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Small intestinal Neuroendocrine Neoplasms (SI-NENs) are the most common primary malignancy of the small bowel. The aim of this study is to define the survival of patients with an SI-NEN in Auckland, Aotearoa New Zealand (AoNZ).A retrospective study of all patients diagnosed with a jejunal or ileal SI-NEN in the Auckland region between 2000 and 2012 was performed. The New Zealand NETwork! Registry was searched to identify the study cohort. Retrospective data collection was performed to collect stage, survival and follow up data.One hundred and seven patients were included in the study. The mean age of patients was 62.8 years (SD 11.9). The 5 and 10-year disease-specific survival for all patients was 66.1% (95% CI 56.5-75.7%) and 61.8% (95% CI 51.8-71.8%), respectively. Ten-year disease-specific survival was 100% for stage I and II, 74% (95%CI 61.7-84.4%) for stage III and 33.9% (95%CI 16.9-35.6%) for stage IV SI-NEN. Eleven of 40 (27.5%) patients with stage III disease had recurrence and 3 of 7 (42.8%) patients with stage IV disease had recurrence. In patients with stage IV disease, neither primary resection (HR 2.25, 95% CI 0.92-5.5) nor distant resection (HR 1.72, 95% CI 0.63-4.7) were significantly associated with a disease-specific or overall survival benefit.This study demonstrates that stage at SI-NEN diagnosis is associated with survival, but resection of the primary or distant metastases in patients with stage IV disease is not. There was no recurrence in patients with stage I or II disease after complete resection.

BACKGROUND Gene therapy is a promising treatment for protein deficiency disorders such as hemophilia B. However, low tissue selectivity and efficacy are limitations of systemic vector delivery. The authors hypothesized that selective transfection of rat superficial inferior epigastric artery flaps could provide systemic delivery of coagulation factor IX, preventing the need for systemic vector administration. METHODS Minicircle DNA containing green fluorescent protein, firefly luciferase, and human coagulation factor IX were created. Vector constructs were validated by transfecting adipose-derived stromal cells isolated from Wistar rat superficial inferior epigastric artery flaps and evaluating transgene expression by fluorescence microscopy, bioluminescence, and enzyme-linked immunosorbent assay. Minicircle DNA luciferase (10 and 30 μg) was injected into murine (wild-type, C57/BL/6) inguinal fat pads (n = 3) and followed by in vivo bioluminescence imaging for 60 days. Wistar rat superficial inferior epigastric artery flaps were transfected with minicircle DNA human coagulation factor IX (n = 9) with plasma and tissue transgene expression measured by enzyme-linked immunosorbent assay at 2 and 4 weeks. RESULTS Transfected adipose-derived stromal cells expressed green fluorescent protein for 30 days, luciferase for 43 days, and human coagulation factor IX (21.9 ± 1.2 ng/ml) for 28 days in vitro. In vivo murine studies demonstrated dose-dependence between minicircle DNA delivery and protein expression. Ex vivo rat superficial inferior epigastric artery flap transfection with minicircle DNA human coagulation factor IX showed systemic transgene expression at 2 (266.6 ± 23.4 ng/ml) and 4 weeks (290.1 ± 17.1 ng/ml) compared to control tissue (p < 0.0001). CONCLUSIONS Rat superficial inferior epigastric artery flap transfection using minicircle DNA human coagulation factor IX resulted in systemic transgene detection, suggesting that selective flap or angiosome-based tissue transfection may be explored as a treatment for systemic protein deficiency disorders such as hemophilia B.

