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\u27 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

Systemic Mastocytosis with associated CMML

Systemic mastocytosis refers to a heterogeneous group of clinical disorders characterized by excessive mast cell accumulation in one or multiple organs. Mastocytosis is now considered as a separate disease category in the 2016 WHO classification of myeloid neoplasm and acute leukemia. It is no longer considered as a subgroup of meyloproliferate neoplasms. The clinical presentation of mastocytosis is heterogeneous ranging from skin-limited disease (cutaneous mastocytosis) to a more aggressive form with extra cutaneous presentation (systemic mastocytosis) with or without skin involvement. We are presenting a case of systemic mastocytosis that aroused in a patient who carried diagnosis of CMML for almost 2 years. The worsening B symptoms along with worsening splenomegaly were the driving factor for further investigations including Bone Marrow biopsy which revealed the diagnosis. A 74 year old Caucasian male with past oncology history of Chronic myelomoncytic leukemia diagnosed after persistant monocytosis on complete blood count . Patient presented with gradual onset of low grade fever , weight loss and night sweating , CT abdomen showed hepatosplenomegaly. core biopsy of the liver showed portal and lobular infiltrate consistent with involvement by mastocytes and extra medullary hematopoiesis. The infiltrate was positive for CD117, CD33, CD68, myeloperoxidase and CD163. Patient had bone marrow biopsy which showed increased CD117 positive cells consistent with involvement by systemic mastocytosis. The core biopsy showed multifocal nodules of spindle cells with fibrosis which was morphologically consistent with abnormal mast cells. Immunohistochemistry for CD117 was strongly positive in the spindle cell nodules and scattered polygonal cell nodules. KIT D816V mutation was detected. Patient met criteria for diagnosis of systemic mastocytosis with presence of previous diagnosis of CMML and classified as Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Due to patient multiple comorbiditeis , he was not a candidate for Allo HCT. In an attempt to control his disease , patient was started on dose reduced Dacogen, but his functional status continued to delined and eventually dacogen was discontinued and patient was placed on best supportive car Conclusion Systemic mastocytosis is a rare entity with heterogeneous clinical presentation, highly variable disease course and consequently survival rates.Though recent advances in understanding genetic and molecular basis of disease, bone marrow transplantation remains the only treatment with possible curative potential in patients with advanced form of mastocytosis though carrying substantial mortality risk .Further understanding of Kit mutation might be able to offer a highly effective medication with durable response in a fashion similar to the success story of gleevac with CML treatment

Mucosal Associated Lymphoid tissue of the Skin, A Common Entity in a Rare Location.

Marginal zone (MZ) lymphomas (MZLs) represent a group of lymphomas originating from B lymphocytes of the “marginal zone” which is the external part of the secondary lymphoid follicles. The WHO classifies MZL into 3 entities; extranodal MZL, splenic MZL and nodal MZL. Extranodal marginal zone lymphoma (EMZL) can arise in different tissues, including the stomach, salivary gland, lung, small bowel, thyroid, ocular adnexa and skin. We present a 25 years old female with a history of angioedema and chronic cutaneous eczema who developed an unusual EMZL. Patient presented with a history of rapidly enlarging skin nodule on her left elbow that had been present for almost one year. Over a period of 2-3 weeks she felt the nodule rapidly changed in size and shape. Excisional biopsy of the mass revealed a lymphoid infiltrate based in the reticular dermis and focally extending into the subcutaneous adipose tissue with formation of disrupted lymphoid follicles positive for CD20, CD23 and BCL2 but negative for CD10, Cyclin D1 and SOX11. Diagnosis was consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Patient on presentation did not have any B symptoms other cutaneous lesions, lymphadenopathy or hepatosplenomegaly. PET scan revealed no evidence of abnormal uptake leading to a final Stage IE definition. Patient initiated definitive radiation therapy. EMZL accounts for 5 -10 % of non-Hodgkin lymphoma. It has been described often in organs that are normally devoid of germinal centers. It may arise in reactive lymphoid tissue induced by chronic inflammation in extranodal sites. Primary cutaneous marginal zone lymphoma (PCMZL) is associated with infectious etiologies such as Borrelia burgdorferi and less commonly with viral infections or in relation to autoimmune disorders. Autoimmune disorders, specifically Sjögren\u27s syndrome is associated with a 30-fold increased risk of marginal zone lymphoma. Localized disease can be treated by local radiotherapy, intralesional injections or excision. Widespread skin disease is usually treated with a CD20 directed monoclonal antibody-Rituximab. Patients with PCMZL usually have an indolent clinical course. Extracutaneous dissemination of MALT Lymphoma is uncommon and happens in 6-8 % of patients. The 5 years overall survival is between 98-100%. Family physicians and dermatologists should have a high index of suspicion for this rare lymphoma subtype especially in patients with inflammatory chronic skin conditions and atopy

