Molecular imaging of prostate cancer: Review of imaging agents, modalities, and current status. / Técnicas de imagen molecular en el cáncer de próstata: revisión de radiofármacos, modalidades y evidencia actual.

INTRODUCTION: The clinical course of Prostate cancer (PCa) are markedly diverse, ranging from indolent to highly aggressive disseminated disease. Molecular imaging techniques are playing an increasing role in early PCa detection, staging and disease recurrence. There are some molecular imaging modalities, radiotracers agents and its performance are important in current clinical practice PCa. OBJECTIVE: This review summarizes the latest information regarding molecular imaging of PCa and is designed to assist urologists with ordering and interpreting these modalities and different radiotracers for different patients. EVIDENCE ACQUISITION: A PubMed-based literature search was conducted up to September 2019. We selected the most recent and relevant original articles, metanalysis and reviews that have provided relevant information to guide molecular imaging modalities and radiotracers use. EVIDENCE SYNTHESIS: In this review, we discuss 3 main molecular imaging modalities and 7 radiotracer technologies available. CONCLUSIONS: The use molecular imaging modalities and radiotracers has a unique role in biochemical recurrence and diagnosis of ganglionar and bone progression of PCa. In the present time, no one of these molecular imaging modalities can be recommended over the classical work-up of abdominopelvic CT scan and bone scan, and large-scale and multi-institutional studies are required to validate the efficacy and cost utility of these new technologies.

Multidisciplinary total eradication therapy (TET) in men with newly diagnosed oligometastatic prostate cancer.

To evaluate the outcomes of total eradication therapy (TET), designed to eradicate all sites of visible cancer and micrometastases, in men with newly diagnosed oligometastatic prostate cancer (OMPCa). Men with ≤ 5 sites of metastases were enrolled in a prospective registry study, underwent neoadjuvant chemohormonal therapy, followed by radical prostatectomy, adjuvant radiation (RT) to prostate bed/pelvis, stereotactic body radiation therapy (SBRT) to oligometastases, and adjuvant hormonal therapy (HT). When possible, the prostate-specific membrane antigen targeted 18F-DCFPyL PET/CT (18F-DCFPyL) scan was obtained, and abiraterone was added to neoadjuvant HT. Twelve men, median 55 years, ECOG 0, median PSA 14.7 ng/dL, clinical stages M0-1/12 (8%), M1a-3/12 (25%) and M1b-8/12 (67%), were treated. 18F-DCFPyL scan was utilized in 58% of cases. Therapies included prostatectomy 12/12 (100%), neoadjuvant [docetaxel 11/12 (92%), LHRH agonist 12/12 (100%), abiraterone + prednisone 6/12 (50%)], adjuvant radiation [RT 2/12 (17%), RT + SBRT 4/12 (33%), SBRT 6/12 (50%)], and LHRH agonist 12/12 (100%)]. 2/5 (40%) initial patients developed neutropenic fever (NF), while 0/6 (0%) subsequent patients given modified docetaxel dosing developed NF. Otherwise, TET resulted in no additive toxicities. Median follow-up was 48.8 months. Overall survival was 12/12 (100%). 1-, 2-, and 3-year undetectable PSA's were 12/12 (100%), 10/12 (83%) and 8/12 (67%), respectively. Median time to biochemical recurrence was not reached. The outcomes suggest TET in men with newly diagnosed OMPCa is safe, does not appear to cause additive toxicities, and may result in an extended interval of undetectable PSA.

Second trimester marginal cord insertion is associated with adverse perinatal outcomes.

Objectives: To determine the feasibility in visualizing placental cord insertion (PCI) during second-trimester fetal anatomical survey and the association between marginal cord insertion (MCI) and preterm delivery (PTD) and low birth weight (LBW). Our secondary objectives were to evaluate the association of MCI with adverse composite obstetrical and neonatal outcomes. Methods: A prospective cohort study was performed over a 28-month period. Women with singleton pregnancies presenting for routine anatomical survey between 18 and 22 weeks' gestation were included. PCI site was visualized on 2D grayscale and color Doppler and the shortest distance from the sagittal and transverse planes to the placental edge were recorded. MCI was diagnosed when any of measured distances was ≤2 cm. Correlations were assessed via bivariate chi-squared, independent t-test analyses and Fisher's exact tests. Regression models evaluated associations between MCI and adverse composite outcomes. Results: Three hundred one women were included and PCI was feasible in all cases. The incidence of MCI was 11.3% (n = 34). Baseline characteristics between those with and without MCI were similar, except for story of prior PTD, which was greater among those with MCI (17.65 versus 7.17%, p = .04). MCI was associated with increased likelihood of LBW (RR four; 95%CI, 1.46-10.99) and PTD (RR 3.2; 95%CI, 1.53-6.68); in multivariate analysis, we found associations between MCI and composite adverse obstetrical (RR 2.33; 95%CI, 1.30-4.19) and neonatal (RR 2.46; 95%CI, 1.26-4.81) outcomes. Conclusions: Evaluation of PCI is feasible in all cases. Second-trimester MCI is associated with increased likelihood for LBW, PTD, and composite adverse obstetrical and neonatal outcomes.

