The benefits of the Papanicolaou Society of Cytopathology System for reporting pancreatobiliary cytology: A 2-year review from a single academic institution.

OBJECTIVE: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an essential tool in the diagnosis of pancreatic lesions. The aim of this study was to evaluate the diagnostic accuracy of cytology from EUS-FNA, to correlate the results with the corresponding histopathological diagnoses and to analyse the impact of retrospective assignment of the Papanicolaou Society of Cytopathology (PSC) reporting system categories. METHODS: All pancreatic FNA specimens reported at the Royal Free Hospital during a 2-year period were retrospectively collected and assigned to the PSC system categories. Any available corresponding histological samples were assessed for concordance. RESULTS: In total, 236 cytology specimens from 223 patients were identified, of which 108 (45.8%) had corresponding histology samples. The main reason for cyto-histological discrepancy was sampling error. Interpretive error was identified in one case. Overall, sensitivity was 92.5%, specificity was 100%, diagnostic accuracy of cytology was 95%, false-positive rate was 0% and false-negative rate was 7.5%. The implementation of the new reporting system reduced the number of cases in the atypical category. All cases previously categorised as suspicious or malignant remained in the same category. CONCLUSIONS: EUS-FNA is an accurate method for evaluating pancreatobiliary lesions. The implementation of the Papanicolaou Society of Cytopathology diagnostic system enhances standardisation of the reporting terminology and reduces the number of samples in the non-standardised and equivocal atypical category.

Rates and Outcomes of Breast Lesions of Uncertain Malignant Potential (B3) benchmarked against the National Breast Screening Pathology Audit; Improving Performance in a High Volume Screening Unit.

INTRODUCTION: Our breast screening unit was identified as high outlier for B3 lesions with a low positive predictive value (PPV) compared to the England average. This prompted a detailed internal audit and review of B3 lesions and their outcomes to identify causes and address any variation in practice. PATIENTS AND METHODS: The B3 rate was calculated in 4168 breast core biopsies from 2019, using the subsequent excision to determine the PPV. Atypical intraductal epithelial proliferation (AIDEP) cases were subject to microscopic review to reassess the presence of atypia against published criteria. The B3 rate was re-audited in 2021, and the results compared. RESULTS: Screening cases had a high B3 rate of 12.4% (30% above the national average), and a PPV of 7.7% (9.7% with atypia). AIDEP was identified as a possible cause of this outlier status. On review and by consensus, AIDEP was confirmed in only 66% of cases reported as such, 17% were downgraded, and 16% did not reach consensus, the latter highlighting the difficulty and subjectivity in diagnosis of these lesions. Repeat audit of B3 rates after this extended review revealed a reduction from 12.4% to 9.11%, which is more in line with national standards. CONCLUSION: Benchmarking against national reporting standards is critical for service improvement. Through a supportive environment, team working, rigorous internal review and adherence to guidelines, interobserver variation and outlier status in breast pathology screening outliers can both be addressed. This study can serve as a model to other outlier units to identify and tackle underlying causes.

Helicobacter pylori and gastric cancer.

Gastric cancer remains a major cause of cancer death worldwide. The discovery of Helicobacter pylori Helicobacter pylori and its association with gastric cancer has opened up new insights into its pathogenesis. Gastric cancer pathogenesis is the result of a complex interplay between bacterial, host and environmental factors resulting in a step wise histological progression to neoplasia. H. pylori is a major factor in the early stages of cancer development and the mechanism of action of its virulence factors are being steadily unravelled. It is also now recognised that host genetic polymorphisms also play a complex role interacting synergistically with the bacterial virulence factors. The role of H. pylori in the causation of gastric cancer also raises the possibility of cancer prevention through screening and eradication, actions which may improve outcomes in high risk populations but which may not be cost-effective in areas of low risk. Ultimately, despite the vast improvements in knowledge, as yet there has not been a corresponding improvement in terms of gastric cancer survival rates.