First-line palliative chemotherapy regimens in advanced pancreatic adenocarcinoma include triplet chemotherapy with 5-fluorouracil, oxaliplatin, and irinotecan, and the doublet of nab-paclitaxel plus gemcitabine. Use of triplet chemotherapy in real-world populations is limited by tolerability and nab-paclitaxel is not universally available. Regimens using the combination of cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel may be better tolerated, more widely available, and similarly effective, but no published real-world data exist.A retrospective cohort review of patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma treated with first-line palliative cisplatin, capecitabine, gemcitabine, and either epirubicin or docetaxel chemotherapy at Auckland City Hospital between July 1, 2013 and July 30, 2020. The primary outcome was overall survival (OS). Secondary outcomes were rates of grade 3 or 4 hematological toxicity, rate of febrile neutropenia, number of cycles received, and reasons for discontinuation.Eighty-eight patients were included. Median age was 66 years (range 39-79), 28.4% had unresectable, locally advanced disease and 71.6% metastatic disease. Median OS was 8.5 months. Patients stopped treatment due to disease progression (53.4%), completing 12 cycles (19.3%), or toxicity (10.2%). Grade 4 neutropenia was experienced by 21.6%; 10.2% had febrile neutropenia. There were four treatment-related deaths.This retrospective study in a real-world population demonstrates that chemotherapy with cisplatin, capecitabine, and gemcitabine with epirubicin (PEXG) or docetaxel (PDXG) had similar effectiveness to more commonly used combination regimens. PDXG/PEXG are viable alternatives to nab-paclitaxel plus gemcitabine in countries that have restricted drug funding.

Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients. CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug. We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing. Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).

Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity. Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC–MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases. There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), Unorm p = 0.0004; U/DHUnorm p = 0.0083. These two parameters had a sensitivity of 29%, compared with 57% for the THY challenge test in the same patients. Genotyping for clinically relevant DPYD variants was inferior to either of these pyrimidine phenotyping tests (sensitivity of 14%). The endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than DPYD genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test.

Many specialist groups have developed clinical trial initiatives in response to the growing need for more collaborative research, and these are proliferating in multiple countries across the globe. The Royal Australasian College of Surgeons (RACS), under the direction of Professor John Windsor, established the clinical trials network of Australia and New Zealand (CTANZ). CTANZ supports the Australasian clinical trials in plastic, reconstructive and aesthetic surgery (ACTPRAS) research group which has already facilitated two multicentre, international, collaborative studies.

Prehabilitation is increasingly recognised as a therapeutic option to reduce postoperative complications. Investigating the beneficial effects of exercise on cellular mechanisms, we have previously shown that a single episode of exhaustive exercise effectively stimulates endothelial progenitor cells (a cell population associated with vascular maintenance, repair, angiogenesis, and neovascularization) in correlation with fewer postoperative complications, despite the ongoing debate about the appropriate cell surface marker profiles of these cells (common phenotypical definitions include CD45dim, CD133+, CD34+ and/or CD31+). In order to translate these findings into clinical application, a feasible prehabilitation programme achieving both functional and cellular benefits in a suitable timeframe to expedite surgery is necessary.The objective of this study was to test the hypothesis that a four-week prehabilitation programme of vigorous-intensity interval exercise training is feasible, increases physical capacity (primary outcome) and the circulatory number of endothelial progenitor cells within peripheral blood.In this unblinded, parallel-group, randomised controlled proof-of-concept clinical trial (German Clinical Trial Register number: DRKS00000527) conducted between 01Vigorous-intensity interval training over four weeks was feasible in the exercise group (successful completion by 8 out of 8 patients without any harms), with significant improvements in patients' functional capacity (increased oxygen uptake at anaerobic threshold [intervention group mean + 1.71 ± 3.20 mL/min/kg vs. control group mean -1.83 ± 2.14 mL/min/kg; p = 0.042] and peak exercise [intervention group mean + 1.71 ± 1.60 mL/min/kg vs. control group mean -1.67 ± 1.37 mL/min/kg; p = 0.002]) and a significant increase in the circulatory number of endothelial progenitor cells (proportionate CD45dim/CD14dim/CD133+/CD309+/CD34+/CD31 + subpopulation within the circulating CD45-pool [p = 0.016]).We introduce a novel prehabilitation concept that shows effective stimulation of an endothelial progenitor cell subpopulation within four weeks of preoperative exercise, serving as a clinical cell-mediated intervention with the aim to reduce surgical complications.Institutional funding. DFG (German Research Foundation, 491454339) support for the Article Processing Charge.

