'To see ourselves as others see us'.

Shaw and colleagues, who are medical historians, have published a detailed review of the social history of the British Journal of Anaesthesia (BJA) to celebrate its first 100 years. In this editorial, we note some additional contributions and financial details that are relevant to the development of the BJA into the international high-impact journal it is today.

Development and Validation of Nomograms to Predict Survival in Patients Undergoing Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei of Appendiceal Origin.

Importance: Pseudomyxoma peritoni, a rare condition characterized by mucinous ascites and peritoneal deposits, mainly originates from a ruptured mucinous appendix tumor and is considered an indolent disease but can progress and become fatal. Optimal treatment to improve cure and survival rates involves complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Accurate predictive models are useful in supporting and informing treatment strategies and stratifying patient follow-up. Objective: To evaluate the prognostic significance of clinically important variables and generate validated nomograms to predict overall (OS) and disease-free survival (DFS) following CCRS and hyperthermic intraperitoneal HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin. Design, Setting, and Participants: This retrospective study used prospectively collected data on patients who had cytoreductive surgery (CRS) and HIPEC in a single institution between 1994 and 2018. The cohort was randomly allocated into development (70%) and validation (30%) sets. Univariate and multivariate analyses were performed with Cox proportional hazards regression. Main Outcomes and Measures: A prediction model was developed with significant prognostic factors identified by multivariate analysis. The model's prognostic performance was evaluated with the concordance index (C index). The nomogram was calibrated by comparing the predicted and observed probabilities. Results: Of 2637 CRS and HIPEC operations, 1102 patients (female, 64.4%; median age [IQR], 57.0 [48.0-66.0] years) (41.8%) had CCRS for PMP of appendiceal origin. Elevated tumor markers, peritoneal carcinomatosis index, gastrectomy, and tumor grade were independent predictive factors for DFS. Gender, age, elevated tumor makers, peritoneal carcinomatosis index, and tumor grade influenced OS. The nomograms were generated with respective prognostic factors. The nomograms showed good performance in predicting survival. Median OS of the cohort was 16.5 years (95% CI, 13.7-19.2) with a 5-year probability of survival of 80.2%. The median DFS was 10.3 years (95% CI, 7.2- 13.3) and the 5-year probability of recurrence-free survival was 60.5%. Conclusions and Relevance: Clinically important independent predictors for survival and recurrence were selected to develop the nomograms for OS and DFS. These 2 nomograms are user friendly and useful tools for patient management with clinical trial design applications.

Fear of Cancer Recurrence in peritoneal malignancy patients following treatment: a cross-sectional study.

PURPOSE: To assess Fear of Cancer Recurrence (FCR)-its prevalence, trajectory, and relationship to several demographic and clinical characteristics, and quality of life-in a sample of peritoneal malignancy survivors, up to 5 years post-surgery. METHODS: The Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF) and 36-Item Short-Form Health Survey (SF-36) were used to collect cross-sectional data from peritoneal malignancy survivors to assess their Fear of Cancer Recurrence and quality of life respectively as well as other demographic and clinical data. RESULTS: The results show that more than two-thirds of the participants (N = 301) experience severe/clinical FCR. FCR is relatively stable over time. Younger patients who are struggling with anxiety or depression or receiving professional mental health support at the time of the surgery are at a higher risk of FCR. FCR is associated with a worse quality of life. CONCLUSIONS: Peritoneal malignancy survivors are at a high risk of FCR, and it compromises their psychological, mental, and social well-being (quality of life). IMPLICATIONS FOR CANCER SURVIVORS: Raise awareness about the high risk of FCR in this population and the demographic and clinical factors that are associated with it. Encourage peritoneal malignancy services and health professionals to address FCR in this population by normalizing it and providing support for those struggling with it.

Histone modifiers at the crossroads of oncolytic and oncogenic viruses.

Cancer is a disease caused by loss of regulatory processes that control the cell cycle, resulting in increased proliferation. The loss of control can deregulate both tumor suppressors and oncogenes. Apart from cell intrinsic gene mutations and environmental factors, infection by cancer-causing viruses also induces changes that lead to malignant transformation. This can be caused by both expression of oncogenic viral proteins and also by changes in cellular genes and proteins that affect the epigenome. Thus, these epigenetic modifiers are good therapeutic targets, and several epigenetic inhibitors are approved for the treatment of different cancers. In addition to small molecule drugs, biological therapies, such as antibodies and viral therapies, are also increasingly being used to treat cancer. An HSV-1-derived oncolytic virus is currently approved by the US FDA and the European Medicines Agency. Similarly, an adenovirus-based therapeutic is approved for use in China for some cancer types. Because viruses can affect cellular epigenetics, the interaction of epigenome-targeting drugs with oncogenic and oncolytic viruses is a highly significant area of investigation. Here, we will review the current knowledge about the impact of using epigenetic drugs in tumors positive for oncogenic viruses or as therapeutic combinations with oncolytic viruses.

