Periprocedural Bridging in Patients with Venous Thromboembolism: A Systematic Review.

BACKGROUND Vitamin K antagonists (VKA) are the most widely used anticoagulants, and bridging is commonly administered during periprocedural VKA interruption. Given the unclear benefits and risks of periprocedural bridging in patients with previous venous thromboembolism, we aimed to assess recurrent venous thromboembolism and bleeding outcomes with and without bridging in this population. METHODS We performed a systematic review searching the PubMed and EMBASE databases from inception to December 7, 2017 for randomized and non-randomized studies that included adults with previous venous thromboembolism requiring VKA interruption to undergo an elective procedure, and that reported venous thromboembolism or bleeding outcomes. Quality of evidence was graded by consensus. RESULTS We included 28 cohort studies (20 being single-arm cohorts) with overall 6915 procedures for analysis. In 27 studies reporting perioperative venous thromboembolism outcomes, the pooled incidence of recurrent venous thromboembolism with bridging was 0.7% (95% confidence interval [CI] 0.4-1.2%) and 0.5% (95% CI 0.3-0.8%) without bridging. Eighteen studies reported major and/or non-major bleeding outcomes. The pooled incidence of any bleeding was 3.9% (95% CI 2.0-7.4%) with bridging and 0.4% (95% CI 0.1-1.7%) without bridging. In bridged patients at high thromboembolic risk, the pooled incidence for venous thromboembolism was 0.8% (95% CI 0.3-2.5) and 7.5% (95% CI 3.1-17.4%) for any bleeding. Quality of available evidence was very low, primarily due to a high risk of bias of included studies. CONCLUSIONS Periprocedural bridging increases the risk of bleeding compared to VKA interruption without bridging, without a significant difference in periprocedural venous thromboembolism rates

Prostate-specific membrane antigen (PSMA)-based imaging in localized and advanced prostate cancer: a narrative review.

Combined molecular and morphologic imaging modalities have emerged in recent years as an alternative to conventional imaging in prostate cancer (PC). In particular, novel prostate-specific membrane antigen (PSMA) radiotracers have demonstrated increased sensitivity and specificity for the initial staging of men with clinically localized PC, as well as for PC detection in the setting of biochemical recurrence (BCR). Molecular imaging is increasingly used to guide treatment decisions in these patients-though its impact on survival has yet to be established. Improved PC detection in men with BCR has also helped to identify a subset of patients with oligometastatic disease. The optimal management of oligometastatic PC and the role of metastasis-directed therapies (MDT) are the subjects of ongoing studies. In comparison to clinically localized or biochemically recurrent PC, the role of molecular imaging in men with advanced disease is less established. In metastatic castration-resistant PC (mCRPC), PSMA-based imaging has primarily been investigated as a companion diagnostic tool to predict and monitor response to PSMA-targeted radioligand therapy (RLT). More recent efforts have focused on using molecular imaging to monitor treatment response to conventional chemohormonal therapies. However, despite promising early results, several barriers remain to the widespread use of PSMA-based imaging in metastatic PC: temporary flares in PSMA uptake have been described in a subset of patients after initiation of therapy, and the underlying mechanism and clinical implications of this phenomenon are still poorly understood. Furthermore, whereas PSMA is invariably expressed in hormone-sensitive PC, loss of PSMA expression is increasingly recognized in a subset of mCRPC patients with aggressive disease. Although this may limit the use of PSMA-based imaging as a standalone modality in advanced PC, loss of PSMA uptake may also provide non-invasive and clinically relevant molecular insight on patients' underlying tumor biology

Genomic characterization of treatment-associated small cell neuroendocrine carcinoma of the prostate

Treatment-associated small cell neuroendocrine carcinoma of the prostate (t-SCNC) is an aggressive prostate cancer variant with rising incidence. Although morphologically similar to de novo small cell prostate cancer, t-SCNC is thought to emerge from metastatic castration-resistant prostate cancer (mCRPC) under the selective pressure of prolonged AR-targeted therapies. t-SCNC is associated with a distinct transcriptional landscape, characterized by the upregulation of stem cell-associated and neuronal programs (e.g., SOX2, N-MYC, FOXA2) and decreased canonical AR signaling. In addition, as with other neuroendocrine carcinomas, RB1 loss and inactivating TP53 mutations are key genomic hallmarks of t-SCNC. Nevertheless, despite their histologic, molecular, and clinical differences, there is a striking degree of genomic overlap between t-SCNC and its adenocarcinoma counterpart. This finding underscores the clonal evolution of t-SCNC from mCRPC, as well as the importance of epigenetic mechanisms in regulating tumor phenotype. In this review, we summarize the key genomic, transcriptional, and epigenetic features of t-SCNC and discuss how recent advances in our understanding of molecular drivers of t-SCNC have contributed to improving the diagnosis and treatment of this aggressive disease

Early changes of PSMA PET signal after initiation of androgen receptor signaling inhibitors in mCRPC: An international multicenter retrospective study.

peer reviewedBackground: Androgen receptor signaling inhibitors (ARSi) play a relevant role in the treatment of prostate cancer. A potential influence of ARSi on PSMA expression has been described. We evaluated early changes of PSMA-expression by PET in mCRPC patients. Methods: This retrospective study included 5 international sites. Patients with mCRPC undergoing 68Ga-PSMA-11 PET/CT prior to (PET1) and early after ARSi (PET2 within 29 days maximum) were included. Whole-body (WB) PSMA-positive tumor volume (PSMA-TV) was evaluated using a liver-specific semi-automatically threshold (Affinity 3.0.2, Hermes Medical Solutions). WB PSMA-TV, SUVmean and SUVmax and their respective changes (%) were analyzed. PSA changes between PET 1 and PET2 were evaluated. Median values and ranges are provided. Results: 54 patients were included in the analysis. ARSi was initiated 1 day (range 0 – 28) after PET1 while PET2 was performed 14 days (range 7 – 29) after ARSi initiation. PSA at PET1 and PET2 was 9.5 ng/ml (range 0.2 – 490.0) and 8.7 ng/ml (range 0.1 – 732.0), respectively (p = 0.035): -33.0% (range -98% – +496%). The WB PSMA-TV at PET1 and PET2 was 89.9 ml (0.0 – 3097.0) and 112.2 ml (0.0 – 3133.0) ml, respectively (p = 0.016; change of +6.0% (range -88% – +260%). WB PSMA SUVmean and SUVmax at PET1 and PET2 was 9.0 (range 5.0 – 43.7) and 9.3 (range 0.0 – 42.5) and 26.5 (range 0.0 – 125.0) and 28.5 (range 0.0 – 212.0), respectively (p = 0.194 and p = 0.353): % change of +3 % (-85% – +71%) and 0% (-55% – +232%). Four of 7 patients with PSA increases at PET2 had an increasing PSMA-TV, 6/7 showed an increasing SUVmean and 5/7 presented with an increased SUVmax. Decreasing WB-PSMA-TV in 18/54 (33%) patients was accompanied by decreasing SUVs in 10 of them (56%). Percent PSA change was unrelated to changes in PSMA-TV, SUVmean and SUVmax. Conclusions: PSMA-PET performed early after ARSI revealed slight increases in the WB-PSMA-TV, stable WB-PSMA SUVs while serum PSA decreased in most of the patients. We conclude that ARSi does not have a strong effect on PSMA expression within 30 days after treatment initiation

Real-World Experience with 177Lu-PSMA-617 Radioligand Therapy After Food and Drug Administration Approval

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck