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Abstract Cancer-related anorexia/cachexia syndrome (CACS) is a multifactorial syndrome characterised by tis-sue wasting, particularly lean body mass (LB M), meta-bolic alterations, fatigue, anorexia and reduced food intake. In April 2005 we started a phase III randomised study to establish the most effective and safest treatment for CACS addressing as primary endpoints: LBM, resting energy expenditure (REE), total daily physical activity, interleukin (IL)-6 and tumour necrosis factor (TNF)-αlevels, and fatigue. According to the statistical design the sample size was 475 patients (95 per arm).Eligibility cri-teria: histologically confirmed tumours of any site; weight loss ≥5% in the last 3 months and/or abnormal laboratory values; life expectancy >4 months. Patients were treated with either antineoplastic therapy or sup-portive care. All patients received as basic oral treatment polyphenols plus alpha lipoic acid plus carbocysteine plus vitamins A, C and E. Patients were then randomised to one of the following 5 arms: (1) medroxyprogesterone acetate (MPA)/megestrol acetate (MA); (2) pharmaco-nutritional support containing eicosapentaenoic acid (EPA); (3) L-carnitine; (4) thalidomide; and (5) a combi-nation of all the above agents. Treatment duration was 4 months. Interim analyses were planned after every 100 randomised patients.In September 2008, 280 patients were randomised and 240 were evaluable: M/F 167/113, mean age 62 years (range 30–84), 96% stage IV. A first interim analysis on 125 patients showed a worsening of LBM, REE and fatigue in arm 2 in comparison to the oth-ers and therefore it was withdrawn from the study. A sec-ond interim analysis after the enrolment of 204 patients showed that arm 1 was clearly significantly less effective than the others for primary efficacy endpoints, therefore it was withdrawn from the study. Statistical analysis in September 2008 showed a significant improvement of LB M (by dual X-ray energy absorptiometry), REE and fatigue in arm 5, a decrease of IL-6 in arms 3 and 5, and a decrease of TNF-αin arms 3 and 4. As for toxicity, 1 patient discontinued MPA because of deep vein thrombo-sis and 1 patient discontinued L-carnitine because of severe diarrhoea. In conclusion, the interim results seem to suggest that the most effective treatment for cancer patients with CACS/oxidative stress (OS) should be the combination regimen. The study is in progress. Keywords Cancer-related anorexia/cachexia syndrome·Oxidative stress· Lean body mass· Quality of life· Com -

bined treatment approach

Mediterr J Nutr Metab (2009) 2:29–36

DOI 10.1007/s12349-009-0041-y

New perspective on the nutritional approach to cancer-related anorexia/cachexia: preliminary results of a randomised phase III clinical trial with five different arms of treatment

Francesca Maria Tanca · Clelia Madeddu · Antonio Macciò ·

Roberto Serpe · Filomena Panzone · Giorgia Antoni ·

Elena Massa · Giorgio Astara · Giovanni Mantovani

Received: 26 November 2008 / Accepted: 3 February 2009 / Published online: 1 April 2009

? Springer-Verlag 2009

F.M. Tanca ·C. Madeddu ·A. Macciò ·R. Serpe ·F. Panzone

G. Antoni ·E. Massa ·G. Astara ·G. Mantovani (?)

Department of Medical Oncology, University of Cagliari

S.S. 554, Km 4.500, 09042 Monserrato (Cagliari), Italy

e-mail: mantovan@medicina.unica.it

Introduction

As recently emerged in an international consensus con-ference held in Tampa in December 2007, “cachexia, is a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or with-out loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with wasting disease. Wasting dis-ease is distinct from starvation, age-related loss of mus-cle mass, primary depression, malabsorption and hyper-thyroidism and is associated with increased morbidity”

[1]. Cachexia accompanies the end stage of many chron-ic diseases and especially cancer and therefore is termed “cancer-related anorexia/cachexia syndrome” (CACS).

At the time of cancer diagnosis, 80% of patients with upper gastrointestinal cancers and 60% of patients with lung cancer have already had substantial weight loss. The prevalence of cachexia increases from 50% to >80% before death and in >20% of patients cachexia is the cause of death [2].

Cancer cachexia has a high impact on patient morbid-ity, mortality and particularly quality of life (QL).

Proinflammatory cytokines interleukin (IL)-1 and IL-6, and tumour necrosis factor-α(TNF-α) play a central role in the pathophysiology of CACS. Their chronic action lead to several metabolic alterations characterised by increased resting energy expenditure (REE); reduced dietary intake and supply of energy substrates as a conse-quence of symptoms such as anorexia, nausea and vom-iting; and severe impairment of carbohydrate, protein and lipid metabolism.

Moreover, there is evidence that a chronic, low-grade, tumour-induced activation of the host immune system, which shares numerous characteristics with the “acute-phase response” found after major traumatic events and septic shock, is involved in CACS [3].

Several mechanisms may lead to oxidative stress (OS) in patients with cancer. First of all the altered energy metabolism, which may be a consequence of symptoms such as anorexia/cachexia, nausea and vomiting that pre-vent normal nutrition and thus a normal supply of nutri-ents such as glucose, proteins and vitamins, leading eventually to accumulation of free radicals, i.e., reactive oxygen species (ROS). The second mechanism is a non-specific long-term activation of the immune system with an excessive production of proinflammatory cytokines, which in turn may increase ROS production. The third mechanism leading to OS in patients with cancer may result from the use of antineoplastic drugs; many of them, in particular alkylating agents and cisplatin, are able to produce an excess of ROS and a depletion of crit-ical plasma and tissue antioxidants [4].

However, although much progress has been made in the understanding of the pathophysiologic mechanisms leading to CACS/OS, the development of early and effec-tive interventions aimed at preventing and/or reversing the metabolic changes ultimately leading to muscle wast-ing is far from being attained [5].

The management of CACS/OS is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology.

