Parp Inhibitors and Radiotherapy: A New Combination for Prostate Cancer (Systematic Review).

PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure to radiation leads to both physical and biochemical damage to DNA, prompting cells to initiate three primary mechanisms for DNA repair. Two double-stranded DNA breaks (DSB) repair pathways: (1) non-homologous end-joining (NHEJ) and (2) homologous recombination (HR); and (3) a single-stranded DNA break (SSB) repair pathway (base excision repair, BER). In this scenario, PARPi can serve as radiosensitizers by leveraging the BER pathway. This mechanism heightens the likelihood of replication forks collapsing, consequently leading to the formation of persistent DSBs. Together, the combination of PARPi and radiotherapy is a potent oncological strategy. This combination has proven its efficacy in different tumors. However, in prostate cancer, there are only preclinical studies to support it and, recently, an ongoing clinical trial. The objective of this paper is to perform a review of the current evidence regarding the use of PARPi and radiotherapy (RT) in PCa and to give future insight on this topic.

Prevalence of High-Risk Prostate Cancer Metastasis to Cloquet's Ilioinguinal Lymph Node.

PURPOSE: Cloquet's node, located at the junction between the deep inguinal nodes and the external iliac chain, is easily accessible and commonly excised during pelvic lymph node dissection for prostate cancer. However, we hypothesize that Cloquet's node is not part of lymphatic metastatic spread of prostate cancer. MATERIALS AND METHODS: Between September 2016 and June 2019, 105 consecutive patients with high-risk prostate cancer (cT3a or Grade Group 4/5, or prostate specific antigen >20 ng/ml) underwent a laparoscopic radical prostatectomy and pelvic lymph node dissection. First, Cloquet's node was identified, retrieved and submitted separately to pathology as right and left Cloquet's node. Next, a pelvic lymph node dissection was completed including the external iliac, obturator fossa and hypogastric nodal packets. Each lymph node was cut into 3 mm slices which were separately embedded in paraffin, stained with hematoxylin and eosin, and examined microscopically. RESULTS: The final analysis included 95 patients. In this high-risk population, the median number of nodes removed was 22 (IQR 18-29); 39/95 patients (41%) had lymph node metastasis. The median number of Cloquet's nodes removed was 2 (IQR 2-3). Cloquet's node was negative in all but 1 patient (1.1%), who had very high-risk features and high metastatic burden in the lymph nodes. CONCLUSIONS: In high-risk prostate cancer, metastasis to the ilioinguinal node of Cloquet is rare. Given this low prevalence, Cloquet's node can be safely excluded from the pelvic lymph node dissection template.

Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy.

Since prostate cancer (PCa) was described as androgen-dependent, the androgen receptor (AR) has become the mainstay of its systemic treatment: androgen deprivation therapy (ADT). Although, through recent years, more potent drugs have been incorporated, this chronic AR signaling inhibition inevitably led the tumor to an incurable phase of castration resistance. However, in the castration-resistant status, PCa cells remain highly dependent on the AR signaling axis, and proof of it is that many men with castration-resistant prostate cancer (CRPC) still respond to newer-generation AR signaling inhibitors (ARSis). Nevertheless, this response is limited in time, and soon, the tumor develops adaptive mechanisms that make it again nonresponsive to these treatments. For this reason, researchers are focused on searching for new alternatives to control these nonresponsive tumors, such as: (1) drugs with a different mechanism of action, (2) combination therapies to boost synergies, and (3) agents or strategies to resensitize tumors to previously addressed targets. Taking advantage of the wide variety of mechanisms that promote persistent or reactivated AR signaling in CRPC, many drugs explore this last interesting behavior. In this article, we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of "hinge" treatments with the objective of obtaining an oncological benefit. Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides. All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis.

Can the Abdominal Aortic Atherosclerotic Plaque Index Predict Functional Outcomes after Robot-Assisted Partial Nephrectomy?

