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A plateau in treatment effect can be seen for the current ‘one-size-fits-all’ approach to oesophageal adenocarcinoma (OAC) management using neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT). In OAC, the tumour microenvironment (TME) is largely immunosuppressed, however a subgroup of patients with an immune-inflamed TME exist and show improved outcomes. We aimed to understand the overall immune-based mechanisms underlying treatment responses and patient outcomes in OAC, and in relation to neoadjuvant therapy modality. This study included 107 patients; 68 patients were enrolled in the Australian Gastro-Intestinal Trials Group sponsored DOCTOR Trial, and 38 patients were included from the Cancer Evolution Biobank. Matched pre-treatment and post-treatment tumour biopsies were used to perform multimodality analysis of the OAC TME including NanoString mRNA expression analysis, multiplex and single colour immunohistochemistry (IHC), and peripheral blood mononuclear cell analysis of tumour-antigen specific T cell responses. Patients with the best clinicopathological outcomes and survival had an immune-inflamed TME enriched with anti-tumour immune cells and pathways. Those with the worst survival showed a myeloid T regulatory cell enriched TME, with decreased CD8+ cell infiltration and increased pro-tumour immune cells. Multiplex IHC analysis identified that high intra-tumoural infiltration of CD8+ cells, and low infiltration with CD163+ cells was associated with improved survival. High tumour core CD8+ T cell infiltration, and a low tumour margin infiltration of CD163+ cells was also associated with improved survival. nCRT showed improved survival compared with nCT for patients with low CD8+, or high CD163+ cell infiltration. Poly-functional T cell responses were seen with tumour-antigen specific T cells. Overall, our study supports the development of personalised therapeutic approaches based on the immune microenvironment in OAC. Patients with an immune-inflamed TME show favourable outcomes regardless of treatment modality. However, in those with an immunosuppressed TME with CD163+ cell infiltration, treatment with nCRT can improve outcomes. Our findings support previous studies into the TME of OAC and with more research, immune based biomarker selection of treatment modality may lead in improved outcomes in this deadly disease. [ABSTRACT FROM AUTHOR]

A plateau in treatment effect can be seen for the current 'one-size-fits-all' approach to oesophageal adenocarcinoma (OAC) management using neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT). In OAC, the tumour microenvironment (TME) is largely immunosuppressed, however a subgroup of patients with an immune-inflamed TME exist and show improved outcomes. We aimed to understand the overall immune-based mechanisms underlying treatment responses and patient outcomes in OAC, and in relation to neoadjuvant therapy modality. This study included 107 patients; 68 patients were enrolled in the Australian Gastro-Intestinal Trials Group sponsored DOCTOR Trial, and 38 patients were included from the Cancer Evolution Biobank. Matched pre-treatment and post-treatment tumour biopsies were used to perform multimodality analysis of the OAC TME including NanoString mRNA expression analysis, multiplex and single colour immunohistochemistry (IHC), and peripheral blood mononuclear cell analysis of tumour-antigen specific T cell responses. Patients with the best clinicopathological outcomes and survival had an immune-inflamed TME enriched with anti-tumour immune cells and pathways. Those with the worst survival showed a myeloid T regulatory cell enriched TME, with decreased CD8+ cell infiltration and increased pro-tumour immune cells. Multiplex IHC analysis identified that high intra-tumoural infiltration of CD8+ cells, and low infiltration with CD163+ cells was associated with improved survival. High tumour core CD8+ T cell infiltration, and a low tumour margin infiltration of CD163+ cells was also associated with improved survival. nCRT showed improved survival compared with nCT for patients with low CD8+, or high CD163+ cell infiltration. Poly-functional T cell responses were seen with tumour-antigen specific T cells. Overall, our study supports the development of personalised therapeutic approaches based on the immune microenvironment in OAC. Patients with an immune-inflamed TME show favourable outcomes regardless of treatment modality. However, in those with an immunosuppressed TME with CD163+ cell infiltration, treatment with nCRT can improve outcomes. Our findings support previous studies into the TME of OAC and with more research, immune based biomarker selection of treatment modality may lead in improved outcomes in this deadly disease. [ABSTRACT FROM AUTHOR]

