Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with an overall 5-year survival rate of less than 10%. The 1-year survival rate of patients with locally advanced or metastatic disease is abysmal. The aggressive nature of cancer cells, hypovascularization, extensive desmoplastic stroma, and immunosuppressive tumor microenvironment (TME) endows PDAC tumors with multiple mechanisms of drug resistance. With no obvious genetic mutation(s) driving tumor progression or metastatic transition, the challenges for understanding the biological mechanism(s) of these processes are paramount. A better understanding of the molecular and cellular mechanisms of these processes could lead to new diagnostic tools for patient management and new targets for therapeutic intervention. microRNAs (miRNAs) are an evolutionarily conserved gene class of short non-coding regulatory RNAs. miRNAs are an extensive regulatory layer that controls gene expression at the posttranscriptional level. This review focuses on preclinical models that functionally dissect miRNA activity in tumor progression or metastatic processes in PDAC. Collectively, these studies suggest an influence of miRNAs and RNA-RNA networks in the processes of epithelial to mesenchymal cell transition and cancer cell stemness. At a cell-type level, some miRNAs mainly influence cancer cell–intrinsic processes and pathways, whereas other miRNAs predominantly act in distinct cellular compartments of the TME to regulate fibroblast and immune cell functions and/or influence other cell types’ function via cell-to-cell communications by transfer of extracellular vesicles. At a molecular level, the influence of miRNA-mediated regulation often converges in core signaling pathways, including TGF-β, JAK/STAT, PI3K/AKT, and NF-κB.

Introduction: Patients with severe hemophilia A and anti-factor VIII (fVIII) antibodies (inhibitors) are at risk of significant bleeding during invasive procedures. Prior to the introduction of the bispecific humanized antibody, emicizumab, the standard of care for preventing perioperative bleeding in these patients consisted of repeated doses of bypassing agents such as recombinant activated factor VII (rfVIIa) and activated prothrombin complex concentrates (aPCCs) or high-doses of fVIII products. This practice often prolonged hospital admission and was associated with increased patient-care costs. Prophylaxis with emicizumab has significantly reduced bleeding symptoms in patients with hemophilia A and inhibitors. However, questions regarding the appropriate management of acute bleeding episodes and invasive procedures in patients receiving this novel therapy remain unanswered. Additionally, there are concerns about the hemostatic efficacy and safety of fVIII products and bypassing agents necessary for the management of perioperative bleeding and breakthrough bleeds in patients with inhibitors treated with emicizumab. In this case series, we report on the perioperative management and outcomes of patients receiving emicizumab prophylaxis who underwent invasive procedures. Methods: Patients between the ages of 1 - 60 years old with severe hemophilia A (fVIII activity <1%) with a history of low or high titer inhibitors on emicizumab prophylaxis treated at the Emory Pediatric Hemophilia Treatment Center, the Center for Bleeding and Clotting Disorders at the University of Minnesota Medical Center, the Michigan State University Center for Bleeding and Clotting Disorders, and the Children's Hospital of Michigan/Wayne State University were included in this analysis. All patients were continued on their emicizumab prophylaxis throughout the perioperative period. Due to the potential risk of thrombosis and thrombotic microangiopathy with aPCCs, these agents were avoided and rfVIIa was the preferred bypassing agent. Either recombinant (r) fVIII or plasma-derived (pd) fVIII were used in patients that had known response to high-dose fVIII. Perioperative treatment regimens, bleeding symptoms, and complications were monitored. Results: Seven patients underwent invasive procedures while on emicizumab prophylaxis and an additional two patients had minor procedures performed that required observation alone. These patients have historical peak inhibitor titers, defined as the highest inhibitor titer prior to starting emicizumab ranging from 2.0 - 4,792 BU/mL. Their inhibitor titers prior to the procedure ranged from 0 - 193.3 BU/mL. All patients initiated emicizumab prophylaxis at a median of 12 weeks prior to their procedures (range: 2 - 28 weeks). All 4 of the pediatric patients requiring invasive procedures underwent central venous access device (CVAD) - related procedures. The 3 adult patients requiring invasive procedures underwent removal of an infected penile prosthesis, a complex dental extraction consisting of 4 extractions and 1 alveoloplasty, and a right elbow synovectomy with radial head excision. Six patients were admitted to the inpatient hematology service for observation for a median of 48 hours (range: 24 - 168 hours) following their procedures. No patient required readmission after hospital discharge. All patients experienced minimal blood loss perioperatively, and none required transfusions of blood products. The patient undergoing CVAD removal developed a hematoma at the prior port site noted 1 week post-procedure that responded to rfVIIa 90 mcg/kg once daily for 2 days. A second patient had mild surgical site bleeding 1 week post-procedure, which responded to one dose of rfVIIa (90 mcg/kg). No other patient had bleeding complications, and no patient experienced thrombosis or thrombotic microangiopathy. The perioperative management plans are outlined in Table 1. Conclusions: This is the largest case series outside of the HAVEN series detailing the perioperative management of severe hemophilia A patients with a history of low or high titer inhibitors receiving emicizumab prophylaxis. During these invasive procedures, these patients required decreased dosing of fVIII products or bypassing agents and experienced minimal complications. Minor procedures were able to be completed with observation alone. Disclosures Zimowski: National Hemophilia Association/Shire: Other: Funding for clinical fellowship in Hemostasis/Thrombosis. Batsuli:Bayer: Other: Advisory Board; Genentech: Other: Advisory Board; Octapharma: Other: Advisory Board. Reding:Genentech: Other: Advisory Board. Callaghan:Global Blood Therepeutics: Employment; Amgen: Employment; Octapharma: Honoraria; Novo Nordisk: Employment, Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Equity Ownership; Hema Pharmaceuticals: Honoraria; Roche/Genentech: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria; Sancilio Pharmaceuticals Company: Employment; Pfizer: Employment, Honoraria, Research Funding. Meeks:HEMA Biologics: Other: Advisory Board; Genentech: Other: Advisory Board; Catalyst Biosciences: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board; Bioverativ: Other: Advisory Board; Shire: Other: Advisory Board; Pfizer: Research Funding. Sidonio:Uniqure: Other: Advisory Board; Novo Nordisk: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Kedrion: Research Funding; Shire: Other: Advisory Board, Research Funding; Octapharma: Other: Advisory Board; Biomarin: Other: Advisory Board; Bioverativ: Other: Advisory Board, Research Funding; Grifols: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board.

