiva en todos los estadíos de la enfermedad. Su desarrollo inicial nace de la mano de los avances a fines de la década de 1960 de la inmunología, que permitía la detección y estudio de antígenos de diferentes tejidos y fluidos al ser éstos inyectados en conejos y promover respuesta inmune.Fue Rubin Flocks en 1960 el primero en investigar y descubrir antígenos específicos de la próstata, encontrándolos en tejido prostático benigno y maligno. Hara, un forense japonés, encontró la "gama seminoproteína", que utilizó para detectar semen humano en casos de violación, pero su hallazgo publicado en japonés no tuvo difusión en la comunidad científica anglo-parlante. En 1970 Ablin descubrió en fluido y tejido prostático lo que llamó "antígeno prostático específico", pero no lo caracterizó ni describió. Los investigadores Li y Beling, así como Sensabaugh, se fueron aproximando en sus trabajos al actual PSA, pero estaban también limitados por la tecnología disponible en ese entonces. El Dr T Ming Chu encabezaba un equipo de investigación sobre cáncer de próstata en Nueva York, EEUU, que publicó sus resultados en 1979; fue finalmente él quien recibió la patente por el descubrimiento e identificación del "antígeno purificado de próstata humana" en 1984. Debido a estos trabajos en 1986 la Food and Drug Administration (FDA), de EEUU, aprobó el uso del PSA para monitoreo de recidiva post tratamiento. Se conoció después que el PSA no era específico de próstata sino que se encontraba en otros tejidos y fluidos, pero si se reconoció que era específico de la especie humana. Trabajos posteriores de Papsidero y Stamey fueron ampliando la indicación y utilidad del PSA, pero fue Catalona quien lo utilizó por primera vez como marcador para cáncer de próstata en 1991. Gracias a estos avances, en 1994 la FDA autorizó el uso clínico del PSA para detección temprana del cáncer de próstata

Prostate-specific antigen (PSA) has been since the mid 80's the most commonly used biomarker for measuring current and future risk of prostate cancer, for its early detection and to measure response to treatments and detecting recurrence in all stages of the disease. PSA's early development came along with progress in the field of immunology, which allowed detection and study of antigens from different tissues and fluids when injecting them into rabbits to promote immune response. Rubin Flocks in 1960 was the first to investigate and discover prostate-specific antigens in benign and malignant tissue. Some years later, Hara, a Japanese forensic investigator, found "gamma seminoprotein", that he used to detect human semen in rape cases. However, his work published in Japanese did not reach the Englishspeaking scientific community. In 1970 Ablin discovered both in prostatic fluid and tissue what he called "prostate-specific antigen", but he didn't characterize or describe it. Investigators Li and Beling, and Sensabaugh, approached the current PSA, but they were limited by available technology at that time. Dr T Ming Chu led a research team on prostate cancer in New York, USA and published their results in 1979. He finally received the patent for the discovery of "human purified prostate antigen" in 1984. Due to this work, the Food and Drug Administration (FDA), in USA, approved the use of PSA for monitoring recurrence after treatment. It was later known that PSA was not prostate-specific since it was produced in other tissues and fluids, but it was recognized that it was human species-specific. Works by Papsidero and Stamey showed new indications and utilities for PSA, but it was Catalona who first used it as a marker for prostate cancer in 1991. Thanks to these advances FDA authorized in 1994 the clinical use of PSA for early detection of prostate cáncer

Papel actual del antígeno prostático específico (PSA) y sus derivados en el diagnóstico del cáncer de próstata / Current role of protatic specific antigen (PSA) and its by-products in the diagnosis of prostate cancer