Phase behavior, rheological and mechanical properties of hydrophilic polymer dispersions.

Liquid polymeric systems that can undergo phase change (sol to gel) upon administration into the teat canal of cow's mammary gland can serve as a physical barrier to invading pathogens and can also serve as a reservoir for controlled release of therapeutic agents. The aim of the study was to investigate the phase behavior, rheological and mechanical properties of selected in situ gelling systems. Six in situ gelling polymer formulations were identified using phase behavior studies. Rheological studies revealed pseudoplastic flow with thixotropy. All six formulations showed significantly different viscosity, pseudoplasticity and thixotropy values except for CMC1 and HPMC2 which where statistically similar. The gel strength was dependent on the solvent system used and amount of water in the system. These in situ gelling systems have the potential to serve as a platform for development of intramammary formulations intended for administration into the teat canal of the cow's mammary gland. They can serve as a physical barrier or a matrix for controlled drug release.

On the Biocompatibility and Teat Retention of In Situ Gelling Intramammary Formulations: Cattle Mastitis Prevention and Treatment.

Treatment and prevention of cattle mastitis remains a formidable challenge due to the anatomical and physiological constraints of the cow udder. In this study, we investigated polymeric excipients and solvents that can form, (when combined) novel, non-toxic and biocompatible in situ gelling formulations in the mammary gland of bovine cattle. We also report on a new approach to screen intramammary formulations using fresh excised cow teats. Fourteen hydrophilic polymers and six solvents were evaluated for in vitro cytotoxicity and biocompatibility towards cultured bovine mammary epithelial cells (MAC-T), microscopic and macroscopic examination upon contact with excised cow teats. No significant cytotoxicity (p > 0.05) was observed with polyethylene oxides, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium alginate and xanthan gum. Polycarbophil and carbopol polymers showed significantly higher cytotoxicity (p < 0.05). Concentration-dependent cytotoxicity was observed for glycerin, propylene glycol, polyethylene glycol 400, ethanol, N-methyl-2-pyrrolidone and 2-pyrrolidone, with the 2-pyrrolidone solvents showing higher cytotoxic effects (p < 0.05). In situ gelling formulations comprising hydroxypropyl methylcellulose or carboxymethyl cellulose and solvents in specific ratios were biocompatible at higher concentrations with MAC-T cells compared to alginates. All investigated formulations could undergo in situ sol-to-gel phase transformation, forming non-toxic gels with good biocompatibility in excised cow teats hence, showing potential for use as intramammary carriers for sustained drug delivery.

Nanocarriers: more than tour de force for thymoquinone.

Introduction: Thymoquinone (TQ), 2-isopropyl-5-methylbenzo-1, 4-quinone, the main active constituent of Nigella sativa (NS) plant, has been proven to be of great therapeutic aid in various in vitro and in vivo conditions. Despite the promising therapeutic activities of TQ, this molecule is not yet in the clinical trials, restricted by its poor biopharmaceutical properties including photo-instability.Area covered: This review compiles the different types of polymeric and lipidic nanocarriers (NCs), encapsulating TQ for their improved oral bioavailability, and augmented in vitro and in vivo efficacy, evidenced on various pathologies. Furthermore, we provide a comprehensive overview of TQ in relation to its encapsulation approaches advancing the delivery and improving the efficacy of TQ.Expert opinion: TQ was first identified in the essential oil of Nigella sativa L. black seed. TQ has not been used in formulations because it is a highly hydrophobic drug having poor aqueous solubility. To deal with the poor physicochemical problems associated with TQ, various NCs encapsulating TQ have been tried in the past. Nevertheless, these NCs could be impending in bringing forth this potential molecule to clinical reality. This will also be beneficial for a large research community including pharmaceutical & biological sciences and translational researchers.

Current status and the future of buccal drug delivery systems.

