Medical Therapies to Conquer Surgical Diseases: Gallstone Disease May Be the Next Frontier.

Over the past half century, diseases that were predominantly treated surgically have transitioned to less invasive medical therapies. Such diseases that are now effectively treated with medicine are (1) peptic ulcer disease (PUD), (2) coronary artery disease (CAD), and (3) gastrointestinal stromal tumors (GISTs). Likewise, gallstone disease may soon follow this trend. Currently, the gold standard treatment of symptomatic gallstones is laparoscopic cholecystectomies. Though one of the most common surgeries in the United States, certain cases of acute and gangrenous cholecystitis can be some of the most difficult surgeries to perform. Advancements in neutrophil extracellular trap (NET) inhibitor medical therapies will alter gallstone disease management and the mainstream role of surgical interventions. This focus on less invasive therapies will greatly impact the quality of patient care, financial obligations, and even resident training opportunities.

Water, a powerful tool in surgery.

Inflammation of the gallbladder, also known as acute cholecystitis, may be caused by infection and inflammation of the gallbladder wall due to bile stasis, with or without gallstones. It is one of the most common surgical procedures that are performed laparoscopically. Gangrenous gallbladders are one of the most difficult conditions to treat clinically and surgically, being the cause of many medical malpractice litigations. Gangrenous gallbladders constitute 15% of all laparoscopic surgeries, with the cost of these surgeries being approximately $48,000, compared to other laparoscopic gallbladder surgeries being around $7,000. Dr. Dinesh Vyas and his team have worked together to develop the novel HydroLap, which is a tool that utilizes hydrodissection technology during laparoscopic cholecystectomies to remove the delicate, dead tissue while preserving the healthy tissue of surrounding structures. This decade-long journey began in the operating room and resulted in an innovation that is awaiting Food and Drug Administration (FDA) approval for use in 2023.

National Survey of Sharps Injuries Incidence Amongst Healthcare Workers in the United States.

Purpose: Reporting sharps injuries is crucial for healthcare worker occupational safety. However, these incidents are often underreported, thus posing potentially dangerous working environments. Previous small and limited studies have quantified this underreporting in specific groups of healthcare workers. This study aims to expand on these studies by further quantifying sharps injury incidences through a national study, thus better understanding healthcare reporting behaviors and the reasons for underreporting. Patients and Methods: This is a national, multi-center, cross-sectional study conducted via an online anonymous survey distributed through email among United States attending physicians, fellows, residents, medical students, and nurses of all specialties (ie, surgery, medicine, pediatrics). Data analysis used descriptive statistics and regressive modeling with significance defined as p<0.05. Results: Of over 3000 surveys emailed, 460 (15.3%) healthcare workers responded. The most vulnerable cohort to report sharps injuries were medical students (0.87 injuries per year ±0.69, n=92) and Postgraduate Year (PGY) 1 (0.67±0.81, n=71), PGY2 (0.86±-0.82, n=48), and PGY3 (0.92±0.8, n=45) resident physicians. Healthcare workers in surgical fields reported significantly higher likelihoods (odds ratio=4.61, p<0.001, 95% confidence interval 2.83-7.26) of sharps injuries. Medical students reported sharps injuries the least (40%) and nurses reported sharps injuries the most frequently (71%). The three most common reasons for not reporting sharps injuries included (1) healthcare workers perceiving low infection risk based on patient medical history, (2) fear of peer perception, and (3) belief of lack of reporting utility or that reporting is inconsequential. Conclusion: Medical students and physicians early in training, especially those in surgical fields, are more vulnerable to sharps injuries, but are less likely to report, while nurses are the most likely to report. Dedicated sharps training, education to reduce stigma around injury, and implementing a simplified reporting process may help encourage reporting as well as consistency in reporting, leading to improved workplace safety.

Hydrodissection in Laparoscopic Cholecystectomies for Gangrenous Gallbladders.

To improve the quality of patient care for cholecystectomies for gangrenous gallbladders, multiple innovations have been introduced including laparoscopic and robotic surgery. However, laparoscopic cholecystectomies for gangrenous gallbladders performed by blunt dissection still represents one of the most technically challenging general surgery procedures, with a high rate of iatrogenic complications and suboptimal measures for key surgical parameters such as length of stay, operating time, and blood loss. For this reason, the novel use of surgical techniques such as hydrodissection, which involves the expulsion of normal saline streams at a predetermined pressure, for cholecystectomies for gangrenous gallbladders are of utmost importance. In this manuscript, we explore the application of hydrodissection in cholecystectomies for gangrenous gallbladders.

Screening colonoscopy: The present and the future.

In the United States, colorectal cancer (CRC) is the second leading cause of mortality in men and women. We are now seeing an increasing number of patients with advanced-stage diagnosis and mortality from colorectal cancer before 50 years of age, which requires earlier screening. With the increasing need for CRC screening through colonoscopy, and thus endoscopists, easier and simpler techniques are needed to train proficient endoscopists. The most widely used approach by endoscopists is air insufflation colonoscopy, where air distends the colon to allow visualization of the colonic mucosa. This technique is un-comfortable for patients and requires an anesthetist to administer sedation. In addition, patients commonly complain about discomfort post-op as air escapes into the small bowel and cannot be adequately removed. Current research into the use of water insufflation colonoscopies has proved promising in reducing the need for sedation, decreasing discomfort, and increasing the visibility of the colonic mucosa. Future direction into water insufflation colonoscopies which have shown to be simpler and easier to teach may increase the number of proficient endoscopists in training to serve our aging population.

Checkpoint Inhibitor in a Melanoma Patient With Polyendocrinopathy and Gangrenous Gallbladder With a Mass.

Checkpoint inhibitors are introduced as a therapy for clinical use for various cancers, and clinicians are documenting new adverse effects. This is the first case report to the best of our knowledge of a patient on checkpoint inhibitor presenting with both polyendocrinopathy and gangrenous gallbladder disease with a mass negative for malignancy.71-year-old man presented four years after his initial diagnosis of stage IV, unresectable, non-ulcerated, acryl, lentiginous malignant melanoma. On presentation, he had gangrenous cholecystitis and was treated with laparoscopic cholecystectomy. Incidentally, the patient was diagnosed two years ago with hypothyroidism, hypophysitis, secondary adrenal insufficiency, and pneumonitis, each suspected to be secondary to treatment with pembrolizumab (Keytruda), a monoclonal anti-programmed cell death-1 antibody. He presented to the emergency department for a gallbladder attack and underwent successful laparoscopic cholecystectomy. The intra-operative finding on opening the specimen was an unusual looking exophytic mass but was negative for malignancy on pathology report and reported as gangrenous cholecystitis. His clinical condition before and after surgery was complicated by worsening comorbidities thought to be secondary to pembrolizumab therapy, which required acute care hospitalizations in the weeks before and after his presentation with cholecystitis. The patient had a few admissions from other co-morbidities post-surgery and was doing better. Immunotherapy with pembrolizumab may have secondary and tertiary effects with unusual presentations that are difficult to interpret for the primary oncology team and even tougher to do for community physicians who may subsequently encounter these patients. The relationship of this patient's comorbidities with immune-related adverse events was not apparent until record requests were conducted after surgery and are still not entirely clear after a literature review. More data is needed to guide decision algorithms and to predict which patients may experience these effects.

Biosimilars: Review of current applications, obstacles, and their future in medicine.