Dihydropyrimidine dehydrogenase deficiency is a rare inherited disorder. Approximately 3% of people of European ancestry are likely to have a partial deficiency in this enzyme. These individuals are typically asymptomatic until exposed to 5-fluorouracil (5-FU) or capecitabine (which forms 5-FU) for treatment of gastrointestinal or breast cancer. These individuals are then at considerably increased risk of severe to life-threatening adverse events. There are four well established risk variants within the DPYD gene that encodes dihydropyrimidine dehydrogenase. Although consensus guidelines for genotype-guided dosing of 5-FU and capecitabine have existed for a number of years, the implementation of this type of personalised medicine has not been widely adopted. This viewpoint covers the current state of knowledge about both genotype and phenotype testing, as well as the reported cost-savings and clinical effectiveness of pre-screening patients followed by dose-adjustment. Recent recommendations by agencies and professional societies, both in Europe and the USA, highlight the need for New Zealand oncologists to begin an informed discussion about whether it is now an appropriate time to advocate for routine access to testing for this enzyme deficiency in New Zealand cancer patients.

AIMS: A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case–control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5‐fluorouracil or capecitabine. METHODS: Patients (n = 37) received a 250 mg (per os) dose of THY and a cumulative urine sample was collected for 0–4 h. The urinary amounts of THY and metabolite dihydrothymine (DHT) were determined by liquid chromatography/mass spectrometry. Genomic DNA was analysed for DPYD gene variants. Renal function was estimated from blood creatinine levels. Cases (n = 9) and noncases (n = 23) of severe (grade ≥ 3) gastrointestinal toxicity were defined based on Common Terminology Criteria for Adverse Events. RESULTS: The median THY/DHT ratios were 6.2 (interquartile range 2.9–6.4) in cases, including the 2 patients who were DPYD heterozygous carriers. However, this was not significantly different (P = .07) from the THY/DHT in noncases (median 2.6, interquartile range 2.8–4.2). Although creatinine clearance was lower (P = .001) in cases, renal function could not discriminate cases from noncases. However, logistic regression analysis using both of these explanatory variables could discriminate most cases (receiver operating characteristic area 0.8792, 95% confidence interval 0.72–1.00). CONCLUSIONS: The THY challenge test combined with a patient's renal function may be useful as a phenotypic diagnostic test to detect risk of life‐threatening fluoropyrimidine gastrointestinal toxicity.

Fluorouracil (5-FU), a chemotherapeutic agent widely used in the treatment of numerous common malignancies, causes oral mucositis in a proportion of patients. The contribution of drug transport processes to the development of this toxicity is currently unknown. This work aimed to establish and optimise a simple phenotyping assay for 5-FU uptake into primary buccal mucosal cells (BMC). The uptake kinetics of radiolabelled 5-FU were determined in pooled BMC freshly collected from healthy volunteers. The inter- and intra-individual variability in 5-FU uptake was then assessed across a cohort that included both healthy volunteers and cancer patients. 5-FU uptake into pooled primary BMC was both time and concentration dependent. An Eadie–Hofstee analysis suggested two components; a high-affinity (KM = 3.3 µM) low-capacity ( $$V_{\text{MAX}}$$ = 57.8 pmol min−1 105 viable cells−1) transporter, and a high-capacity ( $$V_{\text{MAX}}$$ = 1230 pmol min−1 105 viable cells−1) low-affinity (KM = 3932 µM) transporter. There was 180-fold variation in the rate of 5-FU uptake into BMC (0.10–17.86 pmol min−1 105 viable cells−1) across the 34 subjects (healthy participants N = 24, cancer patients N = 10). Notably, retesting of a subset of these participants (N = 16) multiple times over a period of up to 140 days demonstrated poor stability of the uptake phenotype within individuals. The uptake of 5-FU into healthy oral mucosal cells is a highly variable process facilitated by membrane transporters at pharmacologically relevant concentrations. This bioassay is simple, minimally invasive, and suitable for phenotypic analysis of drug transport in healthy primary cells.

