January 2022 

With more than 2.8 million reports of antimicrobial resistance per year, it is critical to diagnose and treat  patients with antimicrobials that bacteria are susceptible to [1]. This has been increasingly difficult due to  genetic modifications bacteria induce upon being exposed to an antimicrobial. After undergoing genetic modifications, bacteria could be found to be completely resistant to an antimicrobial that they were once  susceptible to. There are different clinical testing methods that clinicians will use to test bacterial  susceptibility to antimicrobials. One of the more advanced technologies used is Next Generation Sequencing (NGS) in which a bacterial sample will have its entire genome sequenced [2]. In this testing method, bacteria can have their own genome documented which will be available for use to more accurately diagnosing patients,  help categorize bacteria appropriately, and aid in research.  

Increased specificity in identifying bacteria can help identify resistance of antimicrobials. In contrast to some current clinical testing methods, NGS can be used prior to induced resistance in a patient [2]. This could aid in  decreasing the prescribing of unnecessary antimicrobials which would help lessen antimicrobial exposure  and possible induced resistance. Certain known antimicrobial resistance gene sequences can be detected  through NGS and used to help predict future trends in resistance. These findings can be used to update guidelines that reflect these findings which will aid in appropriate antimicrobial use with less negative consequences. 

Due to historical methods of categorizing bacteria, certain bacteria have a taxonomy that do not reflect its  true ancestral genes. Historically, phenotypic characteristics have been used to categorize bacteria but using  NGS has shown genotypic information of differing commonalities in certain bacteria providing us with new  information and ability to categorize bacteria [3].  This will help us have a better understanding of the bacterial  genes and possible resistance trends which can aid in future research. Having genetic material available,  allows us to see similarities and differences in the different organisms and potentially aid with future  therapeutics and clinical strategies to treat patients. 

Even with NGS providing detailed information about genetic material, there are some challenges that it can  face. Bacteria pass down genetic material through different pathways other than replication. Horizontal transfer of genetic material can make it difficult to properly categorize two bacteria and can lead to slight  differences in variation of the genetic sequence, but not enough to categorize the bacteria into a different  category [4]. NGS is also more costly and requires more sensitivity testing, trained personnel, and systematic  restructuring with implementation of new protocols [2].

Overall, NGS can identify resistance earlier and more accurately with a targeted treatment approach. It can  also aid in proper data collection for epidemiologic studies and provide information for research which can  be a useful tool in infectious disease studies. 

References:

[1] Centers for Disease Control and Prevention. 2019 Antimicrobial Resistance Threats Report. https://www.cdc.gov/drugresistance/biggestthreats.html#:~:text=More%20than%202.8%20million%20antibiotic,people%20die%20as%20a%20result. Published November 23, 2021. Accessed January 24, 2022. 

[2] Gwinn M, MacCannell D, Armstrong GL. Next-Generation Sequencing of Infectious Pathogens. JAMA.  2019;321(9):893-894. doi:10.1001/jama.2018.21669 

[3] Ciufo S, Kannan S, Sharma S, et al. Using average nucleotide identity to improve taxonomic assignments in  prokaryotic genomes at the NCBI. Int J Syst Evol Microbiol. 2018;68(7):2386-2392.  doi:10.1099/ijsem.0.002809

[4] Berman, H. Bacterial Species in the Age of Next-Generation Sequencing. American Society of Microbiology.  October 19, 2021. Accessed January 24, 2021. https://asm.org/Articles/2021/October/Bacterial-Species-In the-Age-of-Next-Generation-Se

Esophageal cancer results when the tissue lining the esophagus, which is composed of squamous cells, becomes malignant [1]. Factors that place individuals at higher risk for developing esophageal cancer include alcohol and tobacco consumption, previous injury to the esophagus, obesity, and digestive conditions such as GERD or Barrett’s esophagus. Symptoms of esophagus cancer are trouble swallowing, heartburn, chest pain, unexplained weight loss, indigestion, vomiting, hoarseness, and chronic coughing [3]. It affects roughly 465,000 patients per year, making it the eighth most commonly diagnosed cancer in the world.

