Slow induction of brain death leads to decreased renal function and increased hepatic apoptosis in rats

Background: Donor brain death (BD) is an independent risk factor for graft survival in recipients. While in some patients BD results from a fast increase in intracranial pressure, usually associated with trauma, in others, intracranial pressure increases more slowly. The speed of intracranial pressure increase may be a possible risk factor for renal and hepatic graft dysfunction. This study aims to assess the effect of speed of BD induction on renal and hepatic injury markers. Methods: BD induction was performed in 64 mechanically ventilated male Fisher rats by inflating a 4.0F Fogarty catheter in the epidural space. Rats were observed for 0.5, 1, 2 or 4 h following BD induction. Slow induction was achieved by inflating the balloon-catheter at a speed of 0.015 ml/min until confirmation of BD. Fast induction was achieved by inflating the balloon at 0.45 ml/min for 1 min. Plasma, kidney and liver tissue were collected for analysis. Results: Slow BD induction led to higher plasma creatinine at all time points compared to fast induction. Furthermore, slow induction led to increased renal mRNA expression of IL-6, and renal MDA values after 4 h of BD compared to fast induction. Hepatic mRNA expression of TNF-alpha, Bax/Bcl-2, and protein expression of caspase-3 was significantly higher due to slow induction after 4 h of BD compared to fast induction. PMN infiltration was not different between fast and slow induction in both renal and hepatic tissue. Conclusion: Slow induction of BD leads to poorer renal function compared to fast induction. Renal inflammatory and oxidative stress markers were increased. Liver function was not affected by speed of BD induction but hepatic inflammatory and apoptosis markers increased significantly due to slow induction compared to fast induction. These results provide initial proof that speed of BD induction influences detrimental renal and hepatic processes which could signify different donor management strategies for patients progressing to BD at different speeds

177Lutetium PSMA-radioligandtherapie bij prostaatkanker

177Lu-PSMA is a new, promising treatment option in patients with metastatic castration-resistent prostate carcinoma (mCRPC). The radioactive-labeled medication is given intravenously in 1–6 cycles, in which the β‑radiation causes damage to the cellular DNA and eventually cell death of prostate cancer cells that express PSMA. In mostly retrospective studies, a decrease is seen in the serum-PSA level of ≥ 50% in 40–60% of patients that have been previously extensively treated. A survival benefit is observed, but mostly within non-randomized studies. The toxicity of treatment is relatively mild with grade I–II CTCAE xerostomia in 30–50% of patients and a passing grade III–IV CTCAE hematologic toxicity (thrombocytopenia, leukopenia) in 0–15%. The medication is under study in multiple prospective studies in patients with mCRPC and in one randomized clinical trial. The use of 177Lu-PSMA in patients with earlier phases of disease is explored. Until proven of benefit in RCTs, 177Lu-PSMA therapy remains experimental

Biochemical Persistence of Prostate-specific Antigen after Robot-assisted Laparoscopic Radical Prostatectomy: Tumor localizations using PSMA PET/CT imaging

Since the introduction of radiolabeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), the ability to visualize recurrent prostate cancer has improved substantially. However, the diagnostic accuracy of radiolabeled PSMA PET/CT in patients with biochemical persistence (BCP; i.e., persistently measurable prostate-specific antigen (PSA)-values after robot-assisted laparoscopic radical prostatectomy (RARP)) is largely lacking. Therefore, the aim of this study was to determine the role of PSMA (i.e.,18F-DCFPyL or 68Ga-PSMA-11) PET/CT imaging in patients who experience BCP after RARP and to evaluate the sites of persistent disease on PSMA PET/CT. Methods: A total of 150 consecutive patients with BCP after RARP who underwent radiolabeled PSMA PET/CT imaging were retrospectively evaluated. BCP was defined as any detectable first serum PSA-value after RARP (≥0.1 ng/mL) at least 6 weeks after surgery, in the absence of an undetectable PSA-value after RARP. A multivariable logistic regression analysis was performed to identify predictors for the detection of metastases outside the prostatic fossa (≥miN1) on PSMA PET/CT. Results: A PSMA PET/CT was performed at a median PSA-value of 0.60 ng/mL (interquartile range (IQR) 0.3-2.4) after a median period of 6 months (IQR 4-10) following RARP. In total, 101/150 patients (67%) had lesions with PSMA-expression on PET/CT, of which 89/150 patients (59%) had lesions with increased PSMA-expression sites outside the prostatic fossa. Moreover, 39/150 patients (26%) had PSMA-positive lesions outside the pelvis. On multivariable analysis, higher PSA-values after RARP (P = 0.004) and positive pathological lymph node status (P = 0.006) were independent predictors for ≥miN1. Conclusion: In presence of BCP, a high proportion of patients already had metastatic disease to pelvic lymph nodes or showed evidence of distant metastases, as indicated by PSMA PET/CT. Higher PSA-levels after RARP and positive pathological lymph node status were significantly associated with metastases outside the prostatic fossa. In conclusion, in patients with BCP, PSMA PET/CT imaging is warranted to guide (salvage) treatment strategies