La incorporación del antígeno prostático específico (PSA) a la clínica revolucionó el diagnóstico y modificó la epidemiología del cáncer de próstata (CaP). Aunque le faltan muchas de las características de un marcador tumoral ideal, es el marcador más usado para el diagnóstico y seguimiento de cualquier tipo cáncer. Representa la mejor herramienta clínica de las que disponemos en la actualidad para el cribado y estadificación del CaP. Por contra, la mayor limitación que presenta el PSA es su falta de especificidad tumoral. El empleo de los derivados y de las isoformas moleculares del PSA trata de solventar, al menos en parte, sus limitaciones. De hecho, la utilización del cociente del PSA libre (%fPSA) y de la densidad del PSA (PSAD) aumenta de forma significativa la especificidad del test en el diagnóstico y, el uso de los derivados que evalúan la cinética temporal del PSA (velocidad del PSA (PSAV) y tiempo de duplicación del PSA (PSADT)) representan herramientas de gran utilidad para estimar el pronóstico durante el tratamiento y seguimiento de la enfermedad. El mayor avance que se ha producido en los últimos años ha venido del análisis de la isoforma precursora (-2)pPSA y del índice phi. Ambos marcadores han demostrado mejorar los resultados de sensibilidad y especificidad obtenidos hasta ahora, ocasionando una disminución de biopsias innecesarias. Es probable que con el desarrollo de nuevos marcadores para el CaP que está habiendo, en pocos años se modifique el papel que el PSA tiene en el diagnóstico y en la estadificación de la enfermedad

Incorporation of prostatic specific antigen (PSA) to clinical practice was a revolution in the diagnosis and modified the epidemiology of prostate cancer (PCa). Although it lacks of many characteristics of an ideal tumor marker, it is the marker most used for diagnosis and follow up of any kind of cancer. It represents the best clinical tool we have available today for screening and staging of PCa. On the contrary, its greatest limitation is the lack of tumor specificity. The use of PSA by-products and molecular isoforms tries to solve, at least partially, its limitations. Indeed, the use of FreePSA ratio (%fPSA) ad PSA density (PSAD) increase significantly the specificity of the diagnostic test and, the use of derivatives that evaluate time kinetics of PSA (PSA velocity (PSAV) and PSA doubling time (PSADT)) represents a very useful tool for prognosis estimation during treatment and follow up of the disease. The greatest advance over the last years comes from the analysis of the predecessor isoform (-2) pPSA and the phi Index. Both markers have demonstrated to improve the sensitivity and specificity results obtained to date, resulting in a decrease of unnecessary biopsies. Probably, with the ongoing development of new markers for PCa , the role of PSA on disease diagnosis and staging would be modified in a few years

ProPSA, un nuevo biomarcador para la detección y el manejo del cáncer de próstata / ProPSA, a new biomarker for the detection and management of prostate cancer

La descripción de las nuevas isoformas del PSA libre, como el proPSA, que se asocia a la presencia de cáncer de próstata, ha ampliado las herramientas disponibles para la detección de este tumor. Tras la comercialización de un ensayo para medir [---2] proPSA, una de las fracciones del proPSA, disponemos de datos que avalan el empleo del porcentaje de [---2] proPSA en relación con el PSA libre (%[---2] proPSA) y del prostate health index (phi) que valora conjuntamente [---2] proPSA, PSA libre y PSA total. Los resultados disponibles indican que estos tests permiten reducir el número de biopsias negativas cuando se comparan con el porcentaje del PSA libre. Por otro lado, tanto el %[---2] proPSA como el phi se relacionan con tumores particularmente agresivos, por lo que podrían ser tests útiles para seleccionar qué pacientes podrían beneficiarse de una vigilancia activa y qué pacientes deben ser sometidos a un tratamiento curativo (AU)

The description of new PSA isoforms associated with prostate cancer, such as proPSA, has expanded the available tools for the detection of this tumor. Since the marketing of an assay for the measurement of [---2] proPSA, one of the fractions of proPSA, we have positive data on the use of the percentage of [---2] proPSA in relation to free PSA (%[---2] proPSA) and the prostate health index (phi), which measures [---2] proPSA, total PSA and free PSA together. The available results suggest that the use of these tests would lead to a reduction in the number of negative biopsies compared with the percentage of free PSA. On other hand, both %[---2] proPSA and phi are related to particularly aggressive tumors, so they could be useful to select patients for active surveillance, and to decide which patients must be treated (AU)

Utilidad de los marcadores tumorales como cribado de neoplasia oculta en enfermedad tromboembólica / Role of tumour markers for occult neoplasia screening in thromboembolic disease