On the basis of this rationale, we carried out an open early phase II study according to the Simon two-stage design with the aim of testing the efficacy and safety of an integrated treatment based on pharmacologic nutri-tional support, antioxidants and drugs, all given orally, in a population of patients with advanced cancer and CACS/OS. The efficacy was assessed in terms of clinical response, improvement of nutritional and functional vari-ables, changes of laboratory variables (as indicators of CACS/OS) and improvement of QL. The trial design was an open non-randomised phase II study. On the basis of the Simon two-stage design for phase II studies, the treat-ment is to be considered effective if at least 18/34 patients demonstrate a response in the first stage, while in the second stage 21/39 patients should demonstrate a response.

The treatment plan was diet with high polyphenol content (400 mg) obtained from alimentary sources (onions, apples, oranges, red wine or green tea) or sup-plemented by tablets per os; pharmaco-nutritional sup-port enriched with n-3 PUFA containing eicosapen-taenoic acid (EPA) and DHA; oral progestagen: medrox-yprogesterone acetate (MPA) 500 mg/day; antioxidant treatment with alpha lipoic acid 300 mg/day+carboxy -cysteine lysine salt 2.7 g/day+vitamin E 400 mg/day+vitamin A 30 000 IU+vitamin C 500 mg/day; selective COX-2 inhibitor: celecoxib 200 mg/day orally. The planned treatment duration was 16 weeks. Forty-four patients were enrolled and 39 completed the treatment. At the end of the study, 22 of the 39 patients responded to treatment, achieving a significant improvement of the endpoint variables, i.e., lean body mass (LBM), appetite, IL-6, TNF-α, fatigue and QL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30v3 [EORTC-QLQ-C30]), and there-fore the treatment proved to be effective. As regards safe-ty, it was absolutely well tolerated without any toxic effect [6, 7]. Therefore, a randomised phase III study was warranted.

Aim of the study

In April 2005 we started a phase III randomised study with the aim of establishing which was the most effective and safest treatment in improving the identified “key”variables (primary endpoints) of CACS/OS: increase of LBM, decrease of REE, increase of total daily physical activity, decrease of IL-6 and TNF-α, and decrease of fatigue.

Patients and methods

Study design

The study is a phase III randomised trial. According to the statistical design, the sample comprised 475 patients randomised to one of five arms (95 patients per arm). Random assignment was performed by random-number tables. The protocol was approved by the reference ethics committee. Written informed consent was obtained from all patients. The procedures followed we -re in accordance with good clinical practices and the Helsinki Declaration.

Endpoints

The efficacy primary endpoints (key variables) were increase of LBM, decrease of REE, increase of total daily physical activity, decrease of IL-6 and TNF-α, and decrease in fatigue symptoms. The secondary endpoints were all other variables studied. The safety endpoints were classified as adverse events according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 [8].

Treatment plan

All patients included in the study were given as basic treatment polyphenols (300 mg/d) obtained from alimen-tary sources (onions, apples, oranges, 150 ml of red wine, green tea) or supplemented by tablets (NovaQ, PharmaGam, Italy; one tablet, 300 mg/d) plus antioxidant agents α-lipoic acid (300 mg/d, included in the NovaQ tablet) plus 2.7 g/d of carbocysteine (Fluifort, Dompè, Milan, Italy; one sachet per day) plus 400 mg/d of vitamin E (Sursum, Abiogen Pharma, Pisa, Italy, or Selevis, MarPharma, Italy; one tablet per day) plus 30 000 IU/d of vitamin A and 500 mg/d of vitamin C (included in the Nova Q tablet), all orally. Patients were then randomised to one of the following five treatment arms.-Arm 1.A progestational agent, i.e., 500 mg/d of MPA (Provera, Pfizer Italia, Borgo San Michele (LT), Italy;

one sachet per day) or 320 mg/d of megestrol acetate (MA; Megace, B ristol-Myers Squibb, Rome, Italy;

two tablets, 160 mg/d) was given orally.

-Arm 2.Oral supplementation was given with an EPA-enriched nutritional supplement (2.2 g/d of EPA for ProSure [Abbott, Campoverde di Aprilia (LT), Italy] and Forticare [Nutricia, Milan, Italy], 2 g/d for Resource Support [Novartis, Origgio (V A), Italy]).

This supplementation also contained docosahexaenoic acid, with a high-calorie (range 126–160 kcal/100 ml), high-protein (total protein range 6.65–9 g/100 ml) content. The prescribed dosages were two cartons per day for ProSure, two cartons per day for Resource Support and three cartons per day for Forticare.

-Arm 3.L-carnitine (Carnitene, Biofutura Pharma, Mi -lan, Italy) at 4 g/d (two vials, 2 g/d) was given orally. -Arm 4.Thalidomide (Pharmion S.r.l., Rome, Italy) at 200 mg/d (two tablets, 100 mg/d) was given orally. -Arm 5. Treatment consisted of MPA or MA plus phar-macologic nutritional support plus L-carnitine plus thalidomide.

The planned treatment duration was 4 months

A placebo arm was not included as it was not consid-ered ethical because of the results of our phase II study and because an approved drug for the treatment of cancer cachexia is currently available, i.e., MA and MPA. Eligibility and exclusion criteria

Patient eligibility criteria were an age range of 18–80 years, a histologically confirmed tumour at any site at an advanced stage; loss of 5% of the ideal (or pre-illness) body weight in the previous 3 months and/or abnormal values of proinflammatory cytokines, ROS and antioxi-dant enzymes predictive of the onset of clinical cachexia; and a life expectancy of >4 months.

Patients could be receiving concomitant antineoplas-tic chemotherapy or hormone therapy with curative or palliative intent or supportive care. Exclusion criteria were women of child-bearing age, significant comorbidi-ties, mechanical obstruction changes of patient metabo-lism or body weight, and contraindications to the use of MA/MPA such as a history of thromboembolic events or deep venous thrombosis.

Efficacy endpoints

The following endpoints were evaluated before treatment and at 4, 8, 16 and 24 weeks after treatment.

-LBM was assessed by bioelectrical impedance analy-sis (Bioelectric Impedance Analyser 101, Akern Spa) and, more recently, dual-energy X-ray absorptiometry from January 2007: the latter is currently considered the most reliable method. As a complementary assessment to bioelectrical impedance analysis, we calculated the phase angle (derived from reactance and resistance values), which is related to body mass index, fat mass and LBM. Moreover, the phase angle was shown to have an important prognostic role in patients under surgical, cancer and intensive care and to be an indicator of function and general health.

