Faculty Bibliography

In the spring of 2021, reports of rare and unusual venous thrombosis in association with the ChAdOx1 and Ad26.COV2.S adenovirus-based coronavirus vaccines led to a brief suspension of their use by several countries. Thromboses in the cerebral and splanchnic veins among patients vaccinated in the preceding 4 weeks were described in 17 patients out of 7.98 million recipients of the Ad26.COV2.S vaccine (with 3 fatalities related to cerebral vein thrombosis) and 169 cases of cerebral vein thrombosis among 35 million ChAdOx1 recipients. Events were associated with thrombocytopenia and anti-PF4 (antibodies directed against platelet factor 4), leading to the designation vaccine-induced immune thrombotic thrombocytopenia. Unlike the related heparin-induced thrombotic thrombocytopenia, with an estimated incidence of <1:1000 patients treated with heparin, and a mortality rate of 25%, vaccine-induced immune thrombotic thrombocytopenia has been reported in 1:150 000 ChAdOx1 recipients and 1:470 000 Ad26.COV.2 recipients, with a reported mortality rate of 20% to 30%. Early recognition of this complication should prompt testing for anti-PF4 antibodies and acute treatment targeting the autoimmune and prothrombotic processes. Intravenous immunoglobulin (1 g/kg for 2 days), consideration of plasma exchange, and nonheparin anticoagulation (argatroban, fondaparinux) are recommended. In cases of cerebral vein thrombosis, one should monitor for and treat the known complications of venous congestion as they would in patients without vaccine-induced immune thrombotic thrombocytopenia. Now that the Ad26.COV2.S has been reapproved for use in several countries, it remains a critical component of our pharmacological armamentarium in stopping the spread of the human coronavirus and should be strongly recommended to patients. At this time, the patient and community-level benefits of these two adenoviral vaccines vastly outweigh the rare but serious risks of vaccination. Due to the relatively low risk of severe coronavirus disease 2019 (COVID-19) in young women (<50 years), it is reasonable to recommend an alternative vaccine if one is available. Ongoing postmarketing observational studies are important for tracking new vaccine-induced immune thrombotic thrombocytopenia cases and other rare side effects of these emergent interventions.

INTRODUCTION/BACKGROUND:In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC. AREAS COVERED/METHODS:This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK. EXPERT OPINION/CONCLUSIONS:In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the available evidence is too immature to make recommendations and results from prospective trials are needed.

Pancreatic adenocarcinoma is one of the deadliest human malignancies with the majority of cases diagnosed late in the course of the disease. Cutaneous metastases originating from pancreatic cancer are rare. The most common site reported is the umbilicus. Non-umbilical cutaneous metastases are far less common with only a few cases reported in the literature. Our case involved a 43-year-old man with pancreatic carcinoma who was offered resection and a Whipple procedure was planned. Intraoperatively, the patient was found to have a widely metastatic disease not seen on preoperative imaging. Postoperatively, cutaneous metastasis in the scalp was discovered. Although rare, the recognition of non-umbilical cutaneous metastases of pancreatic adenocarcinoma can be of value because they can not only detect an underlying tumour but also guide management.

UNLABELLED:Liver regeneration, following partial hepatectomy (PHx), occurs through precisely controlled and synchronized cell proliferation, in which quiescent hepatocytes undergo one to two rounds of replication, with restoration of liver mass and function. We previously demonstrated that loss of the Smad3/4 adaptor protein β-2 spectrin (β2SP) is associated with faster entry into S phase, and hepatocellular cancer formation. These observations led us to further pursue the role of β2SP in cell cycle progression in vivo. Liver regeneration studies with PHx in β2SP(+/-) mice reveal a surprising and significant decrease in liver/body weight ratio at 48 hours after PHx in β2SP(+/-) mice in comparison to wildtype mice. At 48 hours after PHx we also observe decreased levels of cyclin E (2.4-fold, P < 0.05), Cdk1 (7.2-fold, P < 0.05), cyclin A, pRb (Ser249/Thr252), proliferative cell nuclear antigen (PCNA), cyclin D1 with elevated levels of pCdk1 (Thr14) (3.6-fold, P < 0.05). Strikingly, at 24 hours elevated levels of p53 (4-fold, P < 0.05), phospho-p53 (ser15 and ser20), and p21 (200-fold, P < 0.05) persisting to 48 hours after PHx further correlated with raised expression of the DNA damage markers pChk2 (Thr68) and γH2AX (S139). However, compromised cell cycle progression with loss of β2SP is not rescued by inhibiting p53 function, and that G(2) /M phase arrest observed is independent and upstream of p53. CONCLUSION/CONCLUSIONS:β2SP deficiency results in dysfunctional hepatocyte cell cycle progression and delayed liver regeneration at 48 hours after PHx, which is p53-independent. β2SP loss may increase susceptibility to DNA damage, impair cell cycle progression, and ultimately lead to hepatocellular cancer.

Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Aggressive research in the last decade has led to a wealth of information about this disease; for example, we now know that more than 80% of sporadic colon tumors contain mutations in the Wnt and TGFβ signaling pathways. The latest avenue of research is revealing the existence of and role for the cancer stem cell (CSC) model, which promotes the idea that malignancies originate from a small fraction of cancer cells that show self-renewal and multi- or pluripotency. The model also endorses that CSCs are capable of initiating and sustaining tumor growth. The body of evidence in favor of the CSC model is rapidly growing and includes analyses from flow cytometry of numerous CSC biomarkers, abnormal signaling pathways, symmetric division, dietary augmentation, and analysis of the behavior of these cells in spheroid culture formation. Although the incidence of death from CRC remains high, fervent research, both basic and translational, is beginning to improve patient outcomes. This paper focuses on stem cell biology in the context of CRC to help understand the mechanisms leading to tumor development and therapy resistance, with possible therapeutic indications.

BACKGROUND:Bioprosthetic mesh used for ventral hernia repair becomes incorporated into the musculofascial edge by cellular infiltration and vascularization. Adipose tissue-derived stem cells promote tissue repair and vascularization and may increase the rate or degree of tissue incorporation. The authors hypothesized that introducing these cells into bioprosthetic mesh would result in adipose tissue-derived stem cell engraftment and proliferation and enhance incorporation of the bioprosthetic mesh. METHODS:Adipose tissue-derived stem cells were isolated from the subcutaneous adipose tissue of syngeneic Brown Norway rats, expanded in vitro, and labeled with green fluorescent protein. Thirty-six additional rats underwent inlay ventral hernia repair with porcine acellular dermal matrix. Two 12-rat groups had the cells (1.0 x 10(6)) injected directly into the musculofascial/porcine acellular dermal matrix interface after repair or received porcine acellular dermal matrix on which the cells had been preseeded; the 12-rat control group received no stem cells. RESULTS:At 2 weeks, adipose tissue-derived stem cells in both stem cell groups engrafted, survived, migrated, and proliferated. Mean cellular infiltration into porcine acellular dermal matrix at the musculofascial/graft interface was significantly greater in the preseeded and injected stem cell groups than in the control group. Mean vascular infiltration of the porcine acellular dermal matrix was significantly greater in both stem cell groups than in the control group. CONCLUSIONS:Preseeded and injected adipose tissue-derived stem cells engraft, migrate, proliferate, and enhance the vascularity of porcine acellular dermal matrix grafts at the musculofascial/graft interface. These cells can thus enhance incorporation of porcine acellular dermal matrix into the abdominal wall after repair of ventral hernias.

BACKGROUND:Transplantation of adipose tissue-resident mesenchymal stem cells has been found to contribute to the establishment of a supportive fibrovascular network. The authors sought to evaluate the potential of human adipose tissue-derived stem cells to integrate with nonanimal stabilized hyaluronic acid as a novel injectable soft-tissue filler. METHODS:Cell proliferation was measured by bromodeoxyuridine incorporation. Interactions of adipose tissue-derived stem cells with hyaluronic acid were documented by scanning electron microscopy. The effect of this combination on procollagen mRNA was assessed by real-time polymerase chain reaction. The potential therapeutic effects were evaluated in an athymic murine photoaged skin model by histology and by high-resolution magnetic resonance imaging. Angiogenesis was assessed by microvessel density analysis. RESULTS:Under in vitro culture conditions, the authors found an equal proliferation capacity of adipose tissue-derived stem cells grown on hyaluronic acid versus controls. Scanning electron microscopy showed enhanced establishment of complex microvillous networks in adipose tissue-derived stem cells adherent to hyaluronic acid compared with controls. Adipose tissue-derived stem cells and hyaluronic acid induced a significant increase in procollagen 1-alpha-2 mRNA expression compared with controls. In an athymic murine photoaged skin model, injection of this combination ablated photoinduced skin wrinkles. Magnetic resonance imaging revealed a consistent and stable volume fill by adipose tissue-derived stem cells and nonanimal stabilized hyaluronic acid at 3 weeks. Adipose tissue-derived stem cells actively incorporated into the hyaluronic acid fill and showed an organized fibrovascular network at 3 weeks. CONCLUSION/CONCLUSIONS:The combination of adipose tissue-derived stem cells and nonanimal stabilized hyaluronic acid holds promise as a tool with which to achieve lasting volume fill in reconstructive surgical soft-tissue augmentation.