U897 Pierre Joly
email: pierre.joly@isped.u-bordeaux2.fr

C Durand

C Helmer

& D Commenges

Estimating life expectancy of demented and institutionalized subjects from interval-censored observations of a Multi-state model

Keywords: Dementia, Institutionalization, Interval-censoring, Life expectancy, Multi-state model, Penalized likelihood

We consider the problem of estimating life expectancy of demented and institutionalized subjects from interval-censored observations. A mixed discretecontinuous scheme of observation is a classical pattern in epidemiology because very often clinical status is assessed at discrete visit times while times of death or other events can be exactly observed. In this work we jointly modelled dementia, institutionalization and death from data of a cohort study. Due to discrete time observations, it may happen that a subject developed dementia or was institutionalized between the last visit and death. Consequently, there is an uncertainty about the precise number of diseased or institutionalized subjects. Moreover the time of onset of dementia is intervalcensored. We use a penalized likelihood approach for estimating the transition intensities of the multi-state model. With these estimators, incidence and life expectancy can be computed easily. This approach deals with incomplete data due to the presence of left-truncation and interval-censoring. It can be generalized to take explanatory variables into account. We illustrate this approach by applying this model to the analysis of a large cohort study on cerebral aging.

Introduction

In longitudinal follow-up of cohort studies, subjects are only intermittently observed. Such discrete observations times produce interval-censored observations. Thus, we lack information about the accurate time of transition between states and we may miss some transitions. Transition intensities may be interpreted, in some cases, as incidence or mortality rates [START_REF] Keiding | Age-specific Incidence and Prevalence: a Statistical Perspective[END_REF]. In our application, we were primarily interested in estimating age-specific incidence of dementia and life expectancy for demented and institutionalized subjects. Knowledge of life expectancy for specific population such as demented or institutionalized subjects is useful to improve management of elderly subjects. Our application is based on the Paquid study [START_REF] Letenneur | Are sex and educational level independent predictors of dementia and alzheimer's disease ? Incidence data from the PAQUID project[END_REF], a prospective population-based cohort focused on the epidemiology of dementia in the elderly population. The study initially included a community-based sample of 3,777 elderly subjects, aged 65 and older. The subjects were selected conditionally on being non-demented and non-institutionalized at baseline. These subjects were followed-up over a 13-year period with 7 intermittent times of follow-up. Over the follow-up, information on onset of dementia and entry in institution was assessed only at planned visits. Thus, we have to deal with several problems. Firstly, due to intermittently observed data, we must jointly model dementia and death, in order not to under-estimate the incidence of dementia [START_REF] Joly | A penalized likelihood approach for an illness-death model with intervalcensored data: application to age-specific incidence of dementia[END_REF]. Secondly, due to baseline selection conditions of the cohort, we have to take into account dementia and institution in the truncation condition. Thus we have to jointly model entry in institution and onset of dementia. Finally, we have to take into account that data were not observed in continuous time. We propose a non-parametric method for estimating the transition intensities in an irreversible multi-state model for interval-censored data. This work is the continuation of [START_REF] Commenges | Multi-state model for dementia, institutionalization and death[END_REF]; however, in this preliminary work, not applied to real data, the institutionalization status was assumed to be observed in continuous time. We treat the problem on institutionalization assessed only at planned visits in the present work. In addition, we estimate life expectancy for demented and institutionalized subjects. This approach also allows analysing risk factors acting on the transition between the different states.

The model is presented in the next section. Estimation of age-specific incidence of dementia and life expectancy is described in section 3. The application and the results are provided in section 4. Section 5 discusses the proposed approach.

The Model

The Multi-state Model

We consider a five-state model with irreversible transitions depicted in Figure 1, where the α hj are the transition intensities of a Markov process X [START_REF] Commenges | Multi-state model for dementia, institutionalization and death[END_REF]. Subjects are in state 0 if they are "healthy" (that is non demented and living at home), in state 1 if they are demented and living at home, in state 3 if they are demented and living in institution and in state 2 if they are non demented and living in institution. State 4, death, is an absorbing state and it is possible to go to this state from all the four other states.

α 01 (t) α 04 (t) α 02 (t) α 14 (t) α 24 (t) α 13 (t) α 34 (t) α 23 (t) ✲ ✛ ❅ ❅ ❅ ❅ ❅ ❅ ❅ | ✒ ❄ ✻ ❅ ❅ ❅ ❅ ❅ ❅ ❅ | ✒ Figure 1:
The five-state model for dementia, institutionalization and death.

