Postoperative fluid therapy in enhanced recovery after surgery for pancreaticoduodenectomy.

Backgrounds/Aims: Optimal intravenous fluid management during the perioperative period for patients undergoing pancreaticoduodenectomy (PD) within the framework of enhanced recovery after surgery (ERAS) is unclear. Studies have indicated that excessive total body salt and water can contribute to the development of oedema, leading to increased morbidity and extended hospital stays. This study aimed to assess the effects of an intravenous therapy regimen during postoperative day (POD) 0 to 2 in PD patients within ERAS. Methods: A retrospective interventional cohort study was conducted, and it involved all PD patients before and after implementation of ERAS (2009-2017). In the ERAS group, a targeted maintenance fluid regimen of 20 mL/kg/day with a sodium requirement of 0.5 mmoL/kg/day was administered. Outcome measures included the mmol of sodium and chloride administered, length of stay, and morbidity (postoperative pancreatic fistula, POPF; acute kidney injury, AKI; ileus). Results: The study included 169 patients, with a mean age of 64 ± 11.3 years. Following implementation of the intravenous fluid therapy protocol, there was a significant reduction in chloride and sodium loading. However, in the multivariable analysis, chloride administered (mmoL/kg) did not independently influence the length of stay; or rates of POPF, ileus, or AKI (p > 0.05). Conclusions: The findings suggested that a postoperative intravenous fluid therapy regimen did not significantly impact morbidity. Notably, there was a trend towards reduced length of stay within an increasingly comorbid patient cohort. This targeted fluid regimen appears to be safe for PD patients within the ERAS program. Further prospective research is needed to explore this area.

Human leucocyte antigen genotype association with the development of immune-related adverse events in patients with non-small cell lung cancer treated with single agent immunotherapy.

INTRODUCTION: Biomarkers that predict the risk of immune-mediated adverse events (irAEs) among patients with non-small cell lung cancer (NSCLC) may reduce morbidity and mortality associated with these treatments. METHODS: We carried out high resolution human leucocyte antigen (HLA)-I typing on 179 patients with NSCLC treated with anti-program death (PD)-1/program death ligand (PDL)-1. Toxicity data were collected and graded as per common terminology criteria for adverse event (CTCAE) v5.0. We used 14.8-week for landmark analysis to address lead-time bias to investigate the correlation between HLA-I/II zygosity, supertypes and alleles with irAE. Furthermore, we assessed the association for irAE with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). RESULTS: Homozygosity at one or more HLA-I loci, but not HLA-II, was associated with a reduced risk of irAE (relative risk (RR) = 0.61, 95% CI 0.33-0.95, P = 0.035) especially pneumonitis or any grade 3 toxicity. Patients with HLA-A03 supertype had a higher risk of developing irAE (RR = 1.42, 95% CI 1.02-2.01, P = 0.039). The occurrence of any irAE was significantly associated with improved CBR (RR = 1.48, P < 0.0001), PFS (HR = 0.45, P = 0.0003) and OS (HR = 0.34, P < 0.0001). CONCLUSIONS: Homozygosity at one or more HLA-I loci may serve as biomarker to predict patients who are unlikely to experience severe irAEs among patients with NSCLC and treated with anti-PD1/PDL1, but less likely to derive clinical benefit. Patients with HLA-I homozygous might benefit from additional therapy.

Prognostic value of HLA-I homozygosity in patients with non-small cell lung cancer treated with single agent immunotherapy.