Introduction In clear cell ovarian cancers (CCOC) limited data is available on genomic evolution with disease progression. Methods 23 FFPE tumours collected from 12 patients with advanced CCOC, and 1 mixed clear cell endometrioid OC, treated at Auckland Hospital from 2003–2017, underwent whole exome sequencing (Macrogen), with matched normal tissue. Results 8 patients had diagnostic samples, 5 had diagnostic and first relapse samples, of these 2 had samples from a second relapse. 10/13 patients had 10 distinct ARID1A mutations, most were indels. In 3 patients ARID1A mutations were present at diagnosis and relapse, in 1 patient ARID1A mutation was present at first and second relapse but absent at diagnosis. Other driver mutations were identified in PIK3CA 2/13, AKT1 2/13, PTEN 1/13, NOTCH1 1/13, SMARCA4 1/13, PPP2R1A 1/13, TP53 1/13 and ARID5B 1/13. Putative driver mutations in ACVR1B and IGF2R were seen in relapse and not diagnostic samples. Three patients had euploid tumours, the remainder had a range of aneuploidy, predominantly in chromosomes 8, 9, 16 and 19. Ploidy remained stable with relapse, except in one chemotherapy-naive patient, who was euploid at diagnosis, and developed loss of heterozygosity (LOH) in several chromosomes at relapse. Tumour mutational burden (TMB) ranged from 10 mutations per MB, with no clear trend with disease progression. In one patient TMB was higher in the primary compared with 2 metachronous metastatic sites. Conclusion There was little change in genomic characteristics with disease progression. One chemotherapy naive patient developed LOH and increased TMB at relapse.

Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity.Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC-MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases.There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), UThe endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than DPYD genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test.

Background Failing to take endocrine therapy (ET) as prescribed (nonadherence) increases risk of morbidity and mortality from breast cancer recurrence. We explored predictors of nonadherence, including demographic, clinical, treatment, and personal factors, among women newly prescribed ET for early stage breast cancer. We also examined predictors of their thoughts about stopping treatment (TST). Methods A baseline survey prior to ET assessed demographics, illness beliefs, beliefs about medicines, fear of recurrence, symptoms, and negative affect. A follow-up survey at 3 months repeated these measures with additional questions about nonadherence and TST. Nonadherence and TST were analyzed using logistic and multiple regression, respectively. Patient record review provided clinical data. The baseline survey was completed by 125 women, with a 96% retention rate at follow-up. Results Thirty-six percent reported nonadherence, and 30% reported TST. Results of regression analyses showed that TST was most strongly associated with symptom severity at follow-up, whereas, lower coherence beliefs, and the absence of comorbid conditions were the strongest predictors of actual nonadherence. Conclusion This is the first longitudinal study to examine concurrently the association of demographic, personal and treatment factors with nonadherence, and TST. Findings have potentially important clinical implications; interventions to improve adherence and reduce TST may need to target women's understanding of their diagnosis and treatment, illness beliefs, and symptoms prior to starting therapy.

Purpose: Duligotuzumab is a dual-action antibody directed against EGFR and HER3. Experimental Design: Metastatic colorectal cancer (mCRC) patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors. Results: Of 134 randomly assigned patients, 98 had RAS ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR) in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab. Conclusions: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared with cetuximab + FOLFIRI. Clin Cancer Res; 24(10); 2276–84. ©2018 AACR.

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II-IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 105 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4+ and CD8+ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

BackgroundTo compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.MethodsParticipants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.ResultsThe ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+and CD8+responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.ConclusionsThe vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.

Fewer than 5% of adult cancer patients participate in clinical trials, with multiple patient, clinician and institutional barriers identified. This study aimed to explore patient factors that impact access to cancer trials in New Zealand.A questionnaire that included demographics and factors that might impact trial participation was circulated via nine district health boards (DHBs) and four cancer foundations to patients with a cancer diagnosis.Between July 2016 and August 2017, 691 patients responded, 62% female and 77% aged50 years. Most patients (86%) would consider trial participation, which differed by income (p=0.0001) but not by age, tumour type or gender. Patients would consider attending another hospital (44%) or relocating (11%); 10% considered trials a last resort. Advantageous factors to participation included: benefiting others (92%), better treatment (82%), more scans and longer follow-up (47% and 51%). Disincentives included fear of randomisation (78%), treatment toxicities (71%), time and cost of more visits (40%) and unspecified future research (32%).Identified barriers to trial participation were similar in New Zealand to other developed countries. In this motivated cohort, patients are very interested in trial participation at any stage of their treatment and did not mind extra travel or tests.

