Hemospray for Life-Threatening Ulcer Bleeding: First Case Report in the United States
October 2013

MDPeter J Sargon
Department of Medicine
Division of Gastroenterology
Advocate Lutheran General Hospital
Park RidgeIL

DOTimothy J Laurie
Department of Medicine
Division of Gastroenterology
Advocate Lutheran General Hospital
Park RidgeIL

Hemospray for Life-Threatening Ulcer Bleeding: First Case Report in the United States

REPORTS JOURNAL acgcasereports.gi.org ACG Case Reports Journal |
1October 201310.14309/crj.2013.5
A 13-year-old boy with metastatic rhabdomyosarcoma presented with biliary obstruction requiring ERCP for stent placement. Re-evaluation after recurrence of symptoms revealed external migration of the stent with formation of a contralateral wall bleeding duodenal ulcer. Endoscopic therapy was not feasible and bleeding persisted despite medical therapy and embolization. Given his life-threatening condition, approval for the use of Hemospray (Cook Medical, Winston-Salem, NC, USA) was obtained. Hemospray was applied to the visualized bleeding sites with subsequent hemostasis. Patient tolerated the procedure well. This is the first use of Hemospray in the United States outside of a clinical trial.ACG Case Reports Journal is a peer-reviewed, open-access publication that provides GI fellows, private practice clinicians, and other members of the health care team an opportunity to share interesting case reports with their peers and with leaders in the field. Visit http://acgcasereports.gi.org for submission guidelines. Submit your manuscript online at

Introduction

Acute upper gastrointestinal hemorrhage in the United States accounts for greater than 300,000 annual hospital admissions and a mortality rate of up to 10%. 1 At the current time, there are various treatment modalities approved for the management of upper gastrointestinal bleeding, which include injection (saline, epinephrine, sclerosants), cautery (heat probes, lasers, argon plasma coagulation, electrocautery), and mechanical therapy (clips, band ligation). 1 In some cases, hemostasis is difficult to achieve and patients may have persistent or recurrent bleeding. Additionally, there are some instances in which the patient's anatomy, the location of a lesion, or severe bleeding makes it difficult to achieve hemostasis with currently available methods. Hemospray (Cook Medical, Winston-Salem, North Carolina, USA) is an alternative method that is currently undergoing trials and the process of FDA approval. Hemospray is a granular, mineral blend nanopowder with clotting abilities that increase the concentration of clotting factors, activate platelets, and form a mechanical plug on an injured blood vessel. 2 According to a trial conducted by Sung et al, it has been indicated that Hemospray can be used for hemostasis of nonvariceal confirmed peptic ulcer bleeding. 3 In that study, 20 patients were recruited and acute hemostasis was achieved in 19 of the 20 patients. The other patient required arterial embolization of a pseudoaneurysm. Additionally, 2 patients had recurrent bleeding within 72 hours, indicated by a hemoglobin drop. No active bleeding was identified on repeat upper endoscopy.

Case Report

We report a case in which hemostatic powder was used to treat a patient with profound thrombocytopenia and recurrent gastrointestinal bleeding secondary to duodenal ulcer disease. The patient was a 13-year-old male with a medical history significant for metastatic rhabdomyosarcoma with pancreatic head mass. He was referred to adult gastroenterology in 2010 for a biliary stricture requiring endoscopic retrograde cholagiopancreatography with sphincterotomy and placement of a biliary stent. Since that time, the patient had undergone multiple stent exchanges including placement of a fully covered self-expandable biliary metal stent in August 2011. This was complicated by acute cholecystitis requiring the placement of a cholecystostomy tube. Since the original diagno-sis of metastatic rhabdomyosarcoma, the patient had undergone multiple courses of chemotherapy over a 4-year time period and was in remission for 3 months after undergoing his most recent course of chemotherapy. However, the patient developed recurrent jaundice, vomiting, and thrombocytopenia. Repeat endoscopic evaluation in February 2012 revealed that the biliary stent had migrated distally and was embedded in the contralateral wall of the duodenum. A large bleeding ulcer was identified where the stent was embedded ( Figure 1). There was also diffuse erythema and edema with oozing proximal to this area. Endoscopic therapy with conventional measures, including epinephrine injection, clip placement, and cautery, was not feasible secondary to the extent of bleeding, mucosal edema, and anatomic changes. gational device exemption for use of hemostatic powder was appropriate. Once approved, a Cook Medical representative was flown out to train us on the use of the Hemospray device. The entire process to obtain approval from the time the letters were written to the time of endoscopy was five days. Upper endoscopy was then performed revealing erythematous, edematous, friable antral mucosa with a mosaic pattern. An adherent clot was seen at the pyloric channel and removed with irrigation and aspiration, revealing an oozing ulcer. The duodenum was also erythematous and edematous. There was diffuse oozing in the antrum and duodenum along with re-identification of the duodenal ulcer. A total of 25-30 g of hemostatic powder was applied to the duodenal ulcer site, the proximal duodenum, the antrum, and the pyloric channel site. After application, there was no further evidence of oozing or active bleeding ( Figure 2). The patient tolerated the procedure well and he was discharged home 6 days later with no further episodes of bleeding. This is the first use of hemostatic powder for the management of upper gastrointestinal bleeding outside of a clinical trial in the United States.  The patient was started on intravenous drips of pantoprazole and octreotide. He underwent urgent embolization of the gastroduodenal artery per interventional radiology. He was transferred to the pediatric intensive care unit for further monitoring and treatment. Over the next week, the patient developed recurrent bleeding despite medical and interventional therapy, requiring multiple blood transfusions. Additionally, he developed worsening thrombocytopenia requiring platelet transfusions. Surgery evaluated the patient and deemed him a non-surgical candidate. Given his lifethreatening condition with transfusion dependency, persistent active bleeding and no feasible medical, endoscopic, or surgical option, we attempted to obtain approval for the use of hemostatic powder.

An investigational device exemption was obtained to use hemostatic powder through the appropriate process involving clearance through our institution's IRB chairperson and chairman of the Department of Medicine. An additional gastroenterologist, who was not involved in the patient's care, reviewed the case to determine whether obtaining an investi-

Discussion

Hemostatic powder is approved for use in Europe and Canada for non-variceal ulcer bleeding and is currently undergoing FDA approval for the same indication in the United States. At this time, there are no major complications or adverse events associated with the use of hemostatic powder. There has been concern for embolization if used in variceal bleeding or larger vessels; however, this has not yet been encountered. The difficulty that we encountered in using hemostatic powder was clumping in a moist or wet environment. As part of the standard procedure, the biopsy port of the endoscope would have to be flushed with an air-filled syringe to avoid clumping within the catheter. However, we still experienced clumping within the catheter if it touched fluid or mucosa that was not fully dry. One can imagine that it may be difficult to have a completely dry environment in a patient with upper gastrointestinal hemorrhage requiring aggressive irrigation.

Based on our review of the literature and personal experience with using the device, there will likely be certain scenarios and circumstances where hemostatic powder will be most helpful. Anatomic location of the lesion may dictate use of hemostatic powder, such as in patients with pyloric channel ulcers, which are difficult to treat with conventional methods. Additionally, large areas of bleeding where it is difficult to identify lesions can be sprayed with the hemostatic powder without the need to target the lesion directly. Applications outside of non-ulcer bleeding will also need to be investigated. At this time, there are no published trials evaluating use of hemostatic powder in variceal bleeding or other non-ulcer etiology of bleeding.

