One-year results of a multicenter controlled clinical trial of triamcinolone in pars plana vitrectomy Purpose To evaluate the 1-year results of using triamcinolone acetonide -LRB- TA -RRB- in pars plana vitrectomy -LRB- PPV -RRB- . Introduction Recently , vitrectomy has been used to treat various vitreoretinal diseases . It still remains a demanding procedure requiring a skilled and experienced surgeon , despite advances in surgical instrumentation and techniques . One major difficulty with this procedure is the transparency of the vitreous . Intra-operative triamcinolone acetonide -LRB- TA -RRB- has been used to address this problem , as it can be injected into the vitreous to visualize the posterior hyaloid or the internal limiting membrane -LRB- ILM -RRB- -LSB- 1 , 2 -RSB- . Several previous reports have demonstrated the usefulness of TA as an adjunct to pars plana vitrectomy -LRB- PPV -RRB- -LSB- 3 -- 13 -RSB- . Although their findings supported the use of TA-assisted PPV , these studies involved relatively small numbers of eyes and were not randomized . In addition , more recent reports on the use of intravitreous TA in patients not undergoing vitrectomy raised concerns about the risks of elevated intra-ocular pressure -LRB- IOP -RRB- -LSB- 14 -- 19 -RSB- . We therefore undertook a multicenter prospective controlled study of TA-assisted pars plana vitrectomy -LRB- PPV -RRB- . Considering the enduring nature of the effect of PPV on ocular tissue , it is important to investigate the long-term results in order to evaluate TA-assisted PPV . Moreover , the crucial issue of the effects on patients ' vision must be explored before TA-assisted PPV can be recommended . The current report presents the 1-year results of the use of TA in PPV , and evaluates the procedure in light of the aforementioned issues . Methods Study design , randomization and sample size The prospective controlled clinical trial took place at eight hospitals in Japan as previously described -LRB- see Acknowledgements below -RRB- -LSB- 13 -RSB- . The patients were assigned to the two groups using a single-blind quasi-randomization approach within the participating clinical centers . Our preliminary study showed that the most important factor influencing the surgical outcome was not the nature of the disease for which PPV was used , but rather the hospital in which the surgery was performed -LRB- data not shown -RRB- . To minimize this bias , equal numbers of patients from each hospital were assigned to each of the study groups . Thus , the patients were assigned by a single-blind quasi-randomization within the participating clinical centers . Briefly , after the patients passed the inclusion/exclusion criteria and gave consent for the study , they were numbered serially at each hospital , and alternate numbers were assigned to the TA-assisted and conventional PPV groups , respectively , as previously described -LSB- 13 -RSB- . Data analysis was performed by an intent-to-treat analysis method . To conceal the allocations at the participating hospitals , the surgeons were not informed of the group to which a patient had been assigned until immediately before surgery . This is the second report of controlled clinical trial of intraocular TA in PPV . Primary outcome was whether the use of TA might reduce the incidence of intraoperative complications . The sample size was determined based upon our preliminary study , and the method has been described elsewhere -LSB- 13 -RSB- . Briefly , the incidence of intraoperative retinal breaks was found to be approximately 15 % in the participating hospitals . The sample size calculation was based on our pilot study data , and was aimed to detect a difference in short-term postoperative complications as reported previously -LSB- 13 -RSB- Eligibility criteria and surgery Institutional review board -LRB- IRB -RRB- / ethics committee approval was obtained from all of the participating clinical establishments , such that all patients undergoing PPV at these hospitals were eligible to enroll in the study . Each patient was fully informed about the nature of the treatment , and provided written consent . The following groups were excluded : -LRB- 1 -RRB- patients with diagnoses that included macular holes ; patients with uveitis , -LRB- 2 -RRB- patients with phakic lenses , -LRB- 3 -RRB- patients who were known to be steroid responders , to have glaucoma , or to have apparent infectious endophthalmitis , and -LRB- 4 -RRB- patients who were undergoing a second PPV . For ethical reasons , if at the time of surgery a surgeon felt that TA was necessary to achieve a successful PPV outcome , it was included in the procedure ; for the purposes of the intent-to-treat analysis , these cases were included within the conventional PPV group . The details of the surgical protocols varied between the hospitals , but the basic procedure was similar . PPV was performed according to a previously reported methodology , either with or without the use of a TA suspension prepared as described elsewhere -LSB- 2 , 13 -RSB- . The recording of the operations , control of surgical quality , use of antibiotics , and termination of the study have been described elsewhere -LSB- 13 -RSB- . During the follow-up period , additional surgeries were performed at each hospital as and when they were needed . For example , filtering surgeries were performed when the intra-ocular pressure -LRB- IOP -RRB- remained at an uncontrollably high level -LRB- 25 mmHg or greater -RRB- even with full medication . Full medication included the use of all latanoprost , beta-blocker , and dorzolamide hydrochloride eyedrops and acetazolamide medicine . Data collection and documentation were performed as previously described -LSB- 13 -RSB- . For the purposes of this study , the adverse events related to surgery were defined as follows : retinal breaks , macular pucker , retinal fibrous membrane formation , retinal detachment , vitreous hemorrhage -LRB- VH -RRB- , rubeosis iridis , optic-disc damage , corneal diseases , and after cataract . The serious adverse events related to surgery were defined as follows : infectious endophthalmitis , retinal degeneration , unexplained optic-disc damage , and unexplained deterioration of vision . Masking and outcome assessment The study records were collected by the principal investigator -LRB- TS -RRB- up until November 2006 . After checking the records for harmful events , the data were sent to the controllers -LRB- YN -RRB- at Kyushu University . The remaining investigators were not permitted access to any information on the outcomes before completion of the analysis . Visual acuity was measured by ophthalmic technicians using the Snellen high-contrast acuity test . IOP was also measured by the ophthalmic technicians , and the findings were reviewed by the physicians . IOP was measured with pneumotonometer . The ophthalmic technicians were not informed of the purpose of the study or the assignment schedule . Anti-glaucoma eye drops and/or acetazolamide were used when an IOP of 22 mmHg or higher persisted for 3 days . Statistical analysis The visual acuity was converted to the logarithm of the minimum angle of resolution -LRB- LogMAR -RRB- , and the baseline value was compared with