Biomarkers in the Development of Individualized Treatment Regimens for Colorectal Cancer

Introduction: Colorectal cancer (CRC) is the third most common and second most deadly malignancy in the world with an estimated 1. 9 million cases and 0.9 million deaths in 2020. The 5-year overall survival for stage I disease is 92% compared to a dismal 11% in stage IV disease. At initial presentation, up to 35% of patients have metastatic colorectal cancer (mCRC), and 20-50% of stage II and III patients eventually progress to mCRC. These statistics imply both that there is a proportion of early stage patients who are not receiving adequate treatment and that we are not adequately treating mCRC patients. Body: Targeted therapies directed at CRC biomarkers are now commonly used in select mCRC patients. In addition to acting as direct targets, these biomarkers also could help stratify which patients receive adjuvant therapies and what types. This review discusses the role of RAS, microsatellite instability, HER2, consensus molecular subtypes and ctDNA/CTC in targeted therapy and adjuvant chemotherapy. Discussion: Given the relatively high recurrence rate in early stage CRC patients as well as the continued poor survival in mCRC patients, additional work needs to be done beyond surgical management to limit recurrence and improve survival. Biomarkers offer both a potential target and a predictive method of stratifying patients to determine those who could benefit from adjuvant treatment

Dual Antibiotic Therapy with Vancomycin and Cefazolin for Surgical Prophylaxis in Total Knee Arthroplasty

Background: Perioperative administration of intravenous antibiotics is a routine part of total knee arthroplasty.  Antibiotic selection is a matter of controversy, and the potential risks and benefits associated with each antibiotic selection need to be considered.  The objective of this study is to examine the effects of routine dual antibiotic prophylaxis with both cefazolin and vancomycin on infection and renal failure after primary total knee arthroplasty (TKA) compared with cefazolin alone. Methods: We performed a retrospective review of primary TKA patients for two years before and two years after routine dual antibiotic prophylaxis was implemented at our institution. 1502 patients were included (567 cefazolin-only and 935 dual prophylaxis).   Results: 2 patients (0.4%) in the cefazolin-only group had a deep surgical site infection, compared with 13 patients (1.4%) in the dual prophylaxis group (p=0.06). 46 patients (8.1%) in the cefazolin-only group had postoperative renal failure, compared with 36 patients (3.9%) in the dual prophylaxis group (p=0.0006). Discussion and Conclusion: Our results did not support the routine use of vancomycin in primary total joint arthroplasty to decrease periprosthetic joint infection. However, we also did not see any clear harm due to renal failure in the routine use of dual antibiotic prophylaxis

GUCY2C as a Target for CAR-T Cells to Treat Pancreatic Cancer

Background: Pancreatic cancer is an extremely deadly cancer with a survival rate of only 10.8%. Currently, surgical resection is the only potentially curative treatment, with modestly improved survival after resection. This low survival rate, and the minority of patients who present eligible for surgery, indicates the clear need for additional therapies. Guanylyl cyclase C (GUCY2C), a transmembrane protein selectively expressed by normal intestinal epithelial cells, but not normal pancreatic cells, is expressed in select pancreatic adenocarcinomas and is available as a potential target for directed therapy. Chimeric antigen receptor (CAR) T cell therapy genetically reprograms a patient’s own T cells to express a receptor that targets tumor antigens. We have previously shown GUCY2C CAR-T cells efficacy in mouse models of intraperitoneal colorectal cancer, as well as subcutaneous gastric and esophageal cancers. GUCY2C CAR-T cell therapy could serve as an adjunct in pancreatic cancer treatment at multiple points along the clinical management pathway including as adjuvant therapy in resected patients, neoadjuvant therapy in borderline resectable patients, and as primary treatment in metastatic patients. Here, we created an orthotopic mouse model of metastasizing human pancreatic cancer that can be used to test the efficacy of GUCY2C-directed CAR T cells at each stage along the patient management continuum. Methods: A GUCY2C-expressing pancreatic adenocarcinoma cell line (AsPC-1) as well as two patient derived xenografts (PDXs) from the National Cancer Institute were acquired. GUCY2C expression was confirmed with RNA, protein and shRNA knockdown. Orthotopic mouse models were created by surgically implanting AsPC-1 cells or PDXs into the pancreatic tail. Luciferase was added to AsPC-1 cells using lentiviral transduction to track tumor growth. Biomarker status of PDXs was established to monitor tumor growth and treatment efficacy. GUCY2C CAR-T cells were used in vitro to demonstrate therapeutic efficacy against AsPC-1 cells. Results: AsPC-1 cells implanted in the pancreatic tail metastasized to liver and lungs, revealed by gross morphology, histology, and quantitative RT-PCR analysis. In that context, luciferase fluorescence permitted monitoring of disease progression by IVIS imaging in vivo, without the need to sacrifice mice. An in vitro killing assay demonstrated that AsPC-1 cells were specifically killed by GUCY2C-directed CAR-T cells, compared to non-directed CAR-T cells. Orthotopic implantation of PDXs produced pancreatic tumors in 100% of recipient mice, which could be monitored using circulating CEA. Conclusions: GUCY2C is expressed in a proportion of pancreatic adenocarcinomas, but not normal pancreatic tissue. We have established the efficacy of our GUCY2C-targeted CAR-T cells in in vivo models of disseminated intraperitoneal colorectal cancer, as well as subcutaneous gastric and esophageal cancers models, in mice. Moving forward, we will use this newly created orthotopic model of pancreatic cancer to explore the efficacy of GUCY2C-directd CAR T cells to treat primary and metastatic tumors, to improve the management of patients along the entire disease continuum

