***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: UNLABELLED Labeled annexin V is widely used to detect cell death in vitro and in vivo . Nearly all studies have been done with annexin V derivatized via amine-directed bifunctional agents ; it was thought that these molecules retained full bioactivity compared with unmodified protein . We now show that this assumption is incorrect by measuring the affinity of annexin V for cells in vitro by quantitative calcium titration under conditions of low membrane occupancy . METHODS Annexin V was modified with 4 different amine-directed agents : the N-hydroxysuccinimide esters of hydrazinonicotinic acid , mercaptoacetyltriglycine , and biotin ; and with fluorescein isothiocyanate . RESULTS In all cases , the membrane-binding affinity was decreased by derivatization , even at very low average stoichiometries . A statistical model based on the Poisson distribution accurately predicted the observed heterogeneity of derivatization as a function of average derivatization stoichiometry . This model also showed that multiply derivatized forms , which are the ones most likely to have compromised bioactivity , contributed disproportionately to the binding and imaging signals . The in vitro binding assay correctly predicted in vivo uptake in a mouse liver model of apoptosis for all proteins tested . The annexin V-128 protein , labeled at a single specific site at the N terminus , showed twice as much apoptosis-specific liver uptake as did all forms of annexin V derivatized r and omly via amino groups . CONCLUSION The membrane-binding activity of annexin V is much more sensitive to amine-directed chemical modification than previously realized . New annexin V molecules labeled by site-specific methods will greatly improve sensitivity for detecting cell death in vivo UNLABELLED Cancer chemotherapy enhances the apoptosis , whereas apoptosis is a suicidal mechanism requiring energy . We determined the relationship between apoptosis and glucose utilization during cancer chemotherapy using (99m)Tc-annexin V ( (99m)Tc-annexin A5 ) and (18)F-FDG and compared their uptake with histologic findings in a rat tumor model . METHODS Allogenic hepatoma cells ( KDH-8 ) were inoculated into the left calf muscle of male Wistar rats ( WKA ) . Eleven days after the inoculation , the rats were r and omly divided into 3 groups : The first group ( n = 7 ) received a single dose of gemcitabine ( 90 mg/kg , intravenously ) , the second group ( n = 8) received cyclophosphamide ( 150 mg/kg , intraperitoneally ) , and the third group ( n = 7 ) was untreated and served as the control group . We injected (99m)Tc-annexin V 48 h after the chemotherapy and then injected (18)F-FDG to all rats 1 h before sacrifice . Six hours after (99m)Tc-annexin V injection , the rats were sacrificed and the organs , including the tumor , were removed and radioactivity was counted . The radioactivities of (18)F and (99m)Tc in the organs were determined using normalization by tissue weight . Histologic evaluation by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling ( TUNEL ) method and the immunostaining of glucose transporter-1 ( GLUT-1 ) were also performed to obtain the indices of apoptosis and glucose utilization , respectively . The rate of positively stained cells was calculated and analyzed statistically . RESULTS After chemotherapy using gemcitabine and cyclophosphamide , the (99m)Tc-annexin V uptake ( percentage injected dose per gram x kg [ ( % ID/g ) x kg ] ; mean + /- SD ) in tumor increased significantly ( 0.062 + /- 0.012 ( % ID/g ) x kg in the gemcitabine-treated group and 0.050 + /- 0.012 ( % ID/g ) x kg in the cyclophosphamide group vs. 0.031 + /- 0.005 ( % ID/g ) x kg in the control group ; P < 0.01 ) . In contrast , the (18)F-FDG in tumor decreased significantly ( 0.483 + /- 0.118 ( % ID/g ) x kg in the gemcitabine group and 0.583 + /- 0.142 ( % ID/g ) x kg in the cyclophosphamide group ) compared with that in the control group ( 0.743 + /- 0.084 ( % ID/g ) x kg ; P < 0.01 ) . In addition , (18)F-FDG uptake in tumor negatively correlated with (99m)Tc-annexin V uptake ( r = -0.75 ; P < 0.01 ) . In the gemcitabine and cyclophosphamide groups , the rate of TUNEL positively stained cells was significantly higher than that in the control group ( 10.2 % + /- 1.7 % and 8.0 % + /- 1.5 % vs. 5.2 % + /- 1.5 % ; P < 0.01 ) , whereas the GLUT-1 expression level showed no definite changes in histologic analyses . CONCLUSION These data indicate that an enhanced apoptotic reaction correlated with suppressed tumor glucose utilization after cytotoxic chemotherapy as determined using radiotracers and histologic evaluation . The increase in (99m)Tc-annexin V and the decrease in (18)F-FDG in tumor can be useful markers for predicting therapeutic outcomes and for prognosis at the early stage of chemotherapy This study reports on the relationship between quantitative 99mTc-HYNIC radiolabelled annexin V tumour uptake measurements , Fas lig and ( FasL ) expression , matrix metalloproteinase-9 ( MMP-9 ) expression , microvessel density ( MVD ) and the number of tumour-infiltrating lymphocytes in squamous cell carcinoma of the head and neck ( SCCHN ) patients . Twenty-eight patients ( 24 men and 4 women ; mean age 59 years , range 43–83 years ) suffering from a primary ( n , number of patients = 22 ) or locally recurrent ( n=6 ) SCCHN were studied . All patients underwent a  spiral CT scan  , allowing estimation of lesion size in three dimensions , and 99mTc-HYNIC annexin V scintigraphy within 1 week of each other . Biopsies or resection of the suspected primary tumour or local recurrence for histopathological analysis were performed on all patients within a period of 10 days following 99mTc-HYNIC annexin V scintigraphy . The percentage uptake of the injected dose of 99mTc-HYNIC annexin V in visible tumour lesions on scintigrams divided by the tumour volume , derived from CT , was related to MVD and to histological score ( HSCORE ) values for MMP-9 and FasL expression as well as to the number of tumour-infiltrating lymphocytes ( CD45 staining ) . Median percentage absolute tumour uptake of the injected dose/cm3 tumour volume derived from tomographic images was 0.0001 % ( SD 0.0001 % ) at 5–6 h p.i . ( range : 0.000007–0.0003 % ) . Mean HSCORE for MMP-9 tumour staining was 2.1 ( SD 0.84 ) . Mean HSCORE for FasL tumour staining was 2.49 ( SD 0.92 ) . At the sites of tumour containing the highest number of vessels , the mean MVD was 20 vessels/field at the hot spot ( range 1–73 ) . The median number of tumour-infiltrating lymphocytes was 500 ( range 100–5,000 ) . The percentage absolute tumour uptake of the injected dose/cm3 tumour volume derived from tomographic images correlated linearly with FasL HSCORES(r=0.47 , P=0.02 ) . No correlation was found between the percentage absolute tumour uptake of the injected dose/cm3 tumour volume derived from tomographic images and MMP-9 HSCORES , MVD or the number of tumour-infiltrating lymphocytes . MVD correlated significantly with MMP-9 HSCORES ( r=0.44 , P=0.03 ) RATIONALE For clinical application , a sufficient reproducibility of 99mTc-HYNIC annexin-V quantitative uptake measurements must be demonstrated to allow a study of cell-death changes induced by chemotherapy over time and intersubject . Thus , the aim of this study was to estimate the intra- , inter- , and day-to-day reproducibility of quantitative 99mTc-HYNIC annexin-V tumor uptake values in patients suffering from head and neck carcinomas . METHODS Thirteen ( 13 ) patients suffering from clinical ly suspected , histologically confirmed squamous head and neck carcinomas were prospect ively included in the study . All patients were scheduled to undergo a spiral computed tomography scan and two 99mTc-HYNIC annexin-V scintigraphies within 3 - 5 days from each other , referred to as day 1 and day 2 of scintigraphy . The percentage of uptake of the injected dose of 99mTc-HYNIC annexin-V in tumor lesions on scintigrams divided by the tumor volume , as derived from CT , was determined twice within an interval of 2 weeks by observer 1 and once by observer 2 on day 1 of scintigraphy and once on day 2 of scintigraphy by observer 1 . RESULTS The mean of the difference for the intra- , inter- , and day-to-day measurements were -3.4 % , 2.4 % , and -6 % , respectively . No systematic bias was observed for the mean of the differences for the intra- , inter- , and day-to-day measurements . The respective confidence intervals for the mean of the differences of intra- , inter- , and day-to-day variability were -8.2%-1.4 % , -2.9%-7.8 % , and -14.7%-2.7 % . CONCLUSION The reproducibility of quantitative 99mTc-HYNIC annexin-V tumor uptake measurements using a manual method appears to be acceptable for clinical use UNLABELLED In tumors the process of apoptosis occurs over an interval of time after chemotherapy . To determine the best timing for detecting apoptosis in vivo with (99m)Tc-annexin V after chemotherapy , we examined the changes in (99m)Tc-annexin V accumulation over time in comparison with those of caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling ( TUNEL ) expression level after cyclophosphamide treatment in an experimental model . METHODS Hydrazinonicotinamide (HYNIC)-annexin V was labeled with (99m)Tc ( (99m)Tc-annexin V ) .  Rats were inoculated with allogenic hepatoma cells ( KDH-8 ) into the left calf muscle . Eleven days after the inoculation , the rats were r and omly divided into the group receiving a single dose of cyclophosphamide ( 150 mg/kg intraperitoneally ) and the control group . (99m)Tc-Annexin V ( 18.5 MBq [ 0.5 mCi ] per rat ) was injected intravenously in the rats 4 , 12 , and 20 h after the treatment and also to the control rats ( n = 5 in each group ) . Radioactivity in tissues was determined 6 h after (99m)Tc-annexin V injection . Immunostaining of caspase-3 and TUNEL were performed to detect apoptosis , and the rates of positively stained cells were calculated . RESULTS (99m)Tc-Annexin V accumulation in tumors significantly increased at 20 h ( 0.077 + /- 0.007 [ % ID/g ] x kg , where % ID/g = percentage injected dose per gram ) but not at 4 or 12 h ( 0.048 + /- 0.008 and 0.052 + /- 0.014 [ % ID/g ] x kg , respectively ) after cyclophosphamide treatment . (99m)Tc-Annexin V accumulation in tumors and the rate of apoptotic cells determined by caspase-3 immunostaining and TUNEL were significantly higher in treated rats 20 h after cyclophosphamide treatment as compared with control rats . CONCLUSION The effective detection of apoptotic tumor response with (99m)Tc-annexin V required 20 h after cyclophosphamide treatment in an experimental model . The present results provide an important basis for determining the best timing of annexin V imaging after the start of chemotherapy in a clinical setting PURPOSE Many anticancer therapies exert their therapeutic effect by inducing apoptosis in target tumors . We evaluated in a Phase I study the safety and the feasibility of (99m)Tc-Annexin V for imaging chemotherapy-induced apoptosis in human cancers immediately after the first course of chemotherapy  . EXPERIMENTAL DESIGN Fifteen patients presenting with 
    Output:
    
Conclusion Quantitative 99mTc-annexin A5 imaging has been investigated in clinical trials for the assessment of apoptotic tumor responses .
A st and ardized uptake value score ( SUV , ΔSUV ) using quantitative SPECT/CT imaging may be a promising approach to the simple , reproducible and semiquantitative assessment of apoptotic tumor changes