-REE was assessed by indirect calorimetry (Medgem, SensorMedics Italia Srl, Italy), which measures oxy-gen consumption per unit time.

-Detailed evaluation of daily physical activity and the associated energy expenditure was carried out with an appropriate electronic device (SenseWear, Armband, SensorMedics Italia Srl), which is able to assess total energy expenditure, i.e., REE plus the energy spent in physical activity; its software is able to identify the specific type of physical activity (e.g., walking, run-ning, lying down) in such a way as to attribute a “functional quality” to patient physical activity.

-Serum levels of proinflammatory cytokines (IL-6, TNF-α) were measured by enzyme-linked immu -nosorbent assays (Immunotech, Marseille, France). -Fatigue was rated by the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF) with a numerical score, with possible total fatigue scores rang-ing from –24 to 96. Results are reported as mean scores. Statistical design

Hypothesising a difference between arms of 20% and considering an αtype error of 0.05 and a βtype error of 0.20, 95 patients had to be enrolled for each arm, with a total of 475 patients. Analysis was performed on an intention-to-treat basis. The most effective arm for the primary endpoint variables was assessed by one-way analysis of variance for repeated measures (or the Kruskal-Wallis test for non-parametric variables). In addition, the arms of treatment were compared for the mean change (of primary endpoints) by t-test for changes. Moreover, the bene?t obtained for primary and secondary endpoints in each arm (changes between base-line and after-treatment values) was assessed using paired Student’s t-test or Wilcoxon signed-rank test when appropriate. Interim analyses were planned every 100 randomised patients to test the efficacy (primary efficacy endpoints) and the toxicity of the different arms of treat-ment. Significance was determined at 5% level.Results

From April 2005 to September 2008, 280 patients were enrolled and 240 were evaluable (male/female ratio 167/113, mean age 62 years, range 30–84). Most patients had stage IV disease (lung 18.2%, breast 16.1%, colorec-tal 15.4%, pancreas 9.6%, head and neck 8.9%, gynaeco-logic tumours 8.9%, stomach 6.4%). Approximately 83% of the patients had 5% weight loss (22.3% were clearly underweight) and 17% of the patients were enrolled on the basis of abnormal laboratory values predictive of the onset of clinical cachexia. At baseline 55% of the patients had an ECOG PS score of 0–1 and 45% had an ECOG PS score of 2–3. Patient clinical characteristics are reported in Table 1. In general, the five treatment arms were not significantly different regarding the main variables (age, weight, body mass index, stage of disease, ECOG PS) dis-tribution. The distribution of different cancer sites and disease stages (almost all stage IV) was well balanced over the five study arms. Compliance to treatment was good. In general, patients had to record the consumption and quantity of prescribed treatments daily and to return empty or unused packages to the investigator.

Table 1 Patient clinical characteristics

n% Patients enrolled from April 2005 to September 2008280 Evaluable patients240 M/F: 167/113

Mean age 62 y, range 30–84

Mean weight 56.4 kg, range 34–90

Body mass index (kg/m2)

<18.55218.6

18.5–2520573.2

>25238.2 Tumour site

Lung5118.2 Breast4516.1 Colorectal4315.4 Pancreas279.6 Head and neck258.9 Gynaecologic tumours258.9 Stomach18 6.4 Biliary duct10 3.6 Kidney6 2.1 Bladder5 1.8 Prostate5 1.8 Others2017.2 Stage

III13 4.6 IV26795.4 Performance status (ECOG)

ECOG 09 3.2 ECOG 114551.8 ECOG 211440.7 ECOG 312 4.3 ECOG Eastern Cooperative Oncology Group

First interim analysis

A first interim analysis was carried out in January 2007 after the enrolment of 125 patients.

The ANOV A test comparing the different treatment arms (for changes between baseline and post-treatment values) showed the following results: a significant improvement of REE score in favour of arm 5 vs.arm 2;

a significant improvement of MFSI-SF score in favour of arms 1, 3 and 5 vs.arm 2; a significant increase in EQ-5D index score in favour of arms 1, 4 and 5 vs.arm 2.

A significant difference (worsening of the primary end-points LBM, REE and MFSI-SF) of arm 2 vs.arms 3, 4 and 5 was observed on the basis of the t-test for changes. Consequently, arm 2 was withdrawn from the study. Second interim analysis

The second interim analysis, carried out in October 2007 after the enrolment of 204 patients, showed a significant improvement of fatigue in arms 3 and 5; a significant decrease of IL-6 in favour of arm 3; and a significant decrease of TNF-αin favour of arms 3, 4 and 5. Therefore, the second interim analysis showed that arm 1 is inferior to the others regarding primary efficacy end-points, therefore it was withdrawn from the study.

Data update at September 2008

The analysis of primary endpoints in 240 evaluable patients in September 2008 showed the following results. LBM evaluated by DEXA showed a significant improve-ment only in arm 5 (p < 0.05), whilst the assessment of LBM by bioimpedentiometry did not show a significant difference in any arm of treatment (Fig. 1). It should be noted that the data reported refer to 77 evaluable patients (25 in arm 3, 26 in arm 4 and 26 in arm 5).

Patients in arm 5 showed a significant decrease of REE assessed by indirect calorimetry (p = 0.02) (Fig. 2).

As for the physical activity evaluation, our data are preliminary and therefore are not yet available for all patients enrolled. However, the data available on 60 patients (20 per arm) showed an increase of number of steps taken by patients in arm 5, and an increase of active energy expenditure and duration of physical activity in arms 4 and 5.

Patients in arm 5 showed a significant decrease of fatigue assessed by MFSI-SF (p = 0.017) (Fig. 3).