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Metastatic breast cancer is responsible for 90% of mortalities among women suffering from various types of breast cancers. Traditional cancer treatments such as chemotherapy and radiation therapy can cause significant side effects and may not be effective in many cases. However, recent advances in nanomedicine have shown great promise in the treatment of metastatic breast cancer. For example, nanomedicine demonstrated robust capacity in detection of metastatic cancers at early stages (i.e., before the metastatic cells leave the initial tumor site), which gives clinicians a timely option to change their treatment process (for example, instead of endocrine therapy they may use chemotherapy). Here recent advances in nanomedicine technology in the identification and treatment of metastatic breast cancers are reviewed.

Sixty-six-year-old female presented with left forearm soft tissue swelling for 2 months. An ultrasound of her left forearm showed a 6.5 cm 3 1 cm 3 3.6 cm soft tissue mass, which was also confirmed by magnetic resonance imaging (Panel A and B). A routine screening mammogram revealed a new 4 mm mass in her left breast. Subsequent left breast needle biopsy and left forearm fine needle aspiration favored an undifferentiated malignant neoplasm of hematolymphoid origin (Panel D) with positive CD4 (Panel E) and positive CD56 (Panel F) markers compatible with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Positron emission tomography (PET) scan showed increased uptake in the left forearm (Panel C), left breast, bilateral pleura, liver, spleen, portocaval lymph nodes, and omental caking. A bone marrow biopsy was negative for malignancy, and shortly thereafter the patient underwent induction therapy with cytarabine and idarubicin. Following progression of metastatic disease on PET scan, the patient received reinduction chemotherapy with mitoxantrone, etoposide, and cytarabine. BPDCN is a rare malignancy formerly recognized as CD41/CD561 hematodermic neoplasm and is suggested to have derived from plasmacytoid dendritic cells. It typically presents in middle-aged or elderly patients with skin or soft tissue involvement and concurrent disseminating disease carrying poor prognosis. BPDCN expresses CD4, CD56, CD123 (interleukin-3 receptor alpha chain), and BDCA-2 (blood dendritic cell antigen 2), whereas expression of TCL1 is helpful when the tissue displays weak expression of aforementioned markers. Treatment involves multiagent chemotherapy followed by subsequent stem cell transplantation for best outcomes. Unfortunately, our patient showed dismal response to chemotherapy, and the originally intended stem cell transplantation could not be instituted due to poor performance status.