Search

Background The outcome of anti-reflux surgery in patients with suspected gastro-oesophageal reflux-induced cough is frequently uncertain. The aims of this study were to assess the efficacy of laparoscopic fundoplication for controlling cough in patients with chronic cough without asthma, who have pathologic gastro-oesophageal reflux, and to identify predictors of response. Methods From a prospective database of 1598 patients who have undergone laparoscopic fundoplication, 66 (4%) with proven gastro-oesophageal reflux disease (GORD) and chronic cough without asthma were studied. All patients underwent gastroscopy and 24-h pH monitoring before operation. Heartburn and regurgitation were assessed using a modified DeMeester score. Severity of cough before and after surgery was self-assessed by the patient using a visual analog scale at a minimum of 12 months post-operatively (median 43 mo; range: 14–104 mo). Patients were considered to have responded to fundoplication if they had no cough or the cough had improved by 50% or more after operation. Results Cough and heartburn/regurgitation were relieved in 61% (40/66) and 90% (44/49) of the patients, respectively. The presence of typical GORD symptoms or oesophagitis, and pH study variables did not predict the response of the cough to fundoplication. Conclusion Refinement in the aetiological diagnosis of chronic cough due to GORD is necessary for improved outcome. Patients diagnosed with GORD-related chronic cough need to be counseled regarding their expectations from anti-reflux surgery.

Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival (P = 0.00047 and P = 0.0014, respectively) and worse overall survival (P = 0.0223 and P = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with BRAF mutation status (P = 0.0389). RNA-sequencing indicated patients with immune “cold” signatures had worse survival, which was associated with CT biomarker, MPP4 (P = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers (P = 0.0028).Implications:CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment.

Kaplan-Meier (log-rank) analysis of MPP4 and SD3 showing the PFS and OS for stage III patients only. a. PFS for MPP4, **p=0.0017, b. OS for MPP4, *p=0.0117, c. PFS for SD3, ***p=0.0003 and d. OS for SD3, **p=0.0094.

Multiplex immunofluorescence staining quantification by Visiopharm Image Analytical System. DAPI nuclei were segmented defining the areas. Then each marker was quantified within this DAPI area. MPP4 low (MelR062) and MPP4 high (MelR166) phenotypes are represented.

Table S1. Patient Characteristics. AJCC: American Joint Committee on Cancer Table S2. Clinical information including histology, stage and survival. Table S3. Univariate analysis of clinico-pathological and CT features. Log-rank (Mantel-Cox) test to determine optimal cut-offs for low/high groups. Table S4. RNAseq immune genes for multiplex analysis.

The association between TMB and SD3/MPP4 is not statistically significant. A. MPP4, not significant, Fisher's exact. B. SD3, not significant, Fisher's exact.

Supplementary Table 1 from Genome-Wide Copy Number Analysis in Esophageal Adenocarcinoma Using High-Density Single-Nucleotide Polymorphism Arrays

Supplementary Figure 2 from Genome-Wide Copy Number Analysis in Esophageal Adenocarcinoma Using High-Density Single-Nucleotide Polymorphism Arrays

Supplementary Figure 1 from Genome-Wide Copy Number Analysis in Esophageal Adenocarcinoma Using High-Density Single-Nucleotide Polymorphism Arrays

We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23–208) per tumor. LOH and gains averaged 33 (range, 3–83) and 31 (range, 11–73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7–57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0–11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development. [Cancer Res 2008;68(11):4163–72]

IntroductionIn 2017 the Dutch Upper Gastrointestinal Cancer Audit Group proposed a ten-item composite measure for a ‘textbook outcome’ (TBO) following oesophago-gastric resection. Studies have shown associations between TBO and improved conditional and overall survival. The aim of this study was to evaluate the use of TBO to assess the outcomes from a single specialist unit in a country, with low incidence of disease, allowing comparisons with international specialist centres. Materials and Methods Retrospective analysis of prospectively collected oesophageal cancer surgery data at a single centre, in Australia, between 2013 to 2018. Multivariable logistical regression assessed association between baseline factors and TBO. Post-operative complications were analysed in two separate groups as Clavien-Dindo ≥2 (CD≥2) and Clavien-Dindo ≥3 (CD≥3). Cox-proportional hazards regression analysis determined the association between TBO and survival. Results 246 patients were analysed, with 50.8% (n=125) achieving a TBO when complications were defined as CD≥2 and 58.9% (n=145) when using CD≥3. Patients aged ≥75, and those with a pre-operative respiratory co-morbidity were less likely to achieve a TBO. Overall survival was not influenced by TBO when complications were defined as CD≥2, however it was higher when a TBO was achieved, and complications were defined as CD≥3 (HR 0.54, 95% CI, 0.35 to 0.84, P=0.007). Conclusion TBO is a multi-parameter metric that allowed benchmarking of the quality of oesophageal cancer surgery in our unit, providing favourable outcomes compared with other published data. There was an association between TBO and improved overall survival when the definition of severe complications was CD≥3. Key Words: Cancer Surgery, Oesophagectomy, Quality Performance Indicators, Textbook Outcome

