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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.

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.

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.

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.

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.

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.

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.

Introduction Colorectal cancer is common and primarily a disease of older people. Colorectal cancer in patients aged 25 years and under is infrequent and may represent a unique subgroup of patients. This study aimed to describe the population of young people in New Zealand diagnosed with colorectal cancer, their tumour characteristics, management and outcomes. Methods A retrospective clinical study was conducted via review of medical records for all patients 25 years of age and under, diagnosed with colorectal adenocarcinoma in New Zealand between 1 January 1997 and 31 December 2007. Results Fifty patients with colorectal adenocarcinoma were identified from the New Zealand Cancer Registry. Seven had a positive family history of colorectal cancer, while eight had predisposing factors (hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, ulcerative colitis, Crohn's disease, regional enteritis). The most common presenting symptoms were abdominal pain and weight loss. Twenty-eight cases presented acutely. Eighteen presented with stage IV disease at diagnosis. Eighteen were referred to a genetics service. Five-year overall survival was 49%. Discussion Those aged 25 years and under that develop colorectal cancer tend to present acutely and move through the secondary care pathway swiftly, being diagnosed at a more advanced stage, and have a poorer prognosis than their adult counterparts. Familial cancers form a more significant component of youth colorectal cancers compared to the older population and input from genetic service should be considered.

Background: Capecitabine and cyclophosphamide are active in patients with advanced breast cancer, have nonoverlapping toxic effects and synergy pre-clinically. We explored the efficacy and toxic effect of an all-oral combination of capecitabine with cyclophosphamide versus capecitabine alone in a multicentre, randomized, phase II study. Patients and methods: Patients with locally advanced or metastatic breast cancer were randomized to treatment with capecitabine given continuously (666 mg/m 2 b.i.d. days 1–28) alone (C) or with oral cyclophosphamide (100 mg/m 2 days 1–14 of a 28-day cycle) (CCy) for up to six cycles. Results: Eighty-two patients were randomized. There was no complete response. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% [95% confidence interval (CI) −13.4 to 29.1]. Significant toxic effect was uncommon: grade ≥3 diarrhoea in 4 (10%) versus 1 (3%) patients; grade ≥3 fatigue in 2 (5%) versus 5 patients (13%) and grade ≥2 hand-foot syndrome in 7 (17%) versus 11 (28%) patients receiving C versus CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy, not significantly different statistically. There was no difference in overall survival. Conclusion: The difference in tumour response suggests a reasonable chance that CCy is superior to C alone.

Optimization of wound healing has been a major goal of medical care throughout history. A myriad of devices, dressings, and therapies have been developed to control the local wound environment, facilitate timely healing, and modulate scar. Despite this, chronic wounds remain a major health burden, scarless wound healing is an aspirational goal, and hypertrophic and keloid scar formation are unpredictable and difficult to treat. Stem cells play a vital role in both wound healing and normal skin homeostasis, prompting their application to wounds and local tissues in efforts to optimize wound healing. However, significant barriers to their use remain, in the form of variable results, regulatory hurdles, expense, poor user-friendliness, and limited cell survival. Stem cell niche engineering is an emerging modality that seeks to facilitate stem cell recruitment, aid the effectiveness of exogenous stem cells, and ultimately result in the reestablishment of stable stem cell populations in support of wound healing and normal skin homeostasis. We examine the stem cell niches of the skin during normal homeostasis and wound healing, explore niche engineering approaches, and identify how these approaches may help address important unmet clinical needs and thereby optimize wound care.

Postoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined. TOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates. The proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients. These results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.

Background Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)-α signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients. Materials and Methods We reduced ESR1 (gene encoding the ER-α protein) mRNA levels using small interfering RNA in ER+ MCF7 breast cancer cells and assayed for transcriptional changes using Affymetrix HG U133 Plus 2.0 arrays. We also compared 1034 ER+ and ER− breast tumors from publicly available microarray data. The principal components of ER activity generated from these analyses and from other published estrogen signatures were compared with ESR1 expression, ER-α IHC, and patient survival. Results Genes differentially expressed in both analyses were associated with ER-α IHC and ESR1 mRNA expression. They were also significantly enriched for estrogen-driven molecular pathways associated with ESR1, cyclin D1 (CCND1), MYC (v-myc avian myelocytomatosis viral oncogene homolog), and NFKB (nuclear factor kappa B). Despite their differing constituent genes, the principal components generated from these new analyses and from previously published ER-associated gene lists were all associated with each other and with the survival of patients with breast cancer treated with endocrine therapies. Conclusion A biomarker of ER-α pathway activity, generated using ESR1-responsive mRNAs in MCF7 cells, when used alongside ER-α IHC and ESR1 mRNA expression, could provide a method for further stratification of patients and add insight into ER pathway activity in these patients.