those at 1 week , 1 month , 3 months , 6 months , and 1 year . The eyes were categorized into the following three groups : -LRB- 1 -RRB- the improved group , in which patients showed a 0.3 logMAR or greater improvement of visual acuity at the final examination compared with baseline , -LRB- 2 -RRB- the deteriorated group , in which patients showed a 0.3 logMAR or worse deterioration of visual acuity at the final examination compared with baseline , and -LRB- 3 -RRB- the unchanged group , in which patients did not meet the criteria of either the improved or the deteriorated group . A Kaplan-Meier survival analysis was used to estimate the probability of improved visual acuity with time after surgery . The improvement or deterioration was analyzed by the log rank test . The earliest time point after surgery at which the events in each category were reported was designated as the time point of each event . We also estimated the multiple-adjusted odds ratio -LRB- OR -RRB- and the 95 % confidence interval -LRB- 95 % CI -RRB- both for TA use and for the other variables , using a logistic regression model . The parameters that were adjusted for included age , gender , and disease diagnosis , which was categorized into the following five groups : proliferative diabetic retinopathy -LRB- PDR -RRB- , diabetic macular edema -LRB- DME -RRB- , rhegmatogenous retinal detachment -LRB- RRD -RRB- , retinal vein occlusion -LRB- RVO -RRB- , and others . A diagnosis of PDR was used as a reference . Even when a single eye received multiple additional surgeries , it was counted as one eye . All statistical analyses were performed using SAS ® -LRB- Proprietary Software Release 8.2 ; SAS Institute Inc. , Cary , NC , USA -RRB- . The differences in diagnosis or surgical intervention between the two groups were compared using a two-tailed Chi-squared test with the Yates ' correction . P values < 0.05 were considered statistically significant . Results Number of eyes In total , 920 patients were initially registered for PPV during this period . Among these , 146 eyes were not included in the study because they did not meet the eligibility criteria or because the patient declined to participate . In total , 774 eyes were randomized , with 391 eyes -LRB- from 216 male and 175 female patients -RRB- assigned to the TA-assisted PPV group and 383 eyes -LRB- 201 male and 182 female patients -RRB- assigned to the conventional PPV group . The mean ages of the patients were 63.5 ± 12.1 years in the TA-assisted PPV group and 63.0 ± 11.3 years in the conventional PPV group . In total , 19 eyes that were originally assigned to the conventional PPV group received unplanned TA based on surgical judgment . The 1-year post-operative follow-up was completed for a total of 305 eyes in the TA-assisted PPV group -LRB- 78.0 % -RRB- and 295 eyes in the conventional PPV group -LRB- 77.0 % -RRB- . The overall follow-up rate was 77.5 % -LRB- Fig. 1 -RRB- . Fig. 1Schematic diagram of the study . TA : triamcinolone acetonide , PPV : pars plana vitrectomy Diagnoses The diagnoses for each group are shown in Table 1 . In both groups , PDR accounted for the largest number of cases , followed by RRD . In both groups , the pattern at the 1-year follow-up was similar to that at the baseline , and the different diagnoses had significantly different distributions within the two groups : the TA-assisted PPV group had a relatively larger number of patients with DME -LRB- P = 0.018 at baseline , P = 0.006 at 1-year follow-up -RRB- and a smaller number of patients with epiretinal membrane -LRB- ERM -RRB- formation -LRB- P = 0.031 at baseline , P = 0.008 at 1-year follow-up -RRB- . Table 1Diseases of each group at baseline and 1 year after surgery TA-assisted PPVConventional PPVBaseline1 yearbaseline1 yearN -LRB- % -RRB- N -LRB- % -RRB- N -LRB- % -RRB- N -LRB- % -RRB- AMD7 -LRB- 1.8 % -RRB- 3 -LRB- 1.0 % -RRB- 3 -LRB- 0.8 % -RRB- 3 -LRB- 1.0 % -RRB- BRVO50 -LRB- 12.8 % -RRB- 41 -LRB- 13.4 % -RRB- 37 -LRB- 9.7 % -RRB- 29 -LRB- 9.8 % -RRB- CRVO11 -LRB- 2.8 % -RRB- 9 -LRB- 3.0 % -RRB- 7 -LRB- 1.8 % -RRB- 6 -LRB- 2.0 % -RRB- DME67 -LRB- 17.1 % -RRB- 60 -LRB- 19.7 % -RRB- 42 -LRB- 11.0 % -RRB- 34 -LRB- 11.5 % -RRB- ERM24 -LRB- 6.1 % -RRB- 19 -LRB- 6.2 % -RRB- 41 -LRB- 10.7 % -RRB- 37 -LRB- 12.5 % -RRB- Lens luxation16 -LRB- 4.1 % -RRB- 11 -LRB- 3.6 % -RRB- 16 -LRB- 4.2 % -RRB- 12 -LRB- 4.1 % -RRB- Macroaneurysm10 -LRB- 2.6 % -RRB- 8 -LRB- 2.6 % -RRB- 9 -LRB- 2.3 % -RRB- 4 -LRB- 1.4 % -RRB- PDR113 -LRB- 28.9 % -RRB- 85 -LRB- 27.9 % -RRB- 131 -LRB- 34.2 % -RRB- 101 -LRB- 34.2 % -RRB- RRD80 -LRB- 20.5 % -RRB- 59 -LRB- 19.3 % -RRB- 77 -LRB- 20.1 % -RRB- 54 -LRB- 18.3 % -RRB- VH6 -LRB- 1.5 % -RRB- 6 -LRB- 2.0 % -RRB- 14 -LRB- 3.7 % -RRB- 11 -LRB- 3.7 % -RRB- Others7 -LRB- 1.8 % -RRB- 4 -LRB- 1.3 % -RRB- 6 -LRB- 1.6 % -RRB- 4 -LRB- 1.4 % -RRB- total383 -LRB- 100 % -RRB- 305 -LRB- 100 % -RRB- 391 -LRB- 100 % -RRB- 295 -LRB- 100 % -RRB- TA ; triamcinolone acetonide : PPV ; pars plana vitrectomy : AMD ; age-related macular degeneration : BRVO ; branch retinal vein occlusion : CRVO : central retinal vein occlusion : DME ; diabetic macular edema : ERM ; epiretinal membrane : PDR ; proliferative diabetic retinopathy : RRD ; rhegmatogenous retinal detachment : VH ; vitreous hemorrhage . There were no significant differences between the two groups in the usage of surgical methods , such as cataract surgery -LRB- phacoemulsification P = 0.724 and pars plana lensectomy P = 0.272 -RRB- , ILM peeling -LRB- P = 0.075 -RRB- and endolaser-photocoagulation -LRB- P = 0.413 -RRB- , or in the use of post-operative tamponade -LRB- sulfur hexafluoride gas P = 0.810 , octa-fluorepropane gas P = 0.756 , room air P > 0.999 , and silicone oil P = 0.831 -RRB- -LSB- 13 -RSB- . Visual acuity The visual acuity in both groups improved over time . In the TA-assisted PPV group , 322 eyes were categorized as improved , 21 were categorized as unchanged , and 48 were categorized as deteriorated . In the conventional PPV group , 312 eyes were categorized as improved , 45 eyes were categorized as unchanged , and 26 eyes were categorized as deteriorated . The log-rank test revealed no significant difference between the two groups regarding the improvement -LRB- P = 0.98 -RRB- or deterioration -LRB- P = 0.26 -RRB- of visual acuity . The logistic regression model also showed that the intra-operative use of TA was not a significant factor for the improvement of visual acuity -LRB- P = 0.91 -RRB- after adjusting for age , gender , and diagnosis -LRB- Table 2 -RRB- . Neither gender -LRB- P = 0.54 -RRB- nor age -LRB- P = 0.31 -RRB- was a significant factor for the improvement of visual acuity . However , PDR diagnosis was a significant factor for the improvement of visual acuity compared with DME -LRB- OR = 0.63 , 95 % CI = 0.478 -- 0.817 , P = 0.0006 ; Table 2 -RRB- . Table 2Factors affecting improvement of visual acuityVariable -LRB- no . of improved eyes/total eyes -RRB- Odds ratio -LRB- 95 % CI -RRB- P-valueTA-assisted PPV -LRB- 322/391 -RRB- vs conventional PPV -LRB- 312/383 -RRB- 1.10 -LRB- 0.860 -- 1.183 -RRB- 0.91 Age1 .00 -LRB- 0.991 -- 1.005 -RRB- 0.54 Gender -LRB- male vs female -RRB- 0.92 -LRB- 0.785 -- 1.080 -RRB- 0.31 DiseasesRD vs PDR1 .04 -LRB- 0.834 -- 1.340 -RRB- 0.71 DME