Communicating imaging findings in peritoneal mesothelioma: the impact of 'PAUSE' on surgical decision-making.

The peritoneal cavity is the second commonest site of mesothelioma after the pleural cavity. There are five histological types of peritoneal mesothelioma with variable symptomatology, clinical presentation and prognosis. Cystic mesothelioma is a borderline malignant neoplasm with a favourable prognosis, well-differentiated papillary mesothelioma is generally a low-grade malignancy, and all other varieties such as epithelioid, sarcomatoid and biphasic mesothelioma are highly malignant types of peritoneal mesothelioma with poor prognosis. Malignant peritoneal mesothelioma was considered inevitably fatal prior to the introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in selected cases where long-term survival and cure could be achieved. However, the survival benefits following CRS and HIPEC mainly depend on completeness of cytoreduction, which come at the cost of high morbidity and potential mortality. Using the acronym 'PAUSE', we aimed at describing the key imaging findings that impact surgical decision-making in patients with peritoneal mesothelioma. PAUSE stands for peritoneal cancer index, ascites and abdominal wall disease, unfavourable sites of involvement, small bowel and mesenteric disease and extraperitoneal disease. Reporting components of 'PAUSE' is crucial for patient selection. Despite limitations of CT in accurately depicting the volume of disease, describing findings in terms of PAUSE plays an important role in excluding patients who might not benefit from CRS and HIPEC.

Managing Recurrent Pseudomyxoma Peritonei in 430 Patients After Complete Cytoreduction and HIPEC: A Dilemma for Patients and Surgeons.

BACKGROUND: Epithelial appendiceal neoplasms are uncommon peritoneal malignancies causing a spectrum of disease including pseudomyxoma peritonei (PMP). The optimal management is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Despite complete CRS (CCRS), recurrence develops in almost 45% of patients. No consensus exists for the optimal treatment of recurrent disease, with treatment strategies including repeat CRS, watch-and-wait, and palliative chemotherapy. This report aims to describe evolving management strategies for a large cohort with recurrence after CCRS. METHODS: This retrospective study analyzed a prospective database of patients with recurrence after CCRS for appendiceal neoplasms from 1994 to 2017 who had long-term follow-up evaluation with tumor markers and computed tomography (CT). RESULTS: Overall, 430 (37.6%) of 1145 PMP patients experienced recurrence at a median of 19 months. Of these 430 patients 145 (33.7%) underwent repeat CRS, 119 (27.7%) had a watch-and-wait approach, and 119 (27.7%) had palliative chemotherapy. The patients with recurrence had a median overall survival (OS) of 39 months, a 3-year survival of 74.6%, a 5-year survival of 57.4%, and a 10-year survival of 36.5%. In the multivariate analysis, the patients who had recurrence within 1 year after primary CRS (hazard ratio [HR], 3.55), symptoms at recurrence (HR, 3.08), a high grade of disease or adenocarcinoma pathology (HR, 2.94), signet ring cells (HR, 1.91), extraperitoneal metastatic disease (HR, 1.71), or male gender (HR, 1.61) had worse OS. The OS was longer for the patients who had repeat CRS (HR, 0.41). The patients who underwent repeat CCRS had a 3-year OS of 87.5%, a 5-year OS of 78.1%, and a 10-year OS of 67.9%. CONCLUSIONS: Dilemmas persist around the optimal management of patients with recurrence after CRS and HIPEC for appendiceal tumors. Selected patients benefit from repeat CRS, particularly those with favorable tumor biology and focal disease.

New insights in the pathology of peritoneal surface malignancy.

