Cholecystectomy in the red centre: a review of the surgical outcomes in Central Australia in a five-year period.

BACKGROUND: Despite the high rates of cholecystectomy in Australia, there is minimal literature regarding the outcomes of cholecystectomy in rural Central Australia within the Northern Territory. This study aims to better characterize the outcomes for patients undergoing cholecystectomy in Central Australia and review clinical and patient characteristics, which may affect outcomes. METHOD: A retrospective case-control study was performed using data obtained from medical records for all patients undergoing cholecystectomy at Alice Springs Hospital in the Northern Territory from January 2018 until December 2022. Patient characteristics were gathered, and key outcomes examined included: inpatient mortality and 30-day mortality, bile duct injury, bile leak, return to theatre, conversion to open, duration of procedure, length of stay, and up-transfer to a tertiary referral centre. RESULTS: A total of 466 patients were included in this study. Majority of the patients were female and there was a large portion of Indigenous Australians (56%). There were no inpatient mortalities, or 30-day mortalities recorded. There were two bile leaks and/or bile duct injuries (0.4%) and two unplanned returned to theatres (0.4%). Indigenous Australians were more likely to require an emergency operation and had a longer median length of stay (P < 0.001). CONCLUSION: Cholecystectomy can be performed safely and to a high standard in Central Australia. Surgeons in Central Australia must appreciate the nuances in the management of patients who come from a significantly different socioeconomic background, with complex medical conditions when compared to metropolitan centres.

Extensive lymphadenectomy may improve survival in node negative oesophageal cancer.

Lymph node metastases are a major prognostic factor in survival of patients with oesophageal cancer. The number of lymph nodes removed during oesophagectomy has been previously proven to be associated with improved survival. The aim of this study was to examine the effect of lymph node harvest on survival specifically in pathologically node negative (pN0) patients with oesophageal cancer. Data were extracted from a prospectively populated single-surgeon database of oesophageal resections for cancer. All consecutive patients with pN0 were included. Patient-specific risk adjusted analysis of overall and disease-free survival was performed to identify the number of lymph nodes associated with improved survival. Inclusion criteria were met by 137 patients (49 squamous cell carcinoma and 88 adenocarcinoma). Adjusted for cancer stage, tumour (histological type, degree of differentiation, lympho-vascular invasion, neo-adjuvant therapy) and patient related factors (age, sex), increased lymph node number was associated with significant improvement in overall (P = 0.045) and disease free (P = 0.030) survival. Lymph node count ≥ 17 was associated with improved overall and disease-free survival. In this cohort of patients with pathologically node-negative oesophageal cancer, lymph node count of 17 or above was associated with significantly improved survival.

Outcomes of patients with pneumatosis intestinalis and/or portal venous gas: a study of factors associated with survival and surgical intervention.

BACKGROUNDS: This study investigated the incidence of, and mortality and management outcomes following, pneumatosis intestinalis and/or portal venous gas on computed tomography. METHODS: A retrospective study of patients identified with pneumatosis intestinalis and/or portal venous gas on computed tomography at a quaternary centre (2013-2021) was performed. Data relating to clinical presentation (including quick sequential organ failure assessment score), co-morbidities (Charlson Comorbidity Index), biochemical data (including peak lactate level), and radiological findings, were obtained. Factors associated with these were assessed by logistic regression. RESULTS: From 16 428 scans, 107 (0.65%) demonstrated pneumatosis intestinalis and/or portal venous gas (mean 65.2 years [SD 15.2]; 60 [56%] male). Overall, 37 patients (35%) had both findings present. Thirty-three deaths (31%) were recorded. Fifty-four patients (51%) underwent surgery. Death was associated with quick sequential organ failure assessment score (score 1: OR 5.71, 95% CI 1.31-24.87; score 2: OR 10.00, 95% CI 1.94-51.54), Charlson Comorbidity Index ≥5 (OR 2.86, 95% CI 1.19-6.84), peak lactate ≥2.6 mmol/L (OR 14.53, 95% CI 4.39-48.14), and concomitant pneumatosis intestinalis and portal venous gas (OR 8.25, 95% CI 3.04-22.38). The presence of free peritoneal fluid (OR 3.23, 95% CI 1.44-7.28) or perforated viscus (OR 5.10, 95% CI 1.05-24.85) were the only predictors for surgery. CONCLUSION: Pneumatosis intestinalis and portal venous gas are rare findings. Despite traditionally portending a poor prognosis, mortality occurred in only one-third of patients. There were clear indicators of mortality viz. sepsis severity, comorbidities, and concomitant pneumatosis intestinalis and portal venous gas. Factors predicting surgery warrant further investigation.