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF

BACKGROUND: There is currently a lack of evidence-based guidelines regarding surveillance for recurrence after esophageal and gastric (OG) cancer surgical resection, and which symptoms should prompt endoscopic or radiological investigations for recurrence. The aim of this study was to develop a core symptom set using a modified Delphi consensus process that should guide clinicians to carry out investigations to look for suspected recurrent OG cancer in previously asymptomatic patients. METHODS: A web-based survey of 42 questions was sent to surgeons performing OG cancer resections at high volume centers. The first section evaluated the structure of follow-up and the second, determinants of follow-up. Two rounds of a modified Delphi consensus process and a further consensus workshop were used to determine symptoms warranting further investigations. Symptoms with a 75% consensus agreement as suggestive of recurrent cancer were included in the core symptom set. RESULTS: 27 surgeons completed the questionnaires. A total of 70.3% of centers reported standardized surveillance protocols, whereas 3.7% of surgeons did not undertake any surveillance in asymptomatic patients after OG cancer resection. In asymptomatic patients, 40.1% and 25.9% of centers performed routine imaging and endoscopy, respectively. The core set that reached consensus, consisted of eight symptoms that warranted further investigations included; dysphagia to solid food, dysphagia to liquids, vomiting, abdominal pain, chest pain, regurgitation of foods, unexpected weight loss and progressive hoarseness of voice. CONCLUSION: There is global variation in monitoring patients after OG cancer resection. Eight symptoms were identified by the consensus process as important in prompting radiological or endoscopic investigation for suspected recurrent malignancy. Further randomized controlled trials are necessary to link surveillance strategies to survival outcomes and evaluate prognostic value. ispartof: DISEASES OF THE ESOPHAGUS vol:36 issue:1 ispartof: location:United States status: published

Gastroesophageal reflux disease (GORD) is defined as troublesome symptoms and/or injury to the oesophageal mucosa consistent with acid exposure [1]. GORD is common, with an age-adjusted global prevalence of 9% but significant variation across the world [2]. The diagnosis can often be made on clinical grounds and is more likely if there is at least a partial response to a proton pump inhibitor (PPI) [3]. Indications for oesophageal testing have been recently updated in international consensus guidelines, which include guidelines where diagnosis is not clearly established [4]. Fundoplication is the use of the gastric fundus to create a high-pressure zone on or around the lower oesophagus and is usually performed laparoscopically. It can be considered in terms of the completeness of the wrap (generally from 90 to 360°), and if less than 360°, whether the wrap is brought anterior to the oesophagus, posterior, or both. The efficacy and side effect profiles of many of the approaches have been subjected to randomised trials: anterior 90 vs 360° [5]; anterior 180 vs 360° [6]; and posterior 270 vs 360° [7]. The relative merits of each have been recently reviewed by Morino and colleagues [8]. Fundoplication is at least as safe and effective as PPI in relieving the symptoms of GORD [9]. For PPI-refractory GORD, fundoplication is more effective than escalating medical therapy [10].

The incidence of oesophageal adenocarcinoma (OAC) is rising in Western countries, with a 5-year overall survival (OS) rate of 14%. Curative treatment based on oesophagectomy is only suitable for ~50% of patients due to late-stage diagnosis. While the addition of preoperative chemotherapy or chemoradiotherapy has improved OS in OAC patients, little is known about the molecular basis of treatment response and patient outcomes. We investigated multi-omics data including whole-genome sequencing, RNA sequencing, methylation profiles and immunohistochemistry from 115 OAC patients mostly from DOCTOR phase II clinical trial that utilized neoadjuvant therapy (ANZCTR-ACTRN12609000665235). We identified genomic features associated with poor OS, such as the APOBEC mutational signature. We also showed that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. RNA sequencing and methylation profiles suggested four immune clusters associated with OS and progression-free survival. The immune-suppressed cluster was associated with worse survival and epithelial-mesenchymal transition signature and enriched with myeloid-derived cells. The immune hot cluster was associated with better survival and enriched with T-cells, myeloid-derived cells, interferon-gamma and alpha responses, and immune markers such as CCL5, CD8A, and NKG7. We investigated multi-omic features of OAC tumours from patients who were part of phase II clinical trial. We discovered prognostic features such as mutational signatures and complex genomic events. We identified distinct immune clusters associated with patient outcomes and the potential of immunotherapy for select clusters. We characterized molecular features of OAC patients which has the potential to predict responses to neoadjuvant therapy and develop better-selected therapy, monotherapy, or combination therapy in the future.

