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Introduction At a national level, understanding preventable mortality after oesophago-gastric cancer surgery can direct quality-improvement efforts. Accordingly, utilizing the Australian and New Zealand Audit of Surgical Mortality (ANZASM), we aimed to: (1) determine the causes of death following oesophago-gastric cancer resections in Australia, (2) quantify the proportion of potentially preventable deaths, and (3) identify clinical management issues contributing to preventable mortality. Methods All in-hospital mortalities following oesophago-gastric cancer surgery from 1 January 2010 to 31 December 2020 were analysed using ANZASM data. Potentially preventable and non-preventable cases were compared. Thematic analysis with a data-driven approach was used to classify clinical management issues. Results Overall, 636 complications and 123 clinical management issues were identified in 105 mortalities. The most common causes of death were cardio-respiratory in aetiology. Forty-nine (46.7%) deaths were potentially preventable. These cases were characterized by higher rates of sepsis (59.2% vs 33.9%, p = 0.011), multiorgan dysfunction syndrome (40.8% vs 25.0%, p = 0.042), re-operation (63.3% vs 41.1%, p = 0.031) and other complications compared with non-preventable mortality. Potentially preventable mortalities also had more clinical management issues per patient [median (IQR): 2 (1–3) vs 0 (0–1), p p = 0.002), intraoperative (18.4% vs 5.4%, p = 0.037) and postoperative (51.0% vs 17.9%, p Conclusions Almost 50% of deaths following oesophago-gastric cancer resections were potentially preventable. These were characterized by higher complication rates and clinical management issues. We highlight recurrent themes in patient management to improve future quality of care.

Variable re-expression patterns in PDX tumors generated from CD271- and CD271+ cells.

The stability of markers that identify cancer cells that propagate disease is important to the outcomes of targeted therapy strategies. In human melanoma, conflicting data exist as to whether hierarchical expression of CD271/p75/NGFR (nerve growth factor receptor) marks cells with enriched tumorigenicity, which would compel their specific targeting in therapy. To test whether these discrepancies relate to differences among groups in assay approaches, we undertook side-by-side testing of published methods of patient-derived melanoma xenografting (PDX), including comparisons of tissue digestion procedures or coinjected Matrigel formulations. We found that CD271− and CD271+ melanoma cells from each of seven patients were similarly tumorigenic, regardless of assay variations. Surprisingly variable CD271 expression patterns were observed in the analyses of sibling PDX tumors (n = 68) grown in the same experiments from either CD271− or CD271+ cells obtained from patients. This indicates unstable intratumoral lineage relationships between CD271− and CD271+ melanoma cells that are inconsistent with classical, epigenetically based theories of disease progression, such as the cancer stem cell and plasticity models. SNP genotyping of pairs of sibling PDX tumors grown from phenotypically identical CD271− or CD271+ cells showed large pairwise differences in copy number (28%–48%). Differences were also apparent in the copy number profiles of CD271− and CD271+ cells purified directly from each of the four melanomas (1.4%–23%). Thus, CD271 expression in patient melanomas is unstable, not consistently linked to increased tumorigenicity and associated with genetic heterogeneity, undermining its use as a marker in clinical studies. Cancer Res; 76(13); 3965–77. ©2016 AACR.

Description of additional methods and procedures used in the study.

Legend for Supplementary Figures S1-S8.

Throughout the world, each year, approximately 250,000 people develop melanoma and 40,000 die from the disease. Melanoma is characteristically a disease of fair-skinned persons exposed to high ambient levels of ultraviolet (UV) radiation. The incidence has doubled over the last 20 years although unlike other countries the rate of increase in Australia has slowed in recent years, possibly due to public education campaigns targeting excessive UV exposure. Globally the incidence in patients over the age of 65 continues to increase and accounts for disproportionately more melanoma-related deaths. Nevertheless, melanoma in younger persons (

Background Pancreatic cancer (PC) remains a highly fatal disease. There is a gap in the literature on the of quality care on survival in a real-world population. Objectives This study: (1) assessed compliance with a consensus set of quality indicators (QIs); and (2) evaluated the association between compliance with these QIs and survival. Methods Data were collected on a core set of quality indicators by the Upper Gastrointestinal Cancer Registry (UGICR) for patients diagnosed with PC between 1 January 2016 and 31 December 2019. Univariable and multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for the association between survival and patient characteristics, hospital characteristics and QIs, stratified by resectability. A multivariable analysis tested the relationship between significant patient and hospital characteristics, patient cluster effects within hospitals and survival. Results 1061 patients were eligible for this study with 52% male, 71% over the age of 65, 23% potentially resectable and 51% with metastatic disease at diagnosis. 52% received some form of cancer directed treatment. Significant association with improved survival were: (1) in the potentially resectable group having adjuvant chemotherapy administered following surgery or a reason documented (HR, 0.29; 95 CI, 0.19-0.46); (2) in the locally advanced group included having chemotherapy ± chemoradiation, or a reason documented for not undergoing treatment (HR, 0.38; 95 CI, 0.25-0.58) and (3) in the metastatic disease group included having documented ECOG at presentation and/or American society of Anaesthesiologists (ASA) performance status at a diagnostic procedure (HR, 0.65; 95 CI, 0.47-0.89), being seen by a medical oncologist and/or a radiation oncologist in the absence of treatment (HR, 0.48; 95 CI, 0.31-0.77), and having disease management discussed at an MDT meeting (HR, 0.79; 95 CI, 0.64-0.96). Conclusion Capture of a concise data set has enabled quality of care to be assessed and an analysis of factors associated with improved survival identified.

