Functional outcomes of hybrid hiatal hernia repair.

Gastroesophageal reflux disease (GERD) results in a total healthcare cost of 12.3 billion dollars to the United States annually. GERD is often seen with hiatal hernias. Our study aims to compare short-term functional outcomes and postoperative symptom relief afforded by hiatal hernia repair with transoral incisionless fundoplication (TIF), together known as hybrid repair, to those of hiatal hernia repair with surgical fundoplication (conventional repair). We performed a retrospective chart review on 112 consecutive patients who underwent robot assisted laparoscopic hiatal hernia repair at a community hospital by a single surgeon. We found that the short-term functional results and symptom relief with hybrid repair were no superior to those with conventional repair. We did not find a significant difference between hybrid and conventional repair in terms of in 30 day complications, ER visits or inpatients admissions. The number of patients who were symptomatic at delayed follow-up was not significantly different between both the groups. As such, short-term functional outcomes and symptom relief with hybrid hiatal hernia repair are no superior to those with conventional repair. Therefore, surgical repair of hiatal hernia with surgical fundoplication remains the standard of care until further data is available on long-term outcomes of the hybrid approach.

Hybrid hiatal hernia repair: is it cost-effective?

Fundoplication is often added to the crural repair for long-term relief of reflux in patients undergoing hiatal hernia repair. Fundoplication can be achieved surgically or with endoscopic means such as trans-oral incisionless fundoplication (TIF). Patients with hiatal hernias larger than 2 cm may undergo surgical hiatal hernia repair with concomitant TIF (hybrid repair). Our study aims to analyze the resources utilized for hybrid repair and compare it with hiatal hernia repair with surgical fundoplication (conventional repair). We conducted a retrospective review of 112 consecutive patients who underwent robotic-assisted hiatal hernia repair. Patients who underwent some form of fundoplication were selected and then divided into two groups-surgical fundoplication (conventional approach) or hybrid approach. This is a pool of patients operated by a single surgeon at a community hospital. Multiple variables were analyzed. The mean operative time was 39 min less; also the mean length of stay was 10 h less in hybrid approach group as compared to conventional repair group. Although statistically significant, there was no meaningful clinical significance to these findings. Cost analysis was performed for direct costs as well as indirect costs. Neither the 30-day outcomes nor the cost-effectiveness for hybrid repair was superior to those of conventional repair. Therefore, in our experience at the community-level hospital, we conclude that hiatal hernia repair with surgical fundoplication is more cost-effective than surgical repair of hiatal hernia with TIF.

Small molecules as antagonists of co-inhibitory pathways for cancer immunotherapy: a patent review (2018-2019).

INTRODUCTION: Therapeutic antibodies blocking co-inhibitory pathways do not attack tumor cells directly, but instead bind to their targeted proteins and mobilize the immune system to eradicate tumors. However, only a small fraction of patients with certain cancer types can benefit from the antibodies. Additionally, antibodies have shown serious immune-related adverse events in certain patients. Small-molecule antagonists may be a complementary and potentially synergistic approach to antibodies for patients with various cancers. AREAS COVERED: The authors review the small molecules as antagonists of co-inhibitory pathway proteins, summarize their preliminary SARs, discuss biochemistry assays used in patents for the development of small molecules as novel antagonists. EXPERT OPINION: The disclosed pharmacophores of small molecules as co-inhibitory pathway antagonists are represented by biphenyl derivatives, biaryl derivatives, teraryl derivatives, quateraryl derivatives, and oxadiazole/thiadiazole derivatives. However, these antagonists are still inferior to therapeutic antibodies in their inhibitory activities due to relatively flat of human co-inhibitory pathways proteins. Allosteric modulators may be an alternative approach. The more safety and efficacy evaluation trials of small-molecule antagonists targeting co-inhibitory pathways should be performed to demonstrate the proof-of-principle that small-molecule antagonists can result in sustained safety and antitumor response in the near future.

Pseudolaric acid B induces mitotic arrest and apoptosis in both imatinib-sensitive and -resistant chronic myeloid leukaemia cells.

The selective BCR-ABL tyrosine kinase inhibitor imatinib is one of the first-line therapies in the management of chronic myeloid leukaemia (CML). However, acquired resistance to this inhibitor, which is especially conferred by the T315I point mutation in BCR-ABL, impedes the efficacy of imatinib therapy. Therefore, the discovery and development of novel agents to overcome imatinib resistance is urgently needed. Pseudolaric acid B (PAB), a small molecule isolated from the traditional Chinese medicine Cortex pseudolaricis, has been reported to be a potential candidate for immune disorders and cancer treatment. However, its effects on CML and the involved molecular mechanism have not been reported. In the current study, by performing both in vitro and in vivo experiments in CML cells, we showed that PAB blocked the cell cycle at G2/M phase and subsequently activated the caspase pathway, cleaved the BCR-ABL protein and inhibited the BCR-ABL downstream pathways, ultimately leading to cell proliferation inhibition, cytotoxicity and apoptosis. These events were observed in both imatinib-sensitive and imatinib-insensitive CML cell lines. Moreover, PAB decreased the viability of primary blood mononuclear cells from CML patients and induced apoptosis in these cells. Our findings suggest that PAB could be used as a novel agent to sensitize imatinib-resistant CML.