Active surveillance is superior to radical nephrectomy and equivalent to partial nephrectomy for preserving renal function in patients with small renal masses: Results from the DISSRM registry.

PURPOSE: We compared renal function outcomes among patients in the surveillance and intervention arms of the DISSRM registry. MATERIALS AND METHODS: Patients were grouped into chronic kidney disease stages by estimated glomerular filtration rate range. Cases were considered up staged if a more advanced chronic kidney disease stage was entered during followup. Chronic kidney disease up staging-free survival was compared among groups using Kaplan-Meier analysis and paired comparisons log rank tests. Multivariate Cox regression identified independent predictors of chronic kidney disease up staging-free survival. RESULTS: A total of 162 patients met the study inclusion criteria, with 68 in the surveillance arm, 65 undergoing partial nephrectomy, 15 undergoing radical nephrectomy, and 14 undergoing cryoablation. Median tumor size was 2.2cm. Mean estimated glomerular filtration rate change was significantly larger for radical nephrectomy vs. surveillance (-9.2 vs. -0.5ml/min/1.73m2) and for radical vs. partial nephrectomy (-9.2 vs. -1.9ml/min/1.73m2) (P = 0.001). No other groups differed significantly. On Kaplan-Meier analysis, patients undergoing radical nephrectomy had significantly worse chronic kidney disease up staging-free survival vs. those treated with partial nephrectomy (P = 0.029), surveillance (P = 0.007), and cryoablation (P = 0.019). No other groups differed significantly. On multivariate analysis, radical nephrectomy independently predicted poor chronic kidney disease up staging-free survival (odds ratio vs. surveillance 30.6, P = 0.001). Neither partial nephrectomy (P = 0.985) nor cryoablation (P = 0.976) predicted poor chronic kidney disease up staging-free survival relative to surveillance. CONCLUSIONS: Patients in the surveillance arm had superior estimated glomerular filtration rate preservation compared to those in the radical nephrectomy but not the partial nephrectomy arm. In certain patients with small renal masses, surveillance and partial nephrectomy may offer comparable renal functional outcomes. This could be partly attributable to a modest estimated glomerular filtration rate decrease associated with surveillance itself. A thorough understanding of the renal functional impacts of treatment modalities is critical in the management of small renal masses.

Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC-A Possible Path Forward.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Optimal weight gain in triplet pregnancies.

OBJECTIVE: To identify appropriate weight gain in triplet gestations, which may aid in reducing the risk of perinatal morbidity within this high-risk cohort. METHODS: This retrospective cohort study evaluated all non-anomalous triplet pregnancies between 23 and 40 weeks' gestation resulting in live births at five tertiary-care medical centers between 1991 and 2011. Subjects were divided by pre-pregnancy BMI into underweight, normal-weight, overweight, and obese groups, and then stratified by low (<0.5 lb/week), moderate (0.5-1.49 lbs/week), or excess weight gain (≥1.5 lbs/week). Primary outcomes included spontaneous preterm birth and preeclampsia. RESULTS: We included 116 mothers and 348 corresponding neonates for final analysis. The incidence of preeclampsia and preterm delivery less than 32 weeks' gestation was 37% and 41%, respectively. The incidence of preeclampsia increased with weight gain per week, but was not statistically different from subjects who gained less weight. We found no statistical correlation between weight gain per week and preterm delivery. CONCLUSION: We found no association between preeclampsia or preterm delivery and increasing weight gain in triplet pregnancies. The association with increased risk for preeclampsia was predominantly due to BMI effect. Based on the current study, recommendations for optimal weight gain in mothers with triplet gestations could not be defined.

Surgeons' physical discomfort and symptoms during robotic surgery: a comprehensive ergonomic survey study.