Age is the major risk factor of dementia (see [START_REF] Launer | Rates and risk factors for dementia and Alzheimer's disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups[END_REF], institutionalization and death and we are mostly interested in age-specific incidence and age-specific mortality. We thus consider a non-homogeneous Markov model where the intensities only depend on age and not on the time since the onset of the disease or the institutionalization.

Patterns of observation and interval censoring

In longitudinal follow-up studies, subjects are only intermittently observed. Thus, dementia and institutionalization statuses are assessed only at discrete time points, corresponding to the planned visits. If a transition toward dementia is observed, the age at the time of transition is interval-censored. On the contrary, once we observed a subject in an institution we can collect the date of institutionalization. Thus, as we observe institutionalization status in continuous time, the age at the time of transition is not interval-censored for these subjects. If a subject who dies was non demented at the last visit, it is not known whether the subject has made the transition towards dementia or not. If a subject who dies was seen at home at the last visit, we try to collect the information about institutionalization; but for some subjects it is not possible to know whether the subject has been institutionalized before death or not. Thus, discrete observations times not only produce interval-censored observations but also an uncertainty about the followed path.

In Figure 2 we propose three examples of follow-up to illustrate the pattern of observation and its relation with interval censoring. subject 1

V 10 V 11 ... V 1k healthy demented V 1k+1 subject 2 V 20 V 21 ... V 2k T I healthy in institution V 2k+1 subject 3 V 30 V 31 ... V 3k
healthy dem and/or inst ? death Subject 1 was seen healthy at the planned visit V 1k and was diagnosed demented at the next planned visit V 1k+1 . The date of transition toward dementia is not known exactly; it is only known to lie between two visits (here between V 1k and V 1k+1 ): there is interval-censoring.

V 3k+1
Subject 2 was seen healthy at the planned visit V 2k and was seen in institution at the next planned visit V 2k+1 . Once we observe a subject in institution we can collect the exact date of institutionalization (here T I is the age at the time of institutionalization). There is no interval-censoring for entry in institution.

Subject 3 was seen healthy at the planned visit V 3k and he died before the next planned visit V 3k+1 . It is not known whether he has made the transition towards dementia. Similarly it is difficult, and some time impossible to know if he was institutionalized before death. This is the most difficult case.

There are other types of possible observation. It is possible to find examples in the sub-sample of the data set used for the application provided in Appendix B. All the possible trajectories are given in the likelihood part.

The Likelihood

The likelihood used in this article is slightly different than the likelihood detailed in [START_REF] Commenges | Multi-state model for dementia, institutionalization and death[END_REF] because the assumptions on the observation of the institutionalization status differ. Subjects are not followedup from the origin (their birth) but from their age at entry in the cohort. Demented and institutionalized subjects at the initial visit are excluded from the sample. This produces a left-truncation that has to be taken into account in the likelihood. We assume that the truncating and censoring mechanisms are independent from the multi-state process (for a discussion on independent censoring see [START_REF] Grüger | The validity of inferences based on incomplete observations in disease state models[END_REF]. This happens for instance if the visits are fixed or are random variables independent of the illness-death process (visits times have been prespecified in advance in the Paquid study), and if loss of follow-up obeys an independent censoring mechanism. The last assumption is difficult to verify in our study and may not hold.

The model is completely specified by the eight transition intensities (see figure 1): α 01 (t), α 02 (t), α 04 (t), α 13 (t), α 14 (t), α 23 (t), α 24 (t), α 34 (t). It is natural to write the likelihood in terms of both transition intensities and transition probabilities p hj (s, t), where p hj (s, t) = P (X t = j|X s = h). Kolmogorov equations allow expressing the latter in terms of the former: Example: likelihood contribution for a subject i not demented and not seen in institution at the time of the last visit V Li . TV i is the time of death or the time of right-censoring (δ V i = 1 if the subject has died). The subject is healthy at V 0i , the beginning of the follow-up; left-truncation is taken into account by using the probability p 00 (V 0i , V Li ) rather than p 00 (0, V Li ) (this amounts to divide the unconditional likelihood by p 00 (0, V 0i ), the likelihood of the condition).

