Leptomeningeal involvement by prostate carcinoma an ominous head of a well-known Hydra.

A 67-year-old male patient presents to the hospital complaining of severe nausea and vomiting failing oral antiemetics. He carries the history of initial diagnosis of stage III prostate cancer. He underwent radical prostatectomy followed by external beam radiation. After 5 years of initial excellent control with androgen deprivation therapy (ADT), imaging study showed retroperitoneal adenopathy denoting ADT failure. His prostate-specific antigen continued to rise while on enzalutamide and then abiraterone reflecting disease progression. He maintained excellent functional capacity through 23 cycles of docetaxel however he started developing hip pain after the last cycle with imaging studies suggesting new hip metastatic disease. Following the first cycle of radium-223, the patient presented with intractable nausea and vomiting. MRI showed a high suspicion of leptomeningeal spread which was confirmed through a meningeal biopsy after lumbar puncture showed negative results. The patient had excellent symptomatic response to high-dose dexamethasone. After receiving whole-brain radiation, the patient opted to be on best supportive care and succumbed to his illness 3 months later.

Journey of TRAIL from Bench to Bedside and its Potential Role in Immuno-Oncology.

Induction of apoptosis in cancer cells has increasingly been the focus of many therapeutic approaches in oncology field. Since its identification as a TNF family member, TRAIL (TNF-related apoptosis-inducing ligand) paved a new path in apoptosis inducing cancer therapies. Its selective ability to activate extrinsic and intrinsic cell death pathways in cancer cells only, independently from p53 mutations responsible for conventional therapeutics resistance, spotted TRAIL as a potent cancer apoptotic agent. Many recombinant preparations of TRAIL and death receptor targeting monoclonal antibodies have been developed and being tested pre-clinically and clinically both as a single agent and in combinations. Of note, the monoclonal antibodies were not the only type of antibodies developed to target TRAIL receptors. Recent technology has brought forth several single chain variable domains (scFv) designs fused recombinantly to TRAIL as well. Also, it is becoming progressively more understandable that field of nanotechnology has revolutionized cancer diagnosis and therapy. The recent breakthroughs in materials science and protein engineering have helped considerably in strategically loading drugs into nanoparticles or conjugating drugs to their surface. In this review we aim to comprehensively highlight the molecular knowledge of TRAIL in the context of its pathway, receptors and resistance factors. We also aim to review the clinical trials that have been done using TRAIL based therapies and to review various scFv designs, the arsenal of nano-carriers and molecules available to selectively target tumor cells with TRAIL.

Role of nanotechnology and gene delivery systems in TRAIL-based therapies.

Since its identification as a member of the tumour necrosis factor (TNF) family, TRAIL (TNF-related apoptosis-inducing ligand) has emerged as a new avenue in apoptosis-inducing cancer therapies. Its ability to circumvent the chemoresistance of conventional therapeutics and to interact with cancer stem cells (CSCs) self-renewal pathways, amplified its potential as a cancer apoptotic agent. Many recombinant preparations of this death ligand and monoclonal antibodies targeting its death receptors have been tested in monotherapy and combinational clinical trials. Gene therapy is a new approach for cancer treatment which implies viral or non-viral functional transgene induction of apoptosis in cancer cells or repair of the underlying genetic abnormality on a molecular level. The role of this approach in overcoming the traditional barriers of radiation and chemotherapeutics systemic toxicity, risk of recurrence, and metastasis made it a promising platform for cancer treatment. The recent first Food Drug Administration (FDA) approved oncolytic herpes virus for melanoma treatment brings forth the potency of the cancer gene therapy approach in the future. Many gene delivery systems have been studied for intratumoural TRAIL gene delivery alone or in combination with chemotherapeutic agents to produce synergistic cancer cytotoxicity. However, there still remain many obstacles to be conquered for this different gene delivery systems. Nanomedicine on the other hand offers a new frontier for clinical trials and biomedical research. The FDA approved nanodrugs motivates horizon exploration for other nanoscale designed particles' implications in gene delivery. In this review we aim to highlight the molecular role of TRAIL in apoptosis and interaction with cancer stem cells (CSCs) self-renewal pathways. Finally, we also aim to discuss the different roles of gene delivery systems, mesenchymal cells, and nanotechnology designs in TRAIL gene delivery.

Successful Treatment of Pyoderma Gangrenosum with Cryoglobulinemia and Hepatitis C.

BACKGROUND: Pyoderma gangrenosum is a rare, ulcerative cutaneous condition that was first described by Brocq in 1916. This diagnosis is quite challenging as the histopathological findings are nonspecific. Pyoderma gangrenosum is usually associated with inflammatory bowel disease, leukemia, and hepatitis C. We describe a rare clinical case of a patient with hepatitis C (HCV), mixed cryoglubinemia, and pyoderma gangrenosum, which was successfully treated with prednisone in combination with the new antiviral medication ledipasvir/sofosbuvir. CASE REPORT: A 68-year-old male with a history of untreated HCV presented to the clinic with a left lower extremity ulcer that had progressively worsened over 4 days after the patient sustained a minor trauma to the left lower extremity. Examination revealed a 2×3 cm purulent ulcer with an erythematous rim on medial aspect of his left lower leg. HCV viral load and genotype analysis revealed genotype 1A with polymerase chain reaction (PCR) showing viral counts of 9,506,048 and cryoglobulinemia. With a worsening and enlarging erythematous ulcer and failure of IV antibiotic therapy, the patient underwent skin biopsy, which showed acanthotic epidermis with superficial and deep perivascular lymphoplasmacytic dermatitis admixed with mild neutrophilic infiltrate. The patient was subsequently started on ledipasvir/sofosbuvir and prednisone with a high suspicion of pyoderma gangrenosum. At one-month follow-up at the hepatology clinic, the patient demonstrated a near resolution of the lower extremity ulcer with undetectable viral load. CONCLUSIONS: Pyoderma gangrenosum is an inflammatory process of unknown etiology, and establishing the correct diagnosis can be a difficult task. For this reason it is prudent for clinicians to consider Pyoderma gangrenosum in their differential diagnosis, especially in the setting of a nonhealing surgical wound or skin infection.