vs PDR0 .63 -LRB- 0.478 -- 0.817 -RRB- 0.0006 * RVO vs PDR1 .21 -LRB- 0.938 -- 1.561 -RRB- 0.14 ERM vs PDR0 .78 -LRB- 0.568 -- 1.061 -RRB- 0.11 Others vs PDR1 .21 -LRB- 0.924 -- 1.579 -RRB- 0.17 CI ; confidence interval : TA ; triamcinolone acetonide : PPV ; pars plana vitrectomy : RVO ; branch retinal vein occlusion + central retinal vein occlusion : DME ; diabetic macular edema : ERM ; epiretinal membrane : PDR ; proliferative diabetic retinopathy : RRD ; rhegmatogenous retinal detachment . * statistically significant Post-operative complications Subgroup analysis In terms of post-operative complications , there was not any statistically significant difference . Fibrous ERM was observed in five eyes -LRB- 1.4 % -RRB- in the conventional PPV group , but in only one eye -LRB- 0.3 % -RRB- in the TA-assisted PPV group . A subgroup analysis showed that this difference was not significant -LRB- P = 0.10 -RRB- . Among the other complications , an IOP increase was found more frequently in the TA-assisted PPV group -LRB- 23 eyes , 5.9 % -RRB- than in the conventional PPV group -LRB- 13 eyes , 3.4 % -RRB- , although this difference was not statistically significant -LRB- P = 0.10 -RRB- . There were no significant differences in the other complications between the two groups -LRB- Table 3 -RRB- . Table 3Post-operative complications in each group TA-assisted PPV -LRB- total 391 eyes -RRB- : n -LRB- % -RRB- Conventional PPV -LRB- total 383 eyes -RRB- : n -LRB- % -RRB- P-value * After cataract18 -LRB- 4.6 % -RRB- 17 -LRB- 4.4 % -RRB- 0.91 Macular pucker23 -LRB- 5.9 % -RRB- 22 -LRB- 5.7 % -RRB- 0.93 IOP increase23 -LRB- 5.9 % -RRB- 13 -LRB- 3.4 % -RRB- 0.10 Retinal detachment9 -LRB- 2.3 % -RRB- 9 -LRB- 2.3 % -RRB- 0.96 Vitreous hemorrhage22 -LRB- 5.6 % -RRB- 29 -LRB- 7.8 % -RRB- 0.28 Fibrous membrane1 -LRB- 0.3 % -RRB- 5 -LRB- 1.4 % -RRB- 0.10 Iris synechiae6 -LRB- 1.5 % -RRB- 4 -LRB- 1.0 % -RRB- 0.55 Others8 -LRB- 2.0 % -RRB- 12 -LRB- 3.1 % -RRB- 0.34 TA ; triamcinolone acetonide : PPV ; pars plana vitrectomy : PPL ; pas plana lensectomy : IOP ; intraocular pressure : * Chi-square test with the Yates ' correction . Additional surgery Although the filtering surgery was more performed in TA-assisted PPV and the removal of vitreous hemorrhage was more performed in conventional PPV , there was not any statistically significant difference between the two groups with respect to causes of additional surgery after PPV . In the TA-assisted PPV group , 22 surgeries were performed -LRB- excluding filtering surgery -RRB- . The most common reasons for additional surgery were removal of silicone oil -LRB- 11 eyes -RRB- , followed by retinal detachment -LRB- eight eyes -RRB- , VH -LRB- six eyes -RRB- , and others -LRB- seven eyes -RRB- . In the conventional PPV group , 26 surgeries were performed -LRB- excluding filtering surgery -RRB- . The most common reasons were VH -LRB- 12 eyes -RRB- , followed by retinal detachment -LRB- nine eyes -RRB- , removal of silicone oil -LRB- seven eyes -RRB- , and others -LRB- six eyes -RRB- . Although there was a tendency for VH to be less common in TA-assisted PPV eyes , no significant difference was found in comparison to conventional PPV -LRB- P = 0.13 ; Table 4 -RRB- . Filtering surgery was more frequently performed in the TA-assisted PPV group -LRB- 15 cases , 3.8 % -RRB- than the conventional PPV group -LRB- seven cases , 1.8 % -RRB- , although this difference was not significant -LRB- P = 0.10 -RRB- . Ten eyes received multiple additional surgeries in TA-assisted PPV group and seven eyes in conventional PPV group . Table 4Causes of additional surgery after PPV TA-assisted PPV -LRB- total 391 eyes -RRB- : n -LRB- % -RRB- Conventional PPV -LRB- total 383 eyes -RRB- : n -LRB- % -RRB- P-value * Silicone removal11 -LRB- 2.8 % -RRB- 7 -LRB- 1.8 % -RRB- 0.36 Retinal detachment8 -LRB- 2.0 % -RRB- 9 -LRB- 2.3 % -RRB- 0.77 Vitreous hemorrhage6 -LRB- 1.5 % -RRB- 12 -LRB- 3.1 % -RRB- 0.14 Filtering surgery15 -LRB- 3.8 % -RRB- 7 -LRB- 1.8 % -RRB- 0.10 Others7 -LRB- 1.8 % -RRB- 6 -LRB- 1.6 % -RRB- 0.81 Total37 -LRB- 9.5 % -RRB- ✝ 32 -LRB- 8.6 % -RRB- ✝ ✝ 0.68 TA ; triamcinolone acetonide : PPV ; pars plana vitrectomy : * Chi-square test with the Yates ' correction : ✝ Ten eyes received multiple additional surgeries : ✝ ✝ Seven eyes received multiple additional surgeries . The survival curve produced by the log-rank test showed that the incidence of additional surgery was not significantly different between the two groups -LRB- P = 0.45 -RRB- . The logistic regression test also showed that the use of TA was not a significant factor for additional surgery after adjustments for gender , age , and diagnosis . However , a diagnosis of PDR was a significant factor for additional surgery in comparison to DME -LRB- P = 0.005 -RRB- , RVO -LRB- P = 0.006 -RRB- , and ERM -LRB- P = 0.02 ; Table 5 -RRB- . None of the variables were related to the requirement for filtering surgery -LRB- Table 6 -RRB- . Table 5Factors affecting additional surgeryVariable -LRB- no . of additional surgery/total -RRB- Odds ratio -LRB- 95 % CI -RRB- P-valueTA-assisted PPV -LRB- 37/391 -RRB- vs conventional PPV -LRB- 32/383 -RRB- 1.23 -LRB- 0.797 -- 1.911 -RRB- 0.35 Age0 .97 -LRB- 0.950 -- 0.984 -RRB- 0.0001 * Gender -LRB- male vs female -RRB- 1.15 -LRB- 0.733 -- 1.797 -RRB- 0.55 DiseasesRD vs PDR0 .60 -LRB- 0.345 -- 1.029 -RRB- 0.06 DME vs PDR0 .29 -LRB- 0.122 -- 0.681 -RRB- 0.005 * RVO vs PDR0 .23 -LRB- 0.084 -- 0.657 -RRB- 0.006 * ERM vs PDR0 .087 -LRB- 0.012 -- 0.631 -RRB- 0.02 * Others vs PDR0 .64 -LRB- 0.299 -- 1.374 -RRB- 0.25 CI ; confidence interval : RVO ; branch retinal vein occlusion + central retinal vein occlusion : DME ; diabetic macular edema : ERM ; epiretinal membrane : PDR ; proliferative diabetic retinopathy : RRD ; rhegmatogenous retinal detachment . * statistically significantTable 6Factors affecting filtering surgeryVariable -LRB- no . of filtering surgery/total -RRB- Odds ratio -LRB- 95 % CI -RRB- P-valueTA-assisted PPV -LRB- 12/391 -RRB- vs conventional PPV -LRB- 5/383 -RRB- 1.74 -LRB- 0.708 -- 4.265 -RRB- 0.23 Age0 .98 -LRB- 0.941 -- 1.018 -RRB- 0.28 Gender -LRB- male vs female -RRB- 1.81 -LRB- 0.696 -- 4.728 -RRB- 0.22 DiseasesRRD vs PDR -- 0.99 DME vs PDR -- 0.99 RVO vs PDR -- 0.99 ERM vs PDR -- 0.99 Others vs PDR0 .83 -LRB- 0.266 -- 2.573 -RRB- 0.74 CI ; confidence interval : TA ; triamcinlone acetonide : PPV ; pars plana vitrectomy : RVO ; branch retinal vein occlusion + central retinal vein occlusion : DME ; diabetic macular edema : ERM ; epiretinal membrane : PDR ; proliferative diabetic retinopathy : RRD ; rhegmatogenous retinal detachment Serious adverse events None of the serious adverse events related to surgery defined in this study -LRB- such as retinal degeneration , endophthalmitis , an unexplained decrease in visual acuity , or optic-disc atrophy -RRB- were observed in either group during the 1-year follow-up . Discussion The first report on this study showed that the intra-operative use of TA significantly decreased the incidence of intra-operative complications associated with PPV , and no adverse events related to surgery were found over a 3-month observation period -LSB- 13 -RSB- . A decreased incidence of intra-operative complications is beneficial ; however , the critical issue is whether the surgery improves the patients ' vision . We therefore followed up the visual acuity , which is a crucial factor influencing vision , for 1 year after surgery . Our results revealed no significant difference in visual acuity between the TA-assisted PPV group and the conventional PPV group after 1 year . As described in the earlier report , which analyzed data from the same eyes , intra-operative retinal breaks and retinal detachment were significantly less frequent in the TA-assisted PPV group than in the conventional PPV group . Nonetheless , the decreased incidence of intra-operative complications did not significantly affect the visual acuity after 1 year . This finding can be explained by the following facts . First , surgical skill is the most important factor for surgical success . As all of the operations in this study were performed by qualified and experienced surgeons , the intra-operative complications were managed so as not to cause serious post-operative complications . Thus , the influence of intra-operative complications on visual acuity might have been minimal . Second , a patient 's vision after vitrectomy might be more strongly affected by a disease diagnosis than by intra-operative complications . Indeed , eyes with PDR were significantly more likely to show improved visual acuity compared with baseline than eyes with DME in the current study . As our present case series included various diseases , the impact of intra-operative complications on post-operative visual acuity might have been masked by another strong factor , such as disease diagnosis , even after adjustments . Third , the eyes in the current study were primarily chosen for the detection of intra-operative retinal breaks , based on the hypothesis that the intra-operative use of TA might decrease their incidence from 15 % to 8 % -LSB- 13 -RSB- . Thus , the sample size might not have been large enough to detect the superiority or inferiority of TA-assisted PPV . For example , in order to detect the difference of post-operative improvement of vision in TA-assisted PPV and conventional PPV based upon the present results , approximately 29,315 cases in each group are necessary with α power of 0.05 and 1-β of 0.8 . However , considering the relative stability of the visual acuity observed here , we are confident that the intra-operative use of TA does not have a positive or negative effect on postoperative visual acuity for 1 year . Additional surgeries carry associated risks and can be costly ; they are thus important when justifying the intra-operative use of TA in PPV . The incidence of additional surgery after vitrectomy was found to be equivalent using both methods . Considering the IOP increase after surgery , the opportunity to use anti-glaucoma eye drops was high in the TA-assisted PPV group -LSB- 13 -RSB- , and the number of filtering surgeries performed during 1 year after TA-assisted PPV was also high ; however , the incidence of additional surgeries was not statistically different between the groups . Several previous reports showed that intravitreous TA injection required filtering surgery , and its frequency was less than 1 % of all treated eyes -LSB- 18 , 19 -RSB- . In contrast to intravitreous TA injection , most of the TA was removed from the eye at the end of the surgery . Thus , it was plausible that the necessity of filtering surgery in TA-assisted PPV was not significant . The other causes of additional surgery occurred at similar frequencies , and there were no significant differences between the groups . A diagnosis of PDR was a significant factor for the requirement for additional surgery , as it was for the improvement of visual acuity . Furthermore , in our earlier report on the 3-month follow-up study , a diagnosis of PDR was found to be a significant risk factor for the occurrence of intra-operative complications . PDR eyes thus appear to have several poor prognostic factors , consistent with the present results . With regard to the post-operative complications , pre-retinal fibrosis appeared to be less common in the TA-assisted PPV group than in the conventional PPV group , although this was not statistically significant . This advantage of TA-assisted PPV has been described in previous reports -LSB- 3 , 5 -- 9 -RSB- . The intra-operative use of TA visualizes the posterior hyaloid clearly , which facilitates its removal -LSB- 6 , 7 -RSB- ; as the residual posterior hyaloid can act as a scaffold for pre-retinal fibrous-membrane formation , its removal could reduce the incidence of post-operative pre-retinal fibrosis -LSB- 5 -- 7 -RSB- . In the current study group , the removal of the residual posterior hyaloid was carried out according to the surgeons ' preference -- some surgeons removed it completely , while others did not . This might have obscured any potential advantage of the intra-operative use of TA in inhibiting post-operative pre-retinal fibrosis . There were clear limitations to our analysis . The number of cases in each study group was primarily chosen to allow the detection of intra-operative complications ; thus , the significance of the intra-operative use of TA might only become clear when studying larger numbers of patients . In addition , the sample size was too small to detect the risk of endophthalmitis . The incidence of endophthalmitis related to PPV was 0.046 % in the conventional PPV group and 0.053 % in the TA-assisted PPV group -LSB- 20 , 21 -RSB- . An analysis of a greater number of cases will thus be necessary to evaluate the risk of endophthalmitis related to TA-assisted PPV . However , the present sample size was large enough to detect several factors that affected post-operative visual acuity or the need for additional surgery . Another limitation was that the post-operative visual acuity was strongly influenced by the diagnosis of disease . Eyes with simple VH clearly had a greater chance of surgery improving vision above the baseline level than did eyes with complicated PDR . In order to evaluate the influence of the intra-operative use of TA on visual acuity more precisely , we are currently performing a study on eyes with the same disease diagnosis . Furthermore , the subgroup of DME or ERM in each group was not completely matched . The interpretation of the results should be done carefully . Additionally , caution must be applied when making generalizations on the basis of our current results , and their application to clinical practice must be undertaken with care . Other factors , such as invasiveness and cost , are also important in seeking justification for this treatment . The success of surgery depends upon various factors , and surgical skill is critical . When considering the likelihood of retinal breaks and their recovery without damaging vision , comparisons of the hazard ratios of TA-assisted PPV and conventional PPV would be valid only if made by individuals who qualify as PPV specialists . In summary , the intra-operative use of TA in PPV did not affect visual acuity over 1 year . As negative or adverse events were not observed in this case series , a more detailed study is warranted to establish the value of TA in PPV .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