The majority of patients undergoing sentinel lymph node biopsy (SLNB) for melanoma will have a negative SLN. The long-term sequelae of a negative result are important when discussing this staging investigation with patients. The objective of this study was to assess rates of lymphoedema and quality of life for these patients. A prospective, cross-sectional study was performed on patients under routine follow-up with a history of melanoma, who had undergone sentinel lymph node biopsy where no metastasis was found (N0) at a high-volume melanoma centre. Relevant limbs were measured to assess for lymphoedema and patients completed the FACT-M quality of life instrument and a study specific questionnaire. A total of 102 patients were recruited. Wound complications were observed in 25% and lymphoedema in 2% of patients. Physical and functional well-being scores were lowest in patients seen within 3 months of their SLNB. Functional well-being and quality of life improved over the 2 years following the procedure. SLNB has low complication rates. The procedure is associated with a short-term impact on patient quality of life and well-being. The vast majority of patients are pleased with the outcomes of this procedure and the information that it provides.

9503 Background: Combination anti-PD(L)1 and BRAF/MEK-targeted therapy (TT) improves PFS in stage IV melanoma vs TT. In stage IV melanoma recent data suggest immunotherapy 1st until progression, rather than BRAF-TT, improves OS, and induction TT upfront adds little benefit. NeoTrio explored the optimal combination of BRAF-TT and anti-PD1 using the NAT platform in pts with stage III melanoma (NCT02858921). Methods: 60 pts with resectable, RECIST measurable stage III (no in-transit) BRAFV600-mutant melanoma were randomized 1:1:1 to 3 arms of 6 wks of NAT followed by complete lymph node dissection (CLND): A) Pembro ALONE (200mg Q3W x 2); B) SEQ - D+T (150mg bd + 2mg od) for 1 wk followed by pembro (200mg x 2); C) CON – D+T+pembro (doses as SEQ). Pts had 46 wks pembro post-CLND. Primary endpoint was the pathological response rate (pRR) and pathological complete response (pCR) at wk 6. Secondary endpoints; RECIST RR at wk 6, event-free survival (EFS), RFS, OS, adverse events (AE) and translational endpoints. Results: At data cutoff 2 Jan 2022, 20 pts per arm had similar baseline characteristics; overall 42% female, med age 53 yrs, 82% BRAF V600E, 62% clinical N1b. Med f/u was 20 months (95% CI 17-31). The pCR rate and pRR were highest in CON arm, and similar in ALONE and SEQ arms (Table). Events (progression before surgery, recurrence after surgery or death) were highest in ALONE arm at this 1st analysis (Table). Assessment of the durability of path response subtypes in each arm is ongoing. Most common Rx related AE were fatigue (65%, 70%, 70%, ALONE, SEQ and CON respectively), pyrexia (0%, 25%, 85%) and rash (50%, 35%, 35%). Gd 3/4 AE occurred in 30%, 25% and 55%, respectively; pyrexia and hepatitis were common in CON during NAT. Rx interruptions during NAT occurred in 0, 3 and 19 pts, respectively; 1, 0 and 8 pts permanently discontinued. Post NAT surgical operability was the same or improved in 81%. Longitudinal analysis of melanoma tissue, microenvironment and microbiome is ongoing. Conclusions: CON D+T+pembro achieved the highest pRR, pCR rate, but with greater toxicity. Recurrences were seen in those with pCR/near pCR in BRAF-TT containing arms, but not in pembro ALONE, in keeping with previous data of NAT with checkpoint inhibitors vs BRAF-TT. Short course of D+T prior to PD1 did not improve path response, despite previous translational data showing increased tumour infiltrating T-cells early-during treatment with D+T. Follow up is ongoing. Clinical trial information: NCT02858921. [Table: see text]

9501 Background: In the OpACIN-neo study, 2 cycles neoadjuvant (neoadj) IPI 1mg/kg + NIVO 3mg/kg (I1N3) have been identified as most favorable dosing scheme with a pathologic response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 24.6 months median follow-up (FU), the 2-year (2y) RFS was 96.9% for patients (pts) with pathologic response versus 35.5% for non-responders (>50% viable tumor; pNR). These data raised the question whether therapeutic lymph node dissection (TLND) could be safely omitted in pts achieving a major pathologic response (MPR; ≤10% viable tumor) in their index node (ILN; largest LN metastasis at baseline), and if additional adjuvant (adj) therapy could improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the phase 2 OpACIN-neo study aiming to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with stage III melanoma were included to receive 2 cycles neoadj I1N3 after marker placement in the ILN. ILN resection was planned at week 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with partial response (pPR; >10 – ≤50% viable tumor) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or dabrafenib plus trametinib (D+T) for 52 weeks ±radiotherapy (RT). Primary endpoints were pRR in the ILN and RFS at 2y. The 2y RFS rates were calculated using a Kaplan Meier based method. Results: Between Nov 2018 and Jan 2020, 99 patients were enrolled and treated with at least 1 cycle of neoadj I1N3. We previously showed a pRR of 72% (95% CI 62 - 80), including 60 (61%) pts with MPR and 11 (11%) pts with pPR. TLND omission in MPR pts resulted in significant reduced surgical morbidity and improved quality of life. There were 27 non-responders of whom 6 developed distant metastasis before ILN resection. Of the other 21 pNR pts, 7 received adj NIVO, 10 adj D+T, 3 no adj therapy, and 1 was lost to FU. After a median FU of 27.9 months (data cutoff Jan 31, 2022), the estimated 2y RFS rate for MPR pts was 93.3% (95% CI 87.2 – 99.9), with 4/60 pts developing a regional relapse. Distant metastasis-free survival (DMFS) was 100%. Of the 11 pPR pts, 4 developed a relapse (all distant), resulting in a 2y RFS and DMFS rate of 63.6% (95% CI 40.7 – 99.5). The 2y RFS rate of the pNR pts was 71.4% (95% CI 54.5 – 93.6), and DMFS 76.2%. At data cutoff, relapse occurred in 2/7 pNR pts with adj NIVO and 3/10 with adj D+T. Final data cutoff is planned mid Feb, 2022. Conclusions: MPR pts in whom TLND was omitted showed a 2y RFS rate of 93.3% and DMFS of 100%, indicating that the ILN procedure and omitting adj therapy could become a safe approach in these pts. Adj systemic therapy in pNR pts seems to improve RFS as compared to historic control (OpACIN-neo), thus should be considered in this unfavorable pNR group. The DMFS rate of 63.6% observed in the pPR group advocates the consideration of adj therapy also for this subgroup in the future. Clinical trial information: NCT02977052.