As for proinflammatory cytokines, IL-6 decreased significantly in arms 3 and 5, and TNF-αdecreased sig-nificantly in arms 3 and 4 (p < 0.05) (Fig. 4).Safety

As for toxicity, no toxicity of any grade was observed. Only one patient, randomised in arm 1, discontinued MPA because of a deep vein thrombosis that occurred during treatment and recovered with the appropriate anti-

Fig. 1Changes of LBM assessed by DEXA in September 2008. LBM showed a significant improvement only in arm 5. *p

< 0.05

Fig. 2Changes of REE by arm of treatment at September 2008. Patients in arm 5 showed a significant decrease of REE assessed by indirect calorimetry. *p < 0.05 vs.

baseline

Fig. 3Changes of MFSI-SF by arm of treatment in September 2008. Patients in arm 5 showed a significant decrease of fatigue assessed by MFSI-SF vs.baseline

coagulant treatment. One patient randomised in arm 3discontinued L -carnitine because of severe diarrhoea (grade 3), which completely resolved after stopping L -carnitine.

Discussion

CACS is one of the most important features of advanced cancer and has a clinically relevant impact on patient QL,outcome and survival. Therefore, the search for a poten-tially effective treatment for CACS/OS must be consid-ered critical among the as yet unavailable oncologic treatments with high impact. However, thus far attempts at CACS/OS therapy with a variety of interventions have had limited success. The predominant features of CACS,i.e., progressive loss of muscle mass and function, have been shown to be only minimally affected by the nutri-tional or pharmacologic tools currently available. Total parenteral nutrition does not prevent the continuing loss of skeletal muscle mass or correct the underlying abnor-malities in metabolic state [9]. The only agents approved for CACS treatment are the synthetic progestagens MPA and MA. Therefore, to date treatment options for cachex-ia are limited. Conversely, a combination of dietary,nutritional and pharmacologic approaches to normalise the metabolic environment may have the potential to reverse CACS and improve the associated symptoms that affect QL [5].

According to this rationale, we previously demon-strated in a phase II study [7] the efficacy of an integrat-ed treatment against CACS/OS. In that study we demon-strated that the body weight increase (1.9 kg) was almost completely sustained by a parallel increase in LBM (1.7kg) that was independently correlated to a decrease in IL-6, thus strengthening the role of proinflammatory cytokines in the pathophysiology of CACS/OS. QL, par-ticularly fatigue symptoms, improved significantly after treatment.

The positive results achieved thus far warranted us to start a randomised phase III study with the aim of com-paring the different single agents for CACS/OS vs.their combination and to test which was the most effective in improving the identified primary endpoints.

The interim results of this phase III study on 125patients have already been reported in a recently pub-lished paper [10]. The safety data did not show any side effects due to anticachectic treatment and no patients had to be withdrawn from the study; no toxicity of any grade according to NCI common terminology criteria was observed. As for efficacy, the first interim analysis showed an improvement of at least one primary endpoint in arms 3, 4 and 5, whereas arm 2 showed no benefit for the primary endpoints LBM, REE and fatigue.

The second interim analysis showed that arm 1 was also less effective compared to other arms for the primary efficacy endpoints. On the basis of these interim analyses,both arm 1 and arm 2 were withdrawn from the study. In our study EPA-enriched nutritional supplementa-tion has demonstrated no benefit on the primary end-points of CACS. Our results are in agreement with those obtained by Fearon et al. [11], who showed that there was no statistically significant benefit from single agent EPA in the treatment of cancer cachexia and concluded that future studies should concentrate on other agents or com-bination regimens. Moreover, a recently published meta-analysis included randomised controlled trials that assessed oral EPA compared with placebo or control in randomised controlled trials of patients with advanced cancer and either a clinical diagnosis of cachexia or self-reported weight loss of 5% or more. There were insuffi-cient data to establish whether oral EPA was better than placebo. Comparisons of EPA combined with a protein energy supplementation vs.a protein energy supplemen-tation (without EPA) in the presence of an appetite stim-ulant (MA) provided no evidence that EPA improves symptoms associated with the cachexia syndrome often seen in patients with advanced cancer [12].

Fig. 4Changes of IL-6 and TNF-αby arm of treat-ment in September 2008. IL-6 decreased significant-ly in arms 3 and 5; TNF-αdecreased significantly in arms 3 and 4. *p < 0.05 post-treatment values vs.pre-treatment values

The present study suggests a limited efficacy of MA/MPA. To date, more than 15 randomised controlled studies have demonstrated that MPA/MA significantly improves appetite, food intake, body weight, and some-times nausea and emesis, whereas in most trials no defi-nite improvement in global QL was observed [13]. The weight gain observed with progestagen administration consists mainly of water and fat mass, but it has virtual-ly no influence on the increase of LBM and therefore on functional activity [14]. Moreover, it should be taken into account that MPA/MA may give rise to some important side effects such as thromboembolism, hyperglycaemia, hypertension, peripheral oedema, alopecia and adrenal insufficiency.

Carnitine may be considered a very intriguing drug: in the present study it was found to be effective in decreasing cytokine. Indeed, in one of our recently pub-lished studies L-carnitine administration (6 g/d for 30 d) proved its efficacy by improving fatigue and increasing LB M and appetite in a population of 12 patients with advanced cancer [15]. These concurrent positive results seem to suggest that carnitine could become a very inter-esting and novel approach in the treatment of CACS/OS.

In conclusion, the interim results obtained so far seem to suggest that the most effective treatment for CACS/OS is a combination regimen including all treatments poten-tially considered effective. This is in keeping with the general consensus that CACS/OS is a multifactorial process and, hence, the effective approach should be multimodal. Alternatively, in the single-agent approach, the most interesting is carnitine. The study is still in progress. The ultimate goal should be that of translating the results obtained in patients with advanced cancer into a prevention trial in a population of patients at risk of developing CACS/OS.

Conclusions

Cancer cachexia may well represent the flip side of the tremendous achievements of modern medicine, as the incidence of cachexia is also a function of survival of chronic illness. Many diseases that rapidly led patients to death just a few years ago are now better controlled by new therapies, and even if we cannot cure and eradicate them, their natural history has significantly increased by months and years. Therefore, it is impossible to ignore that many more patients are now facing the nutritional consequences of prolonged immunological and metabol-ic challenges deriving from ongoing diseases and aggres-sive therapies [16].