Holster et al recently published a case series in which 16 consecutive patients on antithrombotic therapy with upper gastrointestinal hemorrhage were treated with hemostatic powder at the Erasmus MC University Medical Centre in Rotterdam, The Netherlands. Hemostasis was initially achieved in 5 of the 8 (63%) patients on antithrombotic therapy and 8 of the 8 (100%) patients not on antithrombotic therapy (P=0.20). Rebleeding rate was similar in both groups; however, in 4 of the 5 total patients with rebleeding, hemostatic powder was applied to arterial spurting bleeding. 4 It would be beneficial to have future trials investigating the use of hemostatic powder with combination therapy as well as trials investigating its use in non-ulcer bleeding, including variceal bleeding.

Disclosures

Author contributions: P.J. Sargon wrote and edited the manuscript, and is the article guarantor; T.J. Laurie edited the manuscript.

Financial disclosure: No competing financial interests to disclose.

Figure 1 .
1Bleeding duodenal ulcer.

Figure 2 .
2Hemostasis of bleeding duodenal ulcer after application of Hemospray.

ASGE guideline: The role of endoscopy in acute non-variceal upper-GI hemorrhage. D A Adler, J A Leighton, R E Davila, Gastroinest Endosc. 604Adler DA, Leighton JA, Davila RE, et al. ASGE guideline: The role of endoscopy in acute non-variceal upper-GI hemorrhage. Gastroinest Endosc. 2004;60(4):497-504.

Preliminary data on the nanopowder hemostatic agent TC-325 to control gastrointestinal bleeding. S A Giday, Gastroenterol Hepatol. 79Giday SA. Preliminary data on the nanopowder hemostatic agent TC-325 to control gastrointestinal bleeding. Gastroenterol Hepatol. 2011;7(9):620-622.

Early clinical experience of the safety and effectiveness of Hemospray in achieving hemostasis in patients with acute peptic ulcer bleeding. J J Sung, D Luo, J C Wu, Endoscopy. 434Sung JJ, Luo D, Wu JC, et al. Early clinical experience of the safety and effectiveness of Hemospray in achieving hemostasis in patients with acute peptic ulcer bleeding. Endoscopy. 2011;43(4):291-295.

Hemospray in the treatment of upper gastrointestinal hemorrhage in patients on antithrombotic therapy. I L Holster, E J Kuipers, E T Tjwa, Endoscopy. 451Holster IL, Kuipers EJ, Tjwa ET. Hemospray in the treatment of up- per gastrointestinal hemorrhage in patients on antithrombotic therapy. Endoscopy. 2013;45(1):63-66.


A trophic characterization of intertidal consumers on Chilean rocky shores
2013. 2013

Patricio A Camus
Departamento de Ecología
Facultad de Ciencias
Universidad Católica de la Santísima Concepción
Casilla 297Concepción

Paulina A Arancibia
Departamento de Ecología
Facultad de Ciencias
Universidad Católica de la Santísima Concepción
Casilla 297Concepción

Programa de Magister en Ecología Marina
Facultad de Ciencias
Universidad Católica de la Santísima Concepción
Casilla 297ConcepciónChile

M Isidora Ávila-Thieme
Departamento de Ecología
Facultad de Ciencias
Universidad Católica de la Santísima Concepción
Casilla 297Concepción

Programa de Magister en Ecología Marina
Facultad de Ciencias
Universidad Católica de la Santísima Concepción
Casilla 297ConcepciónChile

A trophic characterization of intertidal consumers on Chilean rocky shores

Revista de Biología Marina y Oceanografía Revista de Biología Marina y Oceanografía
482013. 201310.4067/S0718-19572013000300003Article Una caracterización trófica de los consumidores intermareales en costas rocosas de ChileDietniche widthindividual specializationomnivorybody size
Resumen.-En los últimos 50 años, el rol trófico de los consumidores se convirtió en un tópico importante en la ecología de costas rocosas de Chile, centrándose en especies de equinodermos, crustáceos y moluscos tipificadas como herbívoros y carnívoros principales del sistema intermareal. Sin embargo, la dieta y comportamiento de muchos consumidores aún no son bien conocidos, dificultando abordar problemas clave relativos por ejemplo a la importancia de la omnivoría, competencia intra-e inter-específica o especialización individual. Intentando corregir algunas deficiencias, ofrecemos a los investigadores un registro dietario exhaustivo y descriptores ecológicos relevantes para 30 especies de amplia distribución en el Pacífico sudeste, integrando muestreos estacionales entre 2004 y 2007 en 4 localidades distribuidas en 1.000 km de costa en el norte de Chile. Basados en el trabajo de terreno y laboratorio, se presenta : (a) una matriz de consumidores-recursos generada por análisis de alta resolución del contenido intestinal de 6.377 individuos, incluyendo 222 presas (80% identificadas a nivel de especie o género), (b) estimaciones de densidad, tamaño corporal (longitud y peso), amplitud dietaria (a nivel de individuo y especie), y diversidad intra-individual de los consumidores, (c) una ordenación nMDS de la similitud en composición dietaria entre consumidores, e información para cada consumidor sobre importancia relativa y frecuencia de ocurrencia de las presas más comunes. Considerando la amplia dieta omnívora y alta superposición de los consumidores, discutimos su potencial competitivo y el rol de la especialización individual en su carácter generalista, destacando la necesidad de reevaluar su comportamiento y efectos ecológicos en la comunidad intermareal.Palabras clave: Dieta, amplitud de nicho, especialización individual, omnivoría, tamaño corporal Abstract.-In the last 50 years, the trophic role of consumers has become a main research topic in the ecology of Chilean rocky shores, and in other regions. Several studies have typified species of echinoderms, crustaceans and mollusks as the most important herbivores and carnivores of intertidal assemblages. Unfortunately, little is known about the diet and behavior of many consumers, making difficult addressing key issues related to the importance of omnivory, intra-and inter-specific competition, or individual specialization. The goal of this paper is to fill some gaps in the available information and provide researchers with an exhaustive dietary analysis and relevant ecological descriptors for a suite of 30 consumer species distributed along the southeastern Pacific coast. Our data integrate information collected through seasonal samplings conducted between 2004 and 2007 at 4 localities distributed over 1,000 km of coast in northern Chile. Based on laboratory and field work analysis, we present: (a) a consumer-resource matrix obtained from high-resolution analyses of gut contents of 6,377 individuals, including 222 prey items (80% identified at species or genus level); (b) estimates of the density, body size (length and weight), diet width (at individual and species levels), and within-individual diversity of consumer species; (c) an nMDS ordination of the compositional similarity of consumers' diets, and information on the relative importance and occurrence frequency of the most common preys of each consumer. Based on the high frequency of omnivory and the high diet overlap among consumers, we discuss their potential for competition and the role of individual specialization in shaping their generalist character, highlighting the need to reappraise their behavior and ecological effects in the intertidal community.

INTRODUCTION

During nearly 50 years of ecological research on nearshore ecosystems of Chile, few topics have received as much attention as the role and importance of rocky intertidal consumers in population and community processes (e.g., see Castilla & Paine 1987, Santelices 1989, Fernández et al. 2000, Thiel et al. 2007. In this context, a suite of ecologically important invertebrates have been characterized as typical herbivores or carnivores of these systems, comprising some common species of echinoderms (sea stars, sea urchins) and crustaceans, but particularly a diverse group of molluscs including polyplacophorans, key-hole limpets, patellogastropopd limpets and snails.