The outcome of anti-reflux surgery in patients with cough suspected to be induced by gastro-oesophageal reflux disease is frequently uncertain. The aims of this study were to assess the efficacy of laparoscopic fundoplication (LF) for controlling cough in a patient population suffering chronic cough when alternative aetiologies (e.g. asthma) had been excluded and pathologic gastro-oesophageal reflux had been confirmed on ambulatory pH monitoring, and to identify predictors of response. From a prospective database of 1,598 patients who had undergone laparoscopic fundoplication, 66 (4%) had a principal presenting symptom of chronic cough as well as objective evidence of gastro-oesophageal reflux disease (GORD). Patients completed questionnaires for GORD symptoms (modified DeMeester score) and severity of cough (visual analog scale) both before and after LF, and had pre-operative gastroscopy and 24-hour pH monitoring before operation. Patients were considered to have responded to LF if they had no cough or the cough had improved by 50% or more after operation. Follow-up data was available for 66/66 patients (100%), with a median follow-up time of 43 months (range 14–104 months) after operation. Cough was relieved in 40/66 (61%), while typical GORD symptoms (heartburn, regurgitation) was relieved in 44/49 (90%). The presence of typical GORD symptoms, oesophagitis, or pH study variables did not predict the response of the cough to LF. At 1 year, 67% of patients were satisfied with the results of their surgery, 20% were not and 13% were unsure. For comparison, the 1430/1598 patients in the database with no laryngopharyngeal symptoms had a satisfaction rate of 94%. Based on our study and available literature, it appears there are no reliable pre-operative clinical predictors of a satisfactory response of cough to LF. This probably reflects a current inability to obtain an accurate aetiological diagnosis of chronic cough, even in the presence of known abnormal gastro-oesophageal reflux disease. Regardless, in a well-chosen cohort of patients with chronic cough, LF can yield good patient satisfaction rates, albeit less than for patients with typical GORD symptoms.

Background Laparoscopic fundoplication (LF) is the standard surgical procedure for the treatment of gastro-oesophageal reflux disease (GORD). Laparoscopic Roux-en-Y gastric bypass (LRYGB) is commonly performed to achieve weight loss in obese patients, but it also has anti-reflux properties. Hence, in the obese population suffering from GORD, LRYGB could be an alternative to LF. The aim of this trial will be to compare LF and LRYGB in an obese population presenting with GORD and being considered for surgery. Methods This will be an investigator-initiated randomized clinical trial. The research population will be obese patients (BMI 30–34.9 with waist circumference more than 88 cm (women) or more than 102 cm (men), or BMI 35–40 with any waist circumference) referred to a public hospital for consideration of anti-reflux surgery. The primary aim of the study will be to determine the efficacy of LF compared with LRYGB on subjective and objective control of GORD. Secondary aims include determining early and late surgical morbidity and the side-effect profile of LF compared with LRYGB and to quantify any non-reflux benefits of LRYGB (including overall quality of life) compared with LF. Conclusion This trial will determine whether LRYGB is effective and acceptable as an alternative to LF for the surgical treatment of GORD in obese patients Registration number: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12622000636752p (https://www.anzctr.org.au/).

Metastatic melanoma is a fatal malignancy with a high mortality and morbidity. Since the early 1970s, available medical therapies were limited in improving survival. Surgery represented the best chance for a cure. However, surgery could only be offered to selected patients. The current landscape of treatment has radically evolved since the introduction of targeted and immunotherapies including BRAF and MEK inhibitors, and checkpoint blockers, like PD-1 and CTLA-4 antibodies. These new therapies have seen survival rates matching, and in some cases surpassing, that of surgery. Anti-PD1 and CTLA-4 combination treatments are associated with severe side effects and BRAF and MEK inhibitor combinations may trigger initial tumour responses but prolonged use have resulted in the development of resistant tumour clones and disease relapse. This review examines the role of pulmonary metastasectomy for lung metastasis from malignant melanoma in the current landscape of effective targeted therapy and immunotherapy.