Presently there is not a consolidated treatment for cancer cachexia. As progestagens and corticosteroids are obsolete and only partially effective drugs and consider-ing that anti-TNF-αmonoclonal antibody (infliximab) was shown to be ineffective, research interest is current-ly shifting towards the use of different approaches addressing the potential targets involved in the patho-physiology of cachexia. Potential strategies for treating cachexia target skeletal muscle wasting in the presence of adequate nutrition: some potential pharmacological agents include androgens, selective androgen receptor modulators, antimyostatin drugs, growth hormone and insulin-like growth factor. Potential orexigenic agents include melanocortin antagonists and the growth hor-mone secretagogue, ghrelin. However, data demonstrat-ing effectiveness of these agents are lacking. Moreover, we hypothesise, on the basis of our experimental and clinical long-standing experience in this field, that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treat-ments involving different combinations are more likely to be successful [17].

Acknowledgements Work supported by MIUR National Research Project No. 2006067295.

Conflict of interest The authors declare that they have no conflict of interest related to the publication of this manuscript. References

1.Evans WJ, Morley JE, Argiles J et al (2008) Cachexia: a new defi-

nition. Clin Nutr 27:793–799

2.Bruera E (1997) ABC of palliative care. Anorexia, cachexia, and

nutrition. BMJ 315:1219–1222

3.Mantovani G, Macciò A, Massa E, Madeddu C (2001) Managing

cancer related anorexia/cachexia. Drugs 61:499–514

4.Mantovani G, Macciò A, Madeddu C et al (2002) Quantitative

evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status. Int J Cancer 98:84–91

5.Bossola M, Pacelli F, Tortorelli A, Doglietto GB (2007) Cancer

cachexia: it’s time for more clinical trials. Ann Surg Oncol 14:276–285

6.Mantovani G, Madeddu C, Macciò A et al (2004) Cancer-related

anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond current treatment. Cancer Epidemiol Biomarkers Prev 13:1651–1659

7.Mantovani G, Macciò A, Madeddu C et al (2006) A phase II

study with antioxidants, both in the diet and supplemented, phar-maconutritional support, progestagen, and anti cyclooxygenase-2 showing efficacy and safety in patients with cancer related anore-xia/cachexia and oxidative stress. Cancer Epidemiol Biomarkers Prev 15:1030–1034

8.National Cancer Institute (2006) Cancer therapy evaluation pro-

gram: common terminology criteria for adverse events v3.0 (CTCAE). National Cancer Institute, Bethesda

9.Morley JE, Thomas DR, Wilson MM (2006) Cachexia: pathophy-

siology and clinical relevance. Am J Clin Nutr 83:735–743 10.Mantovani G, Macciò A, Madeddu C et al (2008) Randomized

phase III clinical trial of five different arms of treatment for

patients with cancer cachexia: interim results. Nutrition 24:305–313

11.Fearon KC, B arber MD, Moses AG et al (2006) Double-blind,

placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol 24:3401–3407

12.Dewey A, Baughan C, Dean T et al (2007) Eicosapentaenoic acid

(EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev (1);CD004597 13.Berenstein EG, Ortiz Z (2005) Megestrol acetate for the treatment

of anorexia-cachexia syndrome. Cochrane Database Syst Rev

(2):CD00431014.Inui A (2002) Cancer anorexia-cachexia syndrome: current issues

in research and management. CA Cancer J Clin 52:72–91

15.Gramignano G, Lusso MR, Madeddu C et al (2006) Efficacy of

L-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition 22:136–145

16.Mantovani G, Schuster M, Yeh SS et al (2006) Cachexia and

wasting: a modern approach. Springer Verlag International, Heidelberg

17.Argilés JM, López-Soriano FJ, Busquets S (2008) Novel approa-

ches to the treatment of cachexia. Drug Discovery Today 13:73–78

文献综述

细胞工程在生物工程中的应用摘要生物工程包括五大工程，即遗传工程(基因工程)、细胞工程、微生物工程(发酵工程)、酶工程(生化工程)和生物反应器工程。在这五大领域中，前两者作用是将常规菌(或动植物细胞株)作为特定遗传物质受体，使它们获得外来基因，成为能表达超远缘性状的新物种——“工程菌”或“工程细胞株”。后三者的作用则是这一有巨大潜在价值的新物种创造良好的生长与繁殖条件，进行大规模的培养，以充分发挥其内在潜力，为人们提供巨大的经济效益和社会效益。细胞工程是生物工程的一个重要方面。总的来说，它是应用细胞生物学和分子生物学的理论和方法，按照人们的设计蓝图，进行在细胞水平上的遗传操作及进行大规模的细胞和组织培养。当前细胞工程所涉及的主要技术领域有细胞培养、细胞融合、细胞拆合、染色体操作及基因转移等方面。通过细胞工程可以生产有用的生物产品或培养有价值的植株，并可以产生新的物种或品系。关键词：细胞工程；生物技术；应用；培养 1.引言所谓细胞工程，是指以细胞为基本单位进行培养、增殖或按照人们的意愿改造细胞的某些生物学特性，从而创造新的生物和物种，以获得具有经济价值的生物产品。细胞工程根据研究材料的不同，可分为植物细胞工程和动物细胞工程。动物细胞工程和植物细胞工程均主要由两部分构成。其一是上游工程，包含细胞培养、细胞遗传操作和细胞保藏三个步骤。第二则是下游工程，是将已转化的细胞应用到生产实践中去，以生产生物产品的过程。其中细胞培养是细胞工程的技术基础。细胞培养技术也叫细胞克隆技术，在生物学中的正规名词为细胞培养技术。不论对于整个生物工程技术，还是其中之一的细胞工程技术来说，细胞培养都是一个必不可少的过程。动物细胞工程主要技术设计细胞融合、细胞拆合、染色体导入和基因转移这四方面，是从细胞水平、核质水平、染色体水平以及基因水平这四个不同层次来改造细胞。植物细胞工程是以细胞的全能性和体细胞分裂的均等性作为理论依据，在细胞水平上对植物进行操作的育种新技术。 2.动物细胞工程在生物技术中的应用 2.1动物细胞工程的概念动物细胞工程（animal cell engineering）是以动物细胞为基本单位在体外条件下进行培养、繁殖和人为操作，使细胞产生某些人们所需要的生物学特性，从而改良品质，加速繁殖动物个体或获得有用品系的技术。其应用学科：细胞生物学（一级学科）；细胞培养与细胞工程（二级学科）。