Pathology is central to the management of peritoneal surface malignancy. This article highlights some recent advances that have had an impact on patient management or could do so in the near future. Malignant peritoneal mesothelioma, particularly the epithelioid subtype, is amenable to radical therapy in selected cases, and factors such as ki67 proliferation index, expression of BAP1 and mutation in CDKN2A show promise as prognostic indicators. Our understanding of multicystic mesothelioma has improved in recent years; it is a true neoplasm for which surgery may be indicated. Serous carcinomas involving the peritoneum are now known to originate from tubal epithelium. They are of two distinct types, high grade and low grade, which are now recognized as different neoplasms with distinctive features, oncogenesis and behavior. Pseudomyxoma peritonei (PMP) is an unusual condition that usually arises from an appendiceal mucinous neoplasm. Recent consensus in the classification and nomenclature of these lesions is discussed, including the distinction between low grade and high grade appendiceal mucinous neoplasms (HAMN), and the diagnostic criteria for appendiceal adenocarcinoma. PMP is divided into four prognostic groups: acellular mucin, low grade mucinous carcinoma peritonei, high grade mucinous carcinoma peritonei, and high grade mucinous carcinoma peritonei with signet ring cells. The pseudomyxoma microbiome is a promising area for clinical intervention but has been the subject of little research activity. Goblet cell adenocarcinoma (previously known as 'goblet cell carcinoid') is a distinctive type of appendiceal adenocarcinoma. Its behavior correlates with histologic features, but no general consensus for classification has been reached.

Estimating the Prevalence of Pseudomyxoma Peritonei in Europe Using a Novel Statistical Method.

BACKGROUND: The determination of the incidence and prevalence of rare diseases is important for economists and health-care providers. Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer that represents a substantial burden on both patients and health-care systems. The incidence rate was previously approximated at 1-2 people per million per year; this incidence has never been challenged, and the prevalence has not been estimated. METHODS: Epidemiological data from Norway and England were obtained and analysed to calculate a minimum incidence rate based on the number of patients having a first surgical intervention for PMP. A novel method was then used to determine a prevalence rate for PMP, incorporating incidence, death, and cure rates in a multi-year analysis that accounted for the increasing population of Europe over a 10-year period. RESULTS: An incidence rate of 3.2 people per million per year was calculated, with a corresponding estimated prevalence rate of 22 people per million per year. By this calculation, 11,736 people in Europe were estimated to be living with PMP in 2018. CONCLUSION: Incidence and prevalence are essential tools for assessment of the financial and human cost of a disease. For rare diseases, such as PMP, the lack of accurate registries presents a particular challenge in determining such health-related statistical parameters. Based on our calculations, a significant number of people are living with PMP in Europe, underlining the need for appropriate resource allocation to ensure that adequate health-care measures are provided.

Does time to surgery affect patient-reported outcome in proximal humeral fractures? A subanalysis of the PROFHER randomized clinical trial.

AIMS: The aim of this study was to explore whether time to surgery affects functional outcome in displaced proximal humeral fractures. METHODS: A total of 250 patients presenting within three weeks of sustaining a displaced proximal humeral fracture involving the surgical neck were recruited at 32 acute NHS hospitals in the United Kingdom between September 2008 and April 2011. Of the 125 participants, 109 received surgery (fracture fixation or humeral head replacement) as per randomization. Data were included for 101 and 67 participants at six-month and five-year follow-up, respectively. Oxford Shoulder Scores (OSS) collected at six, 12, and 24 months and at three, four, and five years following randomization was plotted against time to surgery. Long-term recovery was explored by plotting six-month scores against five-year scores and agreement was illustrated with a Bland-Altman plot. RESULTS: The mean time from initial trauma to surgery was 10.5 days (1 to 33). Earlier surgical intervention did not improve OSS throughout follow-up, nor when stratified by participant age (< 65 years vs ≥ 65 years) and fracture severity (one- and two-part vs three- and four-part fractures). Participants managed later than reported international averages (three days in the United States and Germany, eight days in the United Kingdom) did not have worse outcomes. At five-year follow-up, 50 participants (76%) had the same or improved OSS compared with six months (six-month mean OSS 35.8 (SD 10.0); five-year mean OSS 40.1 (SD 9.1); r = 0.613). A Bland-Altman plot demonstrated a positive mean difference (3.3 OSS points (SD 7.92)) with wide 95% limits of agreement (-12.2 and 18.8 points). CONCLUSION: Timing of surgery did not affect OSS at any stage of follow-up, irrespective of age or fracture type. Most participants had maximum functional outcome at six months that was maintained at five years. These findings may help guide providers of trauma services on surgical prioritization. Cite this article: Bone Joint J 2020;102-B(1):33-41.

Local Similarity Matrix for Cysteine Disulfide Connectivity Prediction from Protein Sequences.