Purpose SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)–based chemotherapy in patients with previously untreated metastatic colorectal cancer. Patients and Methods Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. Results Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. Conclusion The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

Objectives Adjuvant endocrine therapy for early-stage breast cancer has greatly reduced the morbidity and mortality associated with breast cancer recurrence. Despite this, a significant proportion of women report fears of cancer recurrence. This study examined the associations between fear of cancer recurrence (FoR) and illness perceptions, medication beliefs, and treatment side effects in women taking adjuvant endocrine therapy following breast cancer. Methods A total of 153 post-menopausal women with early-stage breast cancer completed a postal survey. Analyses were conducted to examine the association between FoR and illness perceptions, medication beliefs, treatment side effects, demographic factors, and emotional distress and to identify which of these factors would be most strongly associated with FoR in a regression model. Results All illness perceptions (apart from personal control) were associated with FoR, as were patient beliefs about endocrine therapy. Although treatment side effects, being unemployed, and higher levels of anxiety and depression were associated with FoR, only illness perceptions (identity, treatment control, timeline, and emotional representation) and medication necessity beliefs were significantly correlated with FoR in the final model. Conclusions It appears that, in addition to directly targeting FoR, it may be worthwhile to address the illness and medication beliefs supporting the fear. Additionally, helping women to differentiate everyday symptoms from those indicative of breast cancer may help to reduce fear of recurrence. Statement of Contribution What is already known on this subject? A significant proportion of women report fear of cancer recurrence following breast cancer. The literature shows that illness perceptions, side effects of treatment, and beliefs about medicines are related to fear of recurrence among cancer patients. However, because these variables have often been looked at in isolation, it is not clear whether some perceptions or cues are more likely to relate to fear of recurrence than others. What does this study add? This study shows illness perceptions and medication beliefs are strongly related to fears of cancer recurrence. The results point to ways in which the self-regulatory model of illness may be used to reduce patients' fear of recurrence. The study results show that women with higher fear of recurrence may be balancing a tension between believing that they need to take the medication to protect their future health alongside concerns that the treatment may not be working.

Background Skin cancers of the face and scalp have a propensity to metastasize to the parotid group of lymph nodes. The resection of these secondary tumors and other primary tumors in the parotid region often results in defects requiring flap reconstruction. Pectoralis major flaps are reliable and free flaps are arguably the criterion standard. However, we have found keystone island flaps to be a simple and robust alternative, with low donor-site and patient morbidity. The aim of this article is to share our surgical technique, experience, and outcomes of reconstructing parotid defects with keystone island flaps. Methods The authors retrospectively reviewed 62 patients who had 63 parotid defect reconstructions at a single institution from 2004 to 2009 (5-year period). Results The diseases involved were squamous cell carcinoma (52 cases), melanoma (five cases), basal cell carcinoma (four cases), and others (two cases). Nine patients presented with a previous history of radiotherapy and 33 patients required adjuvant radiotherapy. Seven patients (11 percent) suffered postoperative complications necessitating a return to the operating room. Conclusions Keystone island perforator-based flaps present an alternative to free tissue transfer. From the series presented, it can be seen that reliable and reproducible results are achievable. Clinical question/level of evidence Therapeutic, IV.

The redundant tissues of the anterior neck are well suited as a donor site for fasciocutaneous flaps in head and neck reconstruction, with similar skin quality and numerous underlying perforators. However, historic cadaveric research has limited the use of this as a donor site for the design of long and/or large flaps for fear of vascular compromise. The authors undertook an anatomical study to identify the vascular basis for such flaps and have modified previous designs to offer the versatile and reliable superior thyroid artery perforator (STAP) flap. Forty-five consecutive computed tomographic angiograms of the neck were reviewed, assessing the vascular supply of the anterior skin of the neck. Based on these findings, eight consecutive patients underwent head and neck reconstruction using a flap based on the dominant perforator of the region. In all cases, a perforator larger than 0.5 mm was identified within a 2-cm radius of the midpoint of the sternocleidomastoid muscle at its anterior border. This perforator was seen to emerge through the investing layer of deep cervical fascia as a fasciocutaneous perforator and to perforate the platysma on its ipsilateral side of the neck, proximal to the midline. This was seen to be a superior thyroid artery perforator in 89 of 90 sides and an inferior thyroid artery perforator in one case. Eight consecutive patients underwent preoperative imaging and successful flap planning and execution based on this dominant perforator. The superior thyroid artery perforator (STAP) flap demonstrates reliable vascular anatomy and is well suited to reconstruction of a broad range of head and neck defects.Therapeutic, IV.