p 00 (s, t) = e -A 01 (s,t)-A 02 (s,t)-A 04 (s,t) p 11 (s, t) = e -A 13 (s,t)-A 14 (s,t) p 22 (s, t) = e -A 23 (s,t)-A 24 (s,t) p 33 (s, t) = e -A 34 (s,t) p 01 (s, t) = t s p 00 (s, u)α 01 (u)p 11 (u, t)du p 02 (s, t) = t s p 00 (s, u)α 02 (u)p 22 (u, t)du p 03 (s, t) = t s t u p 00 (s, u) α 01 (u)p 11 (u, v)α 13 (v)+α 02 (u)p 22 (u, v)α 23 (v) p 33 (v,
L i = p 00 (V 0i , V Li ) p 00 (V Li , TV i )α 04 ( TV i ) δ V i + p 01 (V Li , TV i )α 14 ( TV i ) δ V i + p 02 (V Li , TV i )α 24 ( TV i ) δ V i + p 03 (V Li , TV i )α 34 ( TV i ) δ V i
The likelihood contribution for all the different trajectories of the subjects are detailed in Appendix A. This heuristic likelihood can be rigorously justified using the results of Commenges and Gégout-Petit (2007).

Inference is based on maximizing the likelihood. We propose to use a penalized likelihood approach detailed in the next paragraph. Since there are eight transition intensities to estimate in this model we propose a semiparametric approach in order to reduce the number of functions to estimate non-parametrically. We assume proportionality for all transitions intensities towards death:

α 14 (t) = α 04 (t)e θ 14 α 24 (t) = α 04 (t)e θ 24 α 34 (t) = α 04 (t)e θ 34
We also assume proportionality for the transitions towards dementia:

α 23 (t) = α 01 (t)e θ 23
and proportionality for the transitions towards institution:

α 13 (t) = α 02 (t)e θ 13
Keiding et al. (2001) and [START_REF] Klein | Plotting summary predictions in multi-state survival models: probabilities of relapse and death in remission for bone marrow transplantation patients[END_REF], for example, used the same kind of assumption in a multi-state model of bone marrow transplantation. Verifying these assumptions is theoretically possible by considering a more general model, with one more estimation of a transition intensity for example, and using an approximate cross-validation criterion (see Commenges et al., 2007) to compare the two models. We did not do it because of the numerical complexity of this more general model.

The penalized likelihood approach

Usually, intensity functions are expected to be smooth. A possible means to introduce such a priori knowledge, is to penalize the log-likelihood by a term which takes large values for rough functions. The roughness penalty function chosen in our five-state model is the sum of the L 2 norms of the second derivatives of the three intensities α 01 , α 02 and α 04 . In functional analysis, the integrated squared second derivative is a widespread choice for the roughness of a function (see [START_REF] Ramsay | Functional Data Analysis[END_REF]. The penalized log-likelihood is thus defined as:

pl(α 01 , α 02 , α 04 , θ) = l(α 01 , α 02 , α 04 , θ) - k=1,2,4 κ 0k +∞ 0 α ′′ 0k 2 (u)du (2.1)
where l is the full log-likelihood, θ = (θ 14 , θ 24 , θ 34 , θ 13 , θ 23 ) and κ 01 , κ 02 and κ 04 are the three positive smoothing parameters which control the tradeoff between the data fit and the smoothness of the intensity functions. Maximization of (2.1), in the desired class of function, defines the maximum penalized likelihood estimators (MPLE) α01 (.), α02 (.), α04 (.) and θ.

Estimation procedure

The MPLE cannot be calculated explicitly. However, for each transition intensity, it can be approximated using splines. Splines are piecewise polynomial functions which are combined linearly to approximate a function on an interval. We use cubic M-splines, which are normalized B-splines. For more details, see [START_REF] Ramsay | Monotone regression splines in action[END_REF] and Joly et al. (1998). There is one base of splines M 0k (.) = (M 10k (.), ..., M m 0k 0k (.)) T for each transition. Each transition intensity estimator α0k (.) is approximated by a linear combinations of m 0k cubic M-splines α0k (.) = γ0k M 0k (.). The spline function α0. is defined by a sequence of increasing knots and a vector of coefficients γ0. . The first knot is set at 0 or just before the first follow-up time point (for delayed entry) and the last knot is set just after the last follow-up time point. Other knots are put equidistantly between the first and the last one. Theoretically, the more knots, the better the approximation. Increasing the number of knots does not deteriorate the MPLE: this is because the degree of smoothing in the penalized likelihood approach is tuned by the smoothing parameter κ 0. and not by the number of knots. Once a sufficient number of knots is established, there is no advantage in adding more because the more knots, the longer the running time. Usually, we found that a good choice for the number of knots is between 7 and 15. The three vectors of spline's coefficients γ01 , γ02 and γ04 are obtained simultaneously by maximizing pl. When the four vectors γ01 , γ02 , γ04 and θ are obtained, all the functions of interest can be computed, as in a parametric model. To choose the three smoothing parameters, we used an approximate cross-validation criterion (see Commenges et al., 2007). The criterion was maximized using a pseudo-grid method. The model can be generalized to regression models to study explanatory variables using a proportional intensity function model. The regression parameters and the baseline functions are estimated simultaneously. The variance of parameters are computed using the inverse of the matrix of the second derivatives of the penalized likelihood.