9580 Background: Neoadjuvant D+T has a high pathologic response rate and impressive short-term survival. The NeoCombi trial (NCT01972347) enrolled 35 patients with resectable stage III melanoma, with last patient commencing treatment April 19th 2017. We report 5-year outcomes from this trial. Methods: Pts received 12 wks neoadjuvant standard dose D+T, then 40 wks adjuvant D+T. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1 with clinical stage III BRAF V600E/K melanoma. CT and PET scans were performed at baseline and prior to surgery. Pathologic response was determined as per International Neoadjuvant Melanoma Consortium (INMC) criteria and defined as complete (pCR), near complete, partial (pPR) or no response (pNR). CT monitoring was continued 12 wkly thereafter to 2 yrs, then 6 monthly to 3 yrs, then as standard care. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints included relapse free survival (RFS), OS, and toxicity. Results: 35 pts were enrolled, 6 with IIIB, 29 IIIC (7 ITM only) disease (clinical AJCCv7). At data cut August 17th 2021, median F/U was 60 mo (95% CI 56-72). No patients progressed in the neoadjuvant phase, and (49%) had a pCR, 1 near pCR, 6 pPR, 11 pNR. 5-year RFS, DMFS and OS data are shown in the Table. The majority of recurrences occurred within the first 2 years, with no recurrences beyond 3y. 21 patients recurred; 12 (57%) had first recurrence locoregional (6/12 subsequent distant recurrence) and 9 (43%) had first recurrence in distant sites (3/9 in brain). Locoregional recurrence was managed with surgery alone in 4/12, systemic therapy alone in 2/12, or both surgery and systemic therapy in 5/12 (4/5 had adjuvant systemic therapy), 1 pt was observed until distant recurrence. Subsequent systemic therapy in the 15 patients with a distant recurrence included PD-1 based immunotherapy (N=14) and BRAF targeted therapy (N=10). Conclusions: Neoadjuvant D+T in clinical stage III melanoma has impressive early activity, however patients remain at high risk of recurrence. Pathologic response can identify patients at the highest risk of recurrence, offering a chance of alternative adjuvant therapy in non-responders. Clinical trial information: NCT01972347. [Table: see text]

PurposeThe Upper Gastrointestinal Cancer Registry (UGICR) was developed to monitor and improve the quality of care provided to patients with upper gastrointestinal cancers in Australia.ParticipantsIt supports four cancer modules: pancreatic, oesophagogastric, biliary and primary liver cancer. The pancreatic cancer (PC) module was the first module to be implemented, with others being established in a staged approach. Individuals are recruited to the registry if they are aged 18 years or older, have received care for their cancer at a participating public/private hospital or private clinic in Australia and do not opt out of participation.Findings to dateThe UGICR is governed by a multidisciplinary steering committee that provides clinical governance and oversees clinical working parties. The role of the working parties is to develop quality indicators based on best practice for each registry module, develop the minimum datasets and provide guidance in analysing and reporting of results. Data are captured from existing data sources (population-based cancer incidence registries, pathology databases and hospital-coded data) and manually from clinical records. Data collectors directly enter information into a secure web-based Research Electronic Data Capture (REDCap) data collection platform. The PC module began with a pilot phase, and subsequently, we used a formal modified Delphi consensus process to establish a core set of quality indicators for PC. The second module developed was the oesophagogastric cancer (OGC) module. Results of the 1 year pilot phases for PC and OGC modules are included in this cohort profile.Future plansThe UGICR will provide regular reports of risk-adjusted, benchmarked performance on a range of quality indicators that will highlight variations in care and clinical outcomes at a health service level. The registry has also been developed with the view to collect patient-reported outcomes (PROs), which will further add to our understanding of the care of patients with these cancers.

Patients with in-transit melanoma metastases (ITM) experience a diverse spectrum of clinical presentations and a highly variable disease course. There is no standardized treatment protocol for these patients due to the limited data comparing treatment modalities for ITM. This is the first study to describe the disease trajectory and natural history of a large cohort of patients with ITM. A retrospective study of patients treated for ITM between 2004 and 2018 at the Peter MacCallum Cancer Centre was performed. Clinical and pathological characteristics for primary and in-transit episodes were analyzed for predictors of relapse-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival. A total of 109 patients with 303 episodes of ITM were identified: 52 (48%) females, median age 70.1 years (range 35–92). The median RFS for all episodes was 5 months (95% confidence interval [CI] 4.2–5.7). Eighty-seven percent of episodes involving isolated in-transit lesions underwent surgical excision, compared with 17% involving more than five in-transit lesions. A trend was seen between a greater number of lesions and shorter RFS (p = 0.055). The median DMFS was 34.8 months (95% CI 22.8–51.6). Factors associated with shorter DMFS included primary tumor thickness (hazard ratio [HR] 1.08, 95% CI 1.01–1.15; p = 0.026), site of primary tumor (p = 0.008), and BRAF mutation (HR 2.12, 95% CI 1.14–3.94; p = 0.018). Locoregional relapse is common in patients with ITM regardless of treatment modality. Characteristics of the ITM may predict for RFS, while primary tumor characteristics remain important predictors of DMFS.