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

RENAL AND TESTICULAR MYELOID SARCOMA DEFINES ACUTE MYELOID LEUKEMIA EVEN IN THE ABSENCE OF BLOOD AND MARROW INVOLVEMENT

Acute Myeloid Leukemia (AML) is an aggressive hematopoietic neoplasm characterized by rapid clinical progression and universally fatal outcome if left untreated. The neoplastic cells are immature precursor cells that usually originate in the bone marrow and are often noted in the peripheral circulation. Myeloid sarcomas are rare abnormal collection of these cells in extramedullary sites and are now defined as a unique subset of AML as per the WHO classification. Here we describe a patient with AML presenting with a renal and testicular mass, which on biopsy revealed myeloid sarcoma in the absence of blood and bone marrow involvement. A 71 year old male was hospitalized with complaints of nausea, vomiting, confusion and jaundice associated with worsening pruritus in the absence of constitutional symptoms. Medical history notable for chronic kidney disease, Type 2 Diabetes Mellitus and history of localized prostate cancer treated with TURP. Family history of thyroid cancer in his mother. Clinical exam revealed small right testicular non tender mass. Labs revealed a total bilirubin of 11.5mg/dL, creatinine of 3.09 mg/dL, Hemoglobin 13.4g/dL, WBC 9.5k/uL and Platelet count of 283K/uL. Abdominal imaging studies demonstrated a biliary stricture, a 16mm right testicular lesion and a additional right renal mass measuring 4.0 x 3.9 x 2.4 cm. He underwent a right inguinal orchiectomy, which confirmed myeloid sarcoma. Histopathologically, numerous neoplastic cells with enlarged nuclei and mitotic figures were identified with immunohistochemical staining positive for CD45, MPO, CD117, CD68, CD71 and BCL2. A biopsy of the right renal mass also demonstrated myeloid sarcoma, with similar features. He had an ERCP with stent placement for his biliary stricture with negative cytology. Bone marrow biopsy was negative for AML. His challenging clinical presentation, advanced age, medical comorbidities, hyperbilirubinemia, and impaired kidney function, precluded aggressive treatment with standard acute myeloid leukemia induction chemotherapy regimens so a trial of hypomethylating agent (Azacitidine) was successfully initiated. AML is characterized by a rapid clonal proliferation of immature hematopoietic cells in the peripheral blood and bone marrow. It is a heterogeneous disease with regard to acquired genetic alterations, including cytogenetic aberrancies as well as gene mutations and changes in gene expression. The signs and symptoms of AML mostly reflect predominant cytopenias or cytoses and usually a short history (1 to 8 weeks) of constitutional complaints. Myeloid sarcomas are rare extramedullary solid tumors that have resulted in infiltration of organs such as gingiva, skin, lymph nodes and other organs with immature granulocytic precursor cells. The majority of cases are reported in association with coexisting acute myeloid leukemia and infrequently can present in isolation (a harbinger for future blood and marrow involvement). Treatment of myeloid sarcomas follows the AML paradigm. The overall survival of AML is dictated by cytogenetics/ molecular markers and age. Complete remission can be achieved in a group of patients. Relapses occur in the first two years. Leukemic infiltration of the kidney or testicle with myeloid sarcoma is extremely rare and the concurrent presentation is documented in isolated case reports only

ATM Gene Deletion: A Rare Etiology for Hereditary Cancers

Ataxia Telangiectasia Mutated (ATM) gene helps to repair DNA damage and that increased cancer risks are associated with having a mutation in an ATM gene. ATM gene is newer compared to other known hereditary cancer genes. We present a rare care of 66-year-old female with extensive personal and family history of breast and pancreatic cancer had negative imaging surveillance until recent systemic imaging showed new pancreatic head 2.5x2.5 cm mass. Endoscopic ultrasound confirmed invasion of superior mesenteric vein with near confluence. No regional adenopathy was seen. She was felt to be borderline resectable and neoadjuavant chemotherapy was planned. She had a personal history of right breast cancer diagnosed in 1998 status post lumpectomy and axillary lymph node dissection and adjuvant chemotherapy with CMF regimen x 5 cycles and radiation therapy and endocrine therapy with tamoxifen for 5 years. In 2011 she was also diagnosed with rectal well to moderately differentiated adenocarcinoma status post abdominoperitoneal resection on 3/15/2011, 36 lymph nodes were negative, but the surgical circumferential radial margin was positive. She underwent adjuvant radiation therapy with total dose of 45 Gy. There was recurrence in vaginal and bladder wall adenocarcinoma in 2014 for which patient underwent an anterior exenteration. Pathology felt this was endocervical origin of malignancy and patient received megace therapy for 3 years based on hormone receptor positive status. For new diagnosis of pancreatic adenocarcinoma, she was started on Gemcitabine and Abraxane chemotherapy. Given extensive personal and family history of malignancy, she was referred to genetic counsellor. Hereditary cancers panel at invitae laboratory was positive for a heterozygous pathological variant in the ATM gene deletion (exons 62-63). ATM gene is associated with an increased risk for autosomal dominant breast, pancreatic and prostate cancer. Close relatives (children, siblings, and each parent) have up to a 50% chance of being a carrier of this variant. It is essential for treating physicians to educate patients and family members on the risk for subsequent malignancies

Successful Treatment of Pyoderma Gangrenosum With Cryoglobulinemia and Hepatitis C

Objective: Rare disease 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