BACKGROUND: The delivery of drugs through the buccal mucosa has received a great deal of attention over the last two decades, and yet there are not many buccal delivery products available on the market. OBJECTIVE: This review outlines the advantages and disadvantages of buccal drug delivery, provides a historical perspective and discusses representative developmental and marketed drugs. METHODS: The structure of the oral mucosa is briefly described to preface a description of the pathways for drug absorption and a critical discussion of permeation experiments. A brief historical perspective followed by a description of some of the currently marketed products provides a picture of where we are today. An indication is given of likely progress in this area and of the attributes of a successful business entity of the future. CONCLUSION: The authors provide an assessment of the future potential of buccal and sublingual drugs.

Therapeutic prospects of microRNAs in cancer treatment through nanotechnology.

MicroRNAs (miRNAs) represent a new class of diagnostic and prognostic biomarker as well as new therapeutic targets in cancer therapy. miRNAs are gaining significant interest due to extensive advancements in knowledge since their discovery and, more recently, their translational application as therapeutic moieties and targets in the management of disease. miRNAs used in the treatment of cancer would position them as a new class of emerging therapeutic agents. Indeed, numerous candidate miRNAs have been identified as having therapeutic application in the treatment of cancer, but there is still much to learn about how to transform these into effective, patient-compliant, and targeted drug delivery systems. In this mini review, we discuss the utility and potential of nanotechnology in miRNA formulation and delivery with particular emphasis on cancer, including their role in conferring multidrug resistance and metastatic capacity. This review benefits both the formulation and biological scientists in understanding and exploring the new vistas of miRNA delivery using nanotechnology in the cancer clinically.

Nanoparticles in Cancer Treatment: Opportunities and Obstacles.

In the United States, the estimated number of new cancer cases in 2018 will be approx. 1.7 million. Historically, combination chemotherapy has been the primary choice of treatment. However, chemotherapeutics have pharmaceutical limitations, among which include problems with stability and aqueous solubility. Likewise, dose limiting toxicity is significant with nonspecific toxicity to healthy cells, hair loss, loss of appetite, peripheral neuropathy and diarrhea being typical side effects. The emergence of Multidrug resistance (MDR) also presents s a significant challenge for the successful treatment of cancer whereby cancer cells become cross resistant to many of the chemotherapeutic agents used. Nanotechnology presents a new frontier for cancer treatment. It holds potential in minimizing systemic toxicity through the development of functionalized particles for targeted treatment. They also provide an alternative strategy to circumvent multidrug resistance as they have a capacity to by-pass the drug efflux mechanism associated with this phenotype. Aside from the advantages they offer in treatment, nanoparticles are also emerging to be valuable diagnostic entities. This article highlights the various ways nanotechnology is being used to improve the treatment and management of cancer. We also discuss the opportunities and obstacles in this area and provide an up to date review of progress in the treatment of cancer.

In Vitro Evaluation of Novel Phenytoin-Loaded Alkyd Nanoemulsions Designed for Application in Topical Wound Healing.

Phenytoin-loaded alkyd nanoemulsions were prepared spontaneously using the phase inversion method from a mixture of novel biosourced alkyds and Tween 80 surfactant. Exposure of human adult keratinocytes (HaCaT cells) for 48 h to alkyd nanoemulsions producing phenytoin concentrations of 3.125-200 µg/mL resulted in relative cell viability readings using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide of 100% confirming nontoxicity and suggesting cell proliferation activity. Phenytoin-loaded alkyd nanoemulsions generally resulted in higher mean cell viability compared with equivalent concentration of phenytoin solutions, suggesting that the nanoemulsions provided a controlled-release property that maintained the optimum phenytoin level for keratinocyte growth. HaCaT cell proliferation, measured by 5-bromo-2-deoxyuridine uptake, was found to increase following exposure to increasing phenytoin concentration from 25 to 50 µg/mL in solution or encapsulated in nanoemulsions but declined at a drug concentration of 100 µg/mL. An in vitro cell monolayer wound scratch assay revealed that phenytoin solution or nanoemulsions producing 50 µg/mL phenytoin concentration resulted in 75%-82% "scratch closure" after 36 h, similar to medium containing 10% fetal bovine serum as a cell growth promoter. These findings indicate that phenytoin-loaded alkyd nanoemulsions show potential for promoting topical wound healing through enhanced proliferation of epidermal cells.