Paradoxically, very little is known about the diet, feeding patterns and behavior of many of the consumers mentioned above , Aguilera 2011, Aguilera & Navarrete 2011, as well as their trophic roles in the intertidal food web, and their response to climateoceanic variations (Camus 2008a). For instance, the trophic habits of 3 of the most conspicuous and largesized herbivores in Chile, the black sea urchin Tetrapygus niger and the chitons Enoplochiton niger and Acanthopleura echinata, were either virtually unknown or poorly documented a few years ago (see , Sanhueza et al. 2008, Camus et al. 2012. Even for well-known species such as the only 2 keystone predators in this system, the sun star Heliaster helianthus and the muricid snail Concholepas concholepas, the possibility that they may engage in competition or intraguild predation was not suggested until recently (Navarrete & Castilla 2003). In addition, researchers have long acknowledged the fact that herbivores regularly ingest animals in direct or indirect ways (e.g., Santelices & Correa 1985, Santelices et al. 1986, Osorio et al. 1988, López et al. 2003, though only in recent years such phenomenon began to be examined in more detail. Current findings show that animal preys are indeed edible, palatable and digestible for common herbivores such as the chiton Chiton granosus or the key-hole limpets Fissurella limbata and Fissurella picta (Camus et al. 2009), and also that most herbivores make a widespread and consistent consumption of animals, including other herbivores (e.g., Aguilera 2005, Aguilera & Navarrete 2007; see review by Aguilera 2011). The available information thus challenges the trophic status of several species traditionally considered as herbivorous, posing key questions regarding the importance of physiological omnivory, and the roles of trophic omnivory (sensu Pimm & Lawton 1978) and intraguild predation in Chilean intertidal food webs (Aguilera 2005, Camus et al. 2009, Camus et al. 2012. Furthermore, these trophic patterns are in many cases accompanied by sophisticated behaviors ( The new findings do show that the trophic versatility of Chilean consumers is much higher than previously thought. However, some chitons, fissurelids and sea urchins from other regions are known to display detritivorous, carnivorous or omnivorous habits (e.g., Latyshev et al. 2004, Hughes et al. 2005, Grall et al. 2006, or the ability to switch between herbivory and omnivory depending on environmental conditions (Latyshev et al. 2004). Thus, the importance of these findings lies not in the singularity of consumers but in a change of perspective in regard to their foraging and digestive capabilities, and also to the structure and complexity of Chilean intertidal food webs. If omnivory and intraguild predation are present, then food webs should be envisaged as having a higher connectivity involving both a greater number of trophic positions (therefore longer food chains) and a higher occurrence of trophic loops, all of which multiplies the presence of indirect effects and increases their importance in the community (see discussions by Navarrete et al. 2000, Camus et al. 2012.

A detailed knowledge of consumers' diets is then a necessary condition for exploring the scenario mentioned above because, as pointed by Polis (1991), increasing the sampling intensity and taxonomic resolution in diet analyses will inevitably reveal a higher food web complexity. In this regard, indirect diet analyses such as stable isotope ratios have the advantage of providing a temporally integrated view of consumption and assimilation (Layman & Post 2008), but their taxonomic resolution is not sufficient to examine particular interactions at the species level. In contrast, direct analyses (inspection of gut contents) are still the best option for achieving high resolution, but they only inform about recent consumptions (Layman & Post 2008). This latter information could be improved by increasing the spatiotemporal extent of samplings, though at the price of increasing the cost of time and resources. Additionally, direct observations such as gut content analyses usually deal with fragmented or partially digested preys which are not easily identifiable at low taxonomic levels, and their quality depends strongly on taxonomic expertise ). However, low taxonomic resolution bears a high cost, as the fail to identify a high fraction of preys forces their aggregation into coarse or higher-level categories, conveying a significant loss of information and causing that many direct or indirect interactions remain undetected or confounded.

The available data for Chilean consumers show, unfortunately, that information gaps, taxonomic aggregation and/or limited spatiotemporal extent of samplings are rather the rule than the exception (e.g., see Sanhueza et al. 2008, Camus et al. 2012. Consequently, we aim to improve the available knowledge by capitalizing the information collected in a prior community survey conducted seasonally from 2004 to 2007 at 4 rocky intertidal localities in northern Chile. As a parallel goal of this survey, we carried out a systematic collection of individuals of the main consumer species present at each locality for obtaining diet information based on direct analyses of gut contents, making a particular effort to identify prey items at the lowest possible level. Therefore, we herein focus on the diet and basic ecological attributes of a diverse assemblage of invertebrates differing in body size, ecological importance and spatiotemporal occurrence, although most of them are common in at least some areas within or outside northern Chile, and all have geographical ranges extending toward Peru and/or central-southern Chile. The main goals of this paper are: (a) to make available to researchers a detailed account of the richness and composition of preys used by a suite of 30 consumer species widespread along the southeast Pacific coast, in order to fill some important gaps in the trophic ecology of Chilean rocky intertidal shores, and (b) to provide reliable information on the high complexity of these food webs, emphasizing the need of reappraising the behavior and trophic position of consumers in the community, as well as the trophic relationships among intertidal organisms.

MATERIALS AND METHODS

We selected 4 localities ( Fig. 1) distributed over ~1,000 km of coast in northern Chile: Lagunillas (30º06'14''S, 71º22'57'W; south of Coquimbo), Caleta Angosta (28º15'38'S, 71º10'23''W; north of Huasco), Caleta Constitución (23º25'23''S, 70º35'26''W; west coast of Mejillones Peninsula), Río Seco (21º00'05''S, 70º09'54''W; south of Iquique). The 4 assemblages represent a characteristic type of rocky intertidal community found on wave-exposed shores in north-central Chile, and they shared a similar taxonomic composition and ecological structure (see Fernández et al. 2000, Broitman et al. 2001, Thiel et al. 2007. However, Caleta Constitución and Lagunillas locate at or near to prominent upwelling centres at 23º and 30º S, respectively (Camus & Andrade 1999, Thiel et al. 2007, likely receiving higher nutrient loads throughout the year.

Sites were sampled seasonally between winter 2004 and autumn 2007, generating a total of 48 community samples (4 sites x 12 seasons). We indicate both the seasons (pooling localities) and the percentage of samplings in which each species occurred. All the 4 localities were sampled during a same low-tide cycle each season, using the same sampling design, grain and extent in order to minimize spatial biases and account for the patchiness of food resources. At each locality and season, Figure 1. Location of study sites in northern Chile / Ubicación de los sitios de estudio en el norte de Chile we assessed a 150 m stretch of coast line using 45 quadrats (0.25 m 2 ) distributed at the high, mid and low intertidal zones of 5 georeferenced blocks (15 m length) spaced every 15 m, with 9 quadrats per block (three per zone) spaced 5 m horizontally and 1.5 m vertically. While consumer densities were recorded in all the 45 quadrats, we present estimates that use only the quadrats in which individuals were present (zero-values omitted), in order to better reflect their spatial occurrence in the field (detailed descriptions of within-and between-site variability will be presented elsewhere). The vertical distribution of species was quantified as the relative percentage of low-, mid-and high-zone quadrats in which they occurred. For diet analyses, individuals were collected randomly (at daytime) from different tidal levels at the 5 sampling blocks, and then injected with and stored in 8% formaldehyde for preserving gut contents. Collected individuals were mainly adults (including different sizes), not classified by tidal level. We estimated that a sample of 10 individuals may allow recording > 85% of the population diet (Camus et al. , 2012, but in order to minimize sampling impacts, we managed effort by taking smaller numbers when species occurred in lower abundances, and thus collected an average of 9.4 ± 0.2 (SE) individuals per species, site and season. The maximum length and dry biomass (oven dried to constant weight at 70ºC) of collected individuals were recorded in the laboratory.

Gut contents analyses were done on a per-individual basis, and prey items were identified at the lowest possible level. In order to reduce errors and biases, the taxonomic work was conducted by previously trained researchers who used the same criteria, procedures and equipment. When possible, we provide full binomial names for consumers and preys, updated by following the databases WoRMS (World Register of Marine Species; Appeltans et al. 2013) and AlgaeBase (Guiry & Guiry 2013). We note that prey items informed as 'Genus sp.' correspond to species which could be individualized but not identified, while 'Genus spp.' involve two or more species of the same genus which could not be discriminated among. In particular, due to the trophic importance of Ulva and Enteromorpha, and a recent taxonomic revision of their species, we made a distinction between 'Ulva spp.' and 'Ulva spp. (ex Enteromorpha)', as these latter species are well known to researchers, and their morphological differences with Ulva could be important in consumers' choice.