Background: The impact of hospital characteristics on the quality of surgery and survival following oesophagogastric cancer surgery has not been well established in Australia. We assessed the interaction between hospital volume, service capability and surgical outcomes, with the hypothesis that both the quality of surgery and survival are better following treatment in high-volume, high service capability hospitals. Methods: All patients undergoing oesophagectomy and gastrectomy for cancer in Queensland, between 2001 and 2015, were included. Demographic, pathology and outcome data were collected. Hospitals were categorized into high (HV) (≥5 gastrectomies; ≥6 oesophagectomies) and low volume (LV). Hospital service capability was defined as high (HS) and low (LS), and then linked to hospital volume: HVHS, LVHS and LVLS. Higher quality surgery was defined using six perioperative parameters. Univariable comparisons of quality of surgery between hospital groups used chi-squared tests. The 5-year overall survival was compared using log-rank tests and Cox proportional hazard models. Results: For both gastrectomy and oesophagectomy, higher quality surgery occurred more frequently in HVHS hospitals (gastrectomy: HVHS = 44.2%, LVHS = 23.1%, LVLS = 29.1% (P < 0.01); oesophagectomy: HVHS = 34.5%, LVHS = 24.4%, LVLS = 21.7% (P = 0.01)). Following oesophagectomy, the 3- and 5-year overall survival was better following treatment in HVHS (P < 0.01). There was no difference between the groups following gastrectomy. Conclusion: In Queensland, the quality of surgery was higher in HVHS hospitals performing gastrectomy and oesophagectomy; however, the impact on cancer survival was only seen following oesophagectomy.

Based on molecular evidence that melanomas with unknown primary (MUPs) arise from the skin, we hypothesised that sites of MUPs are disproportionately on trunk and lower limbs, sites that are not readily visible to patients and clinicians. We tested this hypothesis by inferring the anatomic site of origin of MUPs from the corresponding known cutaneous sites of melanoma patients with known primary tumours (MKPs). We analysed data from three separate cohorts of patients from Brisbane, Australia (n = 236); Manchester, UK (n = 51) and Padova, Italy (n = 33), respectively, who first presented with stage III melanoma with lymph node metastases. We matched two MKP patients to each MUP patient based on lymph node dissection (LND) site, age and sex, and imputed cutaneous sites of origin of MUPs from their two matched MKPs for study countries, giving two possible sites for each MUP per centre. Overall, results showed that MUP patients were predominantly male, and trunk was the most likely origin, comprising around a third to a half of MUPs across the three cohorts. The remaining MUP inferred sites varied by country. In the Australian cohort, the legs accounted for a third of imputed sites of MUPs, while in the UK and Italian cohorts, the most frequent site was the arms followed by the legs. Our findings suggest the need for regular and thorough skin examination on trunk and limbs, especially in males, to improve early detection of cutaneous melanoma and reduce the risk of metastatic disease at the time of presentation. © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

To quantify the prevalence of anxiety or depression (overall; melanoma-related) among people with high-risk primary melanoma, their related use of mental health services and medications, and factors associated with persistent new-onset symptoms across 4 years post-diagnosis. A longitudinal study of 675 patients newly diagnosed with tumor-stage 1b–4b melanoma. Participants completed the Hospital Anxiety and Depression Scale and answered questions about fear of cancer recurrence, use of medication, and support, serially over 4 years. We identified anxiety and depression trajectories with group-based trajectories models and factors associated with persistent symptoms with logistic regression. At diagnosis, 93 participants (14%) had melanoma-related anxiety or depression, and 136 (20%) were affected by anxiety and/or depression unrelated to melanoma. After 6 months, no more than 27 (5%) reported melanoma-related anxiety or depression at any time, while the point prevalence of anxiety and depression unrelated to melanoma was unchanged (16–21%) among the disease-free. Of 272 participants reporting clinical symptoms of any cause, 34% were taking medication and/or seeing a psychologist or psychiatrist. Of the participants, 11% (n = 59) had new-onset symptoms that persisted; these participants were more likely aged