Design and characterisation of a polyethylene oxide matrix with the potential use as a teat insert for prevention/treatment of bovine mastitis.

This manuscript reports (for the first time) on antibiotic-free polymeric inserts for the prevention and/or treatment of bovine mastitis. Polyethylene oxide (PEO)-based inserts were prepared using different concentrations of various hydrophilic polymers and water-soluble and water-insoluble drug-release-modifying excipients. A simple and scalable melt-extrusion method was employed to prepare the inserts. The prepared inserts were characterised for their dimension, rheological and mechanical properties. The in vitro release of a model bacteriostatic drug (salicylic acid) from the prepared inserts was studied to demonstrate the effectiveness and reproducibility of the melt-extrusion manufacturing method. Further, the in vitro stability of the inserts was evaluated using gel permeation chromatography (GPC) to monitor any change in molecular weight under real-time and accelerated storage conditions. The investigated inserts were stable at accelerated storage conditions over a period of 6 months. PEO inserts have the potential to serve a dual purpose, act as a physical barrier against pathogens invading the teat canal of cows and possibly control the release of a drug.

Modified release drug delivery in veterinary medicine.

To successfully research and develop an animal pharmaceutical dosage form, a diverse array of issues covering basic medicine, pharmacology and technology must be addressed. Societal concerns regarding animal and public health, as well as the rapidly changing farming and economic environments, provide additional challenges that require integration into an already complex web of issues. Here, we examine the drive towards reducing the frequency of administration to animals and the closing of gaps between the human and veterinary drug product development.

Development of an injection molded poly(epsilon-caprolactone) intravaginal insert for the delivery of progesterone to cattle.

This paper reports experiments conducted to research, develop and clinically evaluate an injection molded intravaginal insert manufactured from the biodegradable polyester poly(epsilon-caprolactone). The study demonstrated that it is possible to engineer poly(epsilon-caprolactone) into a shape that is well retained, and can be used as a platform for the controlled delivery of progesterone via the vagina of cows. Field evaluation showed that the poly(epsilon-caprolactone) intravaginal inserts containing 10% (w/w) progesterone were at least as effective clinically as the commercially available CIDR intravaginal insert.

Reengineering of a commercially available bovine intravaginal insert (CIDR insert) containing progesterone.

The purpose of this study was to reengineer a commercially available intravaginal insert containing 1.9 g progesterone (CIDR intravaginal insert) for a 7-day insertion period in cattle. The reengineering process resulted in a reduced initial drug load (1.38 g) and a reduction in the residual drug load following insertion, while at the same time maintaining the biological performance of the insert. The in vitro and in vivo pharmaceutical properties of the commercially available CIDR intravaginal insert were characterized initially to gain a thorough understanding of the factors that affected progesterone release from the insert. The effect of changing a selection of formulation and physical variables of the insert was also investigated (including surface area, drug load, addition of pore forming materials, silicone shore hardness and drug particle size). The knowledge gained from these studies was used to define the characteristics of the reengineered insert which was then manufactured and shown to be bioequivalent and clinically equivalent to the commercially available insert.

Control, communication and monitoring of intravaginal drug delivery in dairy cows.

We present the design of an electronically controlled drug delivery system. The intravaginally located device is a low-invasive platform that can measure and react inside the cow vagina while providing external control and monitoring ability. The electronics manufactured from off the shelf components occupies 16 mL of a Theratron syringe. A microcontroller reads and logs sensor data and controls a gascell. The generated gas pressure propels the syringe piston and releases the formulation. A two way radio link allows communication between other devices or a base station. Proof of principle experiments confirm variable-rate, arbitrary profile drug delivery qualified by internal sensors. A total volume of 30 mL was dispensed over a 7-day-period with a volume error of +/- 1 mL or +/- 7% for larger volumes. Delivery was controlled or overridden via the wireless link, and proximity to other devices was detected and recorded. The results suggest that temperature and activity sensing or social grouping determined via proximity can be used to detect oestrus and trigger appropriate responses.