Standardised uptake values as determined on prostate-specific membrane antigen positron emission tomography/computed tomography is associated with oncological outcomes in patients with prostate cancer

Objectives: To investigate the association between intraprostatic, intratumoral maximum standardised uptake values (SUV max) on prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer (PCa) prior to robot-assisted radical prostatectomy (RARP) and pathology outcomes, including pathological International Society of Urological Pathology score (pISUP) and lymph node (LN) status (pN0/pN1). Patients and Methods: A bi-centric, secondary analysis of two previous, prospective cohort studies was performed in 318 patients with biopsy confirmed PCa and who were scheduled for RARP. Before surgery, patients received a PSMA PET/CT with either 68Ga-PSMA-11 (59% of the patients) or 18F-PSMA (DCFPyL; 41%) as radiotracer. PET/CT images were analysed both visually and semi-quantitatively by measuring the SUV max of the most intense suspect lesion in the prostate. The association between the SUV max of the primary tumour and pre- and postoperative variables was analysed. Results: The SUV max was associated with clinical and biopsy preoperative variables, as well as with pISUP score and pathological tumour stage. Patients with a pISUP of ≤2 showed significantly lower SUV max compared to patients with a pISUP of >2 for both tracers (SUV max 18F-PSMA: median 5.1 vs 9.6, P = 0.002; SUV max 68Ga-PSMA-11: 6.6 vs 8.6, P = 0.003). Moreover, patients with pN1 had significantly higher median SUV max than those with pN0/pNx for both tracers (SUV max 18F-PSMA: 7.9 vs 12.3, P = 0.04; SUV max 68Ga-PSMA-11: 7.6 vs 12.0, P < 0.001). On multivariable logistic regression analysis, the intraprostatic SUV max was an independent predictor of pN1 for both 68Ga-PSMA-11 (per doubling: odds ratio [OR] 1.96, 95% confidence interval [CI] 1.27–3.01)) and 18F-PSMA (per doubling: OR 1.79, 95% CI 1.06–3.03). Conclusion: Intraprostatic, intratumoral PSMA intensity on PET/CT, as semi-quantitatively expressed by SUV max, may be a valuable innovative biomarker in patients with localised PCa, as it is highly associated with known conventional prognostic factors, such as pISUP and LN status

The Predictive Value of Preoperative Negative Prostate Specific Membrane Antigen Positron Emission Tomography Imaging for Lymph Node Metastatic Prostate Cancer

PURPOSE: We sought to identify a subset of patients in whom an extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy for localized prostate cancer could be omitted when preoperative prostate specific membrane antigen positron emission tomography showed no lymph node metastatic prostate cancer. MATERIALS AND METHODS: A total of 434 patients who underwent prostate specific membrane antigen positron emission tomography prior to robot-assisted laparoscopic radical prostatectomy and extended pelvic lymph node dissection were retrospectively analyzed. Patients were excluded from analysis when the prostate specific membrane antigen positron emission tomography showed evidence of distant metastases. The primary outcome was whether a negative for metastases prostate specific membrane antigen positron emission tomography was able to correctly rule out pelvic lymp node metastases after extended pelvic lymph node dissection, ie its negative predictive value. RESULTS: Overall sensitivity, specificity, positive predictive value and negative predictive value of prostate specific membrane antigen positron emission tomography for the detection of pelvic lymp node metastases were 37.9%, 94.1%, 64.3% and 84.4%, respectively. The negative predictive value of prostate specific membrane antigen positron emission tomography in patients with intermediate risk prostate cancer was 91.6% (95% CI 86-97), compared to 81.4% (95% CI 77-86) in patients with high risk prostate cancer. When only assessing patients with <rT3 disease on multiparametric magnetic resonance imaging, 51/52 patients with intermediate risk prostate cancer had a true negative prostate specific membrane antigen positron emission tomography (negative predictive value=98.1%; 95% CI 94-100). CONCLUSIONS: In patients with high risk prostate cancer, extended pelvic lymph node dissection remains the gold standard staging method, as pelvic lymph node metastases are frequently missed in those with no lymph node metastatic prostate cancer on prostate specific membrane antigen positron emission tomography. Patients with intermediate risk prostate cancer and a radiological T-stage <rT3 on multiparametric magnetic resonance imaging are potential candidates to withhold an extended pelvic lymph node dissection in the presence of a "negative for lymph node metastases" prostate specific membrane antigen positron emission tomography