肿瘤标志物检测原理

肿瘤标志物检测原理根据WHO资料，全球范围内恶性肿瘤是人类仅次于心脑血管病的第二大死亡原因，占总死亡人数的22%，并逐年增加。10种常见肿瘤：胃癌、肝癌、食管癌、结直肠肛门癌、白血病、子宫颈癌、鼻咽癌、乳腺癌和膀胱癌。肿瘤的早期发现、早期诊断、早期治疗是患者获得长期生存的最主要途径。以肝癌为例，肿瘤直径＜2cm，5年生存率几乎100%；直径每增加1cm，5年生存率下降20%。肿瘤诊断三大支柱是图像诊断（包括B超、CT、核磁共振）、化学诊断（血清学和免疫学）及细胞学和组织学诊断，而后两者均以肿瘤标志为主要或辅助观察指标。当前，肿瘤标志物的检测已从细胞水平深入到分子基因水平，在检测技术上，它将生物化学、核医学、免疫学、细胞学、病理学、分子生物学等诸多学科融合在一起，不仅使检测的项目有了大幅度的增加，而且检测的特异性和灵敏度也有很大的提高。肿瘤标志物在肿瘤诊断，检测肿瘤复发与转移，判断疗效和预后以及人群普查等方面都有较大的实用价值，而且在肿瘤发生和发展机理研究中也具有重要作用。肿瘤标志物除用于肿瘤诊断外，可为临床肿瘤治疗提供依据及以其为靶，进行肿瘤的靶向治疗及免疫治疗。肿瘤标志学已成为肿瘤学中一个重要的新学科、新领域。肿瘤标志（Tumour Markers）是1978年Herberman在美国国立癌症研究所（NCI）召开的“人类免疫及肿瘤免疫诊断”会上提出的，次年在英国第七届“肿瘤发生生物学和医学”会议被大家确认，并开始引用。肿瘤标志物是指由肿瘤细胞由肿瘤组织和细胞产生的与肿瘤的形成、发生相关的物质，这些物质存在于肿瘤细胞的胞核、胞质、胞膜上或体液中，进入到血液或其他体液或组织中，或是宿主对体内新生物反应而产生并进入到血液或体液或组织中而含量明显高于正常参考值的一类生物活性物质。不存在于正常成人组织而见于胚胎组织,或在肿瘤组织中含量超过正常含量。肿瘤标志物分类目前肿瘤标志物尚无统一的分类和命名，临床常用的肿瘤标志物大多是根据其生物化学和免疫学特性可分为：（1）肿瘤抗原肿瘤胚胎性抗原：甲胎蛋白(AFP)、癌胚抗原(CEA)。白血病系列分化抗原：CD系列。

文献检索概述

《教育研究方法导论》笔记：第五章一、文献检索概述（一）文献：指记录有知识的一切载体，即以载体形式传递知识教育科学文献是记载有关教育科学的情报信息和知识的载体。（二）文献检索在教育研究中的作用 1、全面正确地掌握所要研究问题的情况，帮助研究人员选定研究课题和确定研究方向 2、为教育研究提供科学的论证依据和研究方法 3、避免重复劳动，提高科学研究的效益二、教育文献的种类及主要分布（一）文献的等级 1、一次文献。包括专著、论文、调查报告、档案材料等以作者本人的实践为依据而创作的原始文献，是直接记录事件经过、研究成果、新知识、新技术的文献，具有创造性，有很高的直接参考和借鉴使用价值，但它贮存分散，不够系统。 2、二次文献。是对原始文献加工整理，使之系统、条理化的检索性文献，一般包括题录、书目、索引、提要和文摘等。二次文献具有报告性、汇编性和简明性，是对一次文献的认识，是检索工具的主要组成部分。 3、三次文献。是在利用二次文献基础上对某一范围内的一次文献进行广泛的深入的分析研究之后综合浓缩而成的参考性文献，包括动态综述、专题述评、进展报告、数据手册、年度百科大全以及专题研究报告等。这类综述性文献全面，浓缩度高、覆盖面宽、信息量大、内容新颖.即有综合性、浓缩性和参考性特点。教育科学文献的特点：内容广泛，数量众多。学科复杂。相互交叉渗透，系统性、积累性和继承性强。文献类型以专著论文、研究报告为主。（二）教育文献的主要分布 1、书籍包括名著要籍、教育专著、教科书、资料性工具书（如教育辞书和百科全书）及科普通俗读物。它是教育科学文献中品种最多、数量最大、历史最长的一种情报源。名著要籍指一个时代、一个学科、一个流派最有影响的权威著作，如马克思主义经典作家论教育，中外古今著名教育家、哲学家的教育名著等。它们是人类文化的瑰宝，是治学和研究的基石，因而大都作为必读书、必备书收入各种导读书目。专著（包括论文集）是就教育领域某一学科、某一专门问题进行系统全面深入的论述，内容专深，大多是作者多年研究成果的结晶。专著一般就某个问题发展历史和现状，研究方法和成果，不同学派的观点和争论，以及存在的问题和发展趋势加以论述，并附有大量的参考文献和书目。专著中阐明了作者自己的独到见解，介绍了新颖的材料，通常反映学术研究的最新进展，论述较系统，形式较规范。论文集往往是汇集了许多学者的学术论文，问题集中，论点鲜明，情报容量大，学术价值高。如瞿葆奎先生主编的26卷本大型《教育学文集》则属此种类型。教科书是专业性书籍，具有严格的科学性、系统性和逻辑性。内容一般包括教育科学的基本理论、基础知识、学科领域内的科研成果以及讨论的问题。要求