Biosimilars are a growing drug class designed to be used interchangeably with biologics. Biologics are created in living cells and are typically large, complex proteins that may have a variety of uses. Within the field of gastroenterology alone, biologics are used to treat inflammatory bowel diseases, cancers, and endocrine disorders. While biologics have proven to be effective in treating or managing many diseases, patient access is often limited by high costs. The development of biosimilars is an attempt to reduce treatment costs. Biosimilars must be nearly identical to their reference biologics in terms of efficacy, side effect risk profile, and immunogenicity. Although the manufacturing process still involves production within living cells, biosimilars undergo fewer clinical trials than do their reference biologics. This ultimately reduces the cost of production and the cost of the biosimilar drug compared to its reference biologic. Currently, seven biosimilars have been approved by the United States Food and Drug Administration (FDA) for use in Crohn's disease, ulcerative colitis, and colorectal cancer. There are other biologics involved in treating gastroenterologic diseases for which there are no FDA approved biosimilars. Although biosimilars have the potential to reduce healthcare costs in chronic disease management, they face challenges in establishing a significant market share. Physician comfort in prescribing reference biologics instead of biosimilars and patient reluctance to switch from a biologic to a biosimilar are two common contributing factors to biosimilars' slow increase in use. More time will be needed for biosimilars to establish a larger and more consistent market share compared to their reference biologics. Additional data confirming the safety and efficacy of biosimilars, increased number of available biosimilars, and further cost reduction of biosimilars will all be necessary to improve physician confidence in biosimilars and patient comfort with biosimilars.

Advances in endoscopic balloon therapy for weight loss and its limitations.

The field of medical and surgical weight loss is undergoing an explosion of new techniques and devices. A lot of these are geared towards endoscopic approaches rather than the conventional and more invasive laparoscopic or open approach. One such recent advance is the introduction of intrgastric balloons. In this article, we discuss the recently Food and Drug Administration approved following balloons for weight loss: the Orbera™ Intragastric Balloon System (Apollo Endosurgery Inc, Austin, TX, United States), the ReShape® Integrated Dual Balloon System (ReShape Medical, Inc., San Clemente, CA, United States), and the Obalon (Obalon® Therapeutics, Inc.). The individual features of each of these balloons, the method of introduction and removal, and the expected weight loss and possible complications are discussed. This review of the various balloons highlights the innovation in the field of weight loss.

High throughput RNA sequencing utility for diagnosis and prognosis in colon diseases.

RNA sequencing is the use of high throughput next generation sequencing technology to survey, characterize, and quantify the transcriptome of a genome. RNA sequencing has been used to analyze the pathogenesis of several malignancies such melanoma, lung cancer, and colorectal cancer. RNA sequencing can identify differential expression of genes (DEG's), mutated genes, fusion genes, and gene isoforms in disease states. RNA sequencing has been used in the investigation of several colorectal diseases such as colorectal cancer, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and irritable bowel syndrome.

A Second-Generation Proteasome Inhibitor and Doxorubicin Modulates IL-6, pSTAT-3 and NF-kB Activity in MDA-MB-231 Breast Cancer Cells.

Triple-Negative Breast Cancer (TNBC) has a poor prognosis due to lack of targeted therapy. Doxorubicin (DOX) has failed for multiple reasons, including development of multi-drug resistance, induction of inflammation (IL-6 secretion) and long-term toxicities. DOX is also known to have off target proteasomal activation, justifying the concept of combining it with a proteasomal inhibitor. Our study investigated the therapeutic potential of an irreversible proteasome inhibitor carfilzomib (CARF) alone or in combination with DOX in two TNBC cell lines (MDA-MB-231 and MDA-MB-468). CARF was as effective in inhibiting mitosis in vitro for both cell lines in comparison to DOX alone. CARF performed similar to DOX in inhibiting apoptosis but had better results in reducing proliferation. Further studies in MDA-MB-231 cells demonstrated that CARF also inhibited pro-inflammatory IL-6 secretion and NF κB transcriptional activity while DOX stimulated both IL-6 and NF kappa-B activity. The reduction of IL-6 while using CARF highlights its therapeutic potential and ability to enhance current clinical drug regimens. Furthermore, exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity, pSTAT3 (Tyr705) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX-treated MDA-MB-231 cells. In vivo, CARF treatment resulted in reduced serum IL-6 compared to treatment with DOX in female SCID-NOD mice with MDA-MB-231 cell tumor. A combinational approach using DOX and CARF presents a clinical potential for better efficacy, reduced proliferation, apoptosis, anti-angiogenesis, and less cardiac dysfunction when compared to current treatments using standalone DOX.

Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer.

Colorectal cancer accounts for a significant proportion of cancer deaths worldwide. The need to develop more chemotherapeutic agents to combat this disease is critical. Cyclin dependent kinases (CDKs), along with its binding partner cyclins, serve to control the growth of cells through the cell cycle. A new class of drugs, termed CDK inhibitors, has been studied in preclinical and now clinical trials. These inhibitors are believed to act as an anti-cancer drug by blocking CDKs to block the uncontrolled cellular proliferation that is hallmark of cancers like colorectal cancer. CDK article provides overview of the emerging drug class of CDK inhibitors and provides a list of ones that are currently in clinical trials.

Rapid Extensive Recurrence of Triple Negative Breast Cancer: Are Both Therapy and Cancer Biology the Culprit?

Triple negative breast cancer (TNBC) comprises 17-20% of all breast cancers and is one of the most common breast cancers. The lack of therapy and failure of existing therapy has been a challenge for clinicians. Doxorubicin (DOX) is the first-line therapy, however, it has significant limitations. Rapid extensive recurrence with metastasis in any cancer has been a challenge for surgeons and medical oncologists. The challenge can be due to failure of therapy, drug resistance, or epigenetic changes. Here, we are discussing a stage I breast cancer patient, operated and treated with appropriate chemotherapy with complete response, which recurred in less than 8 months and metastasized to bone, liver and other organs. We are also presenting lab data of the IL-6 secretions on exposure to DOX in one of the most commonly used TNBC cell lines MDA-MB-231. Breast cancer cell line MDA-MB-231 upon exposure to DOX shows an increase in IL-6 levels more than the already elevated IL-6 levels. This might be a reason for early recurrence. We concluded that patients with TNBC might benefit from a standard DOX treatment regimen with an inflammation-blocking agent.

Doxorubicin-Hyaluronan Conjugated Super-Paramagnetic Iron Oxide Nanoparticles (DOX-HA-SPION) Enhanced Cytoplasmic Uptake of Doxorubicin and Modulated Apoptosis, IL-6 Release and NF-kappaB Activity in Human MDA-MB-231 Breast Cancer Cells.

Triple negative breast cancer exhibit increased IL-6 expression compared with matched healthy breast tissue and a strong link between inflammation and cancer progression and metastasis has been reported. We investigated whether doxorubicin-hyaluronan-super-paramagnetic iron oxide nanoparticles (DOX-HA-SPION) would show greater therapeutic efficacy in human triple negative breast cancer cells (TNBC) MDA-MB-231, as was recently shown in drug-sensitive and multi-drug-resistant ovarian cancer cells. Therefore, we measured cellular DOX uptake via confocal microscopy; observed morphologic changes: mitochondrial and nuclear changes with electron microscopy, and quantitated apoptosis using FACS analysis after Annexin V and PI staining in MDA-MB-231 cells treated with either DOX alone or DOX-HA-SPION. We also measured both proinflammatory and anti-inflammatory cytokines; IL-6, IL-10 respectively and also measured nitrate levels in the conditioned medium by ELISA. Inaddition, NF-κB activity was measured by luciferase assay. Confocal microscopy demonstrated greater cytoplasmic uptake of DOX-HA-SPION than free DOX. We also demonstrated reduction of Vimentin with DOX-HA-SPION which is significantly less than both control and DOX. DOX-HA-SPION enhanced apoptosis and significantly down regulated both pro-inflammatory mediators IL-6 and NF-κB in comparison to DOX alone. The secretion levels of anti-inflammatory mediators IL-10 and nitrate was not decreased in the DOX or DOX-HA-SPION treatment groups. Our data suggest that DOX-HA-SPION nanomedicine-based drug delivery could have promising potential in treating metastasized and chemoresistant breast cancer by enhancing the drug efficacy and minimizing off-target effects.