Background Clinical services for Barrett's esophagus have been rising worldwide including Australia, but little is known of the long-term outcomes of such patients. Retrospective studies using data at baseline are prone to both selection and misclassification bias. We investigated the clinical characteristics and outcomes of Barrett's esophagus patients in a prospective cohort. Methods We recruited patients diagnosed with Barrett's esophagus in tertiary settings across Australia between 2008 and 2016. We compared baseline and follow-up epidemiological and clinical data between Barrett's patients with and without dysplasia. We calculated age-adjusted incidence rates and estimated minimally and fully adjusted hazard ratios (HR) to identify those clinical factors related to disease progression. Results The cohort comprised 268 patients with Barrett's esophagus (median follow-up 5 years). At recruitment, 224 (84%) had no dysplasia, 44 (16%) had low-grade or indefinite dysplasia (LGD/IND). The age-adjusted incidence of esophageal adenocarcinoma (EAC) was 0.5% per year in LGD/IND compared with 0.1% per year in those with no dysplasia. Risk of progression to high-grade dysplasia/EAC was associated with prior LGD/IND (fully adjusted HR 6.55, 95% confidence interval [CI] 1.96–21.8) but not long-segment disease (HR 1.03, 95%CI 0.29–3.58). Conclusions These prospective data suggest presence of dysplasia is a stronger predictor of progression to cancer than segment length in patients with Barrett's esophagus. [ABSTRACT FROM AUTHOR]

Motivation Changes in telomere length have been observed in cancer and can be indicative of mechanisms involved in carcinogenesis. Most methods used to estimate telomere length require laboratory analysis of DNA samples. Here, we present qmotif, a fast and easy tool that determines telomeric repeat sequences content as an estimate of telomere length directly from whole-genome sequencing. Results qmotif shows similar results to quantitative PCR, the standard method for high-throughput clinical telomere length quantification. qmotif output correlates strongly with the output of other tools for determining telomere sequence content, TelSeq and TelomereHunter, but can run in a fraction of the time—usually under a minute. Availability and implementation qmotif is implemented in Java and source code is available at https://github.com/AdamaJava/adamajava , with instructions on how to build and use the application available from https://adamajava.readthedocs.io/en/latest/. Supplementary information Supplementary data are available at Bioinformatics Advances online. [ABSTRACT FROM AUTHOR]

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 (< 20 Mut/Mb; 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). [ABSTRACT FROM AUTHOR]

Background: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy. Methods: Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15. Results: Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months. Conclusions: The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies. [ABSTRACT FROM AUTHOR]

Background: Little is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC. Methods: Patients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group. Results: Overall, 129 (19%) of 689 patients included had SRCs (nCT: n = 64; nCRT: n = 65). The SRC group had a more advanced ypT stage (p = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range [IQR]) 2 [0–5] vs. 1 [0–3]; p = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median [IQR] 12 [5–50] vs. 23 [8–164]; p = 0.013), but not OS, compared with the non-SRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT. Conclusions: SRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS. [ABSTRACT FROM AUTHOR]

Background This study assessed and compared the morbidity of nodal dissection in the axilla and groin including sentinel lymph node biopsy ( SLNB), completion lymph node dissection for a positive SLNB ( CLND) and therapeutic lymph node dissection ( TLND) with and without adjuvant radiotherapy ( RT). Methods Patients who had nodal dissection in the axilla or groin for cutaneous melanoma over an 18-year period (1995-2013) were prospectively documented on a database. The median follow-up was nearly 3 years. Early complications and clinically relevant lymphoedema were retrospectively analysed to assess the incidence and differences between the region and type of nodal surgery. Results Included were 1521 patients following nodal dissection in the axilla (916 patients) and groin (605 patients). Less early complications occurred following SLNB in the axilla compared with the groin (5% versus 14%, P = 0.0001). Early complications were similar for CLND and TLND in the groin (49% versus 43%, P = 0.879) and axilla (28% versus 33%, P = 0.607). Moderate to severe lymphoedema rates were similar following axillary SLNB and CLND (6% versus 8%, P = 0.407). The lymphoedema rate for groin SLNB was lower than CLND (10% versus 20%, P = 0.063). No significant difference in lymphoedema rates followed CLND and TLND in each region. Following TLND, RT increased lymphoedema rates. Conclusions Morbidity may occur following SLNB with the groin having a higher rate of early complications and lymphoedema compared with the axilla. The morbidity following CLND and TLND were similar. Lymphoedema rates were increased following RT. [ABSTRACT FROM AUTHOR]