Linking human and veterinary health: trends, directions and initiatives.

The objective of this brief article is to provide an overview of some of the important harmonization efforts that are currently under way within the animal health community. Topics include: scientific networks and interdisciplinary communication; organizations that address animal-related public health concerns; the role of the veterinary pharmaceutical scientist within human health-oriented professional organizations; recent publications pertaining to veterinary pharmacology, pharmaceutics and therapeutics; and the role of global networking in veterinary product research and development.

Vaginal drug delivery: strategies and concerns in polymeric nanoparticle development.

INTRODUCTION: Vaginal infection is widespread and > 80% of females encounter such infections during their lives. Topical treatment and prevention of vaginal infection allows direct therapeutic action, reduced drug doses and adverse effects, convenient administration and improved compliance. The advent of nanotechnology results in the use of nanoparticulate vehicle to control drug release, to enhance dosage form mucoadhesive properties and vaginal retention, and to promote mucus and epithelium permeation for both extracellular and intracellular drug delivery. AREAS COVERED: This review discusses the conflicting formulation requirements on polymeric nanoparticles in order to have them mucoadhesive and retentive in vaginal tract, while able to penetrate through mucus to reach adherent mucus layer or epithelium surfaces to prolong extracellular drug release, or facilitate mucosal permeation and intracellular drug delivery. EXPERT OPINION: Nanoscale systems are potentially useful in topical vaginal drug delivery. A thorough understanding of their mucus penetration and retention behavior as a function of their formulation, size and surface properties, biorecognition, pH, temperature or other stimuli responsiveness is essential for design of therapeutically effective nanomatrices.

Recent developments in buccal and sublingual delivery systems.

INTRODUCTION: There have been several advances in the delivery of drugs through the buccal mucosa over the last 5 years, which have resulted in a number of new buccal delivery products appearing on the market. AREAS COVERED: This review discusses the most recent developments in the area of buccal and sublingual drug delivery, with a focus on marketed drugs. Likely future directions are also considered and reported. EXPERT OPINION: The future potential of buccal and sublingual delivery systems looks favorable. It is envisaged that in the future, buccal and sublingual delivery technologies will provide a platform for the successful delivery of vaccines and antigens. It is also foreseen that physical means of enhancing drug uptake (e.g., sonophoresis, iontophoresis and electroporation) will be commercialized for buccal delivery, thereby expanding the current drug candidate list for this area. The formulation of delivery systems for photosensitizers in photodynamic therapy is a potential emerging area, while buccal and sublingual delivery, in general, is attractive for the development of intellectual property.

Acceptability and compliance of atenolol tablet, compounded paste and compounded suspension prescribed to healthy cats*.

This study was designed to evaluate the cats' acceptance and compliance of the owners and cats towards an extemporaneously prepared palatable compounded atenolol (paste and suspension) formulation in comparison to the commercially obtained tablet, in a randomised, cross-over study design.The three formulations were prescribed twice daily for 6 days to 13 healthy privately-owned cats of 13 different owners, with varying levels of experience in medicating cats. Daily compliance was evaluated via an owner-completed diary, completed after each dose administered. Owner's experience and preference of the formulation was evaluated via questionnaires given prior to, at the end of each treatment protocol, and upon completion of the study. Although compounded suspension was association with fewest missed doses, the majority of cat owners expressed a preference for the divided tablet. Atenolol tablets, compounded paste and suspension acceptance and compliance were comparable. Further work is now required to assess the amount and stability of the active ingredient and the robustness of the paste and suspension formulations prior to any bioavailability comparisons between the formulations.