steroid
diabetic retinopathy
retinal detachment


The

sentinel

node

procedure

in

colon

carcinoma

a

multi-centre

study

in

The

Netherlands

Background

Lymph

node

status

is

the

most

important

predictive

factor

in

colorectal

carcinoma

Recurrences

occur

in

of

the

patients

without

lymph

node

metastases

The

sentinel

lymph

node

-LRB-

SLN

-RRB-

biopsy

is

a

tool

to

facilitate

identification

of

micrometastatic

disease

and

aberrant

lymphatic

drainage

We

studied

the

feasibility

of

in

vivo

SLN

detection

in

a

multi-centre

setting

and

evaluated

nodal

micro-staging

using

immunohistochemistry

-LRB-

IHC

-RRB-

Introduction

Survival

in

patients

with

colon

carcinoma

is

strongly

correlated

with

lymph

node

status

the

disease-free

survival

rate

is

for

patients

with

lymph

node-negative

disease

-LRB-

stage

I/II

-RRB-

but

only

for

those

with

node-positive

disease

-LRB-

stage

III

-RRB-

-LSB-

-RSB-

The

presence

of

lymph

node

metastases

indicates

the

use

of

adjuvant

chemotherapy

in

these

patients

which

increases

the

survival

rate

with

about

-LSB-

-RSB-

Despite

the

favourable

prognosis

of

patients

with

localized

colon

carcinoma

without

regional

lymph

node

metastasis

of

these

patients

will

develop

recurrent

disease

after

apparently

curative

resection

-LSB-

-RSB-

It

is

possible

that

in

this

group

of

patients

small

lymph

node

metastases

have

been

missed

resulting

in

understaging

This

may

be

due

to

an

inadequate

surgical

lymphadenectomy

or

insufficient

pathological

examination

-LSB-

-RSB-

According

to

international

guidelines

meticulous

pathological

examination

of

at

least

lymph

nodes

is

warranted

for

adequate

staging

of

patients

with

colon

carcinoma

-LSB-

-RSB-

However

several

studies

showed

that

the

minimal

number

of

lymph

nodes

necessary

for

correct

staging

varied

considerably

from

to

to

as

many

as

possible

in

the

study

of

Goldstein

et

al.