MicroRNAs potential utility in colon cancer: Early detection, prognosis, and chemosensitivity.

Over the past decade, research has shown that aberrant expression of microRNA (miRNA) is involved in colorectal cancer development and progression. MicroRNAs are small sequences of non-coding RNA that regulate expression of genes involved in important cellular functions, such as cell differentiation, multiplication, and apoptosis. A specific miRNA may display the effects of a tumor suppressor or oncogene. Altered miRNA expression is found in colorectal cancer (CRC) and patterns of miRNA expression correlate with CRC detection and outcome. Studies also have examined the use of circulating serum miRNA and fecal miRNA expression as non-invasive markers for early detection. Here, we review recent evidence demonstrating the potential role of miRNA in CRC and the implications of its use in the diagnosis, prognosis, and management of CRC.

9H-Carbazole-1-carboxamides as potent and selective JAK2 inhibitors.

The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.

Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies.

Nuclear factor kappa B (NF-κB) has an established role in the regulation of innate immunity and inflammation. NF-κB is also involved in critical mechanisms connecting inflammation and cancer development. Recent investigations suggest that the NF-κB signaling cascade may be the central mediator of gastrointestinal malignancies including esophageal, gastric and colorectal cancers. This review will explore NF-κB's function in inflammation-associated gastrointestinal malignancies, highlighting its oncogenic contribution to each step of carcinogenesis. NF-κB's role in the inflammation-to-carcinoma sequence in gastrointestinal malignancies warrants stronger emphasis upon targeting this pathway in achieving greater therapeutic efficacy.

Peer Review and Surgical Innovation: Robotic Surgery and Its Hurdles.

The peer review processes as outlined in the Health Care Quality Improvement Act (HCQIA) is meant ensure quality standard of care through a self-policing mechanism by the medical community. This process grants immunity for people filing a peer review, which is meant to protect whistleblowers. However, it also creates a loophole that can be used maliciously to hinder competition. This is accentuated when surgeons are integrating new technologies, such as robotic surgery, into their practice. With more than 2000 da Vinci robots in use and more than 300 new units being shipped each year, robotic surgery has become a mainstay in the surgical field. The applications for robots continue to expand as surgeons discover their expanding capability. We need a better peer review process. That ensures the peer review is void of competitive bias. Peer reviewers need to be familiar with the procedure and the technology. The current process could stymie innovation in the name of competition.

Strategically Leapfrogging Education in Prehospital Trauma Management: Four-Tiered Training Protocols.

Trauma-related injury in fast developing countries are linked to 90% of international mortality rates, which can be greatly reduced by improvements in often non-existent or non-centralized emergency medical systems (EMS)-particularly in the pre-hospital care phase. Traditional trauma training protocols-such as Advanced Trauma Life Support (ATLS), International Trauma Life Support (ITLS), and Basic Life Support (BLS)-have failed to produce an effective pre-hospital ground force of medical first responders. To overcome these barriers, we propose a new four-tiered set of trauma training protocols: Massive Open Online Course (MOOC) Trauma Training, Acute Trauma Training (ATT), Broad Trauma Training (BTT), and Cardiac and Trauma Training (CTT). These standards are specifically differentiated to accommodate the educational and socioeconomic diversity found in fast developing settings, where each free course is taught in native, lay language while ensuring the education standards are maintained by fully incorporating high-fidelity simulation, video-recorded debriefing, and retraining. The innovative pedagogy of this trauma education program utilizes MOOC for global scalability and a "train-the-trainer" approach for exponential growth-both components help fast developing countries reach a critical mass of first responders needed for the base of an evolving EMS.