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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.

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.

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.

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.

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.

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 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.

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.

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.

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up-regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28-day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty-seven patients entered treatment. The majority of non-DLT were grades 1 and 2. DLT experienced in the first 8-week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m2/day capecitabine days 1–28 with 125 mg/m2/day cyclophosphamide days 1–14 of the 28-day cycle. The recommended phase II dose is therefore 1331 mg/m2/day capecitabine with 100 mg/m2/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.

Purpose This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer. Patients and Methods Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). Results A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens. Conclusion The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

Background: With poor cure rates in gastric cancer using surgery alone, the safety, efficacy and feasibility of preoperative and postoperative chemotherapy was investigated. Methods: Patients with advanced but operable gastric or cardio-oesophageal adenocarcinoma were staged using endoscopy, computed tomography scan and laparoscopy. If considered potentially resectable, they received chemotherapy (epirubicin, cisplatin and 5-fluorouracil) for 9 weeks before and after surgery. Results: Of 59 participants entered, two were found to have metastatic disease and were excluded from the analysis. Of the participants, 10 were women and 47 men; their median age was 58 years (range 27–83 years) and median performance status 0 (range 0–1). Two of the 57 participants commencing chemotherapy did not undergo surgery (one sudden death, one new liver metastases). Grade 3 and 4 preoperative and postoperative toxicity rates were, respectively, neutropenia 22 and 18%, emesis 12 and 14% and other non-haematological toxicity

BACKGROUND Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Survival is poor for patients with advanced-stage HCC, and small trials of tamoxifen for patients with this disease have shown conflicting results. The authors conducted a systematic review of randomized clinical trials to compare the effect of a tamoxifen-containing arm with a nontamoxifen-containing arm in advanced HCC. METHODS Eligible trials were identified from the Cochrane Hepato-Biliary Group register and other databases. Studies were selected for inclusion and their methodologic quality assessed by three independent reviewers. Hazard ratios (HR) were derived for overall survival where possible. Metaanalysis was performed using a fixed-effect model. RESULTS The authors identified 10 randomized trials with a total of 1709 patients. Use of tamoxifen had no effect on median survival (HR, 1.05; 95% confidence interval, 0.94–1.16; P = 0.4) or tumor response rate. The findings were stable in sensitivity analyses and were not affected by publication bias or inclusion of low-quality studies or studies reported in abstract form only. Few adverse events or withdrawals were noted. CONCLUSIONS There was no support for the therapeutic use of tamoxifen in advanced HCC, nor for its use as a control arm in future clinical trials. Cancer 2005. © 2005 American Cancer Society.

Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Whilst local treatments are useful in selected patients, they are not suitable for many with advanced disease. Here, we review phase II and III trials for systemic therapy of advanced disease, finding no strong evidence that any chemotherapy, hormonal therapy, or immunotherapy regimen trialled to date benefits survival in this setting. Many trials were inadequately powered, single centre, and enrolled highly selected patients. From this review, we cannot recommend any therapeutic approach in these patients outside of a clinical trial setting. Including an untreated control arm in clinical trials in HCC is still justified. Every effort should be made to enroll these patients into adequately powered trials, and promising phase II results must be tested in a multicentre phase III setting, preferably against a placebo control arm. Prevention of hepatitis B and C remains vital to decrease deaths from HCC.

Chemotherapy-induced diarrhoea (CID) has a significant impact. A medicinal food product (ReCharge) containing iron-saturated lactoferrin and anhydrous milk fat reduces the detrimental effects of chemotherapy on the gut in animals. We report results of a randomised blinded placebo-controlled phase IIb trial investigating the efficacy and safety of ReCharge in preventing CID. Eligible patients were adults due to start the first cycle of a 2- or 3-week-cycle chemotherapy regimen, had an Eastern Cooperative Oncology Group (ECOG) status of 3 or less, had adequate haematological, liver and renal function and provided written informed consent. Patients (197) were randomised to ReCharge or placebo. They consumed 100-g study product for 2 weeks before and 6 weeks after starting chemotherapy, completed daily diaries for 8 weeks and attended clinic visits until 12 weeks (2-week cycles) or 14 weeks (3-week cycles). The primary outcome was days with CID. The mean number of days with diary-recorded CID was marginally but not statistically significantly lower on ReCharge than placebo (−2.0, 95 % CI (−4.7 to 0.7), p = 0.2). The proportion reporting diarrhoea in the previous cycle at the clinic visit was 30 % lower (p = 0.012) on ReCharge. Missing diary data may have contributed to the discrepancy. No significant differences were found in quality of life or other adverse events. We found no clear evidence that ReCharge reduced CID as measured by patient self-report diary. The converse finding of benefit as recorded at clinic visits and incomplete adherence to diary completion indicates that further research is required into methods for measuring CID.

