A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS: This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2 (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS: 18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION: DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

Single-cell analysis of localized prostate cancer patients links high Gleason score with an immunosuppressive profile.

BACKGROUND: Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry. METHODS: Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa). RESULTS: HGPCa are highly infiltrated by exhausted CD8+ T cells, myeloid cells, and regulatory T cells (TRegs). These HGPCa-infiltrating CD8+ T cells expressed high levels of exhaustion markers including TIM3, TOX, TCF7, PD-1, CTLA4, TIGIT, and CXCL13. By contrast, a high ratio of activated CD8+  effector T cells relative to TRegs and myeloid cells infiltrate the TME of LGPCa. HGPCa CD8+  tumor-infiltrating lymphocytes (TILs) expressed more androgen receptor and prostate-specific membran antigen yet less prostate-specific antigen than the LGPCa CD8+  TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers. CONCLUSIONS: Our study reveals a suppressive TME with high levels of CD8+ T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.

The Impact of Androgen Deprivation Therapy on COVID-19 Illness in Men With Prostate Cancer.

BACKGROUND: TMPRSS2, a cell surface protease regulated by androgens and commonly upregulated in prostate cancer (PCa), is a necessary component for SARS-CoV-2 viral entry into respiratory epithelial cells. Previous reports suggested a lower risk of SARS-CoV-2 among PCa patients on androgen deprivation therapy (ADT). However, the impact of ADT on severe COVID-19 illness is poorly understood. METHODS: We performed a multicenter study across 7 US medical centers and evaluated patients with PCa and SARS-CoV-2 detected by polymerase-chain-reaction between March 1, 2020, and May 31, 2020. PCa patients were considered on ADT if they had received appropriate ADT treatment within 6 months of COVID-19 diagnosis. We used multivariable logistic and Cox proportional-hazard regression models for analysis. All statistical tests were 2-sided. RESULTS: We identified 465 PCa patients (median age = 71 years) with a median follow-up of 60 days. Age, body mass index, cardiovascular comorbidity, and PCa clinical disease state adjusted overall survival (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 0.68 to 1.98, P = .59), hospitalization status (HR = 0.96, 95% CI = 0.52 to 1.77, P = .90), supplemental oxygenation (HR 1.14, 95% CI = 0.66 to 1.99, P = .64), and use of mechanical ventilation (HR = 0.81, 95% CI = 0.25 to 2.66, P = .73) were similar between ADT and non-ADT cohorts. Similarly, the addition of androgen receptor-directed therapy within 30 days of COVID-19 diagnosis to ADT vs ADT alone did not statistically significantly affect overall survival (androgen receptor-directed therapy: HR = 1.27, 95% CI = 0.69 to 2.32, P = .44). CONCLUSIONS: In this retrospective cohort of PCa patients, the use of ADT was not demonstrated to influence severe COVID-19 outcomes, as defined by hospitalization, supplemental oxygen use, or death. Age 70 years and older was statistically significantly associated with a higher risk of developing severe COVID-19 disease.

Effect of Androgen Suppression on Clinical Outcomes in Hospitalized Men With COVID-19: The HITCH Randomized Clinical Trial.