After mastectomy, breast reconstruction is increasingly performed using autologous tissue with the aim of improving quality of life. During this procedure, autologous tissue is excised, relocated, and reattached using microvascular anastomoses at the site of the extirpated breast. The period during which the tissue is ex vivo may allow genetic modification without any systemic exposure to the vector. Could such access permit delivery of therapeutic agents using the tissue flap as a vehicle? Such delivery may be more targeted and oncologically efficient than systemic therapy, and avoid systemic complications. The cytokine IFNγ has antitumor effects, and systemic toxicity could be circumvented by localized delivery of the IFNγ gene via gene therapy to autologous tissue used for breast reconstruction, which then releases IFNγ and exerts antitumor effects. In a rat model of loco-regional recurrence (LRR) with MADB-106-Luc and MAD-MB-231-Luc breast cancer cells, autologous tissue was transduced ex vivo with an adeno-associated viral vector encoding IFNγ. The “Therapeutic Reconstruction” released IFNγ at the LRR site and eliminated cancer cells, significantly decreased tumor burden, and increased survival compared with sham reconstruction (P

Summary Precision oncology guided by genomic research has an increasingly important role in the care of people with cancer. However, substantial inequities remain in cancer outcomes of Indigenous peoples, including Indigenous Māori in Aotearoa New Zealand (New Zealand). These inequities will be perpetuated unless deliberate steps are taken to include Indigenous peoples in all parts of cancer research—as research participants, in research leadership, and in research governance. This approach is especially important when there have been historical breaches of trust that have discouraged their participation in health research. This Personal View describes a precision oncology research roadmap for neuroendocrine tumour research, which seeks to reflect the values of New Zealand's Indigenous Māori people. This roadmap includes facilitating ongoing dialogue, Māori leadership, reciprocity, agreed kawa (guiding principles), tikanga (cultural protocols), and honest monitoring of what is and what is not being achieved. We challenge cancer researchers worldwide to generate locally appropriate roadmaps that honestly assess their practices to benefit Indigenous people internationally.

The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift in plastic and reconstructive surgery. The use of either embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC) in clinical situations is limited because of regulations and ethical considerations even though these cells are theoretically highly beneficial. Adult mesenchymal stem cells appear to be an ideal stem cell population for practical regenerative medicine. Among these cells, adipose-derived stem cells (ADSC) have the potential to differentiate the mesenchymal, ectodermal and endodermal lineages and are easy to harvest. Additionally, adipose tissue yields a high number of ADSC per volume of tissue. Based on this background knowledge, the purpose of this review is to summarise and describe the proliferation and differentiation capacities of ADSC together with current preclinical data regarding the use of ADSC as regenerative tools in plastic and reconstructive surgery.

Sutureless microvascular anastomosis has great translational potential to simplify microvascular surgery, shorten operative times, and improve clinical outcomes. The authors developed a transient thermoreversible microvascular stent using a poloxamer to maintain vessel lumen patency before application of commercially available adhesives to seal the anastomosis instead of sutures. Despite technical success, human application necessitates bovine serum albumin removal from existing formulations; rapid poloxamer transition between states; and increased stiffness for reliable, reproducible, and precise microvascular approximation.Two commercially available poloxamers were used in this study (P407 and P188). After removing bovine serum albumin, each poloxamer was tested at varying concentrations either alone or in combination to determine the optimal preparation for sutureless microvascular anastomosis. Transition temperature and formulation stiffness were tested in vitro by rheometry, with the most promising combinations tested in an established in vivo model.Increasing poloxamer concentration resulted in an increase in stiffness and decrease in transition temperature. Pure P188 without bovine serum albumin, dissolved in phosphate-buffered saline to a 45% concentration, demonstrated desirable rheologic behavior, with precise gel transition and increased gel stiffness compared with our previous formulation of 17% P407 (96 kPa versus 10 kPa). These characteristics were optimal for microsurgical intravascular use, offering surgical precision and control between liquid and solid states, depending on the surgically controlled local temperature.Use of 45% P188 without bovine serum albumin demonstrated optimal rheologic and translational properties as a microvascular stent for sutureless anastomosis. Rapid transition, increased stiffness, and safety profile demonstrate safe translational application for human clinical trials.