BACKGROUND: We aimed to assess the impact of genomic human leukocyte antigen (HLA)-I/II homozygosity on the survival benefit of patients with unresectable locally advanced, metastatic non-small lung cancer treated by single-agent programmed cell death protein-1/programmed death ligand 1 (PD1/PDL1) inhibitors. METHODS: We collected blood from 170 patients with advanced lung cancer treated with immunotherapy at two major oncology centers in Western Australia. Genomic DNA was extracted from white blood cells and used for HLA-I/II high-resolution typing. HLA-I/II homozygosity was tested for association with survival outcomes. Univariable and multivariable Cox regression models were constructed to determine whether HLA homozygosity was an independent prognostic factor affecting Overall Survival (OS) and Progression Free Survival (PFS). We also investigated the association between individual HLA-A and -B supertypes with OS. RESULTS: Homozygosity at HLA-I loci, but not HLA-II, was significantly associated with shorter OS (HR=2.17, 95% CI 1.13 to 4.17, p=0.02) in both univariable and multivariable analysis. The effect of HLA-I homozygosity in OS was particularly relevant for patients with tumors expressing PDL1 ≥50% (HR=3.93, 95% CI 1.30 to 11.85, p<0.001). The adverse effect of HLA-I homozygosity on PFS was only apparent after controlling for interactions between PDL1 status and HLA-I genotype (HR=2.21, 95% CI 1.04 to 4.70, p=0.038). The presence of HLA-A02 supertype was the only HLA-I supertype to be associated with improved OS (HR=0.56, 95% CI 0.34 to 0.93, p=0.023). CONCLUSION: Our results suggest that homozygosity at ≥1 HLA-I loci is associated with short OS and PFS in patients with advanced non-small cell lung cancer with PDL1 ≥50% treated with single-agent immunotherapy. Carriers of HLA-A02 supertype reported better survival outcomes in this cohort of patients.

Assessing the efficacy of TNF-alpha inhibitors in preventing emergency and emergent colectomies.

BACKGROUND AND AIM: Severe ulcerative colitis (UC) is potentially life threatening and is associated with significant morbidity. TNF-∝ inhibitors (Infliximab) were introduced in Australia for the management of medically resistant, acute, severe flares of UC in 2008. The aim of this study is to assess the efficacy of Infliximab in preventing emergent and emergency colectomies for patients with moderate to severe UC by comparing colectomy rates before and after its introduction at our institution. METHODS: This was a retrospective cohort study of all patients who were admitted to the Royal Perth Hospital with a flare of UC between 2002 and 2017. Patients were divided into two cohorts: those admitted prior to the introduction of Infliximab (pre-2008) and those admitted after. We compared data between these two groups, including age, gender, length of admission, use of Infliximab, colectomy, and complications of surgery. We defined emergency surgery as requiring surgery during the index admission and emergent surgery as an operation within 54 weeks. RESULTS: A total of 313 UC cases from 2002 to 2017 were analyzed. There was a decrease in emergency and emergent colectomies from 19.4 to 8% in the post-2008 cohort (P = 0.008). Furthermore, there was a decrease in the proportion of operations performed as emergencies, from 36 to 20%. This resulted in a significantly reduced length of stay (13.4-9.7 days, P < 0.05) and complication rate (36 to 20%, P < 0.05). CONCLUSION: Overall, the need for emergency and emergent operations has drastically reduced at our institution with the introduction of Infliximab. This study has confirmed the efficacy of Infliximab in reducing colectomy rates at our institution.

The relationship between lifestyle and serum neurofilament light protein in Huntington's disease.

OBJECTIVES: Serum neurofilament light protein (NfL) is a promising marker of disease onset and progression in Huntington's disease (HD). This study investigated associations between lifestyle factors and NfL levels in HD mutation carriers compared to healthy age- and sex-matched controls. MATERIALS AND METHODS: Participants included 29 HD mutation carriers and 15 healthy controls. Associations between serum NfL concentrations and lifestyle factors, including cardiorespiratory fitness, social network size and diversity, physical activity, cognitive reserve, smoking status, and alcohol consumption, were examined using a stepwise multivariable linear regression model. RESULTS: Higher NfL levels were associated with lower cognitive reserve, social network size and diversity and cardiorespiratory fitness in HD mutation carriers. Group × lifestyle factor effects were observed between lower serum NfL levels and a greater social network diversity. CONCLUSION: These findings highlight a relationship between lifestyle factors and NfL levels in HD mutations carriers; however, longitudinal studies are required to confirm if these observed relationships persist over time.

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study.

BACKGROUND: PD-1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD-L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD-1 inhibitor pembrolizumab. METHODS: Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6-12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD-L1. RESULTS: CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD-L1+ CTCs (14/25, 64%) had significantly longer progression-free survival (PFS) compared with patients with PD-L1- CTCs (26.6 months vs. 5.5 months; p = .018). The 12-month PFS rates were 76% versus 22% in the PD-L1+ versus PD-L1- CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD-L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052-1.012; p = .026). CONCLUSION: Our results reveal the potential of CTCs as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with melanoma. PD-L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. IMPLICATIONS FOR PRACTICE: The present data suggest that PD-L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.