From the above information, we characterized the trophic niche width of consumers based on 3 simple descriptors: the average number of prey items recorded per individual, the total number of prey items per species (pooling individual data), and the proportion (%) between individual and species prey ranges (100% indicates that individuals use the full resource spectrum of the species). The former 2 variables allow to compare the specialist or generalist character of individuals and species, and the latter estimates the within-individual component of niche width (Bolnick et al. 2002), where decreasing values reflect increasing degrees of individual specialization (i.e., low values represent generalist species formed by specialist individuals). Complementarily, we shown the full list of the algal and animal prey ingested by consumer species, along with the occurrence frequency of their most important prey, estimated as the proportion of times in which a prey was found in a sample of N digestive tracts. Occurrence frequencies cannot inform on the numeric or gravimetric importance of prey in gut contents, but as an indirect estimate of consumption intensity they are useful to make inferences on the trophic activity of consumers. Finally, it provides a graphical representation of the similarity among consumers based on an ordination analysis of the taxonomic composition of their diets, generated by non-metric multidimensional scaling by means of the Jaccard's index.

RESULTS

GENERAL INFORMATION

The diet data presented in this paper were based on 6,377 individuals belonging to 16 genera and 30 species of the phyla Echinodermata (4 species) and Mollusca (26 species), including 6 polyplacophorans, 6 key-hole limpets, 8 patellogastropod limpets, 2 heterobranch pulmonate gastropods, 3 turbinid gastropods, one calyptraeid gastropod, 2 urchins and 2 starfish (see Table  1). The 2 starfish were essentially carnivorous, while the remaining 28 species were trophic omnivores (feeding on 2 or more trophic levels) with mostly herbivorous diets including varying proportions of animal items (see Table  2). Throughout the study, was collected an average of 213 individuals per species, although the totals were highly variable among species in correspondence with their rarity or commonness in the field, ranging from 3 (Fissurella cumingi) to 508 (Tegula atra). Field and laboratory estimations for the 30 species are summarized in Table 1 and described below including correlation analyses (Spearman's coefficient, r S ) among selected variables. We remark that the length and biomass of consumers were measured only for individuals collected for diet analyses, and while such estimates may bear direct relationships with our trophic estimates, they may not accurately represent the actual body size of field populations.

ECOLOGICAL DESCRIPTORS

The mean local population density of species ranged from 4 (Tonicia elegans) to 313.6 (Prisogaster niger) individuals m -2 (Table 1). However, we lack information for 3 species (Chiton magnificus, F. cumingi and Scurria scurra) which were collected manually for diet analyses but remained undetected in our sampling quadrats. In the field, the patchy distribution of most species was better reflected by the density ranges estimated from their occurrence in single quadrats. While in all cases the minimum density was 4 individuals m -2 , the maximum density was ≥ 40 m -2 for 54% of species and ≥ 100 m -2 for 20% of species, though reaching values as high as 3,600 m -2 and 4,840 m -2 for P. niger and T. atra, respectively. Interestingly, the mean local density of consumers was negatively correlated with their length (r S = -0.49, P = 0.0060, n = 27), though showing no significant associations with other variables. Albeit the 27 sampled species tended to be more frequent at one particular intertidal zone (Table 1), 18 of them (67%) occurred through the entire vertical range, 7 (26%) at 2 of the 3 zones (mainly the low and mid zones), and 2 (7%; Tegula tridentata and T. elegans) at the low zone only, suggesting a widespread effect of the consumer assemblage on the community.

The body size of consumer species exhibited strong differences (Table 1), reaching up to 2 and 4 orders of magnitude in length and biomass, respectively, although these two variables were highly correlated (r S = 0.91, P < 0.0001, n = 30). Both in length and biomass, the largest consumer was by far the sun star H. helianthus, followed closely by the polyplacophorans A. echinata and E. niger, while the smallest one was the shell-less pulmonate sea slug O. marginata.

Pooling our 48 site-by-season samplings, the assemblage of 30 consumers as a whole ingested a total number of 222 prey items, although the contribution of species to this total was markedly different (see Table 1). The average number of prey items per individual ranged from 1.4 (Stichaster striatus) and 3.3 (Scurria zebrina) to 17.7 (F. cumingi) and 17.8 (Loxechinus albus), while the total number at the species level ranged from 21 (S. scurra) and 26 (S. zebrina) to 147 (L. albus) and 151 (T. niger). At the species level, most consumers exhibited a wide diet spectrum, as 43% of species had diet ranges ≥ 60 prey, while not less than 6 species consumed each ≥ 110 prey, equivalent to ≥ 50% (and up to 68% in the sea urchin L. albus) of the assemblage's range (Table 1), which points to a high level of diet overlap and functional redundancy at the assemblage level. In addition, the number of prey at individual and species levels were positively associated (r S = 0.54, P = 0.0023, n = 30), suggesting that the diet width of species tends to reflect the generalist or specialist character of their individuals, although the moderate strength of the correlation also indicates that this match is either partial or different among species. Indeed, the within-individual component of niche width (Table 1) was very low (average: 26.2%) ranging from 4.4% (S. striatus) to 59.0% (F. cumingi), and individuals from 15 species consumed less than 10% of the species' diet spectrum (and less than 20% in 26 species). Albeit this result suggests an important degree of individual specialization in contrast with the apparent generalist character of most species, it should be interpreted with caution because the within-individual component was negatively associated with both the number of digestive tracts analyzed per species (r S = -0.85, P < 0.0001, n = 30) and the total number of prey per species (r S = -0.58, P = 0.0008, n = 30). While these correlations show an obvious effect of sampling size, and our data may include sampling biases to some extent, such effect would be largely due to the rarity or commonness of species, which determined the final sampling size, and also to the high taxonomic resolution of diet analyses which increased the total number of items as more samples were available. Table 1 shows the large differences in occurrence among species in the 48 site-by-season samplings, varying from 2.1% (F. cumingi) to 95.8% (E. niger), with 14 species (47%) occurring in at least 50% of samplings and 10 species (33%) in less than 25%. In addition, while several species occurred through all seasons of the year at one or more sites, others were detected irregularly during the study (e.g., Fissurella costata, Chiton cumingsii or Tegula tridentata), or only during short periods (e.g., F. picta or Onchidella marginata). In this context, therefore, species with higher occurrence and larger sample size (e.g., C. granosus or T. atra in Table 1) may tend to show higher diet width and higher individual specialization than rare species (e.g., F. cumingi or F. picta). However, there are also species that deviate from this trend, exhibiting a comparatively high (e.g., C. magnificus or F. nigra) or low (e.g., P. niger or S. striatus) diet width while having a

± SD) and range estimated in the field; vertical distribution, shown as the relative occurrence (%) of individuals at low (L), mid (M) and high (H) intertidal zones; mean body size (± SE) measured as maximum length and dry weight; total number of digestive tracts (NDT) analyzed per species, including the percentage of empty tracts (ET %, in parentheses) when detected; mean number (± SE) of prey items per individual (MPI); total number of prey items per species (TPS); within-individual component of diet width (WIC), estimated as the quotient MPI/TPS (%)