Elderly patients experience a different spectrum of disease and poorer outcomes than younger patients. This study investigated the impact of age and medical comorbidities on the management and outcome of patients ≥65 years.A retrospective review of all patients ≥65 years (481 patients with 525 primary melanomas) presenting with AJCC clinical stage I-II melanoma to an Australian cancer centre between 2000 and 2008.The median age was 74 years (65-94) with a male predominance (313 males, 65.0%) and median tumour thickness of 1.90 mm (IQR = 0.40-2.90, T1 = 33%, T2 = 20%, T3 = 24%, T4 = 23%). Inadequate surgical margins of excision (10 mm) were common in older patients independent of site, thickness and ulceration (OR = 1.04, 95%CI = 1.00-1.07, p = 0.038). Inadequate excision margins were strongly associated with time to local recurrence, independent of age, thickness, ulceration and mitotic rate (HR = 3.00, 95%CI = 1.49-6.03, p = 0.0021), but not time to progression (p = 0.10) or disease specific survival (DSS, p = 0.27). Overall survival (OS) was strongly related to increasing age (HR = 1.04, 95%CI = 1.01-1.07, p = 0.015) and comorbid medical conditions (HR = 1.26, 95%CI = 1.12-1.42, p 0.001), as assessed by the Charlson comorbidity index (CCI). DSS was significantly related to CCI (HR = 1.20, 95%CI = 1.01-1.42, p = 0.041) and not age (p = 0.46), when adjusting for thickness, ulceration and mitotic rate on multivariate analysis.Older patients present with poor prognosis melanomas yet are less likely to receive adequate surgical excision margins resulting in higher rates of local recurrence. In melanoma patients ≥65 years, the increasing number of medical comorbidities explains much of the age related variations in OS and DSS and should be considered when planning treatment.

The stability of markers that identify cancer cells that propagate disease is important to the outcomes of targeted therapy strategies. In human melanoma, conflicting data exist as to whether hierarchical expression of CD271/p75/NGFR (nerve growth factor receptor) marks cells with enriched tumorigenicity, which would compel their specific targeting in therapy. To test whether these discrepancies relate to differences among groups in assay approaches, we undertook side-by-side testing of published methods of patient-derived melanoma xenografting (PDX), including comparisons of tissue digestion procedures or coinjected Matrigel formulations. We found that CD271− and CD271+ melanoma cells from each of seven patients were similarly tumorigenic, regardless of assay variations. Surprisingly variable CD271 expression patterns were observed in the analyses of sibling PDX tumors (n = 68) grown in the same experiments from either CD271− or CD271+ cells obtained from patients. This indicates unstable intratumoral lineage relationships between CD271− and CD271+ melanoma cells that are inconsistent with classical, epigenetically based theories of disease progression, such as the cancer stem cell and plasticity models. SNP genotyping of pairs of sibling PDX tumors grown from phenotypically identical CD271− or CD271+ cells showed large pairwise differences in copy number (28%–48%). Differences were also apparent in the copy number profiles of CD271− and CD271+ cells purified directly from each of the four melanomas (1.4%–23%). Thus, CD271 expression in patient melanomas is unstable, not consistently linked to increased tumorigenicity and associated with genetic heterogeneity, undermining its use as a marker in clinical studies. Cancer Res; 76(13); 3965–77. ©2016 AACR.

Background Squamous cell carcinoma of the scalp is a common clinical problem in an aging population. Despite its high incidence, little has been documented regarding treatment or outcomes. Methods We retrospectively analysed 235 cases treated with curative intent at Peter MaCallum Cancer Centre between 1998 and 2010. The cohort was analysed for its characteristics, management, survival and prognostic factors. Results The patients were primarily male (88%) with a median age of 79 years (range 53–98 years). There was a high proportion of immunosuppressed patients (29%) and stage T2 (48%) tumours. Management included surgery (45%), radiotherapy (28%) and surgery and adjuvant radiotherapy (26%). Median follow up from treatment was 4.5 years. Estimated 5-year overall survival (OS), disease-specific survival and progression-free survival (PFS) were 59, 94 and 51%, respectively. The 5-year cumulative incidence of local and regional relapse was 11 and 7%, respectively. There were four patients who developed distant metastases and died of their disease. Statistically significant prognostic factors identified for poor outcomes for OS and PFS were T2 stage (hazard ratio [1.7 and 2.1) and immunosuppression (HR 3.3 and 3.4). Conclusions We conclude the presence of immunosuppression and T2 stage is prognostic for survival. Further research to establish treatment principles is warranted.