New Zealand has a vibrant research culture, with cancer research that spans the cancer continuum. Our research agenda has both a strong focus on answering questions of international importance, and on addressing research questions of specific national relevance. In this manuscript, we discuss the mechanisms by which cancer research is funded in New Zealand. We outline some of the major challenges currently facing implementation of our cancer research agenda; including levels of research funding, addressing inequalities in cancer outcomes, and current challenges in New Zealand-led clinical trials. We then describe some of the key strengths of New Zealand cancer research, with particular focus on national-level health and social services datasets. Finally, we briefly discuss our new national Health Research Strategy and consider the ramifications of this strategy for the future of cancer research in New Zealand.

We describe a modeling project designed for an ordinary differential equations (ODEs) course using first-order and systems of first-order differential equations to model the fermentation process in beer. The project aims to expose the students to the modeling process by creating and solving a mathematical model and effectively communicating their findings in a technical report. The students are required to produce a simple first-order differential equation and find the solution, given varying initial conditions. The students are also required to analyze a more complex, nonlinear ODE system model of the fermentation process. In dealing with the nonlinear system of equations, we provide the students a Mathematica file to reduce the time spent developing the model, but allow for more time to interpret the model. We also share some perspectives on the implementation of the project, provide alternative implementations, and possible extensions to the project.

CYP2C19 contributes to the metabolism of several chemotherapeutic agents. The CYP2C19 homozygous null function genotype strongly predicts activity phenotype in healthy populations. An additional acquired loss of function has been reported in up to one-third of cancer patients. It is not known whether this phenomenon also occurs in patients with earlier stage or in resected disease. This study investigated whether acquired loss of CYP2C19 function was detectable in patients with stage III–IV or resected gastrointestinal cancer. CYP2C19 genotype was determined in 49 patients, and subjects were probed for CYP2C19 activity on three test occasions. An acquired loss of CYP2C19 activity was observed in 20 % of stage III–IV and 17 % of resected patients at the first test. Significant (p

Aims Serum carcinoembryonic antigen (CEA) is used to detect relapses from colon cancer following initial surgical or adjuvant treatment. There are little data on transient elevations of CEA while receiving chemotherapy in the adjuvant setting. We aimed to review patterns of change in CEA levels while receiving adjuvant chemotherapy and investigate associations between transient rises and patient survival. Methods A retrospective review of patients in Auckland with a new diagnosis of colon cancer in 2001 or 2005 was performed and CEA values were collected. Three patient groups were defined: no increase in CEA; transient elevation in CEA; and persistent elevation in CEA. Kaplan–Meier methods were used to estimate 5-year survival; Cox regression and log-rank P-values were used to compare survival. Results Sixty-one patients with stage II or III disease who had received adjuvant chemotherapy had sufficient CEA data to be included in the analysis. Patients were followed up for a minimum of 7.4 years (or death). The 5-year overall survival was higher in the transient elevation in CEA group 95.0% and the no increase in CEA group 85.2% compared with the persistent elevation in CEA group 42.9%. There was no statistically significant difference in overall survival between the transient elevation group and the no increase group (P = 0.2). Conclusions The group with a transient elevation in CEA during adjuvant chemotherapy did not have a poorer prognosis compared with the group that had no increase in CEA. This will be further examined in a population-based New Zealand-wide study of colorectal cancer diagnosis, treatment and outcome.