Intraoperative nerve monitoring in endocrine surgery: prevalence and reasons for its use in Australia and New Zealand.

BACKGROUND: Intraoperative nerve monitoring (IONM) has increasingly been used in thyroid surgery by general, endocrine and head and neck surgeons. The purpose of this paper was to explore the prevalence and reasons for the usage of IONM in endocrine surgery in Australia and New Zealand. METHODS: A survey was sent to general surgeons registered with the Royal Australasian College of Surgeons involved in endocrine surgery and members of the Australian and New Zealand Endocrine Surgeons. Users were divided into surgeon type, area of work, hospital type and volume of surgery. These data were analysed with univariate and multivariate logistic regression models. RESULTS: Significant differences in IONM usage levels were observed between endocrine and general surgeons, area of work and volume of surgery performed. Endocrine surgeons are significantly more likely to use IONM than general surgeons. Surgeons who work in tertiary hospitals are more likely to use IONM as compared to those working in district hospitals. Surgeons who perform less than 100 thyroidectomies were more likely to be users of IONM. CONCLUSION: IONM is not routinely used in thyroid surgery in Australia and New Zealand. The main reasons for the use of IONM given in our study by routine users were to establish familiarity of equipment and medicolegal reasons. Selective users chose as the most common reasons, a documented pre-existing unilateral nerve paresis or a hostile surgical field. Non-users stated that there was conflicting evidence that it improves outcomes and increased costs.

Can we predict expected adenoma weight preoperatively with reference to the correlation of preoperative biochemical tests with parathyroid adenoma weight?

BACKGROUND: Primary hyperparathyroidism is a prevalent disease with proven benefits for appropriately selected patients who undergo parathyroidectomy. The ability to accurately predict expected single adenoma gland weight as the cause based on preoperative biochemical tests could improve cure rates in a minimally invasive approach. OBJECTIVE: To assess the correlation between parathyroid weight and preoperative parathyroid hormone and calcium levels in patients with primary hyperparathyroidism with a solitary adenoma and determine if these could be used to predict expected parathyroid weight. METHODS: Patients with primary hyperparathyroidism who underwent curative parathyroidectomy from 2013 to 2018 was retrospectively analysed. RESULTS: There is a strong positive correlation r = 0.602 between preoperative PTH levels with respect to parathyroid weight (p < 0.001). There was a moderate correlation r = 0.474 between preoperative adjusted Calcium and PTH weight (p < 0.001). An algorithm was developed to calculate predicted weight of a single adenoma but when tested against cases with hyperplasia and double adenomas during the period, the variability of predicted weight meant it was impossible to differentiate between the causes. Hyperplasia was excluded and 95% of double adenomas excluded however, when parathyroid weight exceeded 1200 mg CONCLUSION: There is a strong correlation between preoperative PTH levels and calcium levels with parathyroid weight. The large variability of predicted parathyroid weight however, precludes the use of biochemical tests alone preoperatively in being able to differentiate between a single adenoma, double adenoma or hyperplasia as the cause in primary hyperparathyroidism. At parathyroid predicted weights above 1200 mg however, all cases of hyperplasia, and 95% of double adenomas excluded.

A diagnostic autoantibody signature for primary cutaneous melanoma.

Melanoma is an aggressive form of skin cancer that is curable by surgical excision in the majority of cases, if detected at an early stage. To improve early stage melanoma detection, the development of a highly sensitive diagnostic test is of utmost importance. Here we aimed to identify antibodies to a panel of tumour associated antigens that can differentiate primary melanoma patients and healthy individuals. A total of 245 sera from primary melanoma patients and healthy volunteers were screened against a high-throughput microarray platform containing 1627 functional proteins. Following rigorous statistical analysis, we identified a combination of 10 autoantibody biomarkers that, as a panel, displays a sensitivity of 79%, specificity of 84% and an AUC of 0.828 for primary melanoma detection. This melanoma autoantibody signature may prove valuable for the development of a diagnostic blood test for routine population screening that, when used in conjunction with current melanoma diagnostic techniques, could improve the early diagnosis of this malignancy and ultimately decrease the mortality rate of patients.

Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma.

Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors (p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.