; occurrence percentage of consumers in 48 site-by-season samplings (PS %), including the seasons (Se, in parentheses) in which they were present throughout the study (sites pooled; seasons numbered correlatively from 1: Fall 2004, to 12: Fall 2007) / Información ecológica básica para un conjunto de 30 consumidores intermareales rocosos estudiados en el norte de Chile. Columnas: densidad media (± DE) y rango estimados en terreno; distribución vertical, mostrado como la ocurrencia relativa (%) de individuos en las zonas intermareales baja (L), media (M) y alta (H); tamaño corporal medio (± EE) medido como longitud máxima y peso seco; número total de tractos digestivos (NDT) analizados por especie, incluyendo el porcentaje de tractos vacíos (% ET, entre paréntesis) cuando fueron detectados; número promedio (± EE) de ítems presa por individuo (MPI); número total de ítems presa por especie (TPS); componente intra-individual de la amplitud de dieta (WIC), estimado como el cuociente MPI/TPS (%); porcentaje de ocurrencia de los consumidores en 48 muestreos sitio x estación (PS %), incluyendo las estaciones (Se, entre paréntesis) en las que estuvieron presentes durante el estudio (sitios agrupados; estaciones numeradas correlativamente desde 1: otoño 2004, a 12: otoño 2007) smaller or larger sample size, respectively. Thus, some important fraction of the observed differences in diet width and individual specialization may likely reflect species-specific attributes rather than sampling effects, and comparisons among species should be made carefully.

Interestingly, the body size of consumers, considered either as biomass (dry weight) or length, showed a positive association with the number of consumed prey (diet width) both at the individual and species level, although this relationship was better reflected by the stronger correlation between biomass and diet width (for individuals: r S = 0.76, P < 0.0001; for species: r S = 0.57, P = 0.0011; n = 30). The fact that empty digestive tracts were notably infrequent suggests that diet data bear small biases, and provides additional support for the above relationship. Indeed, individuals lacking gut contents occurred in only nine species (see Table 1), particularly in S. scurra (15%) and S. striatus (22%), but reaching very low proportions in the remaining seven (0.2 to 2.2%). Table 2 shows the full list of prey ingested by each consumer species, totalizing 222 items corresponding to 101 algae (45.5%) and 121 animals (54.5%), from which 174 (78.4%) were identified at the level of species (54.5%) or genus (23.9%). We indicate the fraction of sites in which each prey was consumed, intended to reflect its spatial incidence in gut contents. However, non-consumed preys were not necessarily absent in the field, and the above fraction should thus not be interpreted as occurrence in the study sites, except in the case of prey consumed in all the 4 sites (therefore present at all sites). Nonetheless, this latter case occurs 462 times in Table 2, often repeated in different columns (consumers) from the same row (prey), indicating not only that many prey were common but also that many consumers shared the same prey at all sites. Indeed, the sum of the total number of prey per species in Table 1 equals 1,874 items, which contains > 8.4 times the grand total of 222 items ingested by the entire assemblage, suggesting an important dietary redundancy among consumers.

DIET COMPOSITION

After an nMDS ordination based on the composition of consumer diets (Fig. 2), the 28 trophic omnivores tended to form a single heterogeneous cluster, though separated from the carnivore starfish H. helianthus and S. striatus which in turn located far from each other, likely in part by the higher ingestion (whether casual or not) of algae by H. helianthus (Table 2) and our smaller sample size for S.  Table 1) / Ordenación multivariada (nMDS, estrés: 0,116) de los consumidores intermareales rocosos basada en la similitud (índice de Jaccard) de la composición taxonómica de sus dietas. Los nombres de las especies fueron abreviados usando la inicial del género y las dos primeras letras del nombre específico (ver los nombres binomiales completos en la Tabla 1) Vol. 48, Nº 3, 2013 Revista de Biología Marina y Oceanografía Values: occurrence frequency of prey, obtained by pooling data from 12 seasonal samplings in 4 sites / Gráficos circulares representando la importancia proporcional de las 5 presas ingeridas con mayor frecuencia por cada especie consumidora. Valores: frecuencia de ocurrencia de las presas, obtenida agrupando los datos de 12 muestreos estacionales en 4 sitios striatus (Table 1). However, both the diet range and the within-individual component of diet width were much higher for H. helianthus than S. striatus (Table 1), which may reflect actual differences in their diet and trophic behavior. The clustering of trophic omnivores (Fig. 2) did not show a clear taxonomic pattern for species belonging to the same genus or class, and the species located most distant from the cluster's center (such as S. scurra, L. albus, T. niger, O. maginata, P. niger and F. cumingi) were those showing extreme or contrasting values for the variables described in previous paragraphs. However, the importance of body size and degree of omnivory was reflected by the relative ordination of consumers along the major cluster axis, with the largest, most omnivorous species and the smallest, most herbivorous ones located, respectively, toward the upper-left and lower-right sectors (Fig. 2). In this context, an inspection of Tables 1 and 2 reinforces the idea that taxonomic relatedness might be little important for explaining the similarities (or differences) among consumer diets.

The eventually low effect of taxonomic relatedness is also reflected by Fig. 3, which shows a series of circle graphs representing the proportional importance of the five preys most frequently ingested by each consumer. Barnacles, mussels and the snail T. atra were the most frequent preys of the carnivores H. helianthus and S. striatus, although the relative importance of prey species was different for the two starfish. For the remaining species, Fig. 3 makes clear that despite important variations in the identity and frequency of their commonest prey, the majority of consumers shared some particular preys to a large extent. The five prey items most often co-used by non-carnivorous species were Codium dimorphum (Chlorophyta; shared by 75.0% of consumers), Hildenbrandia spp. (Rhodophyta; 75.0%), encrusting Corallinaceae (Rhodophyta; 60.7%), Ulva spp. (Chlorophyta; 46.4%) and Pseudulvella sp. (Chlorophyta; 42.9%), and all of them but Ulva corresponded to fleshy or calcified algae of encrusting habit.

DISCUSSION

Rocky intertidal consumers in northern Chile formed a heterogeneous assemblage, including a large core of common species with high spatiotemporal levels of occurrence and several species irregularly present in the study sites. Similarly, an important core of their prey species was consumed in consistently high frequency in time and space, but others remained highly variable, which explains why many consumers' diets appear similar at an overall level, while the number and frequency of preys in their gut contents may still show a high variation within and/or between sites. A number of physical and chemical variation sources on northern Chile, including coastal upwelling and El Niño-Southern Oscillation (see review by Thiel et al. 2007), may strongly influence the occurrence of species from local to regional scales, resulting in high replacement levels. As shown elsewhere (Camus 2008a), each of these communities exhibits a high temporal turnover in the composition of detectable macroscopic species (including consumers and preys), reaching in average up to 40-50% from one season to another. Such dynamical scenario highlights the importance of treating diet as a variable instead of a property of a given population or species.

The consumer assemblage included also a suite of large-sized polyphagous species which, as a whole, would exert a strong consumption pressure on virtually all types of organisms that can be found on rocky substrata, emphasizing the importance of further manipulative experiments evaluating the actual consumption rates. Albeit our dietary study did not include all existing consumers in northern Chile, the negative relation found between body size and density suggests the possibility of an underlying scaling relationship, as previously shown in central Chile (Marquet et al. 1990), which should be explored in regard with processes influencing resources availability, resource allocation and energy use among species (see White et al. 2007).