This study aims to evaluate the abdominal aortic atherosclerotic plaque index (API)'s predictive role in patients with pre-operatively or post-operatively developed chronic kidney disease (CKD) treated with robot-assisted partial nephrectomy (RAPN) for renal cell carcinoma (RCC). One hundred and eighty-three patients (134 with no pre- and post-operative CKD (no CKD) and 49 with persistent or post-operative CKD development (post-op CKD)) who underwent RAPN between January 2019 and January 2022 were deemed eligible for the analysis. The API was calculated using dedicated software by assessing the ratio between the CT scan atherosclerotic plaque volume and the abdominal aortic volume. The ROC regression model demonstrated the influence of API on CKD development, with an increasing effect according to its value (coefficient 0.13; 95% CI 0.04-0.23; p = 0.006). The Model 1 multivariable analysis of the predictors of post-op CKD found that the following are independently associated with post-op CKD: Charlson Comorbidity Index (OR 1.31; p = 0.01), last follow-up (FU) Δ%eGFR (OR 0.95; p < 0.01), and API ≥ 10 (OR 25.4; p = 0.01). Model 2 showed API ≥ 10 as the only factor associated with CKD development (OR 25.2; p = 0.04). The median follow-up was 22 months. Our results demonstrate API to be a strong predictor of post-operative CKD, allowing the surgeon to tailor the best treatment for each patient, especially in those who might be at higher risk of CKD.

Update on the treatment of metastatic renal cell carcinoma.

Metastatic renal cell cancer (mRCC) management has undergone a paradigm shift in recent decades. The first revolution came with the emergence of vascular endothelial growth factor inhibitors; there was a second wave with the unprecedented success of checkpoint inhibitors, and then the latest approach, which is becoming the new care standard in mRCC, of combining these two strategies in different ways. Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival (PFS), overall survival (OS), and objective response rate (ORR) in intermediate and high-risk patients. However, several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place, and so far, the only one for nivolumab/ipilimumab is the frontline setting. The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembroli-zumab/axitinib over sunitinib in favorable-risk mRCC, suggesting that it should no longer be the first line of choice in low-risk patients. Finally, the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS, OS, and ORR, providing a new first-line option among all International Metastatic RCC Database Consortium risk patients. Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib, cabozantinib/atezolizumab, and lenvatinib/pembrolizumab, providing promising grounds upon which to start phase III studies. In addition, other works are using novel therapeutic agents with different mechanisms of action, including telaglenastat (a glutaminase inhibitor), entinostat [an inhibitor of histone deacetylases (HDACs)], and olaparib and talazoparib, poly(ADP-ribose) polymerase inhibitors widely used in other tumors. However, some questions regarding mRCC management still need to be addressed, such as head-to-head comparisons between the current options, treatment sequencing, non-clear cell mRCC, and the role of biomarkers to ascertain the best treatment choice.

Kidney Autotransplantation in the Management of Residual Retroperitoneal Mass in a Germ Cell Tumor.

The main indication for kidney autotransplantation is ureteric disease, although it is also performed to treat renovascular diseases or neoplasms, such as complex intrasinusal kidney tumors or in patients with a solitary kidney. Only a few cases of kidney autotransplantation in the context of resection of complex retroperitoneal masses have been reported in the literature. CASE PRESENTATION: We report the case of a 26-year-old man with history of nonseminomatous germ cell tumor who had undergone a left radical orchiectomy 3 months earlier. Follow-up computed tomography revealed a residual retroperitoneal postchemotherapy mass involving the renal hilum. It was surgically removed via en bloc resection and bench ex vivo nephron-sparing surgery, and subsequently autotransplantation, thereby avoiding the necessity of nephrectomy and the resulting risk of chronic kidney disease. The pathology of the excised specimen demonstrated mixed germ cell tumor, composed of immature teratoma and yolk sac tumor, and confirmed tumor-free margins. CONCLUSIONS: This technique should be taken into account in selected patients as an alternative to radical nephrectomy when a retroperitoneal tumor is unresectable using standard surgical techniques or when a radical nephrectomy is considered, especially in patients with chronic kidney disease or solitary kidney, or in young patients who will potentially need nephrotoxic chemotherapy.

