Clinical pathways and outcomes of patients with Barrett's esophagus in tertiary care settings: a prospective longitudinal cohort study in Australia, 2008-2016.

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.

The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer.

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.

Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus.

Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett's esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE± low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.

The Impact of Signet Ring Cell Differentiation on Outcome in Patients with Esophageal and Gastroesophageal Junction Adenocarcinoma.

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.

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

Long-term Health-related Quality of Life Following Esophagectomy: A Nonrandomized Comparison of Thoracoscopically Assisted and Open Surgery.

OBJECTIVE: The aim of this study was to assess long-term health-related quality of life (HRQL) in patients after thoracoscopic and open esophagectomy. SUMMARY OF BACKGROUND DATA: Trials comparing minimally invasive with open transthoracic esophagectomy have shown improved short-term outcomes; however, long-term HRQL data are lacking. This prospective nonrandomized study compared HRQL and survival after thoracoscopically assisted McKeown esophagectomy (TAMK) and open transthoracic Ivor Lewis esophagectomy (TTIL) for esophageal or gastroesophageal junction (GEJ) cancer. METHODS: Patients with esophageal or GEJ cancer selected for TAMK or TTIL completed baseline and follow-up HRQL assessments for up to 24 months using the EORTC generic and disease-specific measures, QLQ-C30 and QLQ-OES18. Baseline clinical variables were examined between the treatment groups and changes in mean HRQL scores over time estimated and tested using generalised estimating equations with propensity score (generated by boosted regression) adjustment. RESULTS: Of the 487 patients, 377 underwent TAMK and 110 underwent TTIL. Most clinical variables were similar in the 2 groups; however, there were significantly more patients with AJCC stage 3 disease who underwent TTIL than TAMK (54% vs 32%, P < 0.01) and this was reflected in the survival data.Mean symptom scores for pain were significantly higher in the TTIL group than in TAMK for 2 years postoperatively (P = 0.036). In addition, mean constipation scores were significantly higher for the TTIL group, with a 15-point difference in mean score at 3 months postoperatively (P = 0.037). CONCLUSIONS: This large comprehensive nonrandomized analysis of longitudinal HRQL shows that TTIL is associated with more pain and constipation than TAMK.

Primary cutaneous melanoma of the scalp: Patterns of recurrence.

INTRODUCTION: Patients with primary melanoma of the scalp have been reported to have worse disease-related outcomes compared with other anatomical regions. There are few studies in the literature specifically addressing recurrence patterns and treatment outcomes for primary scalp melanoma as a discrete anatomical sub-region. We sought to identify key features adversely influencing disease control and survival and to clarify the role of resection plane, margin, and method of reconstruction in the management of this disease process. METHODS: A retrospective clinical study of medical records was performed evaluating all patients with primary melanoma of the scalp treated at two hospitals in southeast Queensland between 2004 and 2014. RESULTS: A total of 107 patients were eligible for analysis. There were 46 recurrences in 38 patients in the cohort accounting for a recurrence rate of 35.5%. The local recurrence rate was 15.9% with 12 in-transit metastases after diagnosis. Regional and distant recurrence rates were 12.1% and 15%, respectively. At a median follow up of 30.5 months, disease-free survival was 47% and overall survival was also 47%. On multi-variate analysis, the deeper resection plane (sub-galeal) had a lower disease-free survival rate compared with the supra-galeal resection plane (P = 0.032). DISCUSSION: Our results support the hypothesis that primary scalp melanoma represents a unique aggressive subcategory with high rates of in-transit disease and poor disease-related and survival outcomes. There is a need for robust prospective comparative studies to address the significance of resection plane in the management of patients with scalp melanoma.

Serum Glycoprotein Biomarker Discovery and Qualification Pipeline Reveals Novel Diagnostic Biomarker Candidates for Esophageal Adenocarcinoma.