Estimation of age-specific incidence of dementia and life expectancy

Unlike with an "illness-death" model (see [START_REF] Joly | A penalized likelihood approach for an illness-death model with intervalcensored data: application to age-specific incidence of dementia[END_REF] the transition intensity α 01 is not enough to estimate the age-specific incidence of dementia. Using the previously defined transition probabilities, the age-specific incidence of dementia for subjects living at home at 65 years old is:

Ic(t) = p 00 (
This is a weighted mean of the incidences of healthy and institutionalized subjects, the weights being the probabilities of these states at time t. For a similar expression for obtaining death intensity in an illness-death model see, for example, [START_REF] Andersen | Multi-state models in survival analysis: a study of nephropathy and mortality in diabetes[END_REF].

Likewise, obtaining all the transition intensities allows to compute easily life expectancy in institution and life expectancy for demented people. The life expectancy for a subject demented and living at home at age t d is: When the estimators γ01 , γ02 , γ04 and θ are obtained, we have the estimators of all the transition intensities and then de probability functions p 11 , p 13 , p 33 , p 22 and p 23 and then we plug them in 3.1, 3.2, 3.3, 3.4 and 3.5 to obtain estimators of age-specific incidence of dementia and life expectancy. A Bayesian technique for generating confidence bands for each transition intensity was used in [START_REF] Joly | A penalized likelihood approach for an illness-death model with intervalcensored data: application to age-specific incidence of dementia[END_REF]. But, even with the delta-method, we cannot use this technique to compute confidence bands for age-specific incidence and for life expectancy because the relation between transition intensities and these functions is too complex. To obtain confidence bands for these functions we propose to use a parametric bootstrap [START_REF] Efron | An introduction to the Bootstrap[END_REF]. We generated 2000 realizations from the asymptotic distribution of the parameters. For each replication we computed age-specific incidence and life expectancy and for each point considered, we order the 2000 values obtained; the lower bound and the upper bound of our confidence band are respectively given by the 2.5th and the 97.5th empirical percentiles. However, this estimator does not take into account the variability due to the choice of smoothing parameters.

Application: estimation of age-specific incidence of dementia and survival time in institution

The application is based on the Paquid research programme, a prospective cohort study of mental and physical aging that evaluates social environment and health status. The target population consists of subjects aged 65 years and older living at home at the baseline visit in southwestern France. The baseline variables registered included socio-demographic factors, medical history and psychometric tests. Subjects were re-evaluated 1, 3, 5, 8, 10 and 13 years after the initial visit. Demented subjects at the baseline visit were removed from the sample because the initial sample may not be representative. Therefore, this produced a left-truncation problem, subjects living at home and not demented at baseline visit. As mentionned before, the inspection processes for dementia, institutionalization and death are all different. Dates of death are always reported unlike dates of onset of dementia and entry in institution which were assessed only at planned visits. But for entry in institution, unlike for onset of dementia, we can most often collect the exact date of institutionalization when the subject is seen in institution.