Bone metastases from renal cell carcinoma (RCC) are a major cause of morbidity. Post hoc analysis has suggested that bone turnover markers can identify patients at risk of skeletal-related events (SREs) among those receiving zoledronic acid. This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid.Thirty treatment-naive patients with RCC and ≥ 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4-weekly). Bone-specific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). The primary outcome measure was urine N-telopeptide (uNTX) level, with secondary measures of plasma C-telopeptide (CTX), quality of life (Functional Assessment of Cancer Therapy-Bone Pain [FACT-BP], Brief Pain Inventory [BPI]), progression-free survival (PFS), SREs, and safety.After 12 weeks, reduction in mean uNTX and CTX on everolimus plus zoledronic acid relative to everolimus was 68.4% (95% CI, 60.1%-74.9%; P.0001) and 76.2% (95% CI, 67.3%-82.7%; P.0001), respectively. There was no evidence of a difference for FACT-BP (P = .5), but evidence was favorable for BPI Severity (P = .05) and BPI Interference (P = .06). Median PFS was 7.5 months (95% CI, 3.4-11.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.2-6.3) on everolimus (P = .009). Median time to first SRE was 9.6 months (95% CI, 4.3-15.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.6-8.2) on everolimus (P = .03).In this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control.

Standard therapy for advanced or metastatic colorectal cancer consists of 5-fluorouracil plus leucovorin (5-FU/LV) administered intravenously (i.v.). Capecitabine (Xeloda), an oral fluoropyrimidine carbamate which is preferentially activated by thymidine phosphorylase in tumour cells, mimics continuous 5-FU and is a recently developed alternative to i.v. 5-FU/LV. The choice of oral rather than intravenous treatment may affect medical resource use because the two regimens do not require the same intensity of medical intervention for drug administration, and have different toxicity profiles. Here we examine medical resource use in the first-line treatment of colorectal cancer patients with capecitabine compared with those receiving the Mayo Clinic regimen of 5-FU/LV. In a prospective, randomised phase III clinical trial, 602 patients with advanced or metastatic colorectal cancer recruited from 59 centres worldwide were randomised to treatment with either capecitabine or the Mayo regimen of 5-FU/LV. In addition to clinical efficacy and safety endpoints, data were collected on hospital visits required for drug administration, hospital admissions, and drugs and unscheduled consultations with physicians required for the treatment of adverse events. Capecitabine treatment in comparison to 5-FU/LV in advanced colorectal carcinoma resulted in superior response rates (26.6% versus 17.9%, P=0.013) and improved safety including less stomatitis and myelosuppression. Capecitabine patients required substantially fewer hospital visits for drug administration than 5-FU/LV patients. Medical resource use analysis showed that patients treated with capecitabine spent fewer days in hospital for the management of treatment related adverse events than did patients treated with 5-FU/LV. In addition, capecitabine reduced the requirement for expensive drugs, in particular antimicrobials fluconazole and 5-HT3-antagonists to manage adverse events. As anticipated with an oral home-based therapy patients receiving capecitabine needed more frequent unscheduled home, day care, office and telephone consultations with physicians. In the light of clinical results from the phase III trial demonstrating increased efficacy in terms of response rate, equivalent time to progression (TTP) and survival (OS), and a superior safety profile, the results from this medical resource assessment indicate that capecitabine treatment of colorectal cancer patients results in a substantial resource use saving relative to the Mayo Clinic regimen of 5-FU/LV. This benefit is derived principally from the avoidance of hospital visits for i.v. drug administration, less expensive drug therapy for the treatment of toxic side-effects, and fewer treatment-related hospitalisations required during the course of therapy for adverse drug reactions in comparison to patients treated with 5-FU/LV.

Background: Malignant bowel obstruction (MBO) is common in patients with advanced cancer. Aim: To perform a phase II study to assess the feasibility of conducting a phase III trial investigating the therapeutic value of gastrografin in MBO. Methods: Randomized double-blinded placebo-controlled feasibility study. Participants received 100 mL of either gastrografin or placebo. Results: Over 8 months, 57 patients were screened and 9 enrolled (15.8% recruitment rate). Of the 9 enrolled, 4 received gastrografin (with 2 completing assessment) and 5 received placebo (with 4 completing assessment). Conclusions: It is not feasible to conduct a phase III trial using the same study protocol. This study validates the use of the phase II feasibility study to assess protocol viability in a palliative population prior to embarking on a larger trial.