Three-dimensional Model-assisted Minimally Invasive Partial Nephrectomy: A Systematic Review with Meta-analysis of Comparative Studies.

CONTEXT: Use of three-dimensional (3D) guidance for nephron-sparing surgery (NSS) has increased in popularity, especially for laparoscopic and robotic approaches. Different 3D visualization modalities have been developed as promising new tools for surgical planning and intraoperative navigation. OBJECTIVES: To summarize and evaluate the impact of 3D models on minimally invasive NSS in terms of perioperative, functional, and oncological outcomes. EVIDENCE ACQUISITION: A systematic literature search was conducted in December 2021 using the Medline (PubMed), Embase (Ovid), Scopus, and Web of Science databases. The protocol was registered on PROSPERO (CRD42022300948). The search strategy used the PICOS (Population, Intervention, Comparison, Outcome, Study design) criteria and article selection was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The risk of bias and the quality of the articles included were assessed. A dedicated data extraction form was used to collect the data of interest. Meta-analysis was performed using the Mantel-Haenszel method for binary outcomes, with results summarized as the odds ratio (OR), and the inverse variance method for continuous data, with results reported as the mean difference (MD). All effect estimates are reported with the 95% confidence interval (CI) and p ≤ 0.05 was considered statistically significant. All analyses were performed using R software and the meta package. EVIDENCE SYNTHESIS: The initial electronic search identified 450 papers, of which 17 met the inclusion criteria and were included in the analysis. Use of 3D technology led to a significant reduction in the global ischemia rate (OR 0.22, 95% CI 0.07-0.76; p = 0.02) and facilitated more frequent enucleation (OR 2.54, 95% CI 1.36-4.74; p < 0.01) and less frequent opening of the collecting system (OR 0.36, 95% CI 0.15-0.89; p = 0.03) and was associated with less blood loss (MD 23.1 ml, 95% CI 31.8-14.4; p < 0.01). 3D guidance for NSS was associated with a significant reduction in the transfusion rate (OR 0.20, 95% CI 0.07-0.56; p < 0.01). There were no significant differences in rates of conversion to radical nephrectomy, minor and major complications, change in glomerular filtration rate, or surgical margins (all p > 0.05). CONCLUSIONS: 3D guidance for NSS is associated with lower rates of detriment and surgical injury to the kidney. Specifically, a lower amount of nontumor renal parenchyma is exposed to ischemia or sacrificed during resection, and opening of the collecting system is less frequent. However, use of 3D technology does not lead to significant improvements in oncological or functional outcomes. PATIENT SUMMARY: We reviewed the use of three-dimensional tools for minimally invasive surgery for partial removal of the kidney in patients with kidney cancer. The evidence suggests that these tools have benefits during surgery, but do not lead to significant improvements in cancer control or functional outcomes for patients.

[Recurrence and progression after BCG.] / Concepto de recidiva, recurrencia y progresión tras BCG.

BCG is currently the standard of care in intermediate and high risk non-invasive bladder tumors. In high-risk patients treated with BCG up to 30% will recurand 10% will progress within 2 years. Oncological outcomes with bladder preserving strategies are limited so radical cystectomy is recommended after BCG failure. Some promising treatments, such as check point inhibitors (PD1, PDL-1), are being studied for non-responders to BCG. Knowing the management of critical situations during BCG treatment its crucial in daily practice and clinical trials design. The aim of this study is to present these definitions and to remember some important aspect sof BCG management.