Updated Review and Perspective on 20S Proteasome Inhibitors in the Treatment of Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Most lung cancer patients are diagnosed at advanced stages and may benefit from pembrolizumab (anti-PD-1 antibody), cytotoxic chemotherapy and other adjuvant therapies. Despite the availability of various therapies, the response and survival rates have been low. Therefore, the study of different targets for the treatment of lung cancer has been one of the major focuses of cancer research. The ubiquitin proteasome system (UPS) is a crucial regulator of cell homeostasis and plays an essential role in the growth and development of all cells. The UPS is dysregulated in human cancer cells including lung cancer cells. Therefore, targeting UPS is potentially a selective, effective treatment for lung cancer. Bortezomib, a 20S proteasome inhibitor that is clinically approved for the management of multiple myeloma, has been studied in various preclinical and clinical models of lung cancer. Most preclinical studies have shown that a 20S proteasome inhibitor alone and its combination with other chemotherapeutic agents induce apoptosis in non-small cell lung cancer cell lines and animal models. Owing to the impressive preclinical results, many clinical trials were initiated using 20S proteasome inhibitors either as monotherapy or in combination with other conventional lung cancer therapies. Many combinational therapies of 20S PIs with conventional chemotherapy were shown to be well tolerated in clinical trials. However, there have not been any consistent data showing the beneficial effects of such proteasome inhibitor-based therapies. Low clinical efficacy of 20S PIs in lung cancer patients may be due to low drug penetration, the status of 20S proteasomes, oncogene expressions and the inherited or acquired resistance. Potential mechanisms of PI resistance or low or no clinical activity in lung cancer cells might include alteration of apoptotic proteins, overexpression or alteration of ß5 subunit, or upregulation of heat shock proteins. Various cutting-edge strategies to counter this resistance or improve 20S PIs' efficacy in lung cancer cells have been reviewed which include novel combination therapies, new drug delivery systems, development of more potent PIs, and targeting different sites of the UPS. A better understanding of PI resistance mechanisms in lung cancer cells can help improve current clinical treatment strategies and clinical outcomes.

Academic tweeting in #ObGyn. Where do we stand?

Objective To describe the scenario of academic tweeting and utilization of Twitter by editorial board members of the leading journal in obstetrics and gynecology. Methods The Twitter presence of an editorial board members of obstetrics and gynecology journal with an impact factor greater than 4 was determined. Details of their Twitter activity, year of graduation from medical school and gender were analyzed. Median SparkScore™, an online influence measure, of journals was compared to the highest impact factor journals in medicine (New England Journal of Medicine, The Lancet, The British Medical Journal and Journal of the American Medical Association). Results In the six highest impact factor journals in obstetrics and gynecology, 92 of 240 (38.3%) editorial board members had an active Twitter account. The Twitter presence of editorial members of Obstetrics and Gynecology was statistically less when compared to all other journals (P < 0.01). The median number of tweets in the last 24 h and 7 days were 0. Median SparkScore™ for the highest impact factor obstetrics and gynecology journals (24) were lower compared to the highest impact journals in medicine (66) (P = 0.03). Conclusion Editorial board members of the six highest impact factor journals in obstetrics and gynecology are not capitalizing on the dynamic nature of Twitter and its instant convenient access from our smartphones to further academia, when compared to specialties in medicine. There is a need for increased adoption of Twitter among physician leaders in the specialty.

Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents.

BACKGROUND: Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity. OBJECTIVE: To summarize the anti-cancer effects of Disulfiram through a thorough patent review. METHODS: This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy. RESULTS: Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug. CONCLUSION: For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.

A patent review of the ubiquitin ligase system: 2015-2018.

INTRODUCTION: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs. Areas covered: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators. Expert opinion: One strategy to overcome limitations of current 20S proteasome inhibitors is to discover inhibitors of the upstream key components of the UPS, such as E3 enzymes. E3s play important roles in cancer development and determine the specificity of substrate ubiquitination, offering novel target opportunities. E3 modulators could be developed by rational design, natural compound or library screening, old drug repurposes, and application of other novel technologies. Further understanding of mechanisms of E3-substrate interaction will be essential for discovering and developing next-generation E3 inhibitors as effective anticancer drugs.