During our low-tide daytime samplings, most species showed a patchy distribution and several occurred in dense aggregations, as reflected by their large differences between minimum and maximum densities, although their spatial behavior under different conditions has not been studied. Recent analyses in central Chile on C. granosus, F. crassa, Scurria araucana and Siphonaria lessoni showed that, depending on the species, aggregations may be formed during low and/or high tides as well as during resting and/or foraging periods, but also that some species display a positive spatial association when foraging (see Aguilera & Navarrete 2011). However, as northern and central Chile have different climatic/oceanic regimes (Thiel et al. 2007), the characteristics and physiological effects of aggregation might depend on the spatial environmental variation along the coast (e.g., as shown for the periwinkle Echinolittorina peruviana; Rojas et al. 2000, Muñoz et al. 2008, and the possibility that consumers display a geographically consistent behavior remains to be evaluated (e.g., see Sanford 1999, Table 2. Algal and animal prey items (rows) ingested by each consumer species (columns) in northern of Chile throughout the study period (sites pooled), listed by higher taxonomic categories (phylum/division and class). Values in cells correspond to the fraction of the 4 study sites in which each prey was consumed / Ítems presa algales y animales (filas) ingeridos por cada especie consumidora (columnas) en el norte de Chile durante el período de estudio (sitios agrupados), ordenados por categorías taxonómicas superiores (división/phylum y clase). Los valores en las celdas corresponden a la fracción de los 4 sitios de estudio en los que cada presa fue consumida Navarrete & Manzur 2008). More importantly, the similarity in diet among northern Chilean consumers suggests that, if they eventually form inter-specific associations and/or aggregations when foraging, they might exert very strong impacts on prey species at small spatial scales. In this regard, encrusting algae (Codium, Hildenbrandia, Pseudulvella, Corallinaceae) and Ulva spp. were the commonest and most frequently shared prey of the majority of non-carnivore consumers (see also , Sanhueza et al. 2008, Camus et al. 2012, a fact deserving further consideration. In most cases, the importance of these items in gut contents might be explained by their commonness in northern Chilean assemblages, where algae such as Ulva rigida and Hildenbrandia lecanellieri are core species (sensu Hanski 1982) on a geographical scale (i.e., occurring in > 90% of sites and showing the highest mean local coverage; see Camus 2008b). While Codium dimorphum is much more common in central than northern Chile, our community survey (Camus et al., unpublished data) showed that despite it did not reach a measurable coverage in Iquique, its mean local coverage (when present) was 5% in Antofagasta and 12% in Huasco and Coquimbo, being indeed available to consumers. It is also likely that the consumption of C. dimorphum is enhanced by its encrusting habit and the high edibility of its soft fleshy thallus, as suggested by the intense grazing on this species in central Chile (Santelices 1987). As noted in a prior work that included Antofagasta and Coquimbo (Camus & Andrade 1999), typical macroscopic samplings tend to underestimate the importance of several smallsized, juvenile and encrusting algal forms, which occur mostly below and among other larger or erect sessile species, but are consumed in high frequency by grazers, giving the impression of being over-represented in gut contents. In addition, the wide and polyphagous diet of most consumers might be enhanced by the encrusting habit or widespread occurrence of their core algal preys, as grazers likely bulldoze a wide variety of algal and animal items found on the surface and neighbourhood of the algae (including microalgae and larval or early stages). On the other hand, it must be noted that the causes of the dominant presence of encrusting algae in gut contents are not entirely clear so far. Consumers may regularly ingest these algae because of their nutritional importance, or as a consequence of bulldozing their surface while targeting on other preys, or for both reasons (for a general discussion on this subject see Aguilera 2011). In whatever case, such causes should be investigated separately for each consumer species, taking into account that radular morphology may not be a good predictor of feeding patterns, that the widespread ingestion of animal items may have important physiological and ecological consequences (as discussed elsewhere; Camus et al. 2008), and the fact that we still know very little about the actual food items from which consumers' digestive processes ultimately extract nutrients (e.g., see Raffaelli 1985, Greese 1988, Camus et al. 2009. In addition, our daytime low-tide samples reveal that remarkably few of the 6,733 analyzed individuals (and from only nine species) had empty digestive tracts, suggesting that feeding excursions are more frequent than previously thought. Our prior studies (Camus et al. 2009) and laboratory observations in F. picta, F. limbata, C. granosus and T. niger, indicate that the rate of food passage through their digestive tracts might vary from 6 to 14 h, which is high enough as to stimulate the acquisition of new food in the short term (and low enough as to allow a proper detection of food items in gut contents). Thus, a detailed knowledge of the spatial and temporal overlap among consumers species is key to assess their potential for exploitative and interference competition, as examined in central Chile (Aguilera & Navarrete 2011).

In regard with intra-vs. inter-specific dietary differences, we remark that our results should be interpreted with caution and in relative terms, considering some methodological and ecological issues. For instance, prey ranges at the species level are often (though not always) widened by the pooling of individual data and the high resolution of diets, causing that few consumers appear specialized. In contrast, individuals provide fixed information mostly reflecting their recent, short-term foraging activities within their home range, which may tend to overestimate individual specialization and between-individual diversity, especially if resource patchiness is high (Bolnick et al. 2002, Layman & Post 2008. Consequently, as the number of collected individuals correlates with the natural occurrence of consumers, more common species provide larger samples tending to appear more generalized and with a higher degree of individual specialization (for a discussion on sampling effects and related aspects, see Bolnick et al. 2002Bolnick et al. , 2007. In such context, some consumers in northern Chile might be hypothesized as fully specialists or generalists because their prey ranges were, respectively, consistently narrow (e.g., S. striatus, T. tridentata) or wide (e.g., L. albus) both at the species and individual level. However, other consumers (e.g., C. granosus, E. niger, P. niger, S. lessoni, Scurria viridula, T. atra) had a small diet breadth at the individual level (low withinindividual diversity; Bolnick et al. 2002) but, as an effect of pooling individual diets, appeared as generalists at the species level. While the expansion of the population niche is usually considered a result of increasing withinindividual diversity (individuals become generalized), but it may also occur by increasing between-individual diversity, when individuals remain specialized but tend to use different resource states (e.g., if functional tradeoffs limit the abilities of individuals to widen their prey range; see Bolnick et al. 2007Bolnick et al. , 2010, as proposed by the niche variation hypotheses (Van Valen 1965). Such processes are poorly known in Chilean rocky shores, and our results highlight two potentially important aspects requiring further investigation. First, even though northern Chilean consumers show varying levels of within-and betweenindividual diversity, some generalist species may be actually formed by specialized rather than generalized individuals. However, little attention has been paid to the ecological and evolutionary significance of interindividual variations in resource use, which may relate to a diverse array of factors including differences in sex, age, physiology, morphology and animal personality (for a review, see Dall et al. 2012). Furthermore, it is important to note that variations in niche width at population and individual levels may be decoupled and also follow different patterns in different species (Bolnick et al. 2010), which might help to explain the apparently idiosyncratic patterns of some northern Chilean consumers. Second, trophic omnivores, especially those of larger body size, have very similar diets at the species level and their most frequent preys tend to be the same, but the existence or extent of resource limitation and competition in these assemblages remain largely unexplored. In northern Chile, for instance, the proportion of animal items consumed by A. echinata decreases with body size (Camus et al. 2012), suggesting ontogentic variations in diet as larger individuals become more herbivorous. In central Chile, several studies on C. granosus, F. crassa, S. araucana and S. lessoni, show some differences in activity rhythm and homing behavior pattern (orientation and displacement length) among their individuals, and also indicate that, depending on the species, interference competition may be important among either conspecific or heterospecific individuals (Aguilera & Navarrete 2007, 2011, as it was recently confirmed (Aguilera & Navarrete 2012). However, our view of these phenomena may be inaccurate if approached only from aggregated (population or species) levels, and the role of withinpopulation variation should not be disregarded as individual specialization might be effective in reducing intra-and inter-specific competition.