Breast reduction is a common procedure used to improve physical and aesthetic factors associated with breast hypertrophy. This study investigated how surgical technique alone affects the risk factors for complications and profiled differences between techniques. Complications were assessed by the use of time-to-event methods.Patient information was extracted from a cohort of 283 patients. Demographic, surgical, and follow-up information was analyzed for patients undergoing surgical procedures using the inferior pedicle Wise pattern (IPWP) and modified Hall-Findlay (MHF) techniques. The patients managed with the IPWP technique were considered control subjects. The failure rates were described using the Kaplan-Meier failure estimator to provide a true estimate of the experienced complication rates.Overall, few differences were noted between the groups except for total tissue removed. The overall failure (complication) rate at 6 months was 18.8%, with 9% of all the patients experiencing a major complication that required operative intervention/revision. As expected, the period with the greatest risk of complication was the first month after surgery. Surgical technique, total tissue removed, and age were nonpredictive of complications. Overall, the IPWP group had significantly more total tissue removed than the MHF group (median difference, 227 g; P=0.002). There was no evidence of a learning curve when an experienced surgeon moved from the one technique to the other.At 6 months after surgery, 19% of patients are expected to have experienced a complication. There appears to be few differences in outcomes between the techniques of breast reductions used, and the success or otherwise almost certainly relates to factors independent of surgical technique and includes patient selection, operative skill, and experience. Time-to-event analysis provides a precise assessment and description of the complication profile.This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.

IntroductionThere is a lack of evidence on the best method for rehabilitating extensor tendon injuries in zones V and VI. The purpose of this study was to evaluate the outcomes of modified relative motion splinting compared with immobilization following repair of extensor tendons in zones V and VI.MethodsA retrospective analysis compared the outcomes of relative motion splinting with immobilization. Sixteen patients (16 fingers) were treated by conventional immobilization splinting for four weeks (immobilization group) followed by mobilization with avoidance of ‘at-risk/heavy’ activities for a further 4–6 weeks. Twenty-three patients (23 fingers) were treated with the modified relative motion splint (mRMS group) during the day and a resting splint worn overnight for the first four weeks. The relative motion splint was continued for ‘at-risk/heavy’ activities for a further 4–6 weeks.ResultsThe mRMS group demonstrated statistically significant improvement in range of motion compared with the immobilization group. This effect was most marked at six weeks ( P = 0.0194, two-way mixed ANOVA) with the mRMS group achieving a 12% higher mean percentage total active motion ( P = 0.0076, Mann-Whitney U test). Results were similar for both groups 12 weeks postoperatively. Differences in return to work times between groups were statistically significant ( P = 0.0062, Mann-Whitney U test). Average return to work was 9.4 weeks for the immobilization group and 3.3 weeks for the mRMS group, equating to a 42 days earlier return to work for the mRMS group. There was no incidence of tendon rupture in either group.ConclusionThis study demonstrates that modified relative motion splintage (finger based without wrist component) can be applied in the postoperative management of single zone V or VI extensor tendon repairs. The main advantages of this protocol, compared with immobilization include the small simple splint design, and straightforward patient instructions that enable earlier mobilization, functional hand use and return to both daily living and work.

BACKGROUND: Radical inguinal lymphadenectomy (RIL) for bulky metastatic melanoma and non-melanoma skin cancers of the inguinal region, while shown to improve morbidity and survival oncologically, can result in substantial morbidity from wound complications. Skin defects cannot be closed primarily and the substantial dead space predisposes to seroma, wound dehiscence and infection. Despite the clear need for reconstructive options, extended series describing reconstruction of large inguinal defects in this setting have not been reported. METHODS: A prospectively entered, retrospectively reviewed study of 20 consecutive patients undergoing quadriceps keystone island flaps (QKIF) for the closure of complicated inguinal defects is described. RESULTS: There was 100% flap survival, with no partial or complete flap losses. A reduction in wound breakdown/dehiscence from reported rates was seen, with four patients (20%) having wound breakdown, compared to double that rate in reported series. Other wound complications comprised six patients (30%) with mild wound infections, seven patients (35%) with seromas and two patients (10%) with haematomas. CONCLUSION: The QKIF is an effective means of reconstructing inguinal defects after RIL, particularly in high-risk patients, and is technically simpler than other reconstructive techniques advocated for this purpose. Furthermore, the QKIF offers patients with advanced disease (where management is primarily palliative) a potentially improved quality of life with reduced operative morbidity.

The rental market's failure to provide housing for low-income immigrants now entering Australia has raised issues about the immigrants’ housing requirements and how these can be met. To date, only ...

e15678Background: In a Cochrane meta-analysis of 5 randomised phase 2 trials CIM administered perioperatively with curative-intent surgery for CRC was associated with reduced mortality (HR 0.53, 95...

e18851Background: Despite the importance of clinical trials, fewer than 5% of adult cancer patients are enrolled in them. Multiple patient (pt), clinician and institutional barriers have been ident...