Optimal management of regional lymph nodes for thin cutaneous melanoma is uncertain. We evaluated regional lymph node involvement and 5-year melanoma-specific survival (MSS) in patients with thin (≤1 mm) primary melanoma.Patients with a melanoma, American Joint Committee on Cancer Staging 8th Edition pT1a (0.8 mm) or pT1b (ulceration; and/or 0.8-1.0 mm), diagnosed during 2001-2015 were identified from the Queensland Oncology Repository. We extracted demographic, pathology and clinical details, including sentinel lymph node biopsy (SLNB), regional nodal dissection and nodal recurrence. Poisson regression was used to assess recurrence risk in patients who did not undergo SLNB. The 5-year MSS was calculated using the Kaplan-Maier method with Cox regression to compare survival outcomes according to SLNB performance.Of the 27 824 eligible patients, 240 (0.9%) underwent SLNB. One hundred and seventy-eight patients (0.6%) without SLNB had nodal recurrence. Of the 4848 patients with a pT1b lesion, 166 (3.4%) had SLNB with 12 (7.2%) positive; of the remainder, 99 (2.1%) had clinical recurrence. Risk of recurrence was higher in males, nodular subtype and T1b lesions and lower if patients were aged60 years. The 5-year MSS was similar for observed and SLNB cohorts (99.66% versus 98.92%) but worse for T1b lesions (98.90%) and clinical nodal recurrence (66.89%).Overall prognosis for T1 melanoma is excellent with nodal involvement being rare. However, the American Joint Committee on Cancer 8th Edition T1b melanoma correlates with significantly worse 5-year MSS and increased regional nodal recurrence (notably for 0.8-1.0 mm lesions with ulceration). Further characterization of high-risk groups for nodal positivity that impacts patient outcome is needed for the pT1 melanoma cohort.

Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON). ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (

Background: The incidence of oesophageal adenocarcinoma (OAC) is rapidly increasing and despite improvements in treatment, the five-year survival rate remains poor. Prognostic biomarkers that address the genomic heterogeneity in this highly complex disease will aid the development of precision therapeutics and improve patient survival. The aim of this study was to determine whether circulating tumour DNA (ctDNA) has prognostic significance as a biomarker in OAC patients.Methods: We profiled 209 blood and tumour samples from 57 OAC patients. Using a panel of 77 cancer genes, we sequenced ctDNA in plasma samples (n=127) which were taken at multiple time points pre- and post-therapy. In parallel, we sequenced matched tumour samples from 39 patients using the same gene panel. To assess whether the ctDNA profile reflected the tumour heterogeneity, we sequenced additional multi-region primary tumour samples (n=17). In addition, we analysed whole-genome and whole-exome sequencing data from primary tumours for a subset of 18 patients. Results: Using a tumour agnostic approach, we found that detectable ctDNA variants in post-treatment plasma samples were associated with worse disease specific survival. To evaluate whether the ctDNA originated from the primary tumour, we performed a tumour informed analysis which confirmed post-treatment ctDNA variants were associated with worse survival. To determine whether ctDNA could be used as a clinical follow-up test, we assessed blood samples from multiple time points before and after treatment, in a subset of patients. Results showed that the variant allele frequency of ctDNA variants increased with disease recurrence. Conclusion: This study demonstrates that ctDNA variants can be detected in patients with OAC and this has potential clinical utility as a prognostic biomarker for survival.

Aim This study assessed the responsiveness and convergent validity of two preference-based measures; the newly developed cancer-specific EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D) relative to the generic three-level version of the EuroQol 5 dimensions (EQ-5D-3L) in evaluating short-term health related quality of life (HRQoL) outcomes after esophagectomy. Methods Participants were enrolled in a multicentre randomised controlled trial to determine the impact of preoperative and postoperative immunonutrition versus standard nutrition in patients with esophageal cancer. HRQoL was assessed seven days before and 42 days after esophagectomy. Standardized Response Mean and Effect Size were calculated to assess responsiveness. Ceiling effects for each dimension were calculated as the proportion of the best level responses for that dimension at follow-up/post-operatively. Convergent validity was assessed using Spearman’s correlation and the level of agreement was explored using Bland–Altman plots. Results Data from 164 respondents (mean age: 63 years, 81% male) were analysed. HRQoL significantly reduced on both measures with large effect sizes (> 0.80), and a greater mean difference (0.29 compared to 0.16) on QLU-C10D. Both measures had ceiling effects (> 15%) on all dimensions at baseline. Following esophagectomy, ceiling effects were observed with self-care (86%), mobility (67%), anxiety/depression (55%) and pain/discomfort (19%) dimensions on EQ-5D-3L. For QLU-C10D ceiling effects were observed with emotional function (53%), physical function (16%), nausea (35%), sleep (31%), bowel problems (21%) and pain (20%). A strong correlation (r = 0.71) was observed between EQ-5D-3L anxiety and QLU-C10D emotional function dimensions. Good agreement (3.7% observations outside the limits of agreement) was observed between the utility scores. Conclusion The QLU-C10D is comparable to the more widely applied generic EQ-5D-3L, however, QLU-C10D was more sensitive to short-term utility changes following esophagectomy. Cognisant of requirements by policy makers to apply generic utility measures in cost effectiveness studies, the disease-specific QLU-C10D should be used alongside the generic measures like EQ-5D-3L. Trial registration: The trial was registered with the Australian New Zealand Clinical Trial Registry (ACTRN12611000178943) on the 15th of February 2011.