While Chilean rocky intertidal food webs might not have a higher complexity than those of other marine or continental environments (see Dunne et al. 2004, Thompson et al. 2007, they are certainly much more complex than previously thought (Camus et al. , 2012. Our data show that most consumers are omnivores linked to a very high number of predators and preys of varying trophic positions, often connecting to top and basal species simultaneously and likely engaged in complex intraguild interactions (see Camus et al. 2008). Such combination of intricate structure and high connectivity, along with the potential role of body size and individual behavior, may be key for understanding the functioning and stability of these food webs (Neutel et al. 2002, Berlow et al. 2008, Petchey et al. 2008.

Morales & Camus 2005 1 , Morales et al. 2006 2 , Aguilera & Navarrete 2011), stressing the need of reappraising the role of these consumers in the community.

Figure 2 .
2Multivariate ordination (nMDS, stress: 0.116) of rocky intertidal consumers based on the similarity (Jaccard's index) of the taxonomic composition of their diets. Species names are abbreviated by the initial letter of the genus and the first two letters of the specific name (see full binomial names in

Figure 3 .
3Circle graphs representing the proportional importance of the 5 preys ingested in highest frequency by each consumer species.

Table 1 .
1Ecological descriptors obtained for a suite of 30 rocky intertidal consumers studied in northern Chile. Columns: species; mean density (
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Table 2. Continued / Continuación
Table 2. continued / Continuación
ACKNOWLEDGMENTSWe thank financial support from CONICYT, Chile (grant FONDECYT 1040425), and Dirección de Investigación UCSC (grant FAA 2-2012). We are grateful to Karen Daroch, Daniela López, Christian Ibáñez, Arturo Navarrete and Felipe Opazo for field and laboratory assistance. We also thank the valuable and constructive comments made by two anonymous reviewers. P.A. Arancibia and M.I. Ávila-Thieme thank financial support (Tuition remission, Stipend and Teaching assistance fellowships)from Programa de Magíster en Ecología Marina, Facultad de Ciencias, UCSC.
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Validation of a prognostic scoring system for locally recurrent nasopharyngeal carcinoma treated by stereotactic radiosurgery

Daniel Tt Chua email@example.com
Department of Clinical Oncology
Queen Mary Hospital
The University of Hong Kong
Hong Kong

Kwan-Ngai Hung email@example.com
Department of Surgery
Queen Mary Hospital
The University of Hong Kong
Hong Kong

Victor Lee email@example.com
Department of Clinical Oncology
Queen Mary Hospital
The University of Hong Kong
Hong Kong

C Y Sherry
Ng
Department of Clinical Oncology
Queen Mary Hospital
The University of Hong Kong
Hong Kong

Janice Tsang firstname.lastname@example.com
Department of Clinical Oncology
Queen Mary Hospital
The University of Hong Kong
Hong Kong

BMC Cancer

Validation of a prognostic scoring system for locally recurrent nasopharyngeal carcinoma treated by stereotactic radiosurgery
10.1186/1471-2407-9-131BioMed Central Page 1 of 6 (page number not for citation purposes) Research article * Corresponding author
Background: Selection of patients with local failure of nasopharyngeal carcinoma (NPC) for appropriate type of salvage treatment can be difficult due to the lack of data on comparative efficacy of different salvage treatments. The purpose of the present study was to validate a previously published prognostic scoring system for local failures of NPC treated by radiosurgery based on reported results in the literature.Methods:A literature search yielded 3 published reports on the use of radiosurgery as salvage treatment of NPC that contained sufficient clinical information for validation of the scoring system. Prognostic scores of 18 patients from these reports were calculated and actuarial survival rates were estimated and compared to the original cohort used to design the prognostic scoring system. The area under the receiver operating characteristic curve was also determined and compared between the current and original patient groups.Results:The calculated prognostic scores ranged from 0.32 to 1.21, with 15 patients assigned to the poor prognostic group and 3 to the intermediate prognostic group. The actuarial 3-year survival rates in the intermediate and poor prognostic groups were 67% and 0%, respectively. These results were comparable to the observed 3-year survival rates of 74% and 23% in the intermediate and poor prognostic group in the original reports. The area under the receiver operating characteristic curve for the current patient group was 0.846 which was similar to 0.841 in the original group.Conclusion:The previously published prognostic scoring system demonstrated good prediction of treatment outcome after radiosurgery in a small group of NPC patients with poor prognosis. Prospective study to validate the scoring system is currently being carried out in our institution.

Background Loco-regional control rate of nasopharyngeal carcinoma (NPC) has improved significantly in the past decade due to the advances in imaging, radiotherapy technique, and the use of combined modality treatment. The reported 5year local control rates of NPC in modern series ranged from 81 to 85%, with control rates exceeding 90% for patients with T1 disease [1,2]. Despite the improved outcome in local control, local recurrence still represents a major cause of mortality and morbidity in advanced stage disease, and management of local failure remains an important and challenging issue in NPC.

Aggressive salvage treatment is generally recommended for local recurrence since long-term control can still be achieved in some patients. When the recurrent tumor is confined to the nasopharynx, both nasopharyngectomy and brachytherapy can be used with a long term control rate of 52-72% [3][4][5]. Patients with more extensive or bulky disease however often required external beam reirradiation, but treatment outcome with conventional radiotherapy was unsatisfactory with a poor survival rate and a high incidence of late complication [6,7]. The use of intensity-modulated radiotherapy (IMRT) in retreatment of NPC allows better sparing of normal tissues while delivering high dose to the target, and preliminary reports using IMRT for re-irradiation of NPC showed good shortterm control with a relatively low incidence of severe toxicities [8]. Stereotactic radiotherapy has also been employed in the treatment of local failures of NPC, with long term control rates of 53 to 86% [9][10][11][12]. Compared to other salvage treatments, stereotactic radiotherapy has the advantage of being applicable to deep-seated tumor such as recurrence in the skull base or intracranium. Stereotactic radiotherapy also allows better sparing of critical structures that are in close vicinity to the target. No direct comparison of different salvage treatment techniques for NPC has ever been reported, and the choice of treatment largely depends on the tumor extent, available expertise, and patient/clinician preference. On the other hand, it is important to identify prognostic factors that may predict good or poor outcome using specific salvage treatment and use them clinically to select patient for appropriate type of salvage treatment. A prognostic scoring system for locally recurrent NPC treated by stereotactic radiosurgery was reported by us previously [13]. In order to validate the scoring system, we collected relevant data from published literature on the use of radiosurgery for local failures of NPC and compared the performance of the prognostic scoring system in this patient group with the original one used to design the scoring system.

Methods

Prognostic factors of a cohort of 48 patients with local failure of NPC treated by stereotactic radiosurgery in our institution were identified and a prognostic scoring was then designed to predict treatment outcome. All these patients were treated by stereotactic radiosurgery using a modified linear accelerator and a median dose of 12.5 Gy (range: 12 to 18 Gy) was delivered to the target. Briefly, 5 factors were included in the scoring system: age, recurrent/ persistent disease, recurrent T (rT) stage, tumor volume, and previous salvage treatment. In staging the recurrent tumor, the same 1997 American Joint Committee on Cancer stage classification system [14] used for staging of primary tumor in newly diagnosed NPC was adopted: T1 if tumor is localized in nasopharynx, T2 if tumor has extend to nasal fossa, parapharyngeal space or oropharynx, T3 if there is evidence of skull base or other para-nasal sinus involvement, and T4 if there is extension into intracranium, orbit, hypopharynx or cranial nerve involvement. The relative risks associated with these factors were represented by the estimated risk coefficient obtained by the Cox proportional hazards regression model and the value ranged from 0.05 to 0.39. A score of 0 was assigned if the adverse factor was not present, or a value equal to the estimated risk coefficient if the factor was present. The relative risk of failure after radiosurgery for each patient (prognostic score) was then estimated by summing the relative risk of individual factors. Patients were then grouped to the following subgroups based on the calculated prognostic score: good prognostic group with a score of 0, intermediate prognostic group with a score > 0 to 0.5, and poor prognostic group with a score > 0.5. 5-year local relapsefree rates in the good, intermediate and poor prognostic groups were 100%, 42.5% and 9.6%, respectively. The corresponding 5-year survival rates were 100%, 51.1% and 0%.