Background and ObjectivesPatients with in-transit melanoma metastasis have longer median survival than patients with distant metastatic disease. Furthermore, local disease control is an important endpoint for symptom management. The treatment of unresectable loco-regional recurrence or in-transit disease has been historically managed with a combination of treatments including surgery, radiotherapy, isolated limb infusion or perfusion as well as systemic therapies. Intralesional PV-10 has been used at Peter MacCallum Cancer Centre since 2010, and the current report presents a retrospective analysis of patient outcomes, reporting the response rates, durability of responses, and observed toxicities.MethodsRecords were analyzed retrieving details of 19 patients treated with PV-10 over a 4-year period from 2010 to 2014. Medical records were reviewed for these patients and data extracted.ResultsNineteen patients with in-transit melanoma were treated with intralesional PV-10 between 2010 and 2014. Disease control (complete or partial response or disease stability) was achieved in 68% of patients with 26% having a complete response. This was achieved with minimal associated toxicity.ConclusionsPV-10 is an effective, durable, well-tolerated treatment tool with an acceptable side effect profile for the management of unresectable in-transit melanoma. J. Surg. Oncol. 2016;114:380-384. (c) 2016 Wiley Periodicals, Inc.

Background Recommended margins for thick cutaneous melanoma (Breslow thickness >4 mm; T4) have decreased over recent decades. Optimal margins and the role of sentinel node biopsy (SNB) in thick head and neck melanoma remain controversial. Methods A single-center review was conducted of patients treated between 2002 and 2012 assessing the impact of excision margins and sentinel lymph node status on locoregional recurrence and melanoma-specific survival (MSS). Results One hundred eight patients were identified. Median age was 71.1 years and median Breslow thickness was 6.0 mm. Median follow-up was 40 months. Locoregional recurrence occurred in 27% and there was no significant reduction in recurrence with margins ≥2 cm (p = .17). Increasing margins did not improve survival (p = .58). Fifty-nine patients (55%) underwent SNB, of which 27% were positive. There was a trend toward longer survival for patients who were sentinel lymph node-negative (p = .097). Conclusion Wider margins do not significantly improve locoregional recurrence or MSS. Sentinel lymph node involvement reflects a poor prognosis. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Background As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and methods From 2009, patients with stage 3 melanoma routinely underwent PET +/− MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes. Results One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%−83%. Negative scans had predictive values of 89%−96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%−84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

Sentinel lymph node biopsy (SLNB) is a sensitive test for detecting subclinical nodal metastatic disease in patients with melanoma without evidence of lymph node involvement. The prognostic significance of SLN positivity in patients with melanoma >4 mm thick (T4) is unclear. The survival curves in the current AJCC staging system suggest that the status of the SLN is not predictive of outcome for patients with T4 melanoma. Patients with primary T4 melanoma without clinical nodal involvement who underwent SLNB between 2002 and 2012 at Peter MacCallum Cancer Centre were included in the analysis with chart review performed to collect clinical, pathological, and outcome data. A meta-analysis was performed including similar studies of SLNB in T4 melanoma, which reported overall survival (OS) data. Of 217 patients who underwent SLNB, 78 patients had a positive SLN (36 %). The 5-year OS for SLNB negative and positive patients was 68 and 45 %, respectively [hazard ratio (HR) 2.82; 95 % CI 1.76–4.51; P = .001]. On multivariate analysis, the only predictors of OS were the status of the SLN (HR 2.88; 95 % CI 1.75–4.73) and the presence of satellitosis (HR 2.59; 95 % CI 1.30–5.76). The meta-analysis identified 10 studies that met the inclusion criteria. All reported similar findings, demonstrating a significant difference in OS according to sentinel lymph node status; the pooled analysis of 2104 patients demonstrated an overall HR for OS according to SLNB status of 2.3 (95 % CI 1.95–2.71). SLNB provides important prognostic information for patients with T4 melanoma. This information is important when stratifying patients for clinical trials.

Introduction Metastasectomy can provide durable disease control for selected patients with metastatic melanoma. Vemurafenib is a BRAF kinase inhibitor which has demonstrated significant improvement in disease-specific survival in patients with metastatic melanoma with a BRAF gene mutation. This study examined the efficacy and safety of metastasectomy during treatment with vemurafenib. Methods A retrospective review was performed of all patients receiving vemurafenib at Peter MacCallum Cancer Centre. Patient records were reviewed to identify patients undergoing surgery within 30 days of vemurafenib therapy. Descriptive statistics and survival analysis were performed. Results Nineteen patients underwent 21 metastasectomies including craniotomy (57%), spinal decompression (14%), small bowel resection (14%), lung resection (9.5%) and neck dissection (4.5%). Indications for surgery were: an isolated residual focus of disease (n = 2); isolated progressive disease in the setting of stability elsewhere (n = 9); and symptomatic disease (n = 8). Grade 2 or higher surgical complications occurred in 19% of cases and there was one peri-operative death. Median post-operative survival was seven months. There was a trend toward improved post-operative survival for patients with longer duration of vemurafenib therapy (P = 0.04) and for those undergoing elective surgery (P = 0.07). Conclusion Resection of oligometastatic disease during BRAF-targeted therapy is safe. Selected patients have durable post-operative disease control. J. Surg. Oncol. 2015 111:980–984. © 2015 Wiley Periodicals, Inc.