Clinical verification of 18F-DCFPyL PET-detected lesions in patients with biochemically recurrent prostate cancer

PURPOSE: Radiolabeled Prostate-Specific Membrane Antigen (PSMA) PET/CT is the current standard-of-care for lesion detection in patients with biochemically recurrent (BCR) prostate cancer (PCa). However, rigorous verification of detected lesions is not always performed in routine clinical practice. To aid future 18F-radiolabeled PSMA PET/CT interpretation, we aimed to identify clinical/imaging characteristics that increase the likelihood that a PSMA-avid lesion is malignant. MATERIALS AND METHODS: 262 patients with BCR, who underwent 18F-DCFPyL PSMA PET/CT, were retrospectively analyzed. The malignant nature of 18F-DCFPyL PET-detected lesions was verified through any of the following metrics: (1) positive histopathological examination; (2) additional positive imaging; (3) a ≥50% decrease in Prostate-Specific Antigen (PSA) following irradiation of the lesion(s). RESULTS: In 226/262 PET scans (86.3%) at least one lesion suspicious for recurrent PCa was detected ('positive scan'). In 84/226 positive scans (37.2%), at least one independent verification metric was available. PSMA PET-detected lesions were most often confirmed to be malignant (PCa) in the presence of a CT-substrate (96.5% vs. 55.6% without CT-substrate), with SUVpeak ≥3.5 (91.4% vs. 60.0% with SUVpeak2 PET-positive lesions (94.1% vs. 64.2% in patients with 1-2 PET-positive lesions; p<0.001-0.03). CONCLUSIONS: In this study, the clinical verification of 18F-DCFPyL PET-positive lesions in patients with BCR was performed. Diagnostic certainty of PET-detected lesions increases in the presence of characteristic abnormalities on CT, when SUVpeak is ≥3.5, when PSA-levels exceed 2.0 ng/mL or in patients with more than two PET-positive lesions

Prostate Specific Membrane Antigen Positron Emission Tomography/Computerized Tomography in the Evaluation of Initial Response in Candidates Who Underwent Salvage Radiation Therapy after Radical Prostatectomy for Prostate Cancer

PURPOSE: We assessed predictors of short-term oncologic outcomes of patients who underwent salvage radiation therapy for biochemical recurrence after robot-assisted laparoscopic radical prostatectomy without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography. MATERIALS AND METHODS: We retrospectively analyzed 194 patients with biochemical recurrence after robot-assisted laparoscopic radical prostatectomy who underwent prostate specific membrane antigen positron emission tomography/computerized tomography prior to salvage radiation therapy. Patients with lymph node or distant metastases on restaging imaging or at the time of extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy were excluded, as were patients who received androgen deprivation therapy during or prior to salvage radiation therapy. A multivariable logistic regression analysis was performed to assess predictors of treatment response, defined as prostate specific antigen value ≤0.1 ng/ml after salvage radiation therapy. RESULTS: Overall treatment response after salvage radiation therapy was 75% (146/194 patients). On multivariable analysis, prostate specific antigen value at initiation of salvage radiation therapy (OR 0.42, 95% CI 0.27-0.62, p <0.001), pathological T stage (pT3a vs pT2 OR 0.28, 95% CI 0.11-0.69, p=0.006; pT3b vs pT2 OR 0.26, 95% CI 0.09-0.71, p=0.009) and local recurrent disease on imaging (OR 5.53, 95% CI 1.96-18.52, p=0.003) were predictors of treatment response. CONCLUSIONS: Salvage radiation therapy in patients without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography showed a good overall treatment response of 75%. Higher treatment response rates were observed in patients with lower prostate specific antigen values at initiation of salvage radiation therapy, those with local recurrent disease on imaging and those with lower pathological T stage (pT2 vs pT3a/b)