Targeted modification of furan-2-carboxaldehydes into Michael acceptor analogs yielded long-acting hemoglobin modulators with dual antisickling activities.

Sickle cell disease (SCD) is the most common genetic disorder, affecting millions of people worldwide. Aromatic aldehydes, which increase the oxygen affinity of human hemoglobin to prevent polymerization of sickle hemoglobin and inhibit red blood cell (RBC) sickling, have been the subject of keen interest for the development of effective treatment against SCD. However, the aldehyde functional group metabolic instability has severly hampered their development, except for voxelotor, which was approved in 2019 for SCD treatment. To improve the metabolic stability of aromatic aldehydes, we designed and synthesized novel molecules by incorporating Michael acceptor reactive centers into the previously clinically studied aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF). Eight such derivatives, referred to as MMA compounds were synthesized and studied for their functional and biological activities. Unlike 5-HMF, which forms Schiff-base interaction with αVal1 nitrogen of hemoglobin, the MMA compounds covalently interacted with ßCys93, as evidenced by reverse-phase HPLC and disulfide exchange reaction, explaining their RBC sickling inhibitory activities, which at 2 mM and 5 mM, range from 0% to 21% and 9% to 64%, respectively. Additionally, the MMA compounds showed a second mechanism of sickling inhibition (12%-41% and 13%-62% at 2 mM and 5 mM, respectively) by directly destabilizing the sickle hemoglobin polymer. In vitro studies demonstrated sustained pharmacologic activities of the compounds compared to 5-HMF. These findings hold promise for advancing SCD therapeutics.

A case of rare gastric metastasis of invasive lobular carcinoma of the breast.

Breast cancer is the most common type of cancer diagnosed among women worldwide. It significantly contributes to cancer-related mortality in females. Early-stage breast cancers have a high cure rate. However, distant metastasis of breast cancer due to haematological and lymphatic spread often leads to a poor prognosis. Gastric and duodenal metastasises are rarely observed in invasive lobular carcinoma of the breast. Early diagnosis is challenging due to the non-specific symptoms, the limited specificity of radiological investigations and the difficulty in obtaining adequate tissue biopsy. Herein, we report the clinical, radiological, and macroscopic features of a 72-year-old female with rare gastric metastasis of breast cancer and likely concurrent duodenal metastasis.

Trends in outcomes with adoption of indocyanine green angiography in postmastectomy reconstruction.

BACKGROUND: Indocyanine green angiography (ICGA) aims to reduce ischaemic complications by supplementing intraoperative perfusion assessment of mastectomy flaps. Learning curves for this technology have not been analysed. We evaluated changes in patient outcomes with increasing case volume after ICGA adoption in postmastectomy reconstruction. METHODS: Single-institution retrospective analysis of 320 implant-based reconstructions following mastectomy using ICGA from 2015, when it was introduced, to 2021. Cases chronologically divided into tertiles and complications amongst groups evaluated. Trends in ischaemic complications plotted using weighted moving average. CUSUM analysis determined after how many cases plateau was reached. Number of ischaemic complications prior to plateau calculated with AUC analysis. RESULTS: Ischaemic complications decreased over time (Group 1, 15.1%; Group 2, 11.2%; Group 3, 4.7%, P = 0.034). Cases of delayed reconstruction increased over time (Group 1, 6.6%; Group 2, 28%; Group 3, 22.4%; P < 0.001). Our institution reached plateau of 10% ischaemic complications after 160 cases. Mean incidence of ischaemic complications decreased from 16.9% during the first 160 cases to 3.8% after plateau was reached (P < 0.001). Eleven extra breasts (6.9%) experienced ischaemic complications, that may have been avoided if operated by surgeons after the first 160 cases. CONCLUSIONS: There was increased tendency towards a conservative approach of delaying reconstruction and decreased rates of ischaemic complications with increasing case volume after ICGA implementation. A significant number of cases were needed to reach plateau of minimal ischaemic complications. This data could encourage development of standardized protocols for this technology to shorten learning curves for improved patient outcomes.

Characterization of the Escherichia coli pyridoxal 5'-phosphate homeostasis protein (YggS): Role of lysine residues in PLP binding and protein stability.

The pyridoxal 5'-phosphate (PLP) homeostasis protein (PLPHP) is a ubiquitous member of the COG0325 family with apparently no catalytic activity. Although the actual cellular role of this protein is unknown, it has been observed that mutations of the PLPHP encoding gene affect the activity of PLP-dependent enzymes, B6 vitamers and amino acid levels. Here we report a detailed characterization of the Escherichia coli ortholog of PLPHP (YggS) with respect to its PLP binding and transfer properties, stability, and structure. YggS binds PLP very tightly and is able to slowly transfer it to a model PLP-dependent enzyme, serine hydroxymethyltransferase. PLP binding to YggS elicits a conformational/flexibility change in the protein structure that is detectable in solution but not in crystals. We serendipitously discovered that the K36A variant of YggS, affecting the lysine residue that binds PLP at the active site, is able to bind PLP covalently. This observation led us to recognize that a number of lysine residues, located at the entrance of the active site, can replace Lys36 in its PLP binding role. These lysines form a cluster of charged residues that affect protein stability and conformation, playing an important role in PLP binding and possibly in YggS function.