Objetivo: Evaluar la eficacia de los marcadores tumorales (MT) dentro del cribado avanzado para la detección de neoplasia oculta, en pacientes que han presentado enfermedad tromboembólica (ETE). Material y métodos: Estudio retrospectivo entre enero 2007 y diciembre de 2008 diagnosticados de ETE en nuestro centro. Se evaluaron los siguientes marcadores tumorales: antígeno carcinoso 19.9 (Ca 19.9), antígeno carcinoso 125 (Ca 125), antígeno carcinoso 15.3 (Ca 15.3), antígeno carcinoma embrionario (CEA), alfafetoproteína(AFP) y antígeno específico de próstata (PSA), tomando una determinación dentro del mes siguiente del diagnóstico de ETE. Criterios de inclusión: TVP de MMSS o MMII, TEP diagnosticados por prueba de imagen, clínica aguda. Criterios de exclusión: neoplasia previa conocida, TVP no idiopática, imposibilidad de seguimiento. Resultados: El 63,4% eran hombres, el 36,6% mujeres, con edad media de 62,8 años. El análisis estadístico se hizo en función de 122 pacientes, de los 199 iniciales, con un seguimiento medio de 38 meses. Al finalizar el estudio no se encontraron diferencias significativas en cuanto a la incidencia posterior de neoplasia respecto a los pacientes con valores de MT positivos de los negativos (Ca 125: p=0,161; Ca 15.3: p=0,930; CEA: p=0,703; PSA: p=0,382; AFP: 100% pacientes con valores negativos). Exceptuando el Ca 19.9 (p<0,000). Conclusiones: Como conclusión a nuestro estudio, el uso de MT como cribado de cáncer oculto posterior a un evento trombótico, no ha permitido la detección de los pacientes que desarrollaron una neoplasia durante el seguimiento (AU)

Objective: To evaluate the use of the tumour markers (TM) as part the advanced screening of occult neoplasia, in patients with thromboembolic disease (TED). Material and methods: A retrospective study was conducted between January 2007 and December 2008 on patients diagnosed with TED in our centre. The sample included 63.4% males, and 36.6% females, with a mean age of 62.8 years. The following TM were evaluated in a blood sample taken within one month after the diagnosis of TED: cancer antigen 19.9 (Ca 19.9), cancer antigen 125 (Ca 125), cancer antigen 15.3 (Ca 15.3), embryonic carcinoma antigen (CEA), alpha fetoprotein (AFP), and prostate specific antigen (PSA). The inclusion criteria were, DVT of lower and upper limbs, TEP diagnosed by imaging technique, acute clinic signs. Exclusion criteria: previous known neoplasia, non-idiopathic DVT, impossibility of follow-up. Results: The statistical analysis was performed on the basis of 122 patients out of 199 initially included, with an average follow-up of 38 months. At the end of the study no significant differences were found as regards the subsequent finding of a neoplasia in patients with positive TM values compared with those with negative values (Ca 125: P=0.161; Ca 15.3: P=0.930; CEA: P=0.703; PSA: P=0.382; AFP: 100% patients with negative values). Exempting the Ca 19.9 (P<0.000). Conclusions: As a conclusion of our study, TM as extensive screening of early stages of cancer after TED, is not useful for detecting an occult neoplasia during follow-up (AU)

Consideraciones sobre el valor del antígeno prostático específico en los pacientes tratados con 5-alpha reductasa / Considerations about the value of prostate specific antigen in patients treated with 5-alpha reductase

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Antitumor activities of PSMA×CD3 diabodies by redirected T-cell lysis of prostate cancer cells.