Numbers of observed women and men diagnosed as demented and in institution over the 13 years of follow-up are detailed in Table 1. In a previous work [START_REF] Joly | A penalized likelihood approach for an illness-death model with intervalcensored data: application to age-specific incidence of dementia[END_REF] we found that the age-specific incidence of dementia was different between women and men. It is also well known that the age-specific risk of death is higher in men than in women, especially in France [START_REF] Robine | European perspectives on healthy aging in women[END_REF]. Thus we separately estimated the transition intensities for women and men. We used 7 knots for each intensity function. Figure 3 displays age-specific incidence of dementia for women and men. We observe, as in [START_REF] Joly | A penalized likelihood approach for an illness-death model with intervalcensored data: application to age-specific incidence of dementia[END_REF], that the estimate of age-specific incidence of dementia is slightly higher for men than for women under 79 years old and slightly higher for women than for men after this age. We give in Table 2 the estimates of the parameters θ and the corresponding standard errors. Figures 4 and5 display the life expectancy for women and men, respectively for subjects developing dementia and entered in institution. In Figure 4, we plot the life expectancy for women and men demented at home as a function of age. In Figure 5 we plot the life expectancy for women and men in institution and not demented as a function of age. Whatever the age, the life expectancy is higher for women than for men but the difference is decreasing with age. We give some selected values in Table 3. There seems to be a contrast between institutionalized women and men. While women in institution have a higher estimated life expectancy when they are non demented versus when they are demented, the reverse is true for men. Subjects in institution may have some other diseases, but this does not explain the contrast between institutionalized women and men. Note however that the difference for men is small with regard to the confidence interval.

Discussion

In this paper we propose an estimation method applied to multi-state model with interval-censoring. Our work was mainly motivated by two major issues: estimation of age-specific incidence of dementia and life expectancy for demented or institutionalized subjects. With interval-censoring and a high risk of death for demented and institutionalized subjects, there is an underestimation of the incidence of dementia using a (two-state) survival analysis approach. It is then important to take interval-censoring into account. The proposed penalized likelihood approach in a multi-state model yields a method for analyzing such data and for providing estimators of the intensity functions, which cannot easily be estimated using conventional nonparametric methods. Once the intensity functions are obtained, age-specific incidence and life expectancy can easily be computed. Moreover, the penalized likelihood approach yields smooth estimates of the transition intensities without making the strong assumption that it belongs to a given parametric model. The proposed approach can be applied to semi-Markov models as well as to non-homogeneous Markov models and can be generalized to regression models to deal with explanatory variables. The approach can easily be extended to models with reversible transitions if there is no interval-censoring in the reversible transitions. If there is interval-censoring, there may be an infinite number of transitions between two observations, which is hard to treat in non homogeneous Markov models. In the same way right-truncation can be accomodated. The program was written in FORTRAN 77 and is available on request.

In France, the higher mortality rate in men compared to women is well known. This work shows that there are also large differences in life expectancy according to sex, even after institutionalization or dementia, although the difference is decreasing with age. These data have public health implications, in the case of demented people and of institutionalized residents.

Subject diagnosed demented at V R (δ D = 1)

• If δ I = 0 (not institutionalised T I = TV ) L = p 00 (V 0 , V L )p 01 (V L , V R )p 11 (V R , TV )α 14 ( TV ) δ V

Figure 2 :

 2 Figure 2: Examples of follow-up of three subjects 1, 2 and 3.

Figure 3 :

 3 Figure 3: Age-specific incidence of dementia for women (-) and men (---).

Figure 4 :

 4 Figure 4: Life expectancy for demented subjects living at home as a function of age:women (-) and men (---).

Figure 5 :

 5 Figure 5: Life expectancy for institutionalized non demented subjects as a function of age: women (-) and men (---).

•

  If δ I = 0 (not known institutionalised but T I < TV )L = p 00 (V 0 , V L )p 01 (V L , V R )p 11 (V R , T I ) p 11 (T I , TV )α 14 ( TV ) δ V + p 13 (T I , TV )α 34 ( TV ) δ V • If δ I = 1 (institutionalised) -If T I < V L L = p 00 (V 0 , T I )α 02 (T I )p 22 (T I , V L )p 23 (V L , V R )p 33 (V R , TV )α 34 ( TV ) δ V -If V L < T I < V R L = p 00 (V 0 , V L ) p 01 (V L , T I )α 13 (T I )p 33 (T I , V R ) + p 00 (V L , T I )α 02 (T I )p 23 (T I , V R ) p 33 (V R , TV )α 34 ( TV ) δ V -If T I > V R L = p 00 (V 0 , V L )p 01 (V L , V R )p 11 (V R, T I )α 13 (T I )p 33 (T I , TV )α 34 ( TV ) δ V

Table 1 :

 1 Observed number of women and men demented and in institution over the 13 years of follow-up.

		Women Men Total
		2133 1540 3673
	diagnosed as demented	396 189	585
	in institution	342 113	455
	dead*	1038 939 1977
	* dead over the 13 years of follow-up include subjects
	previously diagnosed as demented or institutionalized.