Benchmarks in colorectal surgery: multinational study to define quality thresholds in high and low anterior resection.

BACKGROUND: Benchmark comparisons in surgery allow identification of gaps in the quality of care provided. The aim of this study was to determine quality thresholds for high (HAR) and low (LAR) anterior resections in colorectal cancer surgery by applying the concept of benchmarking. METHODS: This 5-year multinational retrospective study included patients who underwent anterior resection for cancer in 19 high-volume centres on five continents. Benchmarks were defined for 11 relevant postoperative variables at discharge, 3 months, and 6 months (for LAR). Benchmarks were calculated for two separate cohorts: patients without (ideal) and those with (non-ideal) outcome-relevant co-morbidities. Benchmark cut-offs were defined as the 75th percentile of each centre's median value. RESULTS: A total of 3903 patients who underwent HAR and 3726 who had LAR for cancer were analysed. After 3 months' follow-up, the mortality benchmark in HAR for ideal and non-ideal patients was 0.0 versus 3.0 per cent, and in LAR it was 0.0 versus 2.2 per cent. Benchmark results for anastomotic leakage were 5.0 versus 6.9 per cent for HAR, and 13.6 versus 11.8 per cent for LAR. The overall morbidity benchmark in HAR was a Comprehensive Complication Index (CCI®) score of 8.6 versus 14.7, and that for LAR was CCI® score 11.9 versus 18.3. CONCLUSION: Regular comparison of individual-surgeon or -unit outcome data against benchmark thresholds may identify gaps in care quality that can improve patient outcome.

Cost-effectiveness of indocyanine green angiography in postmastectomy breast reconstruction.

BACKGROUND: Mastectomy skin flap necrosis is a major complication of skin- or nipple-sparing mastectomy. Indocyanine green angiography (ICGA) is a novel technology that can identify flaps at risk of necrosis, but there is paucity of cost-effectiveness data particularly in the Australian context. We evaluated its cost-effectiveness in breast reconstruction surgery. METHODS: Single-institution retrospective study of 295 implant-based breast reconstructions using ICGA compared with 228 reconstructions without ICGA from 2015 to 2020. Costs were calculated using Medicare item numbers and micro-costing analysis. Break-even point analysis determined the number needed to break-even. Cost-utility analysis compared probabilities of ischaemic complications and utility estimates derived from surveys of surgeons to fit into a decision model. RESULTS: There were 295 breast reconstructions using ICGA with a total cost of AU$164,657. The average cost of treating an ischaemic complication was AU$21,375. Use of ICGA reduced the ischaemic complication rate from 14.9% to 8.8%. Ischaemic complications were prevented in 18 breasts resulting in gross cost savings of AU$384,745 and net savings of AU$220,088. Three hundred eighteen cases using ICGA are needed to break-even. The decision model demonstrated a baseline cost difference of AU$1,179, a quality-adjusted life-years (QALY) difference of 1.77, and an incremental cost-utility ratio (ICUR) of AU$656 per QALY favouring ICGA. CONCLUSIONS: Routine use of ICGA during implant-based breast reconstruction is a cost-effective intervention for the reduction of ischaemic complications in the Australian setting. ICGA use was associated with a gain of 1.77 additional years of perfect health at a cost of AU$656 more per year.

Clinicopathologic and survival differences between adenocarcinoma of the distal oesophagus and gastro-oesophageal junction.

BACKGROUND: The incidence of adenocarcinoma of the distal oesophagus (DO) and gastro-oesophageal junction (GOJ) are increasing. They may represent differing disease processes. This study aimed to assess clinicopathological and survival differences between patients with DO and GOJ adenocarcinomas. METHODS: Data were extracted from a prospective single-surgeon database of consecutive patients undergoing an open Ivor-Lewis oesophagectomy for oesophageal adenocarcinoma (distal oesophagus, Siewert type I and II). Differences in clinicopathological characteristics and survival were evaluated and prognostic factors examined using univariate and multivariate survival analyses. RESULTS: The data were available for 234 patients who underwent an oesophagectomy between 1992 and 2019. DO tumours had higher rates of Barrett's oesophagus (P < 0.001), presented with lower tumour stage (P = 0.02) and were more likely to be associated with fewer lymph nodes resected (P = 0.003) than GOJ tumours. The median overall survival for distal oesophageal tumours was 29.2 months, while gastro-oesophageal tumours was 38.6 months. Kaplan Meier analysis did not show a difference in overall survival between the two groups (P = 0.08). However, when adjusted for potential confounders, GOJ tumours were associated with a reduced adjusted hazard of death (adjusted HR 0.58, 95% CI 0.36-0.92, P = 0.022) compared with DO tumours. CONCLUSION: This study suggests that GOJ cancers have different clinicopathological characteristics and improved survival compared to DO tumours.