Importance: SARS-CoV-2 entry requires the TMPRSS2 cell surface protease. Antiandrogen therapies reduce expression of TMPRSS2. Objective: To determine if temporary androgen suppression induced by degarelix improves clinical outcomes of inpatients hospitalized with COVID-19. Design, Setting, and Participants: The Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) phase 2, placebo-controlled, double-blind, randomized clinical trial compared efficacy of degarelix plus standard care vs placebo plus standard care on clinical outcomes in men hospitalized with COVID-19 but not requiring invasive mechanical ventilation. Inpatients were enrolled at 14 Department of Veterans Affairs hospitals from July 22, 2020, to April 8, 2021. Data were analyzed from August 9 to October 15, 2021. Interventions: Patients stratified by age, history of hypertension, and disease severity were centrally randomized 2:1 to degarelix, (1-time subcutaneous dose of 240 mg) or a saline placebo. Standard care included but was not limited to supplemental oxygen, antibiotics, vasopressor support, peritoneal dialysis or hemodialysis, intravenous fluids, remdesivir, convalescent plasma, and dexamethasone. Main Outcomes and Measures: The composite primary end point was mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at day 15 after randomization. Secondary end points were time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a temperature within reference range, maximum severity of COVID-19, and the composite end point at 30 days. Results: The trial was stopped for futility after the planned interim analysis, at which time there were 96 evaluable patients, including 62 patients randomized to the degarelix group and 34 patients in the placebo group, out of 198 initially planned. The median (range) age was 70.5 (48-85) years. Common comorbidities included chronic obstructive pulmonary disorder (15 patients [15.6%]), hypertension (75 patients [78.1%]), cardiovascular disease (27 patients [28.1%]), asthma (12 patients [12.5%]), diabetes (49 patients [51.0%]), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9 patients [9.4%]). For the primary end point, there was no significant difference between the degarelix and placebo groups (19 patients [30.6%] vs 9 patients [26.5%]; P = .67). Similarly, no differences were observed between degarelix and placebo groups in any secondary end points, including inpatient mortality (11 patients [17.7%] vs 6 patients [17.6%]) or all-cause mortality (11 patients [17.7%] vs 7 patents [20.6%]). There were no differences between degarelix and placebo groups in the overall rates of adverse events (13 patients [21.0%] vs 8 patients [23.5%) and serious adverse events (19 patients [30.6%] vs 13 patients [32.4%]), nor unexpected safety concerns. Conclusions and Relevance: In this randomized clinical trial of androgen suppression vs placebo and usual care for men hospitalized with COVID-19, degarelix did not result in amelioration of COVID-19 severity. Trial Registration: ClinicalTrials.gov Identifier: NCT04397718.

Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets. METHODS: Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort. RESULTS: Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)-expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies (P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = -0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells (P < .005) and lower numbers of activated NK cells (P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model. CONCLUSION: These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353).

Translating the Immunobiology of SBRT to Novel Therapeutic Combinations for Advanced Prostate Cancer.

Stereotactic body radiotherapy (SBRT) is an increasingly used radiation modality for the treatment of both localized and metastatic prostate cancer. Substantial data suggests that prostate cancer may be more sensitive to higher doses of radiation per fraction due to its low α/ß ratio. This increased sensitivity raises important questions as to how SBRT should be combined with systemic therapy for clinically significant prostate cancer, including whether androgen deprivation therapy retains its beneficial effects when combined with SBRT. Furthermore, pre-clinical and clinical data suggest pronounced immunomodulatory effects of SBRT, including observed improvements in T cell priming and trafficking. These data support investigational strategies combining SBRT with immunotherapy. Here we aim to review the data for the use of SBRT in both the local and metastatic disease settings as well as ongoing translational and clinical research examining combinations with ADT, immunotherapy and other targeted agents.

Analysis of exposure to electromagnetic fields in a healthcare environment: simulation and experimental study.

Recent advances in wireless technologies have lead to an increase in wireless instrumentation present in healthcare centers. This paper presents an analytical method for characterizing electric field (E-field) exposure within these environments. The E-field levels of the different wireless communications systems have been measured in two floors of the Canary University Hospital Consortium (CUHC). The electromagnetic (EM) conditions detected with the experimental measures have been estimated using the software EFC-400-Telecommunications (Narda Safety Test Solutions, Sandwiesenstrasse 7, 72793 Pfullingen, Germany). The experimental and simulated results are represented through 2D contour maps, and have been compared with the recommended safety and exposure thresholds. The maximum value obtained is much lower than the 3 V m(-1) that is established in the International Electrotechnical Commission Standard of Electromedical Devices. Results show a high correlation in terms of E-field cumulative distribution function (CDF) between the experimental and simulation results. In general, the CDFs of each pair of experimental and simulated samples follow a lognormal distribution with the same mean.

Patient safety and electromagnetic protection: a review.