Barbed sutures have unidirectional circumferential shallow barbs, which distribute tension throughout the wound and close wound securely without the need to tie knots.We compare two different methods of wound closure in elective plastic surgical cases: barbed 3/0 V-Loc™180 suture and smooth 3/0 Maxon™ sutures, both polyglyconate monofilament synthetic absorbable sutures. We assessed the aesthetic long-term results with a minimum two year follow up.This is a prospective, randomized controlled study with internal control. A single surgeon performed all cases. Patients who underwent elective operations that involved long wound closure were enrolled in the study. Each patient acted as their own internal control with half their wound being sutured with 3/0 V-Loc™180 barbed suture and the other half with smooth 3/0 Maxon™ deep dermal sutures and then a subcuticular skin closure. In both groups, the superficial fascial system was closed with 1 Vicryl interrupted sutures on both sides. Long-term cosmesis was evaluated using the modified Hollander cosmesis score by review of standardized postoperative photographs by 9 blinded plastic surgeons and specialist registrars.The study reports on 33 female patients. The time taken for wound closure was significantly reduced using the barbed suture (p 0.001). There was no difference in the complication ratio in either group. Two-year aesthetic outcome was significantly superior when using the barbed suture (p = 0.0075).Barbed sutures closure of long wounds is faster and produces a better long-term aesthetic outcome than smooth sutures.

The primary tumor side is emerging as a prognostic factor for patients with liver metastatic colorectal cancer (mCRC). In a combined analysis of data from 2 randomized studies, the addition of selective internal radiation therapy to first-line chemotherapy in patients with mCRC was associated with statistically and clinically significant overall survival gains for patients with a right-sided primary tumor. Background: The primary tumor side is emerging as a major prognostic factor for patients with metastatic colorectal cancer (mCRC). We examined the survival data from 2 randomized studies to determine whether the outcomes differ between patients with mCRC with right-sided primary (RSP) tumors and those with left-sided primary (LSP) tumors after selective internal radiation therapy (SIRT) plus mFOLFOX6 (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) chemotherapy, versus chemotherapy alone. Patients and Methods: Separate and combined analyses were performed on the data from the SIRFLOX and FOXFIRE global trials, which compared chemotherapy plus SIRT with chemotherapy alone for patients with mCRC liver metastases. The primary tumor side data were prospectively collected. The principal outcome measure was overall survival (OS) stratified by treatment and primary tumor side. Results: In the combined analysis of all 739 patients enrolled, SIRT had no effect on OS (median OS, 24.3 vs. 24.6 months; hazard ratio [HR], 1.021; P = .810). For the 179 patients (24.2%) with a RSP tumor, OS was improved with the addition of SIRT (median, 22.0 vs. 17.1 months HR, 0.641; P = .008). The addition of SIRT was not associated with a significant difference in OS among the 540 patients with a LSP tumor (median, 24.6 vs. 26.6 months; HR, 1.120; P = .264). A test of treatment interaction by primary tumor side was statistically significant for RSP and SIRT (P = .002). Conclusion: The addition of SIRT for patients with RSP tumors, but not for those with LSP tumors, was associated with a statistically and clinically significant OS gain. (C) 2018 Elsevier Inc. All rights reserved.

Three-dimensional bioprinting has garnered immense interest over the past decade based on its potential to provide a means to rapidly manufacture replacement body parts that replace like with like and are immediately biocompatible. Despite promising advances in bioprinting, it is still immensely difficult to reproduce the delicate structure-function relationships of complex tissues and organs using this approach. In this way, the bioprinting of functional autologous solid organs (e.g., kidney or heart) remains an aspirational goal. However, the formation of more simple tissues such as adipose tissue for breast reconstruction, represents a lower-hanging fruit in translational bioprinting research. The ability to bioprint autologous fat tissue would be transformational in the management of breast cancer patients. This centers around the combination of great need for breast reconstruction in today's society and a lack of an ideal form of breast reconstruction characterized by simplicity along with a low complication profile. Here, we present the current state of the art and future perspectives on 3D bioprinting for the breast as this approach transitions from the bench to the bedside.