BACKGROUND: It is commonly believed that robotic surgery systems provide surgeons with an ergonomically sound work environment; however, the actual experience of surgeons practicing robotic surgery (RS) has not been thoroughly researched. In this ergonomics survey study, we investigated surgeons' physical symptom reports and their association with factors including demographics, specialties, and robotic systems. METHODS: Four hundred and thirty-two surgeons regularly practicing RS completed this comprehensive survey comprising 20 questions in four categories: demographics, systems, ergonomics, and physical symptoms. Chi-square and multinomial logistic regression analyses were used for statistical analysis. RESULTS: Two hundred and thirty-six surgeons (56.1 %) reported physical symptoms or discomfort. Among those symptoms, neck stiffness, finger, and eye fatigues were the most common. With the newest robot, eye symptom rate was considerably reduced, while neck and finger symptoms did not improve significantly. A high rate of lower back stiffness was correlated with higher annual robotic case volume, and eye symptoms were more common with longer years practicing robotic surgery (p < 0.05). The symptom report rate from urology surgeons was significantly higher than other specialties (p < 0.05). Noticeably, surgeons with higher confidence and helpfulness levels with their ergonomic settings reported lower symptom report rates. Symptoms were not correlated with age and gender. CONCLUSION: Although RS provides relatively better ergonomics, this study demonstrates that 56.1 % of regularly practicing robotic surgeons still experience related physical symptoms or discomfort. In addition to system improvement, surgeon education in optimizing the ergonomic settings may be necessary to maximize the ergonomic benefits in RS.

PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies. METHODS: A great deal of progress has been made in defining the clinical utility of this class of PET agents through predominantly small and retrospective clinical studies. The most compelling data to date has been in the setting of biochemically recurrent PCa, where PSMA-targeted radiotracers have been found to be superior to conventional imaging and other molecular imaging agents for the detection of locally recurrent and metastatic PCa. RESULTS: Early data, however, suggest that initial lymph node staging before definitive therapy in high-risk primary PCa patients may be limited, although intraoperative guidance may still hold promise. Other examples of potential promising applications for PSMA PET imaging include non-invasive characterization of primary PCa, staging and treatment planning for PSMA-targeted radiotherapeutics, and guidance of focal therapy for oligometastatic disease. CONCLUSIONS: However, all of these indications and applications for PCa PSMA PET imaging are still lacking and require large, prospective, systematic clinical trials for validation. Such validation trials are needed and hopefully will be forthcoming as the fields of molecular imaging, urology, radiation oncology and medical oncology continue to define and refine the utility of PSMA-targeted PET imaging to improve the management of PCa patients.

Does early second-trimester sonography predict adverse perinatal outcomes in monochorionic diamniotic twin pregnancies?

OBJECTIVES: To determine whether intertwin discordant abdominal circumference, femur length, head circumference, and estimated fetal weight sonographic measurements in early second-trimester monochorionic diamniotic twins predict adverse obstetric and neonatal outcomes. METHODS: We conducted a multicenter retrospective cohort study involving 9 regional perinatal centers in the United States. We examined the records of all monochorionic diamniotic twin pregnancies with two live fetuses at the 16- to 18-week sonographic examination who had serial follow-up sonography until delivery. The intertwin discordance in abdominal circumference, femur length, head circumference, and estimated fetal weight was calculated as the difference between the two fetuses, expressed as a percentage of the larger using the 16- to 18-week sonographic measurements. An adverse composite obstetric outcome was defined as the occurrence of 1 or more of the following in either fetus: intrauterine growth restriction, twin-twin transfusion syndrome, intrauterine fetal death, abnormal growth discordance (≥20% difference), and very preterm birth at or before 28 weeks. An adverse composite neonatal outcome was defined as the occurrence of 1 or more of the following: respiratory distress syndrome, any stage of intraventricular hemorrhage, 5-minute Apgar score less than 7, necrotizing enterocolitis, culture-proven early-onset sepsis, and neonatal death. Receiver operating characteristic and logistic regression-with-generalized estimating equation analyses were constructed. RESULTS: Among the 177 monochorionic diamniotic twin pregnancies analyzed, intertwin abdominal circumference and estimated fetal weight discordances were only predictive of adverse composite obstetric outcomes (areas under the curve, 79% and 80%, respectively). Receiver operating characteristic curves showed that intertwin discordances in abdominal circumference, femur length, head circumference, and estimated fetal weight were not acceptable predictors of twin-twin transfusion syndrome or adverse neonatal outcomes. CONCLUSIONS: In our cohort, only second-trimester abdominal circumference and estimated fetal weight discordances in monochorionic diamniotic twin pregnancies were predictive of adverse composite obstetric outcomes. Twin-twin transfusion syndrome and adverse neonatal outcomes were not predicted by any of the intertwin discordances measured.