-LSB-

-RSB-

In

addition

in-depth

pathological

examination

of

lymph

nodes

by

immunohistochemical

staining

for

cytokeratin

or

reverse

transcriptase

polymerase

chain

reaction

-LRB-

RT-PCR

-RRB-

may

reveal

micrometastases

that

could

have

been

missed

by

routine

haematoxylin

and

eosin

-LRB-

H&E

-RRB-

examination

Several

authors

have

reported

a

decreased

survival

rate

when

micrometastases

are

detected

in

colon

carcinoma

-LSB-

-RSB-

The

possible

benefit

of

adjuvant

therapy

in

this

group

of

patients

is

not

clear

yet

These

-LRB-

ultra

-RRB-

staging

techniques

are

time

consuming

labour

intensive

and

costly

For

optimal

staging

in

depth

examination

of

only

the

sentinel

lymph

node

-LRB-

SLN

-RRB-

could

be

helpful

In

colon

carcinoma

the

SLNs

are

defined

as

the

first

one

to

four

blue-stained

nodes

with

the

most

direct

lymph

drainage

from

the

primary

tumour

They

have

the

greatest

potential

to

harbour

metastatic

disease

when

present

enabling

focussed

examination

with

multi-level

micro-sectioning

of

the

SLNs

to

provide

a

more

efficient

and

cost-effective

detection

of

micrometastases

In

addition

patterns

of

aberrant

lymphatic

drainage

can

be

visualized

with

SLN

mapping

which

may

lead

to

a

more

extended

resection

Several

studies

have

reported

varying

results

of

the

SLN

procedure

in

colon

carcinoma

-LSB-

-RSB-

This

study

presents

the

results

of

the

SLN

procedure

in

six

Dutch

hospitals

The

primary

aim

of

this

study

is

to

test

the

accuracy

and

sensitivity

of

the

SLN

procedure

in

a

multi-centre

setting

Furthermore

we

looked

at

upstaging

and

possible

aberrant

lymphatic

drainage

Materials

and

methods

This

study

was

performed

between

May

and

May

in

five

teaching

hospitals

and

one

university

hospital

All

procedures

were

supervised

by

one

of

the

coordinating

surgeons

-LRB-

Plukker

Braat

-RRB-

Only

patients

with

histologically

proven

primary

colon

carcinoma

were

included

in

the

study

Patients

with

distant

metastases

or

gross

lymph

node

involvement

as

shown

by

pre-operative

examinations

or

palpation

during

surgery

were

excluded

The

procedure

was

only

performed

when

one

of

the

study

coordinators

was

available

for

supervision

-LRB-

Plukker

Braat

Kelder

-RRB-

The

study

was

approved

by

the

local

scientific

ethics

committee

and

all

patients

had

given

informed

consent

Patients

with

rectal

cancer

were

excluded

from

the

study

SLN

mapping

was

carried

out

through

an

open

procedure

by

injection

of

ml

Patent

Blue

with

a

tuberculin

syringe

and

needle

sub-serosally

in

four

quadrants

around

the

tumour

The

sub-serosal

injection

was

carried

out

before

vascular

ligation

Within

to

min

after

the

blue

dye

injection

the

SLN

could

be

identified

by

following

the

blue-stained

lymphatic

vessels

leading

to

the

blue-stained

SLN

These

lymph

nodes

were

tagged

with

a

long

suture

SLNs

were

defined

as

the

first

one

to

four

blue-stained

lymph

nodes

seen

within

the

regional

basin

After

marking

of

the

SLNs

routine

resection

was

performed

If

the

SLN

was

found

outside

the

normal

lymphatic

basin

we

performed

an

extended

resection

The

tumour

and

all

lymph

nodes

were

examined

according

to

standard

guidelines

-LSB-

-RSB-

If

the

SLNs

were

negative

after

routine

H&E

staining

they

were

sectioned

at

intervals

and

examined

at

three

levels

with

H&E

as

well

as

immunohistochemistry

on

cytokeratins

-LRB-

or

-RRB-

Metastases

between

and

mm

were

referred

to

as

micrometastases

Metastases

smaller

than

mm

were

referred

to

as

isolated

tumour

cells

-LSB-

-RSB-

Upstaging

was

defined

as

the

presence

of

micrometastases

or

isolated

tumour

cells

after

immunohistochemistry

-LRB-

IHC

-RRB-

in

patients

with

a

negative

lymph

node

status

after

H&E

Definitions

See

Fig.

Identification

rate

is

the

number

of

patients

with

one

or

more

SLNs

identified

-LRB-

b

-RRB-

the

total

number

of

procedures

-LRB-

a

-RRB-

Negative

SLNs

were

false

negative

if

one

of

the

other

regional

lymph

nodes

-LRB-

non-SLNs

-RRB-

were

tumour

positive

-LRB-

d

-RRB-

The

accuracy

of

the

SLN

procedure

suggests

a

conformity

of

the

SLN

status

and

the

regional

nodal

status

i.e.

the

total

number

of

patients

with

a

positive

SLN

-LRB-

c

-RRB-

the

number

of

patients

with

a

true-negative

SLN

-LRB-

e

-RRB-

the

number

of

patients

with

an

identified

SLN

-LRB-

b

-RRB-

Sensitivity

is

the

number

of

patients

with

a

positive

SLN

-LRB-

c

-RRB-

The

total

number

of

node

positive

patients

-LRB-

c

d

-RRB-

Upstaging

is

the

number

of

patients

with

positive

SLNs

by

IHC

-LRB-

g

-RRB-

the

number

of

patients

who

were

node

negative

by

H&E

examination

-LRB-

e

g

-RRB-

Fig.