肿瘤与癌症文献综述

肿瘤与癌症摘要：癌症是一大类恶性肿瘤的统称。癌细胞的特点是无限制、无止境地增生，使患者体内的营养物质被大量消耗；癌细胞释放出多种毒素，使人体产生一系列症状；癌细胞还可转移到全身各处生长繁殖，导致人体消瘦、无力、贫血、食欲不振、发热以及严重的脏器功能受损等等。与之相对的有良性肿瘤，良性肿瘤则容易清除干净，一般不转移、不复发，对器官、组织只有挤压和阻塞作用，但癌症（恶性肿瘤）还可破坏组织、器官的结构和功能，引起坏死出血合并感染，患者最终由于器官功能衰竭而死亡。到了科学高速发展的今天，我们有理由相信癌症并非不治之症。致力于自然医学研究的医学专家们研究发现：负离子对抑制癌细胞转移有令人鼓舞的效果，重要的是利用自然因子负离子对癌症患者治疗对机体无任何损害，没有任何毒副作用。关键词：肿瘤与癌症、预防、诊断、治疗 1、引言癌症是医学术语，其为最常见的恶性肿瘤, 但也有人将癌症和恶性肿瘤混合使用。中医学中称岩，为由控制细胞分裂增殖机制失常而引起的疾病。癌细胞除了分裂失控外，还会局部侵入（英语：Infiltration (medical)）周遭正常组织甚至经由体内循环系统或淋巴系统转移到身体其他部分[1][2]。癌症有许多类型，而病症的严重程度取决于癌细胞所在部位以及恶性生长的程度，以及是否发生远端转移。医生可以根据受检查者的活体组织切片或经手术取得的组织，甚至是生物标记的含量做出诊断。多数癌症根据其类型、所处的部位和发展的阶段可以治疗甚至治愈。一旦诊断确定，癌症通常以结合手术、化疗和放射疗法的方式进行治疗。随着科学研究的进步，开发出许多针对特定类型癌症的药物，也增进治疗上的效果。如果癌症未经治疗，通常最终结果将导致死亡[3]。癌细胞持续生长而不受外在讯息调控，可能是原本正常的原癌基因被激活，将细胞引入到癌变状态，但主要还是因为一些与控制细胞分裂有关的蛋白质出现异常，如肿瘤抑制基因的功能失常。导致这种局面，可能是为该蛋白编码的DNA因突变而出现了损伤，转译而出的蛋白质因此也出现错误。要将一个正常细胞转化成一个恶性肿瘤细胞通常需要许多次突变发生，或是基因转译为蛋白质的过程受到干扰[2]。引起基因突变的物质被称为致癌物质，又以其造成基因损伤的方式可分为化学性致癌物与物理性致癌物。例如接触放射性物质，或是一些环境因子，例如，香烟、辐射、酒精。还有一些病毒可将本身的基因插入细胞的基因里中，激活癌基因。但突变也会自然产生，所以即使避免接触上述的致癌因子，仍然无法完全预防癌症的产生。发生在生殖细胞的突变有可能传至下一代。各个年龄层的人都有可能产生癌症，由于DNA的损伤会随着年龄而累积增加，年纪越大得到癌症的机会也随之增加。美国每年逝世的5个人当中有一人是因癌症致死，这一数字在世界范围则是十万分之一百到三百五十[1]。癌症在发达国家中已成为主要死亡原因之一。2、名称由来、分类、辨析与命名 2.1分类现今癌症分类主要以肿瘤来源组织的细胞类型和其生物学行为作为依据。在病理学上，每一个系统和器官的肿瘤都有详尽的分类。分类一方面是为了诊断的需要，统一术语。另一方面则是出于预后方面的原因。以下的类别较为一般所接受：根据肿瘤的发展，可分成：良性肿瘤、恶性肿瘤。良性肿瘤指肿瘤细胞未发生转移与侵入周遭组织的情形，反之则称为恶性肿瘤，多数会影响生理功能的肿瘤都是恶性肿瘤。

文献检索(完整版)

武汉工程大学文献检索课综合实习报告检索课题（中英文）：Today’s average car cortains more than 15000 separate, individual parts that must work together.These parts can grouped into four major categories:engine,body,chassis and electrical equipment. 现代汽车有超过15000个零件组成，分成几个必须在一起工作的功能部分，重要包括4个功能部分：引擎，车身，底盘和控制。姓名: X X 学号：系（院）：总成绩______________________ 班级（文献检索课）：说明及要求 1、本报告中的题录格式书写要求：第一作者、文献标题、文献出处（刊名、年、卷期、起止页码），参照以下格式： Morse SP. Factors in the emergence of infectious disease. Emerg Infect Dis 1995; 53(2): 117-21 2、若指定数据库查不到相关文献，写出检索式，在“检出篇数”一项内填写零。 3、检出篇数指按检索词或检索式实际检出的篇数，而非经人工筛选的切题篇数。列出题录可经人工筛选出最切题的。 4、检索式包括检索词、字段限定、检索途径（简单或高级检索等） 5、在检索结果不理想时，如检出篇数为零时可进行检索词调整，在报告中应对检索策略作说明。 6、“综合检索实习报告”为本课程考核形式，5月30日前由各班班长统一收齐后交报告的打印稿。如两份检索报告相同，两份都记为零分。

【重磅】文献检索-在线作业

文献检索_在线作业_1 交卷时间：2016-10-3111:30:47 一、单选题 1. (5分) ? A.“维普中文科技期刊”全文数据库 ? B.中国统计数据库 ? C.中国学术会议论文全文数据库 ? D.中国期刊网全文数据库纠错得分：5 知识点：文献检索展开解析答案B 解析 2. (5分) ? A.作者 ? B.作者单位 ? C.发表时间 ? D.题名纠错得分：5 知识点：文献检索展开解析答案C 解析可检索到国家及各省市地方统计机构的统计年鉴、海关统计、经济统计快报等月度及季度统计资料的数据库是（）。从CNKI 数据库中记录以下字段，（）是跟查找原文无关的。

3. (5分) ? A.标准文献能 ? B.期刊论文 ? C.专利文献 ? D.会议文献纠错得分：5 知识点：文献检索展开解析答案B 解析 4. (5分) ? A.二次文献 ? B.三次文献 ? C.一次文献 ? D.零次文献纠错得分：5 知识点：文献检索展开解析答案C 解析 5. (5分) ? A.逻辑非 ? B.逻辑与特种文献不包括（）。直接以自己的生产、科研、社会活动等实践经验为依据生产出来的文献，为（）。布尔逻辑算符不包括（）。