Resection of isolated renal cell carcinoma metastases of the pancreas: outcomes from the Johns Hopkins Hospital.

PURPOSE: This study aims to assess outcomes and characteristics associated with resection of metastatic renal cell carcinoma (mRCC) to the pancreas. MATERIALS AND METHODS: From April 1989 to July 2012, a total of 42 patients underwent resection of pancreatic mRCC at our institution. We retrospectively reviewed records from a prospectively managed database and analyzed patient demographics, comorbidities, perioperative outcomes, and overall survival. Cox proportional hazards models were used to evaluate the association between patient-specific factors and overall survival. RESULTS: The mean time from resection of the primary tumor to reoperation for pancreatic mRCC was 11.2 years (range, 0-28.0 years). In total, 17 patients underwent pancreaticoduodenectomy, 16 underwent distal pancreatectomy, and 9 underwent total pancreatectomy. Perioperative complications occurred in 18 (42.9%) patients; there were two (4.8%) perioperative mortalities. After pancreatic resection, the median follow-up was 7.0 years (0.1-23.2 years), and median survival was 5.5 years (range, 0.4-21.9). The overall 5-year survival was 51.8%. On univariate analysis, vascular invasion (hazard ratio, 5.15; p = 0.005) was significantly associated with increased risk of death. CONCLUSIONS: Pancreatic resection of mRCC can be safely achieved in the majority of cases and is associated with long-term survival. Specific pathological factors may predict which patients will benefit most from resection.

First-trimester sonographic prediction of obstetric and neonatal outcomes in monochorionic diamniotic twin pregnancies.

OBJECTIVES: The purpose of this study was to investigate whether discordant nuchal translucency and crown-rump length measurements in monochorionic diamniotic twins are predictive of adverse obstetric and neonatal outcomes. METHODS: We conducted a multicenter retrospective cohort study including all monochorionic diamniotic twin pregnancies with two live fetuses at the 11-week to 13-week 6-day sonographic examination who had serial follow-up sonography until delivery. Isolated nuchal translucency, crown-rump length, and combined discordances were correlated with adverse obstetric outcomes, individually and in composite, including the occurrence of 1 or more of the following in either fetus: intrauterine growth restriction (IUGR), twin-twin transfusion syndrome (TTTS), intrauterine fetal death (IUFD), growth discordance (≥ 20%), and preterm birth before 28 weeks' gestation. Correlations with adverse composite neonatal outcomes were also studied. A receiver operating characteristic curve analysis and a logistic regression analysis with a generalized estimating equation were conducted. RESULTS: Fifty-four of the 177 pregnancies included (31%) had an adverse composite obstetric outcome, with TTTS in 19 (11%), IUGR in 21 (12%), discordant growth in 14 (8%), IUFD in 14 (8%), and preterm birth before 28 weeks in 10 (6%). Of the 254 neonates included in the study, 69 (27%) were complicated by adverse composite neonatal outcomes, with respiratory distress syndrome being the most common (n = 59 [23%]). The areas under the curve for the combined discordances to predict composite obstetric and neonatal outcomes were 0.62 (95% confidence interval, 0.52-0.72), and 0.54 (95% confidence interval, 0.46-0.61), respectively. CONCLUSIONS: In our population, nuchal translucency, crown-rump length, and combined discordances in monochorionic diamniotic twin pregnancies were not predictive of adverse composite obstetric and neonatal outcomes.

Patient acceptance of non-invasive testing for fetal aneuploidy via cell-free fetal DNA.