SLN

Sentinel

lymph

node

pts

patients

Results

The

SLN

procedure

was

performed

in

patients

Tumour

characteristics

are

shown

in

Table

Figure

shows

the

total

number

of

patients

and

SLN

results

At

pathological

examination

a

mean

of

nodes

per

specimen

was

found

per

hospital

this

varied

between

and

-LRB-

respectively

-RRB-

The

mean

number

of

SLNs

was

per

patient

The

SLN

was

identified

in

out

of

patients

-LRB-

-RRB-

One

of

the

two

failed

procedures

was

in

a

patient

with

a

carcinoma

in

the

sigmoid

colon

surrounded

by

a

concurrent

diverticulitis

The

other

patient

had

extended

lymph

node

metastases

with

angio-invasion

at

pathological

examination

In

patients

lymph

node

metastases

were

identified

at

the

pathological

examination

this

includes

the

one

case

where

the

SLN

procedure

failed

because

of

extensive

lymph

node

metastases

-LRB-

of

-RRB-

This

one

case

with

lymph

node

metastases

and

a

failed

procedure

was

excluded

from

further

statistical

analysis

on

the

SLN

procedure

leaving

node-positive

patients

in

the

final

analysis

In

patients

the

SLN

was

positive

either

with

H&E

staining

or

with

IHC

resulting

in

a

sensitivity

of

-LRB-

of

-RRB-

in

the

group

of

patients

with

a

successful

SLN

procedure

If

we

leave

out

the

patients

who

had

a

positive

sentinel

node

only

after

IHC

the

sensitivity

is

of

-LRB-

-RRB-

In

of

SLN-positive

patients

the

SLN

was

the

only

involved

lymph

node

-LRB-

-RRB-

In

of

lymph

node-positive

patients

metastases

were

found

only

after

IHC

In

four

patients

these

were

micrometastases

whereas

in

five

cases

isolated

tumour

cells

were

found

Therefore

without

IHC

the

number

of

node-positive

cases

would

have

been

minus

which

is

This

corresponds

to

a

total

of

node-negative

cases

by

H&E

in

the

group

with

a

successful

SLN

procedure

With

IHC

the

upstaging

is

of

or

The

SLN

was

negative

in

patients

In

patients

the

non-SLNs

were

also

negative

This

results

in

a

negative

predictive

value

of

-LRB-

of

-RRB-

One

of

the

three

patients

with

a

false-negative

SLN

had

lymph

node

metastases

with

extra-nodal

growth

in

the

non-SLN

In

another

patient

a

small

tumour

deposit

was

found

in

the

mesocolon

right

next

to

the

primary

tumour

This

was

classified

as

according

to

the

American

Joint

Committee

on

Cancer

classification

although

it

is

unclear

whether

this

is

a

true

lymph

node

metastasis

or

some

kind

of

in

transit

metastasis

The

last

patient

with

a

positive

non-SLN

showed

micrometastases

at

H&E

examination

in

a

small

peritumoural

lymph

node

Aberrant

lymphatic

drainage

was

seen

in

three

patients

-LRB-

-RRB-

In

two

cases

the

SLN

was

found

on

the

left

side

of

the

middle

colic

artery

in

patients

with

a

tumour

in

the

ascending

colon

In

both

cases

an

extended

right

hemicolectomy

was

performed

The

third

patient

had

a

tumour

near

the

rectosigmoid

junction

with

a

high

para-aortal

SLN

Therefore

we

performed

an

extended

left

sided

resection

en-bloc

with

a

partial

para-aortal

dissection

of

these

lymph

nodes

contained

metastases

All

other

SLNs

were

found

in

the

mesocolon

in

close

proximity

to

the

tumour

In

these

cases

the

central

lymph

node

as

identified

by

the

pathologist

was

always

a

non-SLN

The

accuracy

of

the

SLN

procedure

in

this

study

was

as

the

pathological

status

of

the

SLN

corresponds

with

the

definitive

lymph

node

status

in

of

the

patients

Table

characteristicsCharacteristicsValuesTumour

location

Right

Left

Sigmoid

11 214 348

number

of

lymph

number

of

Discussion

With

an

identification

rate

of

accuracy

of

sensitivity

of

and

negative

predictive

value

of

this

study

shows

that

it

is

possible

to

perform

the

SLN

procedure

properly

in

patients

with

localized

colon

carcinoma

in

a

multi-centre

setting

Other

multi-centre

studies

showed

varying

results

of

this

technique

-LRB-

Table

-RRB-

-LSB-

-RSB-

Our

results

correlate

with

those

from

other

larger

studies

which

show

accuracy

and

sensitivity

rates

of

and

respectively

-LSB-

-RSB-

Most

smaller

studies

show

worse

results

with

low

accuracy

and

success

rates

and

corresponding

low

sensitivity

rates

and

negative

predictive

values

-LSB-

-RSB-

In

one

study

the

time

between

injection

of

the

blue

dye

and

identifying

the

SLN

was

too

long

leading

to

a

larger

number

of

SLNs

-LSB-

-RSB-

It

is

very

likely

that

not

all

of

these

blue

nodes

were

true

SLNs

In

the

study

by

Bertagnolli

et

al.