Table 2 :

 2 Estimates of θ (with standard errors) for women and men

		Women	Men
	θ 14 (Dm → D)	1.13 (0.18)	2.25 (0.17)
	θ 24 (I → D)	1.29 (0.17)	1.79 (0.18)
	θ 34 (Dm+I → D)	1.83 (0.11)	1.57 (0.18)
	θ 13 (Dm → Dm+I) 1.83 (0.15)	2.39 (0.24)
	θ 23 (I → Dm+I)	0.92 (0.19)	-0.84 (1.04)

Table 3 :

 3 Estimated life expectancy for subjects, healthy, in institution and/or with dementia, for women and men for different ages with 95% confidence intervals (parametric boostrap with 2000 replications)

	Women

Appendix A

Likelihood

In principle all the indicators and times of observations should be indexed by i (example L i , δ V i , ...); we will omit this for the sake of simplicity.

We have three indicators: δ V = 1 if the subject is deceased, δ I = 1 if the subject is known institutionalised and δ D = 1 if the subject is diagnosed demented. V 0 is the age at the entrance in the cohort. TV is the age at death or at right-censoring for death, T I is the age at the time of institutionalization or at right-censoring for the institutionalization. V L is the age at the last visit without dementia and V R is the age at the first visit with dementia (for subject diagnosed demented).

Subject not demented at the time of the last visit V L (δ D = 0)

Sub-sample of 40 men followed during 13 years: Paquid research programme.


N Stefanakis

R Gribonval

Underwater acoustic imaging: physically-motivated sparse models and validation on real data

Outline

Classical approach to sonar: beamforming (BF)

Beam at emission (E(θ))

Beam at reception (R(φ))

In a nutshell:

A beam = focus on a quasi-planar region (θ or φ).

Forming E or R beams = apply gains/delays to transducers.

E(θ) beam ∩ R(φ) beam = image point in direction (θ, φ).
Successive pings = successive beams with varying angles.

BF imaging = linear estimator b BF Wm for some W.

Limit.: resolution (primary lobe), artifacts (sidelobes), not 3D imaging.

Sparse approaches to sonar: state of the art Physically-motivated sparsity: most of the points in the 3D space are not scatterers (air, water).

m = Φb b sparse ⇒ b CS = arg min b b 1 + µ m -Φb 2 2
From:

P. Boufounos, Compressed sensing for over-the-air ultrasound, ICASSP 2011.

But: tests are on simple synthetic data.

Our focus

Challenges when moving from synthetic to real data.

New sparse model, validity of the sparse models on real data.

Outline

Problem statement

From synthetic to real data imaging New sparse models and model validation

Conclusion

From tic to real data: challenges

Processing real data implies:

Handling a 3D grid with a higher number of points;

Detecting targets that are not located on the grid points;

Detecting complex-shape objects rather than a simple pattern like a square;

Using non-ideal transducers with directivity patterns and calibration issues;

Handling phase issues: propagation, modulation by a carrier frequency;

Processing noisy measurements.

Experimental features

General settings

Discretization & dimensionality issues

Full tank discretized with step λ: K = 48.10 6 voxels in the grid. Measurement length: 13.10 6 samples.

Problem size OMP: naive → efficient implementation

      m       =       Φ                 b           ∈ C 13.

OMP implementation

Residue initialization: r ← m; Sparse support initialization:

Ω ← ∅; for K = 1 to K max do Atom selection: k ← arg max k | a k , r | O (N T N R N P × K ) → O (N T log N e + N R N P K ) Sparse support update: Ω ← Ω ∪ k Sparse representation update: b Ω ← Φ + Ω m (adaptive update) Residue update: r ← m -Φ Ω b Ω end for Output: b OMP ← b Ω .
Directional scattering model: principle New papers in preparation

  : direct problem Successive emission sequences, or pings, indexed by p. e p,i : emission at emitter i, ping p. m p,j : measurement at receiver j, ping p. b k : backscattering coefficient at position k. τ ik + τ kj : propagation delay. Direct problem: ∀p, j, t, m p,j (t) = k b k i e p,i t -τ ik -τ kj In a matrix form, m = Φb Underwater acoustic imaging (inverse) problem m = Φb Goal: estimate vector b from measurement vector m and known matrix Φ (made with delayed versions of the emitted signals).