An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling.

Aromatic aldehydes that bind to sickle hemoglobin (HbS) to increase the protein oxygen affinity and/or directly inhibit HbS polymer formation to prevent the pathological hypoxia-induced HbS polymerization and the subsequent erythrocyte sickling have for several years been studied for the treatment of sickle cell disease (SCD). With the exception of Voxelotor, which was recently approved by the U.S. Food and Drug Administration (FDA) to treat the disease, several other promising antisickling aromatic aldehydes have not fared well in the clinic because of metabolic instability of the aldehyde moiety, which is critical for the pharmacologic activity of these compounds. Over the years, our group has rationally developed analogs of aromatic aldehydes that incorporate a stable Michael addition reactive center that we hypothesized would form covalent interactions with Hb to increase the protein affinity for oxygen and prevent erythrocyte sickling. Although, these compounds have proven to be metabolically stable, unfortunately they showed weak to no antisickling activity. In this study, through additional targeted modifications of our lead Michael addition compounds, we have discovered other novel antisickling agents. These compounds, designated MMA, bind to the α-globin and/or ß-globin to increase Hb affinity for oxygen and concomitantly inhibit erythrocyte sickling with significantly enhanced and sustained pharmacologic activities in vitro.

Enhancing the membrane activity of Piscidin 1 through peptide metallation and the presence of oxidized lipid species: Implications for the unification of host defense mechanisms at lipid membranes.

Piscidins are host-defense peptides (HDPs) from fish that exhibit antimicrobial, antiviral, anti-cancer, anti-inflammatory, and wound-healing properties. They are distinctively rich in histidine and contain an amino terminal copper and nickel (ATCUN) binding motif due to the presence of a conserved histidine at position 3. Metallation lowers their total charge and provides a redox center for the formation of radicals that can convert unsaturated fatty acids (UFAs) into membrane-destabilizing oxidized phospholipids (OxPLs). Here, we focus on P1, a particularly membrane-active isoform, and investigate how metallating it and making OxPL available influence its membrane activity. First, we quantify through dye leakage experiments the permeabilization of the apo- and holo-forms of P1 on model membranes containing a fixed ratio of anionic phosphatidylglycerol (PG) and zwitterionic phosphatidylcholine (PC) but varying amounts of Aldo-PC, an OxPL derived from the degradation of several UFAs. Remarkably, metallating P1 increases membranolysis by a factor of five in each lipid system. Conversely, making Aldo-PC available improves permeabilization by a factor of two for each peptide form. Second, we demonstrate through CD-monitored titrations that the strength of the peptide-membrane interactions is similar in PC/PG and PC/PG/Aldo-PC. Thus, peptide-induced membrane activity is boosted by properties intrinsic to the peptide (e.g., charge and structural changes associated with metallation) and bilayer (e.g., reversal of sn-2 chain due to oxidation). Third, we show using oriented-sample 15N solid-state NMR that the helical portion of P1 lies parallel to the bilayer surface in both lipid systems. 31P NMR experiments show that both the apo- and holo-states interact more readily with PC in PC/PG. However, the presence of Aldo-PC renders the holo-, but not the apo-state, more specific to PG. Hence, the membrane disruptive effects of P1 and its specificity for the anionic lipids found on pathogenic cell membrane surfaces are simultaneously optimized when it is metallated and the OxPL is present. Overall, this study deepens our insights into how OxPLs affect peptide-lipid interactions and how host defense metallopeptides could help integrate the effects of antimicrobial agents.

Immunohistochemistry in screening for heritable colorectal cancer: what to do with an abnormal result.

Recent developments in our understanding of molecular genetics have transformed screening and diagnostic practices for Lynch syndrome. The current standard involves universal tumour analysis of resected colorectal cancer (and ideally polypectomy) specimens using immunohistochemistry and molecular techniques. Patients with abnormal immunohistochemical findings are subsequently referred for definitive mutational testing. This review relates the molecular pathogenesis of Lynch syndrome to current immunohistochemistry-based screening strategies and discusses the interpretation and clinical implications of screening results.