Dual Pathology in a Patient with Right Lower Quadrant Pain

Meckel diverticula are remnants of the omphalomesenteric duct. They have 2% incidence in the general population, are usually asymptomatic, and tend to be diagnosed incidentally. The generally held principle had been that asymptomatic cases do not require resection, as exemplified by a 2008 systematic review of over 200 studies. However, a recent series reported an increased risk of malignancies, and recommended mandatory resection. We present a case of Meckel diverticulitis with concurrent infiltrative appendiceal carcinoid in a patient with right lower quadrant pain.     

A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2

Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP₃Rs), inhibiting pro-apoptotic Ca²⁺ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP₃R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP₃ Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP₃R interaction and thus inducing Ca²⁺-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton’s tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP₃R interaction.     

Phase I Trial of Selective Internal Radiation Therapy for Chemorefractory Colorectal Cancer Liver Metastases Progressing After Hepatic Arterial Pump and Systemic Chemotherapy

IntroductionThis prospective study assessed the safety and outcomes of selective internal radiation therapy (SIRT) using yttrium-90 (⁹⁰Y) resin microspheres as a salvage therapy for liver-predominant metastases of colorectal cancer in patients with documented progression after hepatic arterial chemotherapy (HAC) and systemic chemotherapy.Patients and MethodsWe recruited 19 patients who had received a mean of 2.9 prior lines of chemotherapy and ≥ 1 line of HAC. Dose-limiting toxicities (grade 3 or higher) were catalogued using Common Terminology Criteria for Adverse Events version 3.0. At 4 to 8 weeks and 3 to 4 months post SIRT, responses were assessed by carcinoembryonic antigen (CEA), and quantitative imaging using Response Evaluation Criteria in Solid Tumors (RECIST) and PET Response Criteria in Solid Tumors (PERCIST). Liver progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methodology.ResultsMedian follow-up was 31.2 months after SIRT. Within 6 weeks of SIRT, 3 patients (15.8%) experienced grade 3 toxicity. There was no incidence of radiation-induced liver disease. Responses by RECIST, PERCIST, and CEA were, respectively, 0%, 20%, and 32% at 4 to 8 weeks and 5%, 33%, and 21% at 3 to 4 months post SIRT; 53% of patients had stable disease (by RECIST) at 3 to 4 months. Of 19 patients, 4 (21.1%) had liver ablation, 9 (47%) received additional HAC, and 17 (89%) received systemic chemotherapy after SIRT. Median LPFS, PFS, and OS after SIRT were 5.2 months, 2.0 months, and 14.9 months, respectively.ConclusionSIRT was well tolerated and did not prohibit subsequent treatment, resulting in a median OS of 14.9 months in this heavily pretreated population.     

Blocking “don't eat me” signal of CD47-SIRPα in hematological malignancies,an in-depth review

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.     

High rates of potentially infectious exposures between immunocompromised patients and their companion animals: an unmet need for education

A cross‐sectional survey of 265 adult patients with haematological malignancy, haemoglobinopathy or human immunodeficiency virus was performed to determine the potential risk of infection from animal exposures. One hundred and thirty‐seven (52%) owned an animal; the majority were dogs (74%) and cats (39%), but 14% owned birds and 3% reptiles. Eighty percent engaged in behaviour with their animals that potentially put them at risk of zoonotic infections. The most frequent behaviours were picking up animal faeces 72 (52%), cleaning animal areas 69 (50%) and allowing animals to sleep in the same bed 51 (37%). Twenty‐eight percent allowed the animal to lick their face. Of all patients, 80 (30%) had been bitten or scratched by an animal. Only 16% of those who owned pets could recall receiving education regarding safe behaviours around animals. These immunocompromised patients are at risk of infection through exposure to pets. Our study highlights the need for increased education of patients regarding how to remain safe around their pets.