-LSB-

-RSB-

patients

were

operated

on

by

different

surgeons

in

different

hospitals

A

mean

of

three

procedures

per

surgeon

seems

insufficient

to

adequately

learn

this

technique

It

is

known

that

the

learning

curve

of

the

SLN

in

colon

carcinoma

stabilizes

after

about

five

procedures

-LSB-

-RSB-

To

minimize

technical

failures

the

procedure

in

our

study

was

performed

by

a

few

surgeons

under

direct

supervision

of

one

of

the

two

surgeons

coordinating

this

study

-LRB-

Braat

Plukker

-RRB-

Apart

from

too

few

procedures

the

worse

results

in

some

studies

might

be

explained

by

inclusion

of

patients

with

advanced

disease

Some

studies

included

patients

with

clinically

apparent

stage

III

or

stage

IV

disease

-LSB-

-RSB-

Widespread

lymph

node

metastases

could

result

in

obstruction

of

lymphatic

channels

and

lymphatic

drainage

is

bypassed

to

other

-LRB-

non-sentinel

-RRB-

lymph

nodes

This

phenomenon

is

called

skip-metastasis

It

was

noted

in

one

of

the

patients

with

a

false-negative

SLN

in

our

study

who

had

advanced

lymphatic

metastases

with

extra-nodal

growth

Patient

selection

is

therefore

important

for

a

reliable

SLN

procedure

in

colon

carcinoma

In

fact

the

SLN

procedure

is

not

useful

in

patients

with

clinically

apparent

stage

III

or

stage

IV

disease

as

false-negativity

rates

will

be

higher

Moreover

in

these

patients

metastases

will

be

easily

found

at

routine

pathological

examination

and

the

SLN

procedure

will

not

have

any

additional

value

The

SLN

procedure

could

be

useful

in

those

patients

with

-LRB-

micro

-RRB-

metastases

that

would

not

be

identified

with

routine

pathological

examination

Furthermore

the

failed

procedure

in

one

of

our

patients

with

concurrent

diverticulitis

also

suggests

the

importance

of

an

undisturbed

lymphatic

drainage

for

a

successful

SLN

procedure

Table

Results

of

multi-centre

studies

of

the

SLN

procedure

in

colon

cancerStudyNumber

of

patientsNumber

of

centresIdentification

rate

-LRB-

-RRB-

Accuracy

-LRB-

-RRB-

Sensitivity

-LRB-

-RRB-

Upstaging

-LRB-

-RRB-

Bilchik

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

et

al.

-LSB-

-RSB-

and

or

We

saw

aberrant

lymphatic

drainage

in

three

patients

-LRB-

-RRB-

This

percentage

correlates

with

the

literature

-LSB-

-RSB-

In

this

study

of

these

aberrant

SLNs

showed

metastases

However

potentially

these

aberrant

SLNs

are

the

only

lymph

nodes

containing

metastasis

as

shown

in

a

previous

study

-LSB-

-RSB-

In

an

experimental

situation

it

seems

justified

to

perform

an

extended

resection

in

these

cases

Further

study

should

be

performed

to

justify

an

extended

resection

in

the

daily

practice

Literature

not

clearly

indicates

how

many

nodes

should

be

examined

to

accurately

predict

lymph

node

status

-LSB-

-RSB-

One

study

showed

that

a

colon

specimen

usually

contains

about

lymph

nodes

and

that

more

than

of

the

lymph

nodes

containing

metastases

are

smaller

than

mm

-LSB-

-RSB-

It

is

also

known

that

the

prognosis

in

node-negative

patients

with

colon

carcinoma

is

better

when

more

lymph

nodes

have

been

examined

-LSB-

-RSB-

Taking

this

into

account

the

pathologist

takes

only

a

sample

of

the

lymphatic

basin

of

a

resected

colon

specimen

even

when

international

guidelines

are

followed

which

state

that

at

least

lymph

nodes

are

needed

for

adequate

staging

-LSB-

-RSB-

The

mean

number

of

lymph

nodes

in

our

study

is

not

enough

to

predict

lymph

node

status

according

to

the

international

guideline

This

fact

could

theoretically

lower

the

chance

to

detect

metastases

in

non-SLN

and

thus

could

lower

the

false-negative

rate

However

we

did

not

find

any

differences

in

false

negative

rates

between

the

two

hospitals

with

a

mean

number

of

nine

and

ten

examined

nodes

-LRB-

cases

-RRB-

and

the

hospitals

with

more

than

examined

nodes

-LRB-

cases

-RRB-

With

regards

to

upstaging

most

studies

show

an

upstaging

of

-LSB-

-RSB-

However

they

calculated

upstaging

by

dividing

the

number

of

IHC-positive

patients

by

the

total

number

of

patients

-LRB-

Fig.

of

in

our

group

-RRB-

We

think

it

is

better

to

consider

upstaging

solely

in

the

H&E

node-negative

group

as

this

is

the

group

to

be

upstaged

by

IHC

Using

this

method

we

find

upstaging

in

our

series

In

addition

to

this

true

upstaging

patients

with

a

SLN

as

the

only

site

of

metastases

could

have

been

possibly

upstaged

as

conventional

pathological

dissection

of

the

mesentery

might

have

missed

this

lymph

node

The

SLN

procedure

with

patent

blue

might

be

able

to

improve

adequacy

of

the

lymph

node

examination

by

selecting

the

right

lymph

nodes

even

small

nodes

less

than

mm

to

be

examined

in

depth

by

the

pathologist

We

found

the

SLN

to

be

the

single

lymph

node

with

metastasis

in

-LRB-

-RRB-

of

the

patients

-LRB-

Fig.

f

-RRB-

Possible

upstaging

might

play

a

role

here

but

we

can

not

prove

this

As

we

believe

that

even

isolated

tumour

cells

are

important

for

staging

we

assigned

patients

with

micrometastases

or

isolated

tumour

cells

to

the

group

of

node-positive

patients

It

must

be

remarked

however

that

these

cases

were

also

used

for

the

calculation

of

upstaging

Our

idea

of

the

biological

importance

of

micrometastases

and

isolated

tumour

cells

is

based

on

a

recent

meta-analysis

that

showed

that

micrometastases

detected

retrospectively

by

RT-PCR

correlated

better

with

overall

survival

than

IHC

and

carried

significant

prognostic

value

-LSB-

-RSB-

Regarding

the

detection

of

micrometastases

two

studies

showed

a

high

reliability

of

the

SLN

concept

to

predict

micrometastases

and/or

isolated

tumour

cells

also

in

non-SLNs

Therefore

it

seems

sufficient

to

perform

IHC

only

on

the

SLN

while

examining

the

non-SLNs

with

H&E

-LSB-

-RSB-

Prospective

studies

are

needed

to

evaluate

the

potential

benefit

of

systemic

chemotherapy

in

patients

with

these

micrometastases

A

reliable

SLN

procedure

might

facilitate

this

intensive

pathological

examination

by

allowing

focussed

examination

of

only

the

SLN

and

thereby

aid

in

a

better

patient

selection

for

adjuvant

therapy

in

the

future

O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

micrometastasis
minimal residual disease