AIM: Although prostate cancer is one of the most commonly diagnosed malignancies in men, there is no effective curative therapy for the advanced disease. Therefore, the aim of the present study was to generate prostate-specific membrane antigen (PSMA)×CD3 diabodies as a novel treatment option for this tumor. METHODS: A PSMA×CD3 diabody and a covalently linked single-chain diabody were constructed from the anti-PSMA single-chain Fv fragment D7 and an anti-CD3 single-chain Fv fragment. The fusion proteins were periplasmatically expressed in Escherichia coli. The binding properties were tested on PSMA-expressing C4-2 prostate cancer cells and CD3(+) Jurkat cells by flow cytometry. For in vitro functional analysis, a cell viability assay was used. T-cell activation was determined by flow cytometry. In vivo activity of the diabody was tested in SCID mice reconstituted with human peripheral blood lymphocytes bearing C4-2 tumor xenografts. RESULTS: Bacterial expression levels were significantly higher for the diabody (1-1.5 mg/l culture) compared with the single-chain diabody (0.2-0.4 mg/l culture). Specific binding on CD3-expressing Jurkat cells and PSMA-expressing C4-2 cells was shown with both diabody formats. In vitro, both diabodies proved to be potent agents for retargeting human CD4(+) and CD8(+) lymphocytes to lyse C4-2 prostate cancer cells. The formation of conjugates between T cells and target cells with clustering of the diabody at sites of interaction could be shown. SCID mice reconstituted with human peripheral blood lymphocytes bearing C4-2 tumor xenografts with the diabody showed an efficient inhibition of tumor growth. CONCLUSION: Both diabody formats showed a highly efficient and specific T cell-mediated killing of prostate cancer cells and are encouraging for further development in preclinical and clinical studies.

Utilidad de cortes seriados en biopsias prostáticas / Utility of Seriated Sections in Prostate Biopsies

Introducción: Con el empleo rutinario del antígeno prostático específico se detectan con mayor frecuencia carcinomas focales y proliferaciones atípicas de acinos pequeños (ASAP, atypical small acinar proliferation [sigla en inglés]). El número de cortes por cilindro que debe practicarse para detectar la mayoría de ellos se desconoce. Métodos: Revisamos 250 biopsias prostáticas por sextantes en el periodo 2008-2011. El promedio de cilindros por biopsia fue de 14. En cada caso se practicaron además del corte original, con 3 niveles histológicos, otros 3 cortes con 3 niveles (total: 12 niveles). En las biopsias con lesiones focales se practicó estudio inmunohistoquímico. La frecuencia de lesiones focales se comparó con un estudio previo de 1.000 biopsias donde se realizó un solo corte con tres niveles histológicos. Se anotaron los datos clínicos y de laboratorio. Resultados: Hubo 16 lesiones focales (6,4%); 7 (2,8%) correspondieron a carcinomas focales y 9 (3,6%) a proliferaciones atípicas. En el estudio previo se encontraron 13 (1,3%) carcinomas focales y 29 (2,9%) casos con proliferaciones atípicas. Conclusiones: Hubo un aumento del 4,2 al 6,4% de lesiones focales y un incremento de carcinomas del 1,3 al 2,8%. Aunque realizar cortes adicionales rutinariamente tiene inconvenientes prácticos, podría realizarse en pacientes con alta sospecha clínica de carcinoma (en particular jóvenes) o en los que existan antecedentes de proliferaciones glandulares atípicas compatibles con carcinoma (AU)

Introduction: With the routine use of prostate specific antigen, focal carcinomas and atypical small acini proliferation (ASAP) are currently detected more frequently. The number of sections per cylinder needed to detect most of them is still unknown. Methods: We reviewed 250 sextant prostate biopsies in the 2008-2011 period. The average number of cylinders per biopsy was 14. In each case, in addition to the original sections with three histological levels, three more sections were performed with three levels (total: 12 levels). Biopsies with focal lesion were analyzed immunohistochemically. The frequency of focal lesions was compared to a previous study of 1000 biopsies in which a single section was made with three histological levels. The main clinical and laboratory data were recorded. Results: There were 16 focal lesions (6.4%). Seven (2.8%) corresponded to focal carcinomas and nine (3.6%) to atypical proliferation. In the previous study, thirteen (1.3%) focal carcinomas and 29 (2.9%) cases with atypical proliferation were found. Conclusions: There was an increase of 4.2% to 6.4% of focal lesions carcinomas increased from 1.3% to 2.8%. Making additional sections in all biopsies may have practical drawbacks. However, they could be performed in patients with high clinical suspicion of carcinoma (especially in young patients), or when there is a history of atypical glandular proliferations consistent with carcinoma in previous biopsies (AU)