Thirty-day mortality has been proposed to be a useful indicator of avoidable harm to patients from systemic anticancer therapies (SACT). As a quality assurance tool, we assessed the 30-day mortality rate at Auckland City Hospital and compared this with international standards.Clinical characteristics and treatment details of medical oncology patients who died within 30 days of SACT from October 2014-September 2015 were collected and compared with data from a similar series performed from October 2008-September 2009. SACT was limited to chemotherapy or biologic agents.From October 2014-September 2015, 1,965 patients received 2,145 treatment regimens. Forty-seven patients (2.2%) died within 30 days of SACT. Treatment was given with palliative intent in 42 patients (in 89%) and curative intent in five (11%). Mortality rates did not change with time (2.8% in 2009 vs 2.2% in 2015). Of the patient who died within 30 days, ECOG performance status at the time of chemotherapy was one in 16 patients (34.0%), two in nine patients (19.1%) and 3/4 in nine of the 47 patients (19.1%). All patients treated with curative intent had a PS of 0 or 1. Most patients who died within 30 days were on first- or second-line therapy (45 and 38% respectively). Two-thirds of patients with a PS of 3/4 were receiving first-line therapy. Approximately half the patients died during their first cycle of therapy (48.9%).Our local 30-day mortality data compares favourably to international benchmarks of 5% and has not increased over time. Performance of similar studies locally and nationally should be undertaken to continue to assess and improve the quality of our patient care.

There is no standard treatment for recurrent glioblastoma multiforme (GBM). Retreatment with temozolomide (TMZ) is one treatment option. We reasoned this could be more effective if combined with a vaccine that preferentially targeted TMZ-resistant cells. To test the feasibility and safety of such an approach, a phase 1 trial was conducted in which patients with GBM tumors relapsing after standard chemoradiotherapy were retreated with TMZ in combination with a vaccine consisting of monocyte-derived dendritic cells (DC) pulsed with autologous tumor cells that had previously been exposed to TMZ in vivo in the course of primary treatment. Of 14 participants, nine patients completed the initial phase of priming vaccinations and two cycles of TMZ, one proved to have radionecrosis, one rapidly progressed, and in three the yield of DC vaccine was insufficient to proceed with treatment. Other than expected toxicities related to TMZ, there were no adverse events attributable to the combined treatment. Two patients had objective radiological responses. Six month progression-free survival was 22 %, similar to retreatment with TMZ alone. Anti-tumor immune responses were assessed in peripheral blood mononuclear cells using interferon-γ ELISpot, with two patients meeting criteria for a vaccine-induced immune response, one of whom remained disease-free for nearly three years. Another patient with an anti-tumor immune response at baseline that was sustained post-vaccination experienced a 12-month period of progression-free survival. In summary, the combined treatment was safe and well-tolerated but feasibility in the recurrent setting was marginal. Evidence of immune responses in a few patients broadly correlated with better clinical outcome.

In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid). These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status. Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials used high-dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its pro-oxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C-induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high-dose IV vitamin C in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging. Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical trial.

Background: Percutaneous needle fasciotomy (PNF) is a minimally invasive technique used to manage Dupuytren’s contracture.We compared outcomes of PNF versus open fasciectomy (OF) to examine the suitability of PNF in Australia. Method: Ar etrospective cohort study using two questionnaires regarding Dupuytren’s treatment was used to assess patients with uncomplicated primary disease. The primary outcomes were immediate and medium-term correction of contracture (2-year mean follow-up to time of survey). Secondary outcomes were patient satisfaction and complications including tendon/nerve injury, infection, skin necrosis and vascular damage. Results: One hundred fifty-five out of 191 surveys were returned (81%). The final analysis included 125 cases (65%), 73 PNF and 52 OF. No significant differences were observed between both groups with regards to follow-up time, gender, smoking status, co-morbidities or preoperative deformity grade. No significant differences were observed in terms of immediate or medium-term deformity correction, tendon/nerve injury or circulatory complications. The postoperative infection rate was higher with OF, with these patients 7.57 (95% confidence interval 1.56, 36.77; P = 0.01) times as likely to have a postoperative infection as patients undergoing PNF. A higher number of patients who underwent PNF were told that they would require another operation (30% versus 12%; P = 0.02). Satisfaction scores were similar (OF 33.2 versus PNF 32.6; P = 0.82). Conclusion: The OF and PNF procedures provide comparable deformity correction for uncomplicated primary Dupuytren’s disease in the immediate perioperative period. The reduced side effect profile of PNF should prompt surgeons to consider incorporating it in their practice for the first-line management of uncomplicated primary Dupuytren’s disease.