3542Background: DpR has recently been proposed as a measure of efficacy that predicts the long-term treatment outcome for mCRC. DpR is a continuous measure that defines the nadir of tumor response,...

Summary Background Locally advanced head and neck cancer often requires wide resections of the cheek and parotid gland, and in an ageing population preferred reconstructive options aim to avoid lengthy operating times or high risk surgery. While most large parotid defects traditionally require free flap reconstruction, we describe a new and versatile locoregional flap that has been shown to be reliable, simple and safe. Methods We describe the cervico-submental (CSM) keystone-design perforator island flap for head and neck reconstruction, including an analysis of 33 consecutive patients with a range of head and neck defects. The flap was raised based on perforators of the external carotid artery and its branches, and designed to overlay the C2/C3 dermatomes (an aide memoire for flap design). The indications, and surgical technique are described. Results In 33 consecutive patients, no major complications were encountered. Five patients developed superficial infections, one developed post-operative bleeding and one patient developed partial tip necrosis. Theatre time was considerably shorter than our alternative reconstructive options. Conclusion The CSM keystone-design perforator island flap is a novel and versatile flap, which can be used in a range of advanced cheek and parotidectomy defects, and may enable improved surgical management in an increasingly elderly and high-risk population.

Background: Use of autologous tissue is ideal in breast reconstruction; however, insufficient donor tissue and surgical and donor-site morbidity all limit its use. Tissue engineering could provide replacement tissue, but only if vascularization of large tissue volumes is achievable. The authors sought to upscale their small-animal adipose tissue-engineering models to produce large volumes of tissue in a large animal (i.e., pig).Methods: Bilateral large-volume (78.5 ml) chambers were inserted subcutaneously in the groin enclosing a fat flap (5 ml) based on the superficial circumflex iliac pedicle for 6 (n = 4), 12 (n = 1), and 22 weeks (n = 2). Right chambers included a poly(L-lactide-co-glycolide) sponge. Other pedicle configurations, including a vascular pedicle alone (n = 2) or in combination with muscle (n = 2) or a free fat graft (n = 2), were investigated in preliminary studies. Serial assessment of tissue growth and vascularization by magnetic resonance imaging was undertaken during growth and correlated with quantitative histomorphometry at chamber removal.Results: All chambers filled with new tissue by 6 weeks, vascularized by the arteriovenous pedicle. In the fat flap chambers, the initial 5 ml of fat expanded to 25.9 +/- 2.4, 39.4 +/- 3.9, and 56.5 ml (by magnetic resonance imaging) at 6, 12, and 22 weeks, respectively. Adipose tissue volume was maintained up to 22 weeks after chamber removal (n = 2), including one where the specimen was transferred on its pedicle to an adjacent submammary pocket.Conclusion: The first clinically relevant volumes of tissue for in situ and remote breast reconstruction have been formed with implications for scaling of existing tissue-engineering models into human trials. (Plast. Reconstr. Surg. 128: 1206, 2011.)

Purpose From February 2001 to February 2002, 946 patients with advanced GI stromal tumors (GISTs) treated with imatinib were included in a controlled EORTC/ISG/AGITG (European Organisation for Research and Treatment of Cancer/Italian Sarcoma Group/Australasian Gastro-Intestinal Trials Group) trial. This analysis investigates whether the response classification assessed by RECIST (Response Evaluation Criteria in Solid Tumors), predicts for time to progression (TTP) and overall survival (OS). Patients and Methods Per protocol, the first three disease assessments were done at 2, 4, and 6 months. For the purpose of the analysis (landmark method), disease response was subclassified in six categories: partial response (PR; > 30% size reduction), minor response (MR; 10% to 30% reduction), no change (NC) as either NC− (0% to 10% reduction) or NC+ (0% to 20% size increase), progressive disease (PD; > 20% increase/new lesions), and subjective PD (clinical progression). Results A total of 906 patients had measurable disease at entry. At all measurement time points, complete response (CR), PR, and MR resulted in similar TTP and OS; this was also true for NC− and NC+, and for PD and subjective PD. Patients were subsequently classified as responders (CR/PR/MR), NC (NC+/NC−), or PD. This three-class response categorization was found to be highly predictive of further progression or survival for the first two measurement points. After 6 months of imatinib, responders (CR/PR/MR) had the same survival prognosis as patients classified as NC. Conclusion RECIST perfectly enables early discrimination between patients who benefited long term from imatinib and those who did not. After 6 months of imatinib, if the patient is not experiencing PD, the pattern of radiologic response by tumor size criteria has no prognostic value for further outcome. Imatinib needs to be continued as long as there is no progression according to RECIST.