Validation of the scoring system was performed using published data from the literature. A literature search was performed in Pubmed http://www.pubmed.com using the words "nasopharyngeal carcinoma" and "radiosurgery". Only published papers using radiosurgery for treatment of persistent and recurrent nasopharyngeal carcinoma were considered, and papers on the use of radiosurgery as a boost treatment following primary radiotherapy were excluded. Papers containing sufficient information on patient and disease characteristics for calculation of scoring system were then included in this study. Prognostic scoring system of individual patient was calculated and actuarial tumor control and/or survival rates in different prognostic groups were then estimated and compared with our published results. The performance of the scoring system was also further examined comparing the area under the receiver operating characteristic (ROC) curve in the current and original patient groups.

Results

A search in Pubmed using the specified keywords yielded 34 publications. Of these, 8 were reported by us and these were excluded from the validation study. The remaining 26 papers were carefully reviewed for inclusion into the study, and only 3 papers contained sufficient data on individual patient and disease characteristics for the purpose of estimation of prognostic scores. The prognostic score of individual patient was calculated based on the available information in the published manuscripts (Table 1). In case the prognostic score could not be calculated due to missing information, the mean score was obtained by estimating the lowest and highest score for that patient. The first paper by Chen et al [15] included 11 patients with rT4 disease with radiosurgery given to tumor extended to skull base and intracranium. In Chen's series, radiosurgery was performed using a modified linear accelerator, and a median dose of 14 Gy (range: 10 to 15 Gy) was delivered to the target. The calculated prognostic scores in Chen's series ranged from 0.32 to 0.8 with 10 patients classified as poor prognostic group and 1 patient as intermediate prognostic group. In the second paper by O'Donnell et al [16], two patients received radiosurgery using Gamma Knife (Elekta, Sweden) with a dose of 14 Gy, and both were classified as intermediate prognostic group. In the third paper by Kocher et al [17], 5 patients received radiosurgery using modified linear accelerator with a median dose of 20 Gy (range: 15 to 24 Gy) for local failure of nasopharyngeal carcinoma, and the calculated scores ranged from 0.75 to 1.21 thus all 5 patients were classified as poor prognostic group.

Data of all these patients were pooled together according to their prognostic group for comparison. Only overall survival rate was analyzed since local control status was not clearly defined as an endpoint in most patients. In the current cohort, the actuarial 3-year survival rates in the intermediate and poor prognostic groups were 67% and 0%, respectively. These results were comparable to the observed 3-year survival rate of 74% in the intermediate prognostic group and 31% in the poor prognostic group as described in our original report. Figure 1 shows the survival curves according to prognostic groups in the current and original cohorts. Although none of the patients in the current cohort belonged to the good prognostic group and there were few in the intermediate prognostic group, the survival curve of those assigned to the poor prognostic group was similar in both cohorts, suggesting that the scoring system is at least useful in predicting poor outcome in poor prognostic group after radiosurgery. To further assess the performance of the prognostic scoring system, the area under the ROC curve was calculated. If the performance of the scoring system resembles flipping a coin in predicting treatment outcome, the area under the ROC curve is close to 0.5. If the area is 1.0, then the model has 100% sensitivity and specificity in predicting outcome regardless of cut-off point. Figure 2 shows the ROC curves for overall survival for the current cohort and the original cohort used to design the scoring system. The calculated area under the ROC curve for the current cohort was 0.846 (95% C.I.: 0.66, 1.03) which is comparable to 0.841 (95% C.I.: 0.731, 0.952) in the original cohort, suggesting good predictive performance using the scoring system.

Discussion

Treatment of local recurrence of NPC is usually recommended since a proportion of patients with local failure can still be successfully salvaged. In a retrospective review of 319 patients with isolated local failure of NPC, patients who received salvage treatment had a significantly better survival rate than those without salvage treatment, and patient who received surgery or re-irradiation had a better survival rate than those treated by chemotherapy alone [18]. Several salvage treatments including nasopharyngectomy, brachytherapy and external beam re-irradiation are commonly employed for local failure of NPC, and the choice of treatment is largely determined by the extent and site of recurrence as well as available expertise. For patient with recurrent disease that is amenable to more than one treatment option, few reports are available to address the relative efficacy of different types of salvage treatment [19], and the decision is largely a matter of patient and/or clinician preference. Since prospective randomized trial to compare different treatments in salvaging local failure is difficult to conduct due to the falling incidence of recurrence and the highly specialized nature of different salvage treatments, it is important to review prognostic factor in order to identify patients that are likely to benefit from specific type of salvage treatment.

Our previously published prognostic scoring system is a simple and objective way to assess possible benefits of radiosurgery for local failures of NPC.

The prognostic factors included in the scoring system have also been identified in patients with recurrent NPC treated by surgery, brachytherapy and/or external beam re-irradiation. Most series also reported T stage and time to recurrence as significant prognostic factors for local control and/or survival [6,7,20,21]. The most consistent prognostic factor being reported was rT stage, and patients treated for advanced T stage generally suffered from poor tumor control and short survival time. Despite these similarities in prognostic factors, our scoring system cannot be applied directly to patients using salvage treatments other than radiosurgery, since the system is optimally modeled to the original data based on a group of patients with dis-Comparison of survival curves according to prognostic groups from original patient group (solid line) and the current patient group (dashed line) Figure 1 Comparison of survival curves according to prognostic groups from original patient group (solid line) and the current patient group (dashed line). For current patient group, only the poor prognostic group was shown due to absence or small number of patients in other prognostic groups.

Receiver operating characteristic curve for predicting overall survival after radiosurgery using prognostic scoring system in cur-rent patient group (top) and original patient group (bottom) Figure 2 Receiver operating characteristic curve for predicting overall survival after radiosurgery using prognostic scoring system in current patient group (top) and original patient group (bottom).

ease that were technically feasible for radiosurgery. Thus the weighting for rT4 disease is relatively small in the scoring system since majority of our patients did not have rT4 disease. In clinical practice, rT4 is an important poor prognostic factor and likely to carry a heavier weighting in patients treated by other means.

There are two major limitations of the current patient data set that we used to validate our scoring system. One limitation is the relatively small number of patients due to the lack of individual patient data available from most published reports. The other limitation is over-representation of patients in the poor prognostic group, reflecting the selection of those with relatively poor prognosis for radiosurgery in the literature, thereby limiting the validation of the scoring system to this particular prognostic group only. We are currently applying the prognostic scoring system in our institution to select patients with local failures of NPC for radiosurgery. This prospective exercise will provide additional data useful for validation in patients with good and intermediate prognostic groups since these are the patients likely to be selected for radiosurgery.

Conclusion

The previously published prognostic scoring system demonstrated good prediction of treatment outcome after radiosurgery in a small group of NPC patients with poor prognosis. Prospective study to validate the scoring system is currently being carried out in our institution.

Table 1 :
1Prognostic factors and calculated score of patients included in the current validation studyPatient Age/score rT stage/score Persistent vs recurrent disease/scoreTumor volume (cc)/
score

Prior salvage/score Prognostic score Prognostic group

(page number not for citation purposes)
Competing interestsThe authors declare that they have no competing interests.Authors' contributionsDTTC designed the scoring system, carried out the review of literature for validation, and drafted the masnucsript. KNH and SN participated in the study design and performed the statistical analysis. VL and JT participated in the design of the scoring system and helped to draft the manuscript. All authors read and approved the final manuscript.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/131/pre pub
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