Letermovir for Prophylaxis and Pre-emptive Therapy of Cytomegalovirus Infection in Paediatric Allogeneic Haematopoietic Cell Transplant Patients.

BACKGROUND: Cytomegalovirus (CMV) infection is a frequent event in patients undergoing allogeneic haematopoietic cell transplantation (HCT) and is associated with increased morbidity and mortality due to eventual progress to end-organ disease. Letermovir prophylaxis for CMV infections has become a standard of care in adult HCT recipients due to its efficacy and high tolerability. However, it is not yet approved for paediatric patients. OBJECTIVE: In a retrospective single-centre observational study we evaluated the use of letermovir for prophylaxis or pre-emptive treatment of cytomegalovirus (CMV) infection in seropositive paediatric HCT recipients receiving the compound outside of clinical trials. The primary endpoint was CMV reactivation requiring a change of medication. METHODS: A total of 17 patients (seven female/ten male; median age 12.2 [range 3.5-19] years, median body weight 39.5 [range 15-63] kg; median follow-up time 463.7 [range 41-1022] days) were identified who were started on oral (14) or intravenous (3) followed by oral (2) letermovir shortly after neutrophil engraftment at doses determined on the basis of age, weight, and concomitant cyclosporine use. RESULTS: Five patients had no evidence of viral replication (prophylactic use), while 12 patients had varying extents of viral replication (pre-emptive therapy). A change of therapy was required in one patient due to a sustained increase in CMV viral load, and in two patients, letermovir was stopped without later reactivation after initiation of palliative care for recurrent leukaemia. Of the 14 patients who completed treatment, 3 had evidence of transient viral replication after end of treatment that required no further antiviral treatment. No patients (of 17) discontinued letermovir due to an adverse event. CONCLUSION: Letermovir was effective in controlling CMV infection in seropositive paediatric allogeneic HCT recipients and was overall well tolerated. Pending completion of the still ongoing paediatric investigation plans, letermovir will be an important adjunct to our options for control of infectious complications in this special population.

MED15 overexpression in prostate cancer arises during androgen deprivation therapy via PI3K/mTOR signaling.

Androgen deprivation therapy (ADT) is the main therapeutic option for advanced prostate cancer (PCa). After initial regression, most tumors develop into castration-resistant PCa (CRPC). Previously, we found the Mediator complex subunit MED15 to be overexpressed in CRPC and to correlate with clinical outcome. Therefore, we investigated whether MED15 is implicated in the signaling changes taking place during progression to CRPC. Immunohistochemistry (IHC) for MED15 on matched samples from the same patients before and after ADT reveals significantly increased MED15 expression after ADT in 72%. A validation cohort comprising samples before and after therapy confirmed our observations. Protein analysis for pAKT and pSMAD3 shows that MED15 correlates with PI3K and TGFß activities, respectively, and that hyper-activation of both pathways simultaneously correlates with highest levels of MED15. We further show that MED15 protein expression increases in LNCaP cells under androgen deprivation, and via EGF mediated PI3K activation. PI3K/mTOR and TGFß-receptor inhibition results in decreased MED15 expression. MED15 knockdown reduces LNCaP cell viability and induces apoptosis during androgen deprivation, while cell cycle is not affected. Collectively, MED15 overexpression arises during ADT via hyper-activation of PI3K/mTOR signaling, thus MED15 may serve as a predictive marker for response to PI3K/mTOR inhibitors. Furthermore, MED15 is potentially a therapeutic target for the treatment of CRPC.

Comparison of different prostatic markers in lymph node and distant metastases of prostate cancer.

Prostate cancer is mostly diagnosed at an early stage; however, some tumors are diagnosed in a metastatic stage as cancer of unknown primary origin. In order to allow specific treatment in the case of prostate cancer presenting as cancer of unknown primary origin, it is important to determine the tumor origin. Prostate-specific antigen is used as a diagnostic marker for prostate cancer but the expression declines with progression to castration-resistant prostate cancer. Aim of this study was to identify the most informative marker constellation, which is able to detect metastatic prostate cancer at high sensitivity. The widely used prostate cancer markers such as prostate-specific antigen, prostate-specific acid phosphatase, androgen receptor, prostate-specific membrane antigen, prostein, and ETS-related gene were investigated for their sensitivity to detect prostatic origin of metastases. Expression of prostate-specific antigen, prostate-specific acid phosphatase, androgen receptor, prostate-specific membrane antigen, prostein, and ETS-related gene was determined on archived tissue specimens consisting of benign prostatic tissue (n=9), primary prostate cancer (n=79), lymph node metastases (n=58), and distant metastases (n=39) using immunohistochemistry. The staining intensity was categorized as negative (0), weak (1), moderate (2), and strong (3). All markers except ETS-related gene were able to detect at least 70% of lymph node metastases and distant metastases, with prostate-specific antigen, androgen receptor, and prostate-specific membrane antigen having the highest sensitivity (97%, 91%, and 94%, respectively). A further increase of the sensitivity up to 98% and 100% could be achieved by the combination of prostate-specific antigen, prostate-specific membrane antigen, or androgen receptor for lymph node metastases and for distant metastases, respectively. The same sensitivity could be reached by combining prostate-specific membrane antigen and prostein. Our data show that a combined staining of at least two prostate markers should be utilized to identify metastases as originating from prostate cancer.