METHODS: A segment of jejunum from a 6-week-old, 6.4-kg Yucatan miniature swine was mechanically and enzymatically digested to form organoid units (OU) consisting of epithelium and mesenchyme. These were loaded onto a biodegradable scaffold and implanted into either the omentum or subcutaneous tissue of the autologous animal. After 4 weeks, TESI was harvested and analyzed by histology and immunofluorescence for epithelium (villin, e-cadherin, Muc2, chromogranin A), lamina propria (PDGFRa), smooth muscle (a-SMA), nerves (Tuj), and progenitor cells (Sox9).

Background: Duligotuzumab (MEHD, MEHD7945A) is a novel dual-action humanized IgG1 antibody that blocks EGFR and HER3 binding, inhibiting all major ligand-dependent HER complex signaling. MEHD is active in multiple tumor models, including models resistant to anti-EGFR or anti-HER3. Emerging data in CRC suggest a role for HER3 in de novo and acquired resistance to anti-EGFR therapy. Methods: This open-label, randomized Phase II study enrolled patients (pts) with KRAS exon 2 wt mCRC who progressed on/after oxaliplatin-containing chemotherapy. Pts received a combination of MEHD (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1w) + FOLFIRI (q2w) until progression or intolerable toxicity. Endpoints included progression-free survival (PFS), and objective response rate (ORR), overall survival (OS), and adverse events (AEs). Tumor samples were mandatory and underwent biomarker analysis for ERBB3, NRG1 and EGFR ligand expression by qRT-PCR, and ERBB3 by IHC. The primary efficacy analysis was conducted in patients with RAS wt tumors (no mutations detected in KRAS or NRAS exons 2, 3; exon 4 mutations pending). Results: Of 134 randomized patients, 98 were RAS ex2/3 wt (53 MEHD); median age 63 years, ECOG 0-1. As of 21Aug14, 11 pts remain active. Efficacy results (Table) show no benefit of MEHD + FOLFIRI; ORR was lower in the MEDH arm. No relationship was seen between PFS or ORR and mRNA expression for ERBB3 or NRG1, or ERB3 expression by IHC. There were fewer rash events of any grade in the MEHD arm (79% and 93%) but more diarrhea (89% and 66%). Incidence of Grade ≥ 3 AEs was similar between arms (87% and 89%); however, the frequency of SAEs was higher in the MEHD arm (55% and 48%). Cumulative dose intensity and duration of treatment with FOLFIRI were lower in the MEHD arm. Conclusions: MEHD + FOLFIRI did not improve outcomes of pts with RAS ex2/3 wt mCRC compared to cetuximab + FOLFIRI. Updated efficacy, safety and biomarker data will be presented. All ptsMEHD7945A + FOLFIRICetuximab + FOLFIRIHazard Ratio or Odds Ratio (90% CI)(n = 53)(n = 45)PFS events39 (74%)33 (73%)1.40 (0.94-2.08)Median PFS, mo (90% CI)6.9 (4.9-7.6)5.7 (5.5-7.7)OS events18 (34%)19 (42%)0.85 (0.49-1.46)Median OS, mo (90% CI)NE (12.0-NE)12.4 (10.0-NE)ORR,% (90% CI)17.0 (9.8-26.6)33.3 (21.8-46.1)0.41 (0.18-0.91)CI = confidence interval. NE = not estimated Citation Format: Andrew G. Hill, Michael Findlay, Matthew Burge, Christopher Jackson, Pilar Garcia Alfonso, Leslie Samuel, Vinod Ganju, Meinolf Karthaus, Alessio Amatu, Mark Jeffery, Maria DiBartolomeo, John Bridgewater, Andrew Coveler, Manuel Hidalgo, Amy V. Kapp, Roxana Sufan, Bruce McCall, Elicia Penuel, Andrea Pirzkall, Josep Tabernero. Randomized phase II study of duligotuzumab + FOLFIRI versus cetuximab + FOLFIRI in 2nd-line patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT110. doi:10.1158/1538-7445.AM2015-CT110

3502 Background: The SIRFLOX study was designed to assess the efficacy and safety of combining FOLFOX chemotherapy (± bev) with SIRT using yttrium-90 (Y-90) resin microspheres as first-line treatme...