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.

Tratamiento del paciente con carcinoma de próstata en progresión bioquímica resistente a castración / Treatment of the patient with castration-resistant biochemical progression of prostate cancer

El carcinoma de próstata resistente a castración (CPRC) se define como la progresión tumoral a pesar de unos niveles eficaces de castración. (testosterona sérica < 50 ng/dL). La progresión bioquímica requiere al menos dos incrementos sucesivos en la cifra de antígeno prostático específico (PSA), separados al menos una semana, y con un valor mínimo de 2 ng/mL. In pacientes con bloqueo androgénico completo, se debe suspender al antiandrógeno antes del diagnóstico de CPRC. El CPRC es una entidad heterogénea. El valor basal de PSA y la velocidad de PSA parecen ser los factores pronósticos más importantes en pacientes con recidiva bioquímica como única manifestación del CPRC. Algunos de estos pacientes pueden ser seguidos sin tratamiento hasta la progresión de la enfermedad. Debido a que un gran porcentaje de tumores que progresan a pesar de la castración siguen siendo hormonodependientes, el empleo de otras terapias hormonales ha sido el tratamiento preferido para la mayoría de estos pacientes. Junto con los inhibidores de la esteroidogénesis suprarrenal, se están investigando actualmente otros enfoques más novedosos para inhibir el efecto del receptor androgénico activado sobre la célula tumoral. Recientemente, ha habido un importante desarrollo de la inmunoterapia, que ha demostrado incrementar la supervivencia en pacientes con CPRC oligosintomáticos. La quimioterapia de primera y segunda línea en CPRC se asocia con incremento de supervivencia, pero generalmente se recomienda para pacientes con metástasis. Hasta que estén disponibles los resultados de ensayos clínicos actualmente en marcha, el tipo y secuencia de tratamientos para los pacientes con CPRC y recaída bioquímica debe realizarse de forma individualizada(AU)

Castration resistant prostatic carcinoma (CRPC) is defined as tumor progression despite an effective castration (serum testosterone levels < 50 ng/dL). Biochemical progression requires at least two successive increases from the previous lowest value of serum prostate-specific antigen (PSA) spaced at least a week, and with a minimum value of 2 ng/mL. In patients receiving complete androgen blockade, antiandrogen should be discontinued prior to diagnosis of CRPC. CPRC is a heterogeneous entity. Baseline PSA and PSA velocity seem to be the most important prognostic factors in patients with biochemical relapse as the only manifestation of CRPC. Some of these patients can be followed without treatment until disease progression. Because of a large proportion of tumors progressing under androgen deprivation therapy remain hormone-dependent, the use of other hormonal therapies has been the preferred treatment for the majority of these patients. Besides inhibitors of adrenal steroidogenesis, other novel hormonal approaches are currently under investigation to avoid the effect of the activated androgenic receptor on the tumor cell. In recent years there has been an important development of immunotherapy, which has demonstrated to increase survival in CRPC oligosymptomatic patients. First and second line chemotherapy in CRPC are associated with an increase in overall survival, but they are usually recommended for patients with metastases. Until the results of ongoing trials are available, the type and timing of the treatment for patients with CRPC and biochemical recurrence should be individualized(AU)

Valor diagnóstico de segundas biopsias prostáticas en varones de riesgo. Estudio estratificado por valor de PSA / Diagnostic value of the second prostate biopsies in males of risk. Study stratified by value of PSA

OBJETIVO: Valorar el rendimiento diagnóstico de la segunda biopsia prostática (BP). PACIENTES Y MÉTODOS: Un total de 116 varones con BP previa de benignidad fueron sometidos a 2 o más BP por sextantes guiadas con ultrasonidos (US). Los criterios de inclusión fueron: BP previa sospechosa (PIN), PSA elevado, TR o US sospechoso.RESULTADOS: El tiempo medio transcurrido entre la primera y siguiente biopsia fue de 13 ± 11 meses. Se obtuvieron 35 malignas y 4 premalignas en las segundas biopsias realizadas, lo que da un rendimiento diagnóstico global del 33,6%. Cuando estratificamos por valor de PSA, obtenemos que con PSA 10 ng/ml, de 34,6%. CONCLUSIÓN: La repetición de la biopsia seriada de próstata en pacientes de riesgo, mejora el rendimiento diagnóstico y elimina los falsos negativos de carcinoma. prostático

OBJETIVE: To value the diagnostic yield of the second prostate biopsy (BP). PATIENTS AND METHODS: To 116 males with BP previous to kindliness surrendered to 2 or more BP for sextants guided with ultrasounds (US). The criteria of inclusion were: BP previous suspicious (PIN), high PSA, TR or suspicious US. RESULTS: The average time passed between the first and following biopsy was 13 ± 11 months. 35 malignant and 4 premalignant ones were obtained in the second realized biopsies, which gives a diagnostic global yield of 33.6%. When we stratify for value of PSA, we obtain that with PSA 10 ng/ml of 34,6%. CONCLUSION: The repetition of the serial biopsy of prostate in patients of risk, improves the diagnostic yield and eliminates the false negatives of prostate carcinoma

Oil-in-water liposomal emulsions: characterization and potential use in vaccine delivery.

Emulsification of mineral oil by phospholipids donated by liposomes composed of dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, cholesterol, and lipid A by extrusion resulted in the formation of oil-in-water liposomal emulsions containing a substantial number of intact liposomes. Increasing the proportion of liposomes from 25 mM to 150 mM phospholipid and increasing the oil content from 2.5% (v/v) to 42.5% (v/v) changed the flow characteristics of the emulsions from fluid liquid-like to viscous. Likewise, the degree of stability of the emulsions was liposomal phospholipid concentration-dependent, ranging from partial emulsification in the range 25-100 mM to complete stabilization in the range 125-150 mM. Despite some loss of liposome integrity, as evidenced by the release of liposomal trapped glucose, emulsification of liposomes containing encapsulated prostate-specific antigen (PSA) exhibited antigen-specific immunostimulation in mice. These results suggest that liposomes containing encapsulated antigen can serve as constituents for the formulation of oil-in-water vaccines.