Objectives Melanoma treatment in the elderly can entail complex decision making. This study characterizes the presentation, management, and outcome of melanoma in the very elderly. Method Retrospective review of all patients in their 85th year or older presenting to a tertiary referral cancer centre between 2000 and 2012 with American Joint Committee on Cancer stages 0–II cutaneous melanoma. Results 127 patients, 26 with in-situ disease and 101 with stages I–II disease, were included. For invasive primary disease, the median age was 87 years (IRQ = 86–89). Most patients had melanomas with poor prognoses at diagnosis: 49.5% were ulcerated, 68.3% mitotically active (mitotic rate ≥ 1), and the median tumor thickness was 3.7 mm (IQR = 1.7–5.8). Nodular melanomas were the most frequent subtype (31.7%, 32/101). Only 66.3% received an excision margin ≥ 10 mm. Suboptimal excision margins were associated with increased risk of local recurrence (HR = 6.87, 95% CI = 5.53–8.20, p = 0.0045) but not poorer disease specific survival (DSS, p = 0.37) or overall survival (OS, p = 0.19). Sentinel node biopsy (SNB) did not influence survival (DSS, p = 0.39, OS, p = 0.78). Median OS was 33 months. Overall, one-third (34.7%) of patients died from causes other than melanoma during the follow up period. In patients aged ≥ 90 only 1 patient (4.3%) died from melanoma, while 10 patients (43.5%) died of other causes. Conclusions Older patients have thick, mitotically active and frequently ulcerated melanomas. An excision margin ≥ 10 mm should be considered to reduce risk of local recurrence. SNB did not impact on survival. With increasing age, patients will more commonly die of causes other than melanoma regardless of the extent of surgical care.

An externally accredited ISO 9001 Quality Management System is a prerequisite for tendering for many public-sector projects, leaving SMEs little choice but to implement a such a system. A link between the motivation behind implementation of a Quality Management System and its effectiveness has been found through quantitative analysis of survey results in recent studies. These studies have suggested that systems deployed for external reasons, such as marketing purposes or to access tendering opportunities, may lead to superficial implementation. However, no studies have examined the mechanisms behind the link between motivation for implementation and Quality Management System effectiveness, in detail and in context using case study analysis. This paper aims to fill this gap in knowledge.The case study examines the effectiveness of implementation of a Quality Management System in a mid-sized Mechanical Electrical and Plumbing contractor in Northern Ireland. Five interviews with key individuals are undertaken and analysed using qualitative analysis software. The company’s Quality Management System documents are used for comparison with actual practice, with observations made of Quality Management System records at site and head office.The findings indicate that, although they take great pride in the quality of their work, most interviewees perceive a disconnect between the Quality Management System and the delivery of quality ‘on the ground.’ The inclusion of irrelevant procedures fosters the perception of the system as a paperwork exercise required only to maintain accreditation. This leads to the situation where ‘stretching the truth,’ backdating documents and deception in ISO 9001 procedures become commonplace in the organisation. The desire to hold ISO 9001 accreditation for the ‘certificate on the wall’ creates a culture which undermines its implementation and gives tacit permission to take shortcuts to retain accreditation.

The prognosis for patients with stage IV melanoma has historically been extremely poor and there have until recently been no effective treatment options. The last 3 years have seen a seismic shift in the management of these patients with the entry to the clinic of a number of novel agents with proven efficacy. These agents fall into two main classes: molecular-targeted therapy and immunotherapy. Molecular therapies have primarily targeted the mitogen-activated protein kinase pathway, most notably with oral inhibitors targetting oncogenic BRAF. Immunotherapy agents such as ipilimumab, and more recently antibodies against PD-1 boost the host immune response against the melanoma. It is important for surgeons to be aware of these advances for a number of reasons. Firstly, to be able to inform their patients of the general options available in the event of disease progression. Secondly, these agents are currently being assessed in the adjuvant setting and are likely to demonstrate efficacy for earlier stages of disease. Finally, it is important for surgeons to be able to advocate on their patients' behalf to minimize the lag time between publication of these promising results and the availability of these agents in the clinic. Furthermore, patients with advanced melanoma should be offered participation in clinical trials in order to refine the indications for these agents to maximize their chance of benefit.

The majority of melanomas are thin lesions with an excellent prognosis; however, significant tumor heterogeneity exists, and a small percentage of patients with early-stage disease may progress to metastatic recurrence. This study aimed to assess whether prognostic factors previously shown to be significant in predicting stage I and stage II melanoma recurrence were consistent in a large prospectively collected patient cohort, and to identify novel prognostic factors associated with early recurrence to inform follow-up protocols. There were 1029 patients with stage I and stage II melanoma included in the analysis, of whom 123 developed a recurrence during follow-up (median 2.13 years). Multivariable analysis identified ulceration, presence of mitoses, Clark level, presence of lymphovascular invasion, and a history of autoimmune disease as factors independently associated with recurrence. These data identified patients with stage I-II melanoma with very low-risk for recurrence: no ulceration, zero mitoses, a low Clark level, no lymphovascular invasion, and possibly no history of autoimmune disease. These patients do not require intensive follow-up: 12 monthly reviews and full skin checks may be appropriate. Ongoing research into prognostic factors for recurrence in early-stage melanoma is important.

The sudden change in environmental munificence level in the construction sectorduring the period 2007 – 2015 provides a natural experiment to investigate strategicand operating actions of firms, particularly during an environmental jolt. Statistics onbusiness failures corroborate that neither academics nor practitioners have succeededin guiding strategic action during periods of environmental jolt. Despite the recentincrease of turnaround research in the general management domain, its use in theconstruction management realm remains underexplored. To address this researchgap, five exploratory case studies of an ongoing PhD study were used to examine theturnaround strategies of construction contractors during a period of economiccontraction and growth. The findings show that, although retrenchment is oftenconsidered to be a short-term strategy, this is clearly not the case; with the majority ofcontractors maintaining the strategy for 6-7 years. During the same period,internationalization became critical, with the turnaround process shifting towardsstrategic reorientation that altered the firms' market domain. The case studies furthersuggest that strategic and operational actions resonate quite well with contemporarypractice-based approaches to strategy making. The findings provide valuableassistance for construction contractors in dealing with organisational decline and indeveloping a successful turnaround response.