We report an integrated pipeline for efficient serum glycoprotein biomarker candidate discovery and qualification that may be used to facilitate cancer diagnosis and management. The discovery phase used semi-automated lectin magnetic bead array (LeMBA)-coupled tandem mass spectrometry with a dedicated data-housing and analysis pipeline; GlycoSelector (http://glycoselector.di.uq.edu.au). The qualification phase used lectin magnetic bead array-multiple reaction monitoring-mass spectrometry incorporating an interactive web-interface, Shiny mixOmics (http://mixomics-projects.di.uq.edu.au/Shiny), for univariate and multivariate statistical analysis. Relative quantitation was performed by referencing to a spiked-in glycoprotein, chicken ovalbumin. We applied this workflow to identify diagnostic biomarkers for esophageal adenocarcinoma (EAC), a life threatening malignancy with poor prognosis in the advanced setting. EAC develops from metaplastic condition Barrett's esophagus (BE). Currently diagnosis and monitoring of at-risk patients is through endoscopy and biopsy, which is expensive and requires hospital admission. Hence there is a clinical need for a noninvasive diagnostic biomarker of EAC. In total 89 patient samples from healthy controls, and patients with BE or EAC were screened in discovery and qualification stages. Of the 246 glycoforms measured in the qualification stage, 40 glycoforms (as measured by lectin affinity) qualified as candidate serum markers. The top candidate for distinguishing healthy from BE patients' group was Narcissus pseudonarcissus lectin (NPL)-reactive Apolipoprotein B-100 (p value = 0.0231; AUROC = 0.71); BE versus EAC, Aleuria aurantia lectin (AAL)-reactive complement component C9 (p value = 0.0001; AUROC = 0.85); healthy versus EAC, Erythroagglutinin Phaseolus vulgaris (EPHA)-reactive gelsolin (p value = 0.0014; AUROC = 0.80). A panel of 8 glycoforms showed an improved AUROC of 0.94 to discriminate EAC from BE. Two biomarker candidates were independently verified by lectin magnetic bead array-immunoblotting, confirming the validity of the relative quantitation approach. Thus, we have identified candidate biomarkers, which, following large-scale clinical evaluation, can be developed into diagnostic blood tests. A key feature of the pipeline is the potential for rapid translation of the candidate biomarkers to lectin-immunoassays.

Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett's esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival.

Refining the care of patients with pancreatic cancer: the AGITG Pancreatic Cancer Workshop consensus.

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.

Patterns of Recurrence in Patients with Stage IIIB/C Cutaneous Melanoma of the Head and Neck Following Surgery With and Without Adjuvant Radiation Therapy: Is Isolated Regional Recurrence Salvageable?

BACKGROUND: Understanding recurrence patterns is vital for guiding treatment. This study describes recurrence patterns for patients with stage IIIB/C head and neck melanoma (HNM) after therapeutic lymph node dissection (TLND) ± adjuvant radiation therapy (RT). We also report outcomes for salvage therapy for patients with isolated regional relapse. METHODS AND MATERIALS: A single-institution prospective database of 173 patients with American Joint Committee on Cancer (AJCC) stage IIIB/C HNM undergoing TLND between 1997 and 2012 was retrospectively reviewed. Timing and patterns of recurrence were reviewed. Univariable and multivariable analyses were undertaken using the Kaplan-Meier and Cox regression methods to determine factors predictive of recurrence. Median follow-up was 32 months. RESULTS: Adjuvant RT was administered to 66/173 (38 %) patients. Patients selected for RT had a higher AJCC stage and had more extracapsular invasion. The 5-year distant, cervical nodal and in-transit recurrence rates were 38, 10, and 13 %, respectively, following surgery alone compared with 60, 17, and 31 %, respectively, for the adjuvant RT group. The head and neck regional 5-year recurrence rate (combining in-basin nodal and in-transit) was 23 % for the entire cohort. Isolated cervical recurrence occurred in 19 patients: 17/19 underwent salvage surgery (10/17 patients received RT after salvage surgery) and 2/19 had RT alone. However, distant recurrence occurred in 12/19 salvage patients, with most occurring within 12 months, while 4/19 were disease free. CONCLUSIONS: Using a selective approach for adjuvant RT, isolated cervical recurrence after TLND is uncommon. Isolated cervical recurrence can be salvaged effectively with further local therapy; however, distant disease frequently follows.