Accurately predicting three dimensional protein structures from sequences would present us with targets for drugs via molecular dynamics that would treat cancer, viral infections, and neurological diseases. These treatments would have a far reaching impact to our economy, quality of life, and society. The goal of this research was to build a data mining framework to predict cysteine connectivity in proteins from the sequence and oxidation state of cysteines. Accurately predicting the cysteine bonding configuration improves the TM-Score, a quantitative measurement of protein structure prediction accuracy. We provided state of the art Qp and Qc on the PDBCYS and IVD-54 Datasets. Furthermore, we have produced a Local Similarity Matrix that compares favorably to the default PSSMs generated from PSI-Blast in a statistically significant way. Our Qp for SP39, PDBCYS, and IVD-54 were 90.6, 80.6, and 68.5, respectively.

Counting Intraepithelial Lymphocytes: A Comparison Between Routine Staining and CD3 Immunohistochemistry.

Counting intraepithelial lymphocytes (IELs) is a key part of the assessment of duodenal biopsies. Immunohistochemistry (IHC) for CD3 can aid identification of lymphocytes in this context, but it is not evident that counts on hematoxylin and eosin (H&E) and CD3 are comparable. This study aimed to compare the IEL counts in duodenal biopsies using H&E stains and CD3 IHC, and to examine the interobserver variability. Thirty-five paired H&E and CD3 sections were reviewed by 6 pathologists who counted the number of IELs per 100 enterocytes. The counts were categorized into groups: normal (<25 lymphocytes), mildly raised (25-40 lymphocytes), and markedly raised (>40 lymphocytes). CD3 IHC was associated with significantly higher IEL counts than H&E. Four cases with normal H&E counts had raised counts with CD3. There was moderate agreement between observers for both H&E and CD3. Lack of concordance between CD3 and H&E IEL counts suggests that counts derived from the 2 methods may not be comparable to each other and should not be considered equivalent. There was no significant improvement in interobserver variability with CD3 IHC.

Routine monitoring for heparin-induced thrombocytopenia following lower limb arthroplasty: Is it necessary? A prospective study in a UK district general hospital.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition associated with heparin administration. Many orthopaedic units routinely prescribe low-molecular-weight heparins as thromboprophylaxis after hip and knee arthroplasty. HYPOTHESIS: We postulated that routine platelet monitoring following heparin administration is of no clinical benefit. We therefore asked: firstly, what was the rate of thrombocytopenia in a large population of patients undergoing lower limb arthroplasty? Secondly, did this rate justify routine platelet monitoring? MATERIALS AND METHODS: Unless contraindicated, all patients (n=1999, 53.05% female, mean age 69.23 years) at a UK district general hospital undergoing hip and knee arthroplasty were given daily prophylactic enoxaparin. Platelet counts were obtained between the 8th and 10th postoperative days and compared to preoperative baseline. A > 50% fall in platelet count was classified as "possible HIT". The minimal acceptable risk of thrombocytopenia was defined using The American College of Chest Physicians (ACCP) 2012 guidelines, which recommend monitoring platelet counts in patients receiving heparin where the expected risk of HIT is>1% and by descriptive cost-benefit analysis based on the cost of routine platelet monitoring in the clinical setting. RESULTS: Complete results were available for 1361 (68.1%) patients, comprising: 653 primary hips, 22 revision hips, 1 hip resurfacing, 665 primary knees, 19 revision knees and 1 unicompartmental knee replacement. Mean platelet level was 281.9×109/L preoperatively and 527.83×109/L postoperatively. Forty-four patients (3.2%) experienced a postoperative fall in platelet levels. However, no patient experienced a drop in platelets to less than 50% of the preoperative value. DISCUSSION: The incidence of HIT in the elective arthroplasty population is low. Therefore, routine postoperative monitoring of platelets is not necessary in this population of patients. LEVEL OF EVIDENCE: II, prospective study.

Residue Adjacency Matrix Based Feature Engineering for Predicting Cysteine Reactivity in Proteins.

Free radicals that form from reactive species of nitrogen and oxygen can react dangerously with cellular components and are involved with the pathogenesis of diabetes, cancer, Parkinson's, and heart disease. Cysteine amino acids, due to their reactive nature, are prone to oxidation by these free radicals. Determining which cysteines oxidize within proteins is crucial to our understanding of these chronic diseases. Wet lab techniques, like differential alkylation, to determine which cysteines oxidize are often expensive and time-consuming. We utilize machine learning as a fast and inexpensive approach to identifying cysteines with oxidative capabilities. We created the original features RAMmod and RAMseq for use in classification. We also incorporated well-known features such as PROPKA, SASA, PSS, and PSSM. Our algorithm requires only the protein sequence to operate; however, we do use template matching by MODELLER to acquire 3D coordinates for additional feature extraction. There was a mean improvement of RAM over N6C by 22.04% MCC. It was statistically significant with a p-value of 0.015. RAM provided a significant increase over PSSM with a p-value of 0.040 and an average 70.09% improvement MCC.