Background: International literature recommends centralising gastric cancer surgery, however, with volumes that define ‘high-volume resection’ being higher than those in most major centres in Australia and New Zealand. These reports rarely focus on the difference between total (TG) and partial gastrectomy (PG). We assessed the impact of resection volume and service capability on operative mortality, morbidity and surgical quality in patients who had a PG and TG. Methods: Patients who had gastrectomy for adenocarcinoma, between 2001 and 2015, were collected from the Queensland Oncology Repository. Hospitals were characterised by cases-per-annum (high-volume [HV] ≥ 5 and low-volume [LV] < 5) and hospital service capability as (high-service [HS] and low-service [LS]), giving three hospital groups: HVHS, LVHS and LVLS. Chi-squared tests were used to compare post-operative mortality, morbidity, failure to rescue (FTR) from complications and surgical quality between these three groups. Results: There were 426 patients who had a TG and 827 having PG. HVHS centres performed 59% of PG with high surgical quality rates of: HVHS = 53%, LVHS = 34% and LVLS = 46% (p < 0.01). Surgical complications were highest in LVLS (LVLS = 19%, LVHS = 11%, HVHS = 11%; p = 0.02). There was no difference in 30-day mortality nor in FTR. For TG, HVHS performed 67% of these procedures, with lower 30-day mortality (2%) and FTR rates (5%) compared with LVHS (7%, 22%) and LVLS (12%, 28%; p < 0.01). There was no difference in operative morbidity and surgical quality between hospital groups. Conclusion: Despite the ‘high-volume’ threshold for gastrectomy being the lowest described in the literature, we have shown that centralisation to HVHS centres was associated with lower operative mortality for TG and improved quality of surgery for PG.

Australia and New Zealand have the highest incidence and mortality rates for melanoma in the world. Local surgery is still the standard treatment of primary cutaneous melanoma, and it is therefore important that surgeons understand the optimal care pathways for patients with melanoma. Accurate staging is critical to ensure a reliable assessment of prognosis and to guide treatment selection. Sentinel node biopsy (SNB) plays an important role in staging and the provision of reliable prognostic estimates for patients with cutaneous melanoma. Patients with stage III melanoma have a substantial risk of disease recurrence following surgery, leading to poor long-term outcomes. Systemic immunotherapies and targeted therapies, known to be effective for stage IV melanoma, have now also been shown to be effective as adjuvant post-surgical treatments for resected stage III melanoma. These patients should be made aware of this and preferably managed in an integrated multidisciplinary model of care, involving the surgeon, medical oncologists and radiation oncologists. This review considers the impact of a recent update to the American Joint Committee on Cancer (AJCC) staging system, the role of SNB for patients with high-risk primary melanoma and recent advances in adjuvant systemic therapies for high-risk patients.

Background Isolated limb infusion (ILI) is a minimally invasive treatment for patients with locally advanced extremity melanoma. Most studies combine results of upper-limb ILI (UL-ILI) and lower-limb ILI (LL-ILI), leaving UL-ILIs relatively underreported as LL-ILIs comprise the vast majority in these reports. However, differences between the two procedures may be clinically important. The aim of this study was to evaluate the efficacy and toxicity of UL-ILI in an Australian multi-center setting. Patients and methods 316 ILI procedures for melanoma performed between 1992 and 2008 in five Australian institutions were analyzed. In all institutions melphalan (±actinomycin D) was circulated in the isolated limb for 20–30 min. Results Baseline patient characteristics for UL-ILI (n = 27) and LL-ILI (n = 289) were similar, except that more men underwent UL-ILI (66% vs. 38%; p = 0.007) and disease in LL-ILI was mostly located on the distal limb (p = 0.02). Median tourniquet times were shorter for UL-ILI (38 vs. 48 min; p = 0.04) and UL-ILI patients experienced less limb toxicity (Grade III/IV in 24% vs. 31%; p = 0.01). Complete response (CR) rates were similar: 33% after LL-ILI (p = 0.70), 30% after UL-ILI, while overall response (OR) rates were higher after LL-ILI: (76%) than UL-ILI (59%; p = 0.05). No difference in survival was seen. Conclusions UL-ILI is safe to perform and effective, resulting in low limb toxicity. CR rates were similar to those for LL-ILI, but OR rates were lower for UL-ILI. It may be possible to improve OR rates achieved by UL-ILI by optimizing perioperative factors, while maintaining low toxicity.