Supportive care needs, anxiety, depression and quality of life amongst newly diagnosed patients with localised invasive cutaneous melanoma in Queensland, Australia.

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.

Prospective study of patterns of surgical management in adults with primary cutaneous melanoma at high risk of spread, in Queensland, Australia.

BACKGROUND: Knowledge of variation in diagnosis and surgery in high-risk primary melanoma patients is limited. We assessed frequency and determinants of diagnostic procedures, wide local excision (WLE) and sentinel lymph node biopsy (SLNB). METHODS: People in Queensland newly diagnosed with melanoma, clinical stage 1b or 2, were recruited prospectively. Patient information was collected from questionnaires and pathology records. Differences in surgical procedures in relation to host and tumor characteristics were assessed. RESULTS: In 787 participants, primary melanoma was diagnosed by surgical excision (74%), shave (14%), punch (12%) or incisional (1%) biopsy. General practitioners (GPs) diagnosed 80%. Diagnostic procedure differed by remoteness of residence, health sector, treating doctor's specialty and melanoma site and thickness. 766 patients had WLE, 86% by surgeons. Of 134 residual melanomas, 13 (10%) were ≤ 1 mm at diagnosis but > 1 mm at WLE, mostly after shave biopsy. SLNB was performed in 261 (33%) patients. SLNB was more common in those under 50, in remoter locations or treated by GP initially, and less common with head and neck melanoma. CONCLUSION: Diagnostic and surgical procedures for primary melanoma vary substantially and partial biopsy can influence initial tumor microstaging. Patient, tumor and doctor characteristics influence SLNB practice.

Treatment results of curative gastric resection from a specialist Australian unit: low volume with satisfactory outcomes.

BACKGROUND: The incidence of gastric cancer is decreasing in Australia, yet it remains a common cause of cancer-related mortality. Surgical resection remains the cornerstone of curative treatment. High-volume specialized units have reported superior perioperative and oncological outcomes. The role of D2 lymphadenectomy has been controversial as a result of concerns over increased morbidity. Our aim is to report the perioperative and oncological outcomes of curative gastric resection from a specialist Australian upper GI unit. METHODS: Data from a prospectively maintained database were reviewed for all patients undergoing curative resection for gastric adenocarcinoma from a single unit during a 12-year period. Perioperative and long-term outcomes were compiled. RESULTS: There were 255 curative gastric resections during 12 years. An R0 resection was performed in 96 % with a perioperative mortality rate of 1.6 %. A D2 dissection was performed in 85 % of cases in the past 6 years, with no increase in perioperative morbidity or mortality detected. The 5-year overall survival was 53 %. CONCLUSION: Our results demonstrate that both short- and long-term outcomes of surgical resection in gastric cancer patients, comparable to international high-volume centers, can be achieved in an Australian upper GI unit. A D2 lymph node dissection can be performed safely without any increase in perioperative risk in a specialist unit that has the necessary training but also the perioperative support structures to manage these complex patients.

Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance. METHODS: Whole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define 'shared' (between both samples) and 'private' (present in one sample) mutations. RESULTS: Mutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones. CONCLUSIONS: This study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.

Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma.

The poor treatment response of oesophageal adenocarcinoma (OAC) leads to low survival rates. Its increasing incidence makes finding more effective treatment a priority. Recent treatment improvements can be attributed to the inclusion of the tumour microenvironment (TME) and immune infiltrates in treatment decisions. OAC TME is largely immunosuppressed and reflects treatment resistance as patients with inflamed TME have better outcomes. Priming the tumour with the appropriate neoadjuvant chemoradiotherapy treatment could lead to higher immune infiltrations and higher expression of immune checkpoints, such as PD-1/PDL-1, CTLA4 or emerging new targets: LAG-3, TIM-3, TIGIT or ICOS. Multiple trials support the addition of immune checkpoint inhibitors to the current standard of care. However, results vary, supporting the need for better response biomarkers based on TME composition. This review explores what is known about OAC TME, the clinical significance of the various cell populations infiltrating it and the emerging therapeutical combination with a focus on immune checkpoints inhibitors.