Recommended margins for thick cutaneous melanoma (Breslow thickness4 mm; T4) have decreased over recent decades. Optimal margins and the role of sentinel node biopsy (SNB) in thick head and neck melanoma remain controversial.A single-center review was conducted of patients treated between 2002 and 2012 assessing the impact of excision margins and sentinel lymph node status on locoregional recurrence and melanoma-specific survival (MSS).One hundred eight patients were identified. Median age was 71.1 years and median Breslow thickness was 6.0 mm. Median follow-up was 40 months. Locoregional recurrence occurred in 27% and there was no significant reduction in recurrence with margins ≥2 cm (p = .17). Increasing margins did not improve survival (p = .58). Fifty-nine patients (55%) underwent SNB, of which 27% were positive. There was a trend toward longer survival for patients who were sentinel lymph node-negative (p = .097).Wider margins do not significantly improve locoregional recurrence or MSS. Sentinel lymph node involvement reflects a poor prognosis. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1373-1379, 2016.

Severely stenosed radiation-induced benign strictures around the level of cricopharyngeus post-radical chemoradiation for head and neck or upper esophageal cancers pose significant management problems. We report our technique of bidirectional assessment and dilatation of pharyngoesophageal strictures in patients with an in situ percutaneous endoscopic gastrostomy (PEG) tube. The upper gastrointestinal surgeon approached the area of stenosis in a retrograde manner through the PEG tube to guide the otolaryngeal surgeon who performed anterograde dilatation via a rigid laryngoscope. Between 2005 and 2009, bidirectional esophageal dilatation was performed on 5 patients at our institution. Video fluoroscopy confirmed improved patency of stenosed esophagus in all cases and good improvement in swallowing ability in 4 patients. The ability to accurately assess pharyngoesophageal strictures using bidirectional visualization and transillumination is the key modification of our technique. We suggest using bidirectional esophageal dilatation on difficult cases with severe pharyngoesophageal stenoses although extreme care is required.

Research has been increasing in recent years into the application of stem cell biology to clinical medicine, particularly its role in the evolution and metastasis of tumours. Stem cells may be the target cell for malignant transformation, and tumour formation could be considered a disorder of stem cell self-renewal pathways. Cancer stem cells have been identified in acute myeloid leukaemia and in breast and central nervous system tumours. Cancer stem cells may have a specific role in tumour metastasis, and their understanding may provide insights into the development of predictive and prognostic markers and specific therapeutic interventions.

peer-reviewed Building Information Modelling (BIM) is growing in pace, not only in design and construction stages, but also in the analysis of facilities throughout their life cycle. With this continued growth and utilisation of the BIM processes, there comes the possibility to adopt such procedures to measure accurately the energy efficiency of buildings; and therefore, their energy usage. To this end, the aim of this research is to investigate if the introduction of BIM Energy Performance Assessment in the form of software analysis provides accurate results, when compared with actual energy consumption recorded. Through selective criterion sampling, three domestic case studies are scrutinised, with baseline figures taken from existing energy providers, the results scrutinised and compared with calculations provided from two separate BIM energy analysis software packages. Of the numerous software packages available, criterion sampling is used to select two of the most prominent platforms available on the market today. The two packages selected for scrutiny are Integrated Environmental Solutions - Virtual Environment (IES-VE) and Autodesk's Green Building Studio (GBS). The results indicate that IES-VE estimated the energy use in region of ±8% in two out of three case studies, while GBS estimated usage approximately ±5%. The findings indicate that the introduction of BIM energy performance assessment, using proprietary software analysis, is a viable alternative to manual calculations of building energy use, mainly due to the accuracy and speed of assessing, even the most complex models. Given the surge in accurate and detailed BIM models and the importance placed on the continued monitoring and control of buildings energy use within today’s environmentally conscious society, this provides an alternative means by which to assess accurately a buildings energy usage, in a quick and cost effective manner.

Bidirectional oesophageal dilatation for severe chemoradiation-induced oesophageal strictures is efficacious in improving luminal patency but ineffective in relieving functional dysphagia.To assess the efficacy of bidirectional oesophageal dilatation in the severely strictured oesophagus induced by radiation therapy following the treatment of head and neck malignancies.The study design was a case series in the setting of a tertiary cancer centre. We carried out a retrospective analysis of patients who underwent bidirectional oesophageal dilatation for oesophageal stricture secondary to radiation therapy for head and neck malignancies over a 5-year period. The parameters of the primary tumour, evaluation of preoperative and postoperative oesophageal dysfunction and complications of the procedure were evaluated.There were nine episodes of bidirectional oesophageal dilatation among five patients with complete or severe oesophageal obstruction. Mean age was 63 years. The procedure was uneventful in all but one patient who was found to have postoperative mediastinitis, and healed completely. Four patients had persistent dysphagic symptoms despite post dilatation video fluoroscopy failing to reveal any significant narrowing of the oesophageal lumen.

