Appendiceal cancer is a rare malignancy, occurring in roughly 1.2 per 100,000 per year. Low grade appendiceal neoplasams (LAMN) in particular can lead to pseudomyxoma peritonei (PMP), and respond ...poorly to systemic chemotherapy. Standard treatment includes cytoreduction surgery (CRS) with addition of heated intraoperative peritoneal chemotherapy (HIPEC). Several centres include early postoperative intraperitoneal chemotherapy (EPIC) however; the literature is mixed on the benefits. We aim to examine the benefits of additional EPIC through a propensity-matched analysis.
Patients with LAMN with PMP who underwent cytoreductive surgery at St George hospital between 1996 and 2020 were included in this retrospective analysis. Propensity score matching was performed with the following used to identify matched controls; sex, age, American Society of Anesthesiologists (ASA) grade, peritoneal cancer index (PCI) and morbidity grade. Outcomes measured included length of stay and survival.
A total of 224 patients were identified of which 52 received HIPEC alone. Propensity matching was performed to identify 52 matched patients who received HIPEC + EPIC. Those receiving HIPEC + EPIC were younger at 54.3 vs. 58.4 years (p=0.044). There was a median survival benefit of 34.3 months for HIPEC + EPIC (127.3 vs. 93.0 months, p=0.02). Median length of stay was higher in those who received EPIC (25.0 vs. 23.5 days, p=0.028).
In LAMN with PMP, the addition of EPIC to HIPEC with CRS improves overall survival in propensity score matched cases but results in prolonged hospitalisation. The use of EPIC should still be considered in selected patients.
To reduce animal testing, there is a need to develop novel in-vitro models for evaluating the retention of bioactive compounds in food and pharmaceutical products. Here, a mucus-mimetic platform was ...developed through a one-step approach based on encapsulating mucin within alginate gel beads. We found that mucins form micron sized aggregates distributed across the surface of the calcium-alginate bead, as shown by environmental scanning electron microscopy (ESEM). Retention of bioactive compounds on the mucin-functionalised surface was tested using a commercial orange drink formulation. To aid flavour retention, different mucoadhesive polymers with varying charge, including anionic, neutral and strongly cationic, were tested for their ability to interact with mucin and aid retaining flavour compounds within the mucin-alginate bead. The alginate-mucin mucus mimic was validated using an ex-vivo bovine tongue, with the flavour retention results showing qualitative agreement. The developed method proved to be a convenient, efficient tool for providing information on the effectiveness of mucoadhesive polymers without variability, safety and sustainability issues associated with an ex-vivo or in-vivo system. We propose that by encapsulating other relevant oral proteins, alongside mucins, current gaps between in-vitro and the ex-vivo systems may be narrowed.
Submaxillary mucin is a major component that defines the makeup and functionality of saliva. Understanding its structure and function during food intake is key to designing appropriate strategies for ...enhancing the delivery of flavour. In the present study, the hydrodynamic integrity of bovine submaxillary mucin was characterised under physiological and acidic conditions and it was shown to have a broad molecular weight distribution with species ranging from 100 kDa to over 2000 kDa, and a random coil type of conformation. A decrease in the pH of mucin appeared to result in aggregation and a broader molecular weight distribution, which was shown to correlate with a release of flavour compounds. Our study also provides indications that
p
-cresol may have an effect on the macromolecular integrity of mucin.
While a good mucoadhesive biopolymer must adhere to a mucus membrane, it must also have a good unloading ability. Here, we demonstrate that the biopolymer pullulan is partially digested by human ...salivary α-amylase, thus acting as a controlled release system, in which the enzyme triggers an increased release of flavour. Our oral processing simulations have confirmed an increase in the bioavailability of aroma and salt compounds as a function of oral pullulan degradation, although the release kinetics suggest a rather slow process. One of the greatest challenges in flavour science is to retain and rapidly unload the bioactive aroma and taste compounds in the oral cavity before they are ingested. By developing a cationic pullulan analogue we have, in theory, addressed the "loss through ingestion" issue by facilitating the adhesion of the modified polymer to the oral mucus, to retain more of the flavour in the oral cavity. Dimethylaminoethyl pullulan (DMAE-pullulan) was synthesised for the first time, and shown to bind submaxillary mucin, while still retaining its susceptibility to α-amylase hydrolysis. Although DMAE-pullulan is not currently food grade, we suggest that the synthesis of a sustainable food grade alternative would be a next generation mucoadhesive targeted for the oral cavity.
The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT ...(Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wild-type and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.
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