The oesophageal adenocarcinoma tumour immune microenvironment dictates outcomes with different modalities of neoadjuvant therapy - results from the AGITG DOCTOR trial and the cancer evolution biobank.

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 multi-modality 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.

Circulating Tumor DNA: A Promising Biomarker for Predicting Recurrence in Patients with BRAF-Negative Melanoma.

For patients with BRAF wild-type stage III and IV melanoma, there is an urgent clinical need to identify prognostic biomarkers and biomarkers predictive of treatment response. Circulating tumor DNA (ctDNA) is emerging as a blood-based biomarker and has shown promising results for many cancers, including melanoma. The purpose of this study was to identify targetable, tumor-derived mutations in patient blood that may lead to treatment alternatives and improved outcomes for patients with BRAF-negative melanoma. Using a CAncer Personalized Profiling by deep Sequencing (CAPP-seq) pan-cancer gene panel, ctDNA from 150 plasma samples (n = 106 patients) was assessed, including serial blood collections for a subset of patients (n = 16). ctDNA variants were detected in 85% of patients, all in targetable pathways, such as vascular endothelial growth factor receptor, epidermal growth factor receptor, phosphatidylinositol 3-kinase/AKT, Bcl2/mammalian target of rapamycin (mTOR), ALK/MET, and cyclin-dependent kinase 4/6. Patients with stage IV melanoma with low ctDNA concentrations, <10 ng/mL, had significantly better disease-specific survival and progression-free survival. Patients with both a high concentration of ctDNA and any detectable ctDNA variants had the worst prognosis. In addition, these results indicated that longitudinal changes in ctDNA correlated with treatment response and disease progression determined by radiology. This study confirms that ctDNA may be used as a noninvasive liquid biopsy to identify recurrent disease and detect targetable variants in patients with late-stage melanoma.

C-reactive protein is a prognostic biomarker in pancreatic ductal adenocarcinoma patients.

AIM: The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is approximately 11% and has only improved marginally over the last three decades. For operable PDAC, resection and adjuvant FOLFIRINOX chemotherapy is standard of care. There is growing interest in perioperative regimens to improve outcomes. The non-randomized Phase II study "Gemcitabine and Abraxane for resectable Pancreatic cancer" (GAP) demonstrated the feasibility of perioperative gemcitabine/abraxane. Long-term survival in PDAC requires an effective immune response; hence, we undertook this translational study of the GAP trial cohort to identify immune-oncology biomarkers for clinical use. METHODS: We combined Nanostring nCounter technology with immunohistochemistry to investigate the correlation between gene expression and overall patient survival. Findings were investigated in samples from the International Cancer Genome Consortium (ICGC, n = 88) and the Australian Pancreatic Genome Initiative (APGI, n = 227). RESULTS: We confirmed that human equilibrative nucleoside transporter 1 (hENT1) expression was not a prognostic marker in PDAC but patients with high levels of hENT1 were more likely to live longer than 24 months post-surgery. Additionally, CD274 (PD-L1) and two novel biomarkers of survival, cathepsin W (CTSW) and C-reactive protein (CRP), were identified in the GAP cohort (n = 19). CRP expression was confirmed in data from the ICGC. Although PD-L1 and CTSW proteins were not significant across all three cohorts, results show that low CRP mRNA and protein expression are associated with longer overall survival in all three patient groups. CONCLUSION: PDAC patients with long survival have higher hENT1 expression levels. Furthermore, CRP expression is a biomarker of poor prognosis following perioperative chemotherapy and resection in PDAC patients and thus may be useful for identifying patients who could benefit from more aggressive adjuvant strategies.

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.