A meeting of the Australasian Gastro-Intestinal Trials Group (AGITG) was held to develop a consensus statement defining when a patient with pancreatic cancer has disease that is clearly operable, is borderline, or is locally advanced/inoperable. Key issues included the need for multidisciplinary team consensus for all patients considered for surgical resection. Staging investigations, to be completed within 4 weeks of presentation, should include pancreatic protocol computed tomography, endoscopic ultrasound, and, when possible, biopsy. Given marked differences in outcomes, the operability of tumours should be clearly identified by categories: those clearly resectable by standard means (group 1a), those requiring vascular resection but which are clearly operable (group 1b), and those of borderline operability requiring vascular resection (groups 2a and 2b). Patients who may require vascular reconstruction should be referred, before exploration, to a specialist unit. All patients should have a structured pathology report with standardised reporting of all seven surgical margins, which identifies an R0 (no tumour cells within a defined distance of the margin) if all surgical margins are clear from 1 mm. Neo-adjuvant therapy is increasingly recommended for borderline operable disease, while chemotherapy is recommended as initial therapy for patients with unresectable loco-regional pancreatic cancer. The value of adding radiation after initial chemotherapy remains uncertain. A small number of patients may be downstaged by chemoradiation, and trimodality therapy should only be considered as part of a clinical trial. Instituting these recommendations nationally will be an integral part of the process of improving quality of care and reducing geographic variation between centres in outcomes for patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of this paper is to determine levels of supportive care needs, anxiety, depression and symptoms amongst patients newly diagnosed with localised invasive primary melanoma and if these varied amongst patients who had a sentinel lymph node biopsy (SLNB). We also considered quality of life compared with general population norms. Methods: Patients newly diagnosed with clinical stage IB-II invasive melanoma were ascertained through Queensland hospitals, specialist clinics and pathology laboratories. Validated surveys measured 46 need items (Supportive Care Needs Survey-Short Form + melanoma subscale), anxiety and depression (Hospital Anxiety and Depression Scale) and quality of life and symptoms (Functional Assessment of Cancer Therapy-Melanoma). Regression models compared outcomes according to whether or not participants had a SLNB. Results: We surveyed 386 patients, 155 before and 231 after wide local excision, of whom 46% reported ⩾1 moderate-level or high-level unmet need. The three highest needs were for help with fears about cancer spreading (17%), information about risk of recurrence (17%) and outcomes when spread occurred (16%). Those who had a SLNB were more likely to report a moderate or high unmet need for help with uncertainty about the future or with lymphoedema (p<0.05). Overall, 32% of participants had anxiety and 15% had depression regardless of performance of SLNB. Melanoma-specific symptoms were worse in SLNB patients (p = 0.03). Compared with the general population, emotional well-being was lower amongst melanoma patients. Conclusions: A substantial proportion of newly diagnosed patients with localised invasive melanoma need further melanoma-specific information and support with psychological concerns. Patients who have a SLNB clear of disease may need help with symptoms after surgery. [ABSTRACT FROM AUTHOR]