Background and objectives In-transit melanoma (ITM) metastases present a therapeutic challenge and management decisions can be difficult. There are multiple treatments available, with differing efficacy, and supported by different levels of evidence. The primary objective was to perform a systematic review and where suitable, a meta-analysis of the literature reporting on the use of locoregional treatments for the management of ITM. Methods An independent review was conducted including a comprehensive search of the National Library of Medicine using PubMed, MEDLINE, Embase, and Cochrane Library databases. Key data were tabulated, synthesized and pooled to calculate relevant weighted effect sizes for each therapy using random-effect models. The statistical heterogeneity was calculated using the Higgins' method. Results Of the initial 32 612 articles identified, 57 original articles satisfied eligibility criteria. Eight treatment modalities were identified comprising: amputation (7); hyperthermic isolated limb perfusion (15); isolated limb infusion (8); carbon dioxide laser (9); PV-10 intralesional therapy (5); IL-2 intralesional therapy (8); imiquimod (7); diphenylcyclopropenone (3). Only amputation and topical imiquimod were suitable for formal meta-analysis. Conclusions All of the assessed therapies have significant selection bias. Variable levels of evidence support the ongoing use of locoregional treatments and these may significantly improve disease-free survival.

The incidence of oesophageal adenocarcinoma (OAC) is rapidly increasing and despite improvements in treatment, the 5-year survival rate remains poor. Prognostic biomarkers that address the genomic heterogeneity in this highly complex disease will aid the development of precision therapeutics and improve patient survival. The aim of this study was to determine whether circulating tumour DNA (ctDNA) has prognostic significance as a biomarker in OAC patients.We profiled 209 blood and tumour samples from 57 OAC patients. Using a panel of 77 cancer genes, we sequenced ctDNA in plasma samples (n = 127) which were taken at multiple time points before and after therapy. In parallel, we sequenced matched tumour samples from 39 patients using the same gene panel. To assess whether the ctDNA profile reflected the tumour heterogeneity, we sequenced additional multi-region primary tumour samples in 17 patients. In addition, we analysed whole-genome and whole-exome sequencing data from primary tumours for a subset of 18 patients.Using a tumour-agnostic approach, we found that detectable ctDNA variants in post-treatment plasma samples were associated with worse disease-specific survival. To evaluate whether the ctDNA originated from the primary tumour, we carried out a tumour-informed analysis which confirmed post-treatment ctDNA variants were associated with worse survival. To determine whether ctDNA could be used as a clinical follow-up test, we assessed blood samples from multiple time points before and after treatment, in a subset of patients. Results showed that the variant allele frequency of ctDNA variants increased with disease recurrence.This study demonstrates that ctDNA variants can be detected in patients with OAC and this has potential clinical utility as a prognostic biomarker for survival.

Objective To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging. Background It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low. Methods Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen. Results SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% (95% confidence interval: 4.6-8.7) and the specificity 98.0% (95% CI: 97.5-98.5). Median cross-sectional area of all SN metastases was 0.13 mm; in US true-positive nodes, it was 6.8 mm. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for ≤1 mm thickness, 11.9% for >4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy. Conclusion In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy.

Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival (P = 0.00047 and P = 0.0014, respectively) and worse overall survival (P = 0.0223 and P = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with BRAF mutation status (P = 0.0389). RNA-sequencing indicated patients with immune “cold” signatures had worse survival, which was associated with CT biomarker, MPP4 (P = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers (P = 0.0028). Implications: CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment.

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2).

Introduction Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response. Methods Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres. Results After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response. Conclusion ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low.