A systematic literature review was carried out to study patient security and possible harmful effects, immunity and interferences on medical devices, and effectiveness and transmission problems in healthcare and hospital environments due to electromagnetic interferences. The objective was to determine already-reported cases of patient security, immunity of medical devices, and transmission/reception failure in order to evaluate safety and security of patients. Literature published in the last 10 years has been reviewed by searching in bibliographic databases, journals, and proceedings of conferences. Search strategies developed in electronic databases identified a total of 820 references, with 50 finally being included. The study reveals the existence of numerous publications on interferences in medical devices due to radiofrequency fields. However, literature on effectiveness, transmission problems and measurements of electromagnetic fields is limited. From the studies collected, it can be concluded that several cases of serious interferences in medical instruments have been reported. Measures of electromagnetic fields in healthcare environments have been also reported, concluding that special protective measures should be taken against electromagnetic interferences by incoming radio waves.

Eficacia de la estimación del peso fetal por ultrasonido para la predicción del bajo peso al nacer / Efficacy of fetal weight estimation by ultrasound for the low birthweight prediction

Se realizó un estudio retrospectivo de 202 nacimientos ocurridos en el hospital "América Arias" desde marzo de 1998 a marzo de 1999, para evaluar la capacidad del ultrasonido en el cálculo del peso fetal y la detección del bajo peso intraútero (menos de 2 500 g), según el número de días transcurridos entre la estimación y el parto (menos de 8, de 8 a 20 y más de 20 días). La eficacia del ultrasonido para detectar el bajo peso al nacer aumentó de manera inversamente proporcional al número de días entre la estimación y el parto. Con menos de 20 días de diferencia, la sensibilidad fue de 91 por ciento y la especificidad de un 83,5 por ciento. El valor predictivo positivo fue de 74,5 por ciento y el valor predictivo negativo de 94,6 por ciento. Se concluyó que el ultrasonido es una herramienta de valor para el cálculo del peso fetal y la detección del bajo peso intraútero(AU)

Eficacia de la estimación del peso fetal por ultrasonido para la predicción del bajo peso al nacer / Efficacy of fetal weight estimation by ultrasound for the low birthweight prediction

Se realizó un estudio retrospectivo de 202 nacimientos ocurridos en el hospital "América Arias" desde marzo de 1998 a marzo de 1999, para evaluar la capacidad del ultrasonido en el cálculo del peso fetal y la detección del bajo peso intraútero (menos de 2 500 g), según el número de días transcurridos entre la estimación y el parto (menos de 8, de 8 a 20 y más de 20 días). La eficacia del ultrasonido para detectar el bajo peso al nacer aumentó de manera inversamente proporcional al número de días entre la estimación y el parto. Con menos de 20 días de diferencia, la sensibilidad fue de 91 por ciento y la especificidad de un 83,5 por ciento. El valor predictivo positivo fue de 74,5 por ciento y el valor predictivo negativo de 94,6 por ciento. Se concluyó que el ultrasonido es una herramienta de valor para el cálculo del peso fetal y la detección del bajo peso intraútero

Reemplazo total de cadera - Hospital Dr. Darío Contreras, 1988-1992 / Hip prosthesis - Hospital Dr. Dario Contreras; 1988-1992

Se realizó un estudio descriptivo de reemplazo total de cadera en el Hospital Dr. Darío Contreras, Santo Domingo, República Dominicana, durante el período 1988-1992. El estudio consistió en la revisión de los expedientes clínicos de los pacientes intervenidos a reemplazo total de cadera, para determinar su edad, sexo, causa etiológica y movimientos articulares. De los 27 casos encontrados el grupo de edad de más incidencia es 61-70 años, con 9 casos (33.3 por ciento ), el sexo femenino 17 casos (62.9), la causa etiológica más frecuente es osteoartritis primaria con 11 casos (40.7 por ciento ) y en los movimientos articulares hubo un aumento después de la cirugía, en especial en la dislocación traumática y fractura de cuello de fémur que casi se logró todos sus movimientos. En función de los resultados, recomendamos medidas preventivas