Major advances in the medical treatment of gastrointestinal tumors ( GISTs) have improved survival for both patients with advanced disease and those diagnosed with high-risk primary tumors. The Consensus approaches to best practice management of gastrointestinal stromal tumors, published in this journal in 2008, provided guidance for the management of GIST to both clinicians and regulatory authorities. Since then, clinical trials have demonstrated the benefit of adjuvant imatinib in high-risk patients, and mature data from advanced GIST studies suggest that a small but significant proportion of patients with advanced disease can achieve long-term benefit with ongoing imatinib treatment. Other evolving management strategies include the controversial use of palliative or debulking surgery to improve outcomes in advanced GIST and the development of promising new multikinase inhibitors, such as regorafenib, which has established benefit in the third-line setting. This review provides an update of recent developments in GIST management and discusses new controversies that these advances have generated. [ABSTRACT FROM AUTHOR]

Objective. We investigate the prevalence of human papillomavirus (HPV) in oesophageal squamous cell carcinoma (OSCC) tissues compared to oesophageal tissue from healthy controls, in an Australian cohort. Methods. We conducted a hospital-based casecontrol study of 99 patients with OSCC and 100 healthy controls to examine the presence of HPV DNA. Paraffin tissues were tested using the PapType high-risk HPV detection and genotyping kit and with INNO-LiPA HPV Genotyping Extra. The biopsy samples were tested for HPV using a PCR-ELISA method based on the L1 consensus primer set PGMY09-PGMY11. Results. HPVDNA of the oncogenic genotype 16 was detected in 1/99 case specimens, a rate of 1010 per 100,000 (95% CI: 30-5500). All control specimens were negative forHPV. Significantly higher rates of smoking, other aerodigestive cancers, andmortalitywere seen among cases than controls. A pooled analysis of this study and the only other Australian case-control study found that 9/321 cases and 0/155 controls were positive for HPV. The pooled odds ratio for HPV being a risk factor for OSCC was 9.35 (95% CI: 0.47-190.33). Conclusion. Our results suggest that in this multifactorial cancer HPV may be an additional risk factor; although a larger, better powered study is needed. [ABSTRACT FROM AUTHOR]

Background Little has been published regarding presenting symptoms, investigations and outcomes for patients with pancreatic cancer in Australia. Data from a series of patients undergoing attempted resection in Queensland, Australia, are presented with the aim of assisting development of consistent strategies in disease management. Methods We reviewed the medical records of 121 patients who underwent attempted surgical resection and who took part in a case-control study between 2007 and 2009. Information relating to symptoms, investigations, surgical procedures and outcomes was captured. Results The mean age was 63 years and 60% were men. The most common presenting symptoms were jaundice (64%) and pain (63%). Over 80% of patients had multiple imaging investigations or laparoscopy prior to surgery. Seventy-eight patients (64%) had a completed resection and 23% of these had involved margins. The presence of metastases and/or involvement of vessels or adjacent structures precluded resection in the remaining patients. The 1-year survival for patients whose resections were completed was 77% compared with 51% for those whose tumours were not resectable ( P = 0.004). There was no 30-day mortality and 68% of patients were alive 1 year after diagnosis. Resections were performed in 11 different hospitals but over 90% of patients underwent their surgery in one of five high-volume centres. Conclusion The Queensland experience is consistent with that reported internationally. A significant proportion of attempted resections was not completed because preoperative staging underestimated disease extent. Most patients with potentially resectable disease are being treated in high-volume centres. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 43-year-old male who was transferred to an institution with haemodynamic instability secondary to haematemesis. The patient has a caustic injury to his oesophagus that culminated in an Ivor Lewis oesophagogastrectomy with an intrathoracic gastric conduit after failed endoscopic management. A number of proposed mechanisms is explored by which vulnerability of the intrathoracic gastric conduit to peptic ulceration is conferred.

The article presents the case studies of a 32-year-old male and a 36-year-old female diagnosed with non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy and enteropathy of the ileum. The authors state that these cases emphasize the importance of performing a thorough intraoperative examination of the small intestine in chronic users of NSAIDs. They also recommend the use of capsule endoscopy and double balloon enteroscopy to diagnose the said conditions.