Summary: Background: Skin self-examinations supplemented with mobile teledermoscopy might improve early detection of skin cancers compared with naked-eye skin self-examinations. We aimed to assess whether mobile teledermoscopy-enhanced skin self-examination can improve sensitivity and specificity of self-detection of skin cancers when compared with naked-eye skin self-examination. Methods: This randomised, controlled trial was done in Brisbane (QLD, Australia). Eligible participants (aged ≥18 years) had at least two skin cancer risk factors as self-reported in the eligibility survey and had to own or have access to an iPhone compatible with a dermatoscope attachment (iPhone versions 5–8). Participants were randomly assigned (1:1), via a computer-generated randomisation procedure, to the intervention group (mobile dermoscopy-enhanced self-skin examination) or the control group (naked-eye skin self-examination). Control group and intervention group participants received web-based instructions on how to complete a whole body skin self-examination. All participants completed skin examinations at baseline, 1 month, and 2 months; intervention group participants submitted photographs of suspicious lesions to a dermatologist for telediagnosis after each skin examination and control group participants noted lesions on a body chart that was sent to the research team after each skin examination. All participants had an in-person whole-body clinical skin examination within 3 months of their last skin self-examination. Primary outcomes were sensitivity and specificity of skin self-examination, patient selection of clinically atypical lesions suspicious for melanoma or keratinocyte skin cancers (body sites examined, number of lesions photographed, types of lesions, and lesions missed), and diagnostic concordance of telediagnosis versus in-person whole-body clinical skin examination diagnosis. All primary outcomes were analysed in the modified intention-to-treat population, which included all patients who had a clinical skin examination within 3 months of their last skin self-examination. This trial was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12616000989448. Findings: Between March 6, 2017, and June 7, 2018, 234 participants consented to enrol in the study, of whom 116 (50%) were assigned to the intervention group and 118 (50%) were assigned to the control group. 199 participants (98 participants in the intervention group and 101 participants in the control group) attended the clinical skin examination and thus were eligible for analyses. Participants in the intervention group submitted 615 lesions (median 6·0 per person; range 1–24) for telediagnosis and participants in the control group identified and recorded 673 lesions (median 6·0 per person; range 1–16). At the lesion level, sensitivity for lesions clinically suspicious for skin cancer was 75% (95% CI 63–84) in the intervention group and 88% (95% CI 80–91) in the control group (p=0·04). Specificity was 87% (95% CI 85–90) in the intervention group and 89% (95% CI 87–91) in the control group (p=0·42). At the individual level, the intervention group had a sensitivity of 87% (95% CI 76–99) compared with 97% (95% CI 91–100) in the control group (p=0·26), and a specificity of 95% (95% CI 90–100) compared with 96% (95% CI 91–100) in the control group. The overall diagnostic concordance between the telediagnosis and in-person clinical skin examination was 88%. Interpretation: The use of mobile teledermoscopy did not increase sensitivity for the detection of skin cancers compared with naked-eye skin self-examination; thus, further evidence is necessary for inclusion of skin self-examination technology for public health benefit. Funding: National Health and Medical Research Council (Australia).

Background: Experimental evidence suggests that dietary intakes of omega-3 and omega-6 polyunsaturated fatty acids have divergent effects on melanoma growth, but epidemiologic evidence on their combined effect is lacking. Methods: In 634 Australian patients with primary melanoma, we assessed prediagnosis consumption of 39 food groups by food frequency questionnaires completed within 2 months of diagnosis. We derived, by reduced rank regression, dietary patterns that explained variability in selected omega-3 and omega-6 fatty acid intakes. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between tertiles of dietary patterns and melanoma thickness >2 mm versus ≤2 mm were estimated using Poisson regression. Results: Overall omega-3 fatty acid intakes were low. Two major fatty acid dietary patterns were identified: “meat, fish, and fat,” positively correlated with intakes of all fatty acids; and “fish, low-meat, and low-fat,” positively correlated with long-chain omega-3 fatty acid intake, and inversely with medium-chain omega-3 and omega-6 fatty acid intakes. Prevalence of thick melanomas was significantly higher in those in the highest compared with lowest tertile of the “meat, fish, and fat” pattern (PR, 1.40; 95% CI, 1.01–1.94), especially those with serious comorbidity (PR, 1.83; 95% CI, 1.15–2.92) or a family history (PR, 2.32; 95% CI, 1.00–5.35). The “fish, low-meat, and low-fat” pattern was not associated with melanoma thickness. Conclusions: People with high meat, fish, and fat intakes, who thus consumed relatively high levels of omega-3 and high omega-6 fatty acid intakes, are more likely to be diagnosed with thick than thin melanomas. Impact: High omega-3 and omega-6 fatty acid intakes may contribute to patients' presentation with thick melanomas.