A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma.

Background: Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK.

Method: We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358).

[NEOADJUVANT CHEMOTHERAPY BEFORE RADICAL CYSTECTOMY - MIGHT IT BE OFFERED SELECTIVELY?].

Introduction: Neoadjuvant cisplatin-based chemotherapy prior radical cystectomy is the standard of care in patients with a muscle invasive bladder cancer. It is intended to treat micro-metastases. However, most patients do not develop metastases even without chemotherapy and are receiving this treatment in vain.

Real-world Israeli single institution experience with PET-PSMA for staging of patients with clinically staged localized prostate carcinoma.

Background: A recent prospective trial, the proPSMA study, showed superior specificity and sensitivity of Positron emission tomography (PET) - Prostate-specific membrane antigen (PSMA) imaging compared standard Computerized tomography (CT) and bone scan for staging of recently diagnosed high-risk local prostate carcinoma for curative intent treatment.

Aim: To share our experience with false-positive PET PSMA scans in newly diagnosed intermediate-risk prostate cancer.

Methods And Results: Here, we report a series of eight patients who underwent systemic staging using PET-PSMA with false-positive results who were ultimately treated with definitive radiation or surgery.

International approaches to protecting and retaining trees on private urban land.

Most studies of urban forest management look at vegetation on public land. Yet, to meet ambitious urban forest targets, cities must attempt to maintain or increase trees and canopy cover on private urban land too. In this study, we review and evaluate international approaches to protecting and retaining trees on private urban land.

Trimodal therapy in T2-4aN0M0 bladder cancer--How to select the best candidate?

The reported results of trimodal treatment (TMT) in muscle-invasive bladder cancer vary widely. We attempted to characterize the profile of ideal candidates for this approach. Between 2000 and 2019, 105 patients (median age 78 years) with T2-4aN0M0 bladder cancer were treated with TMT and analyzed retrospectively.

Immunotherapy Potentiates the Effect of Chemotherapy in Metastatic Melanoma-A Retrospective Study.

Melanoma survival increased with targeted- and immunotherapy agents, yet most patients ultimately progress and require salvage therapy. In our experience, some progressive disease patients on immune-checkpoint inhibitors (ICIs) demonstrate deep and sustained responses to chemotherapy. We hypothesized that ICIs improve the response to subsequent chemotherapy in metastatic melanoma.

Re-treatment with radium-223: 2-year follow-up from an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases.

Background: Radium-223 dichloride (radium-223) is approved for patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no visceral disease using a dosing regimen of 6 injections (55 kBq/kg intravenously; 1 injection every 4 weeks). Early results from international, open-label, phase 1/2 study NCT01934790 showed that re-treatment with radium-223 was well tolerated with favorable effects on disease progression. Here we report safety and efficacy findings from 2-year follow-up of the radium-223 re-treatment study.

Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT).

Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.

Adoptive cell therapy: past, present and future.

The immune system is a potent inhibitor of tumor growth with curative potential, constituting in many eyes the future of antineoplastic therapy. Adoptive cell therapy (ACT) is a form of immunotherapy in which autologous cancer-cognate lymphocytes are expanded and modified ex vivo and re-infused to combat the tumor. This review follows the evolvement of ACT and treatment protocols, focusing on unresolved dilemmas regarding this treatment while providing evidence for its effectiveness in refractory patients.

PET/CT With 68Ga-DOTA-TATE for Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer.

Aim: Castrate-resistant prostate cancer (CRPC) often shows histological evidence of neuroendocrine differentiation (NED). To evaluate the extent of NED in patients with CRPC, we used PET/CT with Ga-[DOTA-Tyr]-octreotate (Ga-DOTA-TATE), a somatostatin analog that binds somatostatin receptor 2 with high affinity. This radiotracer is used in imaging of neuroendocrine tumors.

Immune Monitoring of Patients Treated With a Whole-Cell Melanoma Vaccine Engineered to Express 4-1BBL.

CD8 lymphocytes are mandatory mediators of tumor regression. To enhance their specific antitumor activity, we aimed to improve a melanoma cell-based vaccine by transfecting it with 4-1BB ligand, a costimulatory and immune modulatory molecule. Thirty-four American Joint Committee on Cancer (AJCC) stage IIB-IV patients were vaccinated with a melanoma antigen-rich cell line engineered to express HLA-A2 and 4-1BBL (M20/A2/BBL).

Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival, Biomarkers, and Improved Response to CTLA-4 Blockade.

Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence.

Recognizing the Magnitude of the Challenge.

"Funding Long-Term Care in Canada: Issues And Options" (Adams and Vanin 2016) is a well-argued paper that grounds its recommendations in learnings from other jurisdictions that have tried to enact major reforms to the funding approach for long-term care (LTC). In particular, the paper considers the experience in both the UK and Quebec. The paper correctly highlights the significant difficulty of implementing large structural reforms to deal with LTC funding challenges.

Radical cystectomy vs. chemoradiation in T2-4aN0M0 bladder cancer: a case-control study.

Background: Muscle-invasive bladder cancer is most commonly treated by radical cystectomy. Patients who are too sick to go through this surgery or who are unwilling to accept the mutilation associated with it are referred to chemoradiation. We compared the results of these 2 modalities using age-matched populations.

Contemporary pharmacotherapy for the prevention of skeletal complications in patients with prostate cancer.

Introduction: Bones represent the most common metastatic sites in prostate cancer (PCa) patients, and in addition with androgen deprivation therapy, they represent the causative reasons of bone mineral density loss and the onset of skeletal-related events.

Areas Covered: An extensive search of PubMed/Medline was performed to identify randomized, Phase II/III controlled trials reporting results regarding the prevention of skeletal morbidity in patients with PCa.

Expert Opinion: Preventing bone health is an imperative issue for preserving quality of life and elongate survival and, thus, a concerted effort should be made to monitor skeletal changes and to apply treatment for preventing bone loss.

Activity of cabazitaxel after docetaxel and abiraterone acetate therapy in patients with castration-resistant prostate cancer.

Background: Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation.

Cytologic diagnosis of chordoma in a peritoneal effusion: a case report.

Background: Chordoma, a distinct malignant neoplasm arising from the remnants of the notochord, occurs mostly in patients in the fifth to seventh decade of life. Metastasis occurs in 20-30% of cases. The most common metastatic sites are lungs and, less commonly, other bones and visceral organs.

New pyrimidine- and fluorene-containing oligo(arylene)s: synthesis, crystal structures, optoelectronic properties and a theoretical study.

New pyrimidine containing oligo(arylene)s, notably the pyrimidine-fluorene hybrid systems 13-16, have been synthesised by Suzuki cross-coupling methodology. An efficient synthesis of the key reagent 9,9-dihexylfluorene-2,7-diboronic acid 10 from 2,7-dibromo-9,9-dihexylfluorene 9 is reported. Cross-coupling of 10 with two equivalents of 2-bromopyrimidine, 5-bromopyrimidine and 2,5-dibromopyrimidine gave 2,7-bis(2-pyrimidyl)-9,9-dihexylfluorene 13.