Maximizing Completion of the Two-Dose COVID-19 Vaccine Series with Aid from Infographics

Two of the three COVID-19 vaccines approved in the United States require two doses to reach full efficacy, as do others available elsewhere in the world. The complete series of multidose COVID-19 vaccines offers stronger protection against infection by SARS-CoV-2 compared to single-dose injections with the same vaccines. Achieving perfect community-level adherence is a challenge in any public health campaign, even in non-pandemic times. Vaccines requiring multiple doses combined with a surge of vaccine hesitancy and misinformation that has been witnessed by the public during the COVID-19 pandemic are exacerbating the challenge of ensuring the world’s population achieves a sufficient level of immunity against COVID-19. Here, we describe the results of our study in which we sought to determine whether completion of a two-dose COVID-19 vaccine regimen could be improved by disseminating infographics that explain what the vaccine is and why returning for the second dose is beneficial. Our results show that the proportion of COVID-19 vaccine recipients returning for a second inoculation grew after COVID-19 vaccine infographics were distributed to first-time vaccine recipients. We suggest that extending communication and outreach initiatives into the clinic positively influences the rate of follow-up visits, and that infographics are useful tools to aid and bolster the deployment of COVID-19 vaccines

A Review of the Phytochemical Properties and Pharmacological Uses of the Genus Pistacia L. (Anacardiaceae)

O gênero Pistacia pertence à família Anacardiaceae e é composto por cerca de vinte espécies, sendo as mais comuns P. atlantica, P. chinensis, P. integerrima, P. khinjuk, P. lentiscus, P. terebinthus, P. vera e P. weinmanifolia. Várias partes dessas diferentes espécies são ricas em importantes compostos fitoquímicos, incluindo constituintes de óleo essencial, monoterpenoides, sesquiterpenoides, diterpenoides, triterpenoides, tetraterpenoides, flavonoides, compostos fenólicos, taninos, ácidos graxos, esteroides e outros compostos. A literatura publicada revelou muitos usos farmacológicos para várias espécies. As partes das plantas mais estudadas quanto à composição química foram as folhas, com 36%, seguidas dos frutos, com 19 %. Esses usos incluem efeitos antioxidantes, hepatoproteção, efeitos anti-inflamatórios, efeitos antimicrobianos, propriedades cicatrizantes/analgésicas, propriedades anticancerígenas, digestivo e tratamento de várias condições crônicas. Após a investigação completa sobre este gênero, as propriedades fitoquímicas e usos farmacológicos de nove espécies de Pistacia foram descritas nesta abrangente revisão da literatura

Guanylyl cyclase C as a Diagnostic and Therapeutic Target in Colorectal Cancer

Colorectal cancer remains a major cause of mortality in the USA, despite advances in prevention and screening. Existing therapies focus primarily on generic treatment such as surgical intervention and chemotherapy, depending on disease severity. As personalized medicine and targeted molecular oncology continue to develop as promising treatment avenues, there has emerged a need for effective targets and biomarkers of colorectal cancer. The transmembrane receptor guanylyl cyclase C (GUCY2C) regulates intestinal homeostasis and has emerged as a tumor suppressor. Further, it is universally expressed in advanced metastatic colorectal tumors, as well as other cancer types that arise through intestinal metaplasia. In this context, GUCY2C satisfies many characteristics of a compelling target and biomarker for gastrointestinal malignancies