? C.位置算符 ? D.逻辑或纠错得分：5 知识点：9.2文献检索策略的制定展开解析答案C 解析 6. (5分 ) ? A.查准率 ? B.误检率 ? C.查全率 ? D.漏检率纠错得分：5 知识点：文献检索展开解析答案A 解析 7. (5分 ) ? A.查全率 ? B.漏检率 ? C.查准率 ? D.误检率纠错得分：5 知识点：1.4文献检索基础知识展开解析（）是检索出的相关信息量与检索出的信息总量的百分比。（）是检出的相关文献与检出的全部文献的百分比。

生物与健康文献综述

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胆道恶性肿瘤分子靶向治疗临床研究进展

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文献检索详解

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期刊类［序号］主要责任者．文献题名［J］．刊名，出版年份，卷号(期号)：起止页码．例：［１］袁庆龙，候文义．Ni-P合金镀层组织形貌及显微硬度研究［Ｊ］．太原理工大学学报，2001，32(1)：51-53．专著类 [序号] 作者．书名［M］．出版地：出版社，出版年份．起止页码．例：[1] 刘国钧，陈绍业，王凤翥．图书馆目录［M］．北京：高等教育出版社，1957．15–18．论文集［序号］主要责任者．文献题名[Ｃ]．主编．论文集名．出版地：出版者，出版年：起止页码．例：［６］孙品一．高校学报编辑工作现代化特征［Ｃ］．中国高等学校自然科学学报研究会．科技编辑学论文集(2)．北京：北京师范大学出版社，1998：10-22．学位论文［序号］主要责任．文献题名［Ｄ］．保存地：保存单位，年份．例：［７］张和生．地质力学系统理论［Ｄ］．太原：太原理工大学，1998．报告［序号］主要责任．文献题名［Ｒ］．报告地：报告会主办单位，年份．例：［９］冯西桥．核反应堆压力容器的LBB分析［Ｒ］.北京：清华大学核能技术设计研究院，1997．报纸类［序号］主要责任者．文献题名［Ｎ］．报纸名，出版日期(版次)．例：［13］谢希德．创造学习的思路[Ｎ]．人民日报，1998-12-25(10)．专利［序号］专利所有者．专利题名［P］．专利国别：专利号，发布日期．例：［11］姜锡洲．一种温热外敷药制备方案［Ｐ］．中国专利：881056078，1983-08-12．标准［序号］标准代号，标准名称［S］．出版地：出版者，出版年．例：[１] GB/T 16159—1996，汉语拼音正词法基本规则［S］．北京：中国标准出版社，1996．电子文献[序号］主要责任者．电子文献题名［文献类型/载体类型］．电子文献的出版或可获得地址，发表或更新的期/引用日期(任选)．例：[21] 王明亮．中国学术期刊标准化数据库系统工程的［EB/OL］．https://www.wendangku.net/doc/7d2242495.html,/pub/wml.txt/9808 10-2.html,1998-08-16/1998-10-04．

CAR-T细胞在肿瘤免疫治疗的研究进展和展望文献综述

中国药科大学生物工程文献综述综述题目CAR-T细胞在肿瘤免疫治疗的研究进展和展望英文题目Current situation and development trend of CAR- T cell for tumor immunotheraphy 专业生物制药（卓越工程师）院部生命科学与技术学院学号14404806 姓名龙益如

CAR-T细胞在肿瘤免疫治疗的研究进展和展望 14404806 龙益如摘要：嵌合抗原受体修饰的Ｔ细胞（CAR-T）治疗是一种新型的肿瘤免疫治疗方法。在多种血液肿瘤的临床试验中，CAR-T细胞疗法取得重大突破，在实体瘤的临床试验中也初见成效。但在获得显著疗效的同时, CAR-T也存在持久性、归巢、脱靶效应、神经毒性、细胞因子风暴、插入突变、对实体肿瘤疗效有限等问题。现就CAR-T技术的最新进展及该领域有待解决的问题进行综述，以期初步了解该技术的发展前景及问题分析。关键词：嵌合抗原受体修饰的T细胞；肿瘤；免疫治疗 Current situation and development trend of CAR-T cell for tumor immunotheraphy Abstract：A lot of remarkable results suggested that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics .A novel breakthrough has been made in CAR-T treatment of hematologic tumors and therapeutic potential in clinical studies of solid tumors has been achieved , although there are still many problem for CAR-T on the clinical application such as off-target effect, cytokine storm ,insertion mutagenesis, limited effects for solid tumors. Here, we reviewed the recent advances of CAR-T and problems that need to be solved in this flied. Keyword:Chimeric antigen receptor T cells ; Tumor ;Immunotheraphy

肿瘤试题鼻咽癌

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一、苍耳子中倍半萜类研究进展倍半萜广泛存在于植物、微生物、海洋生物及某些昆虫中, 虽然骨架仅有15 个碳原子, 但由于生物体内微妙的代谢过程而生成形形色色的基本骨架的化合物, 并有复杂的立体结构, 其中很多具有重要的生物功能和生理活性。倍半萜内酯是菊科植物的特征性成分, 这些苦的化合物常含有α, β-不饱和-γ内酯结构片段, 研究表明它是其生物活性的一个主要功能团[1, 2 ]。倍半萜内酯化合物具有抗肿瘤和细胞毒活性, 微生物生长抑制作用(抗菌) , 防治血吸虫病, 皮肤致敏作用, 昆虫拒食作用, 引起脊椎动物中毒和植物生长抑制作用(植物毒素)[3 ]。苍耳属X anth ium L. 植物约有25 种, 广泛分布于世界各地, 我国有3 种及1 变种。苍耳属在世界各地民间主要用于利尿、催吐、催泻, 治前列腺疾病、发烧、淋巴结核、肝炎和癌症[4 ]。由于倍半萜内酯化合物活性的重要性, 也为进一步研究开发苍耳属植物, 特将苍耳属中的倍半萜内酯化合物做一总结。苍耳属中主要含愈创木烷型和裂愈创木烷型内酯化合物。xanthat ion (23) 是活性研究比较多的一个化合物[5～ 7 ] , 化合物(1～ 39) 结构式见图1, 来源及波谱数据见表1。

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