9563 Background: With the evolving treatment landscape in metastatic melanoma, approaches to disease surveillance post resection in stage 3 disease requires reconsideration. We previously reported the outcomes of sub-stage-specific schedules of combined fluorodeoxyglucose-positron emission and computerized tomography (PET/CT) surveillance at high risk of relapse following surgery. The aim of this study was to provide an update on our surveillance protocol with an extended sample size and longer duration of follow-up. Methods: From 2009, patients with AJCC stage 3 melanoma underwent PET/CT scans according to pre-specified schedules based on Bayesian probabilities of sub-stage-specific relapse. Schedules were stage 3A: 6, 18 mo; stage 3B: 6, 12, 18, 24, 36, 48, 60 months; stage 3C: 6, 12, 18, 24, 36 months. Contingency tables were used to evaluate the sensitivity, specificity and predictive values of these schedules. Results: In total, 171 patients (3A: 34; 3B: 93; 3C:44) underwent 553 PET/CT scans with a median follow up of 47 months. Relapses were identified in 65 (38%) patients of which (72%) were asymptomatic at the time of radiologically documented relapse. False positive results occurred in 8%. The positive predictive value (PPV) of an individual scan for diagnosing true recurrence was 77% (64-87%). Negative scans at 6 months had negative predictive values (NPV) between 57% in Stage 3A to 69% in Stage 3B for relapse. Sensitivity and specificity of the overall approach of sub-stage-specific PET/CT surveillance for detecting disease relapse were 70% and 89%, respectively. Evaluable predictive values for detecting disease relapse were: stage 3A: PPV:56%, NPV:76%; 3B: PPV 83%, NPV 86%; stage 3C: PPV 84%, NPV 84%. 32 of 65 patients (49%; 3A: 1; 3B: 7; 3C: 2) underwent resection of relapsed disease and 10 of these patients remained free of disease with a median follow-up of 24 months. Conclusions: Sub-stage-specific PET/CT is effective in detecting asymptomatic recurrence in stage 3 melanoma, and is associated with a high rate of disease resection at relapse.

Metastasectomy can provide durable disease control for selected patients with metastatic melanoma. Vemurafenib is a BRAF kinase inhibitor which has demonstrated significant improvement in disease-specific survival in patients with metastatic melanoma with a BRAF gene mutation. This study examined the efficacy and safety of metastasectomy during treatment with vemurafenib.A retrospective review was performed of all patients receiving vemurafenib at Peter MacCallum Cancer Centre. Patient records were reviewed to identify patients undergoing surgery within 30 days of vemurafenib therapy. Descriptive statistics and survival analysis were performed.Nineteen patients underwent 21 metastasectomies including craniotomy (57%), spinal decompression (14%), small bowel resection (14%), lung resection (9.5%) and neck dissection (4.5%). Indications for surgery were: an isolated residual focus of disease (n = 2); isolated progressive disease in the setting of stability elsewhere (n = 9); and symptomatic disease (n = 8). Grade 2 or higher surgical complications occurred in 19% of cases and there was one peri-operative death. Median post-operative survival was seven months. There was a trend toward improved post-operative survival for patients with longer duration of vemurafenib therapy (P = 0.04) and for those undergoing elective surgery (P = 0.07).Resection of oligometastatic disease during BRAF-targeted therapy is safe. Selected patients have durable post-operative disease control.

Objectives:Assess the efficacy of bidirectional esophageal dilatation in the severely strictured esophagus induced by radiation therapy following the treatment of head and neck malignancies.Methods:Retrospective analysis of 5 patients who underwent bidirectional esophageal dilatation for esophageal stricture secondary to radiation therapy for head and neck malignancies over a 5-year period. The parameters of the primary tumor, evaluation of preoperative and postoperative esophageal dysfunction, and complications of the procedure were evaluated to assess its efficacy.Results:There were 9 episodes of bidirectional dilatation among 5 patients, 3 males and 2 females with a mean age of 63 years. Complete obstruction was demonstrated in 4 patients and severe obstruction was found in one patient during preoperative evaluation. The procedure was uneventful in all but 1 who was found to have postoperative mediastinitis due to microperforations, and healed completely. Four patients had persistent dysphagic symptoms...

Survivorship care plans (SCPs) have been proposed for universal use with the aim of addressing the many unmet needs of cancer survivors. Trials have failed to find a significant impact of SCPs on quality of life outcomes. This study evaluated quality of life, unmet needs, satisfaction with health care and perception of cancer care coordination at the end of treatment in a cohort of women at the end of treatment for early breast cancer. The aim was to identify specific needs to assist in the design of a tailored SCP.Women completed patient-reported measures of health-related quality of life (FACT-B [ES]), unmet needs (CaSUN), satisfaction with medical care and cancer care coordination. Total scores and subscale scores for the whole cohort and results of analysis comparing three age groups were reported.Sixty-eight women (mean age 56) participated. Mean score for FACT-B = 108 and FACT-B (ES) = 167.4. Younger women (51 years) reported a significantly lower quality of life (P = 0.001 for FACT-B, TOI and FACT-B [ES]). Using CaSUN, 76.1% of participants reported at least one unmet need; mean number of unmet needs = 6.2. Younger women reported more unmet needs than older women. The most frequently reported unmet need was fear of cancer recurrence. Overall, participants were very satisfied with medical care and cancer care coordination.Younger women reported poorer quality of life and more unmet needs. SCPs should specifically target younger women and must include strategies to address fear of cancer recurrence if they are to lead to a measureable difference in outcomes.

This research assesses the effectiveness of current MSc. Construction Project Management programmes within the UK and Ireland. A review of published prospectuses is used to create questionnaires for universities, graduates and employers. Responses provide an insight into programme creation and their relative success in addressing the needs of industry and in achieving other educational objectives. Since the majority of learning institutions have attained professional accreditation, it is useful to review these awards and to assess their potential value to both graduates and industry alike. Interviews are conducted with representatives from the main professional accrediting bodies to understand their procedures and rigour in enforcing standards of education and training. The results show that project management education could be further enhanced by the inclusion of more practical learning and that current programmes place greater emphasis on hard skills at the expense of the softer human skills. There is clearly a need for a closer working relationship between academics and practitioners to tackle the perceived gap between theoretical learning and construction practice. Learning institutions can use the findings to improve their programmes and address the education deficiencies identified by the industry, by the professional institutions and by graduates.