Systemic treatment of metastatic pancreatic adenocarcinoma achieves only modest benefits, with evidence indicating a survival advantage with 5-fluorouracil (5-FU) over best supportive care alone, and further advantage of single-agent gemcitabine over 5-FU. There are very few regimens better than single-agent gemcitabine despite multiple trials of cytotoxic and targeted agents. The addition of a platinum agent has improved response rate but not survival. The addition of erlotinib has improved survival but only by a small margin. The use of gemcitabine in multidrug regimens containing one or more of: a platinum agent; fluoropyrimidine; anthracycline; and taxane has demonstrated advantages in response rate, progression-free survival and, in one randomized study, overall survival. After gemcitabine failure, second-line therapy with oxaliplatin and 5-FU provides a further survival advantage. Further advances depend upon the current and future clinical trials investigating enhanced delivery of current agents, new agents and novel modalities, improved supportive care, and treatment more tailored to the individual patient and tumour.

Reversible posterior leucoencephalopathy syndrome is a neurological condition seen in various areas of acute medicine, including the administration of antineoplastic therapies used in haemato-oncology patients. It is a rare complication that has been increasingly recognized. It is characterized by altered mental status, visual disturbance, headache and seizures. Magnetic resonance imaging typically shows vasogenic oedema in the posterior regions of the brain. Although its name suggests reversibility, it may result in an irreversible brain injury without prompt treatment. Therefore, it is vital for treating clinicians to recognize this syndrome. We describe the case of a 55-year-old woman with advanced pancreatic adenocarcinoma, who developed clinical and radiological manifestations consistent with this syndrome as a complication of gemcitabine monotherapy.

Tissue engineering of patient-specific adipose tissue has the potential to revolutionize reconstructive surgery. Numerous models have been described for the production of adipose tissue with success in the short term, but little has been reported on the stability of this tissue-engineered fat beyond 4 months.A murine model of de novo adipogenesis producing a potentially transplantable adipose tissue flap within 4 to 6 weeks was developed in the authors' laboratory. In this study, the authors assess the ability of three-chamber (44-microl volume) configurations shown to be adipogenic in previous short-term studies (autograft, n = 8; open, n = 6; fat flap, n = 11) to maintain their tissue volume for up to 12 months in vivo, to determine the most adipogenic configuration in the long term.Those chambers having the most contact with existing vascularized adipose tissue (open and fat flap groups) showed increased mean adipose tissue percentage (77 +/- 5.6 percent and 81 +/- 6.9 percent, respectively; p0.0007) and volume (12 +/- 6.8 microl and 30 +/- 14 microl, respectively; p0.025) when compared with short-term controls and greater adipose tissue volume than the autograft (sealed) chamber group (4.9 +/- 5.8 microl; p = 0.0001) at 1 year. Inclusion of a vascularized fat flap within the chamber produced the best results, with new fat completely filling the chamber by 1 year.These findings demonstrate that fat produced by tissue engineering is capable of maintaining its volume when the appropriate microenvironment is provided. This has important implications for the application of tissue-engineering techniques in humans.

Aim: The purpose of the study was to determine the feasibility and validity of using health-related quality of life (HRQL) and patient benefit as outcome measures in a phase II trial of octreotide long acting release (LAR) for hepatocellular carcinoma (HCC); and, to determine aspects of HRQL that were most impaired and aspects that changed. Methods: Sixty-three patients with advanced HCC were treated with octreotide LAR. HRQL was assessed monthly with the Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire (FACT-Hep) and the Patient Disease and Treatment Assessment Form (Patient DATA Form). Benefit was assessed directly by asking subjects at 1 month about change from baseline using the Patient Benefit Form. Convergent, discriminative and predictive validity were assessed by testing a priori hypotheses. Results: Seventy-three percent completed a baseline assessment of HRQL. Compliance decreased over time. Fatigue, energy, anxiety, pain, insomnia, and emotional well-being were the most impaired aspects of HRQL on the Patient DATA Form. Convergent validity was supported by 52 of 57 hypothesized correlations. Predictive validity was supported by associations between survival and four aspects of HRQL. Patients' direct assessments of benefit for common symptoms were moderately associated with changes in their scores on the Patient DATA Form. Conclusion: Use of the FACT Hep and Patient DATA Form is feasible in trials of advanced HCC. The validity of the direct measure of patient benefit was questionable, despite its intuitive attraction. Fatigue, anxiety, insomnia, and impaired emotional well-being were prominent, are probably under-recognized in practice, and are worthy of future research.