Canada's Supreme Court abolishes 'promise of the patent'.

The Supreme Court of Canada has done away with the 'promise of the patent' doctrine. This doctrine invalidated patents to numerous otherwise useful inventions from 2005 to 2016. The Supreme Court of Canada has clarified that the statutory utility requirement requires only a scintilla of utility related to the subject matter of the invention. This utility must have been demonstrated or soundly predicted as of the Canadian filing date. The decision brings increased certainty to Canada's patent system and more closely aligns it with international norms.

Functional polyesters enable selective siRNA delivery to lung cancer over matched normal cells.

Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.

Pharmaceutical patent law: the Canadian perspective.

This article provides an overview of the patent regime in Canada, with a focus on issues most relevant to the pharmaceutical industry. The process of applying for a patent is discussed, as well as enforcement and litigation. Recent developments in the case law dealing with patentability requirements - novelty, obviousness, utility and sufficiency - are reviewed. Finally, the impact of recently negotiated trade agreements on Canadian patent law is addressed. In this article, we aim to provide an overview of the patent regime in Canada, with a focus on issues that are particularly relevant to the pharmaceutical industry.

Polystyrene microspheres enable 10-color compensation for immunophenotyping of primary human leukocytes.

Compensation is a critical process for the unbiased analysis of flow cytometry data. Numerous compensation strategies exist, including the use of bead-based products. The purpose of this study was to determine whether beads, specifically polystyrene microspheres (PSMS) compare to the use of primary leukocytes for single color based compensation when conducting polychromatic flow cytometry. To do so, we stained individual tubes of both PSMS and leukocytes with panel specific antibodies conjugated to fluorochromes corresponding to fluorescent channels FL1-FL10. We compared the matrix generated by PSMS to that generated using peripheral blood mononuclear cells (PBMC). Ideal for compensation is a sample with both a discrete negative population and a bright positive population. We demonstrate that PSMS display autofluorescence properties similar to PBMC. When comparing PSMS to PBMC for compensation PSMS yielded more evenly distributed and discrete negative and positive populations to use for compensation. We analyzed three donors' PBMC stained with our 10-color T cell subpopulation panel using compensation generated by PSMS vs.PBMC and detected no significant differences in the population distribution. Panel specific antibodies bound to PSMS represent an invaluable valid tool to generate suitable compensation matrices especially when sample material is limited and/or the sample requires analysis of dynamically modulated or rare events.

Using a simple apparatus to measure direct and diffuse photosynthetically active radiation at remote locations.

Plant canopy interception of photosynthetically active radiation (PAR) drives carbon dioxide (CO2), water and energy cycling in the soil-plant-atmosphere system. Quantifying intercepted PAR requires accurate measurements of total incident PAR above canopies and direct beam and diffuse PAR components. While some regional data sets include these data, e.g. from Atmospheric Radiation Measurement (ARM) Program sites, they are not often applicable to local research sites because of the variable nature (spatial and temporal) of environmental variables that influence incoming PAR. Currently available instrumentation that measures diffuse and direct beam radiation separately can be cost prohibitive and require frequent adjustments. Alternatively, generalized empirical relationships that relate atmospheric variables and radiation components can be used but require assumptions that increase the potential for error. Our goal here was to construct and test a cheaper, highly portable instrument alternative that could be used at remote field sites to measure total, diffuse and direct beam PAR for extended time periods without supervision. The apparatus tested here uses a fabricated, solar powered rotating shadowband and other commercially available parts to collect continuous hourly PAR data. Measurements of total incident PAR had nearly a one-to-one relationship with total incident radiation measurements taken at the same research site by an unobstructed point quantum sensor. Additionally, measurements of diffuse PAR compared favorably with modeled estimates from previously published data, but displayed significant differences that were attributed to the important influence of rapidly changing local environmental conditions. The cost of the system is about 50% less than comparable commercially available systems that require periodic, but not continual adjustments. Overall, the data produced using this apparatus indicates that this instrumentation has the potential to support ecological research via a relatively inexpensive method to collect continuous measurements of total, direct beam and diffuse PAR in remote locations.