OBJECTIVE: To evaluate factors associated with patient acceptance of noninvasive prenatal testing for trisomy 21, 18 and 13 via cell-free fetal DNA. METHODS: This was a retrospective study of all patients who were offered noninvasive prenatal testing at a single institution from 1 March 2012 to 2 July 2012. Patients were identified through our perinatal ultrasound database; demographic information, testing indication and insurance coverage were compared between patients who accepted the test and those who declined. Parametric and nonparametric tests were used as appropriate. Significant variables were assessed using multivariate logistic regression. The value p < 0.05 was considered significant. RESULTS: Two hundred thirty-five patients were offered noninvasive prenatal testing. Ninety-three patients (40%) accepted testing and 142 (60%) declined. Women who accepted noninvasive prenatal testing were more commonly white, had private insurance and had more than one testing indication. There was no statistical difference in the number or the type of testing indications. Multivariable logistic regression analysis was then used to assess individual variables. After controlling for race, patients with public insurance were 83% less likely to accept noninvasive prenatal testing than those with private insurance (3% vs. 97%, adjusted RR 0.17, 95% CI 0.05-0.62). CONCLUSION: In our population, having public insurance was the factor most strongly associated with declining noninvasive prenatal testing.

Maternal thrombocytopenia in pregnancy: diagnosis and management.

Thrombocytopenia is a common complication encountered in pregnancy, and can have a wide range of prognostic implications, from completely benign to life threatening. It is important for obstetricians to be aware of the various causes of thrombocytopenia in pregnancy, and to be able to diagnose and manage these patients. This article reviews the various causes of thrombocytopenia in pregnancy, highlights clinical and laboratory features of the most common and most severe causes, and provides an overview of management for these disorders.

Prediction of proteinuria and microalbuminuria in diabetic pregnancies with a random single void.

OBJECTIVE: To determine whether a single urine specimen could effectively replace the 24 hour (24-h) urine collection in screening for microalbuminuria and proteinuria in pregnant women with pregestational diabetes. MATERIALS AND METHODS: A total of 42 pregnant women with pregestational diabetes mellitus were involved in the eventual analysis. Demographic and clinical variables were collected and analyzed. Urinary Protein (P) to Creatinine (Cr) ratio and microalbumin (MA) to Cr ratios were measured for the spot sample, and the total P, total MA, and serum Cr were measured for the 24-h urine sample. Analysis was done using linear regression and the Pearson correlation coefficient (r). RESULTS: Mean maternal age was 30.8 years, and the mean gestational age at collection was 19.8 weeks. A strong correlation exists between the spot MA to Cr value and 24-h MA, with an r = 0.81 (P < 0.0001). The association between the spot P to Cr ratio and 24-h urinary P was not as strong, r = 0.58 (P < 0.0001). CONCLUSIONS: A strong association between spot MA to Cr ratio and 24-h urinary microalbuminuria may suggest a predictive role for random urine assessment of MA in pregnant pregestational diabetic patients. However, based on our data, the spot P to Cr ratio may be inadequate for assessing proteinuria in pregestational diabetic pregnancies.

Laparoscopic live donor nephrectomy with vaginal extraction: initial report.

The recent decrease in the total number of living kidney transplants coupled with the increase in the number of candidates on the waiting list underscores the importance of eliminating barriers to living kidney donation. We report what we believe to be the first pure right-sided laparoscopic live donor nephrectomy with extraction of the kidney through the vagina. The warm ischemia time was 3 min and the renal vessels and ureter of the procured kidney were of adequate length for routine transplantation. The donor did not receive any postoperative parenteral narcotic analgesia, was discharged home within 24 h and was back to normal activity in 14 days. The kidney functioned well with no complications or infections. Laparoscopic live donor nephrectomy with vaginal extraction may be a viable alternative to open and standard laparoscopic approaches. Potential advantages include reduced postoperative pain, shorter hospital stay and convalescence and a more desirable cosmetic result. These possible, but yet unproven, advantages may encourage more individuals to consider live donation.

Pregnancy in a woman with uterine procidentia: a case report.

BACKGROUND: Uterine prolapse in pregnancy is rare and can either occur during pregnancy or be present before the pregnancy. We present a case of a successful pregnancy in a patient with preexisting uterine procidentia. CASE: A 44-year-old woman with a history of complete uterine prolapse presented with an unplanned pregnancy. Upon initial presentation at 15 weeks she had uterine prolapse with cervical elongation that protruded 10 cm past the introitus. The prolapse persisted until about 30 weeks, during which it was conservatively managed with bed rest, knee-chest positions and local treatment of the desiccated cervix with emollients. The patient had an uncomplicated vaginal delivery and underwent a vaginal hysterectomy, anterior-posterior repair and a sacrospinous ligament fixation a few months later. CONCLUSION: Uterine prolapse in pregnant women with preexisting prolapse will probably resolve in the third trimester without treatment. An otherwise uncomplicated course and a vaginal delivery can be expected.