La BCG es en la actualidad el tratamiento de elección en tumores vesicales no músculo invasivo de riesgo intermedio y alto. De los pacientes de alto riesgo tratados con BCG, hasta un 30% recidivarán y un 10% progresarán en 2 años. Los resultados oncológicos de estos pacientes con estrategias de conservación vesical son modestos, por lo que la cistectomía radicales el tratamiento de elección tras fallo de BCG. Están siendo estudiadas diferentes opciones de tratamiento para pacientes no respondedores a BCG, como son los inhibidores de los puntos de control (PD1, PDL-1). Para el diseño de los ensayos clínicos (EC) y para homogeneizar nuestra práctica clínica diaria, es necesario tener clara la definición de una serie de situaciones, en las que nos podemos encontrar durante un tratamiento con BCG. El objetivo de este trabajo es revisar estas definiciones y recordar algunos aspectos del manejo de la BCG implicados en las mismas.

How to obtain a 3D printed model of renal cell carcinoma (RCC) with venous tumor thrombus extension (VTE) for surgical simulation (phase I NCT03738488).

This is the phase 1 of a multicenter clinical trial (NCT03738488), which aims to assess the efficacy and efficiency of surgery planning with 3D models of renal cell carcinoma (RCC) with venous tumor thrombus extension (VTE) compared to the standard images (CT). The objective of this phase is to obtain a 3D printed model of RCC with VTE that is feasible, accurate, reproducible, suitable for surgical simulation, and affordable. A specific protocol was developed to obtain the computed tomography (CT) image: early arterial and nephrogenic phase. ITK-snap® and VirSSPA Software® were used to segment the areas of interest. The resulting 3D mesh was processed with MeshMixer® and Cura®. Ten models from seven different cases were segmented and printed using different 3D printers and materials. We evaluated the material, scale, wall thickness, anatomy printed, 3D conformation, accuracy compared to the CT, suitability to perform the surgery, material, cost, and time (segmentation + design + fabrication + finishing). The four selected models were printed with a BQ Witbox FDM printer in polyurethane filament with a 0.8 mm wall thickness and 100% scale. All the relevant anatomical structures could be correctly identified, the 3D conformation was maintained with good accuracy compared to the CT and the surgery could be performed on them. Mean design time, model cost and printing time were 8.3 h, 33.4 €, and 38.5 h respectively. Various feasible 3D models of RCC with VTE were obtained after a few attempts. The final models were proved to be reproducible, accurate compared to the CT, and suitable for surgery simulation. The printing process was standardized making it possible to manufacture affordable 3D printed models.

Feasibility and safety of surgical wound remote follow-up by smart phone in appendectomy: A pilot study.

INTRODUCTION: The objective of the present study is to assess the safety and feasibility of the use of telemedicine-based services for surgical wound care and to measure patient satisfaction with telemedicine-based follow-up. MATERIAL AND METHODS: 24 patients were included, they were provided with a corporate mail address. On day 7 after surgery patients sent, via email, an image of their surgical wound together with a completed questionnaire in order to obtain an early diagnosis. Two independent physicians studied this information and the histologic analysis of the specimen. On day 8, all patients underwent face-to-face office examination by a third physician and all of them completed a satisfaction questionnaire at the end of the study. RESULTS: The use of telemedicine-based services showed a sensitivity of 100%, a specificity of 91.6%, a positive predictive value of 75% and a negative predictive value of 100%. Degree of concordance between the two physicians, as regards the necessity of face-to-face follow-up yielded a kappa coefficient of 0.42 (standard error 0.25 and confidence interval 95% (0.92-0.08), which means a moderate agreement between the two evaluations. 94% of patients were satisfied with telemedicine-based follow-up and 93% showed their preference for this procedure over conventional methods. CONCLUSIONS: The telemedicine-based follow-up, has proven to be feasible and safe for the evaluation of early postoperative complications. Patients reported high levels of satisfaction with the procedure. Telemedicine-based follow-up could become standard practice with the development of a specific mobile application.