  In the standard (omnidirectional) scattering model, b k depends on position k only:

Fresh

  i t -τ ik -τ kj New directional scattering model: b ikj depends on the incoming direction from emitter i and outgoing direction to receiver j, m p,j (t) = k i b ikj e p,i t -τ ik -τ kj Directional scattering model: physically-motivated m p,j (t) = k i b ikj e p,i t -τ ik -τ kj Motivations: scatterers are not omnidirectional transducers may not be calibrated: b ikj = γ i b k γ j Directional scattering model: validation Directional scattering model as a sparse model m p,j (t) = k i b ikj e p,i t -τ ik -τ kj Sparsity in the omnidirectional scattering model: ∀k ∈ Ω c , b k = 0 Sparsity in the directional scattering model: ∀k ∈ Ω c , ∀i, j, b ikj = 0 The resulting model is a mixture of: a joint sparse model (Duarte et al., 2005) due to the dependance on receiver j a kind of harmonic sparse model (Gribonval and Bacry, 2003) due to the dependance on emitter i , J. Marchal, V. Emiya, N. Bertin, R. Gribonval, P. Cervenka, Sparse Underwater Acoustic Imaging: A Case Study, submitted to ICASSP 2012.


Caroline Smolders
email: caroline.smolders@psy.kuleuven.be

Mihalis Doumas

Ralf Th

Krampe

Posture and Cognition Interfere in Later Adulthood even without Concurrent Response Production

Keywords: dual task, age differences, posture, cognition PsycINFO Classification code 2330 2340

Introduction

Sensorimotor tasks such as upright stance used to be considered as automatic, requiring minimal cognitive involvement. Dual-task studies assessing concurrent sensorimotor-cognitive performance have challenged this assumption by showing decrements in dual-compared to single-task performance, so-called dual-task costs. A number of age comparative dual-task studies have shown pronounced dual-task costs in older compared with young adults [for an overview see [START_REF] Li | An ecological approach to studying aging and dual-task performance[END_REF]; for exceptions see [START_REF] Kemper | The costs of doing two things at once for young and older adults: Talking while walking, finger tapping, and ignoring speech or noise[END_REF]], and several authors have argued that this reflects increased demands for cognitive resources on the part of sensorimotor processes in the elderly [START_REF] Lindenberger | Memorizing while walking: Increase in dual-task costs from young adulthood to old age[END_REF]Woollacott & Shumway-Cook, 2002). This interpretation, however, has not remained unchallenged. Two issues feature most prominently in the critique raised. First, dual-task studies frequently used identical levels of cognitive task difficulty for all participants, arguably disadvantaging older adults from the start. If relatively more available resources are occupied by a cognitive task that is more difficult for older adults, they can invest fewer resources into the sensorimotor task to begin with. Similarly, a cognitive task not fully occupying young adults' resources, might lead to the erroneous interpretation of "automatic" sensorimotor performance in that group. The second critique concerns concurrent production of motor responses for both tasks, like pressing buttons with the hands. According to [START_REF] Hartley | Age differences in dual-task interference are localized to responsegeneration processes[END_REF], output interference at the level of the "response-bottleneck" is typical in dual-task studies and he argues that the described negative age effects largely reflect differences in peripheral processing stages. Indeed, in his studies, age differences in dual-task performance disappeared when concurrent response production was eliminated or reduced [START_REF] Hartley | Age differences in dual-task interference are localized to responsegeneration processes[END_REF][START_REF] Hartley | Age-related differences and similarities in dual-task interference[END_REF].

The aims of this paper are twofold. First we review adult age comparative studies assessing concurrent sensorimotor and cognitive performance to evaluate whether the evidence for increased cognitive resource demands of sensorimotor performance in later adulthood is indeed susceptible to the described critique. Second, we present a study that compared dual-task costs for concurrent working memory and postural control performances in young and older adults while avoiding the critical shortcomings of earlier studies.

Evidence for pronounced dual-task costs in older adults

Dual-task studies assessing concurrent sensorimotor and cognitive performance have been using sensorimotor tasks such as upright stance [START_REF] Doumas | Working memory and postural control: adult age differences in potential for improvement, task priority, and dual tasking[END_REF][START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF], walking [START_REF] Lovden | Walking variability and working-memory load in aging: a dual-process account relating cognitive control to motor control performance[END_REF], force control [START_REF] Voelcker-Rehage | Effect of motor practice on dual-task performance in older adults[END_REF], tapping (Krampe, Doumas, Lavrysen, & Rapp, under review), and coordination of hand-foot movements [START_REF] Heuninckx | Ipsilateral coordination deficits and central processing requirements associated with coordination as a function of aging[END_REF]. In Tables 1A andB, we present an overview of adult age comparative studies assessing concurrent sensorimotor and cognitive performance. Our listing makes no claims for completeness. We rather focussed on studies in which both sensorimotor and cognitive performances were thoroughly analyzed in their own rights, leaving out, for example a vast literature employing the traditional secondary task paradigm [for a more extensive review, see [START_REF] Li | An ecological approach to studying aging and dual-task performance[END_REF]].