The aggressive nature of the cancer makes it quite difficult to treat, as it is largely asymptomatic until it has progressed to advanced stages. Oftentimes patients with esophageal cancer are ineligible for surgery, so medical treatment options primarily utilized include dilatation, stenting, chemotherapy, radiotherapy, and combined chemoradiotherapy. However, all these palliative treatments report varying response rates and a countless number of side effects, including cardiac and kidney toxicity, nausea and fatigue. Therefore, the main objective of this clinical study was to assess the effects of electrode electrochemotherapy as a new treatment approach for individuals with advanced esophageal cancer. 

Electrochemotherapy is an innovative technique that integrates chemotherapy with electroporation. Persistent high-voltage electrical pulses are directed at tumor cells, which subsequently causes the cell membrane to become increasingly more permeable and porous. The pores then allow molecules, drugs, and chemical agents to effectively enter the cell cytosol which, otherwise, would have been unable to pass due to their large size. In this particular study, researchers opted to introduce the cytotoxic drug bleomycin into the tumor cells via electrochemotherapy. Cytotoxic, or cytostatic, drugs operate by inhibiting the cell division process of these rapidly dividing malignant cells and, thereby, causing cell death.

A phase I clinical study demonstrated that endoscopic electrochemotherapy is safe and effective for tumor resolution in patients with advanced esophageal cancer. Researchers were able to successfully show that electrochemotherapy treatment results in tumor regression, as gastroscopic and PET/MRI images in all patients eight weeks post-treatment exhibited no tumor progression, ulcerated tumor tissue replaced with necrotic tissue, less exophytic tumors, and no dramatic changes of 18F-FDG-activity. Additionally, two of the eight patients showed no signs of visible residual tumors [1].

The pathology of esophageal cancer is imperative to understand in regards to the significance of this therapy, especially considering how highly prevalent yet difficult it is to treat. The esophagus is composed of four distinct layers: the mucosa, submucosa, muscularis, and the adventitia. A majority of esophageal cancer originates in the mucosa, where the nonkeratinized stratified squamous cells become carcinomic, as the lower region of the epithelium of the esophagus becomes inflamed and irritated. The stratified squamous cells are observed to be replaced by columnar cells. This is thought to occur when gastric reflux begins to deteriorate the integrity of the inner esophageal lining, leading to dysplasia [2]. If not readily and properly treated, the tumor begins to invade into the submucosa, muscularis, and adventitia, as well as nearby structures, and eventually results in metastasis. Bleeding is often commonly seen in patients, as the tumor impedes on the nerves and blood vessels located within the esophagus. The tumor can also block the passageway, preventing oral consumption entirely [3].

In conclusion, esophageal cancer is a highly diagnosed form of cancer that affects the squamous cells of the epithelium. The difficulties in treating advanced esophageal cancer has led to novel approaches in medical science to directly treat the condition. Endoscopic electrochemotherapy is a viable treatment that can be used to directly target tumor cells. However, future clinical studies are still warranted in order to comprehensively evaluate the long-term effects of endoscopic electrochemotherapy in respect to quality of life and response rate.

References:

[1] Egeland C, Baeksgaard L, Johannesen HH, Lōfgren J, Plaschke CC, Swensden B, Gehl J, Achiam MP. Endoscopic electrochemotherapy for esophageal cancer: a phase I clinical study. Endoscopy International Open, 2018, 6, 6, pp. E727–E734.

[2] McKinley, Michael P., & Valerie Dean O'Loughlin. Human Anatomy. Boston: McGraw-Hill Higher Education, 2006.

[3] Napier KJ, Scheerer M, Misra S. Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol, 2014, 6, 5, pp.112–120.