Decrements in dual-compared to single-task performance, or dual-task costs (DTCs), suggest that sensorimotor processes require cognitive involvement. As can be seen in Tables 1A andB, patterns of resource allocation in dual-task situations differ across studies, with some showing DTCs in the sensorimotor domain [START_REF] Maylor | Effects of spatial and nonspatial cognitive activity on postural stability[END_REF][START_REF] Shumway-Cook | The effects of two types of cognitive tasks on postural stability in older adults with and without a history of falls[END_REF] others showing DTCs in both domains [START_REF] Lindenberger | Memorizing while walking: Increase in dual-task costs from young adulthood to old age[END_REF][START_REF] Shumway-Cook | Attentional demands and postural control: The effect of sensory context[END_REF], and still others showing trade-offs so that performance in one domain is improved at the expense of performance in the other domain [START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF][START_REF] Rapp | Adaptive task prioritization in aging: Selective resource allocation to postural control is preserved in Alzheimer disease[END_REF]. In general, DTCs are pronounced in older adults. The prevalent theoretical explanation for these age differences is that of diminished resources in later adulthood [for a review of theories explaining dual-task performance, see [START_REF] Lacour | Posture control, aging, and attention resources: models and posture-analysis methods[END_REF]]. However, several authors (e.g., [START_REF] Hartley | Age-related differences and similarities in dual-task interference[END_REF][START_REF] Somberg | Divided attention abilities in young and old adults[END_REF] have argued that attributing age differences in dual-task decrements to a reduction in central resources is premature and have pointed at methodological shortcomings in dual-task studies.

-Insert Tables 1A and B about here-1.2 Age differential single-task performance and concurrent response production Few dual-task studies have equated cognitive challenge and single-task performance levels across age groups and those who did produced a mixture of results. [START_REF] Somberg | Divided attention abilities in young and old adults[END_REF] observed no age differences in divided attention abilities after equating single-task performance levels. In contrast, [START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF] equated single-task cognitive performance levels by individually calibrating task difficulty, and still found agerelated decline in dual-task performance.

A second issue to consider relates to concurrent response production i.e., generating and executing two similar motor programs at the same time. Motor requirements of one task can interfere with those of another task, leading to a central bottleneck or processing limitation and thus produce dual-task decrements irrespective of cognitive demands. For example, muscular control of respiration (involved in speech production) and posture are interrelated; thus the concurrent performance of a posture and a spoken task requires concurrent response production. Most cognitive tasks used in dual-task studies require verbalization such as completing sentences [START_REF] Shumway-Cook | The effects of two types of cognitive tasks on postural stability in older adults with and without a history of falls[END_REF] or repeating a memorized digit sequence [START_REF] Maylor | Age differences in postural stability are increased by additional cognitive demands[END_REF], indicating that concurrent response production is common in dual-task studies. [START_REF] Yardley | Effect of articulatory and mental tasks on postural control[END_REF] were the first to examine the role of concurrent response production in dual-task performance of a sensorimotor and a cognitive task. Young adults performed a posture task and a task involving verbalization and/or attention both separately and concurrently. Results showed that postural performance deteriorated only when performing a spoken task (irrespective of cognitive demands), presumably due to impaired coordination between respiration and posture [START_REF] Navon | The role of outcome conflict in dual-task interference[END_REF]. Likewise, Krampe et al. (under review) observed a pronounced decline in tapping performance when concurrently performing a spoken task rather than an attention demanding 'silent' task. Concurrent response production introduces certain limitations to age-comparative dual-task studies, since empirical evidence suggests age related decrements in generating and executing similar motor programs at the same time. [START_REF] Hartley | Age differences in dual-task interference are localized to responsegeneration processes[END_REF] asked young and older adults to concurrently perform two cognitive tasks requiring similar (e.g., manual) responses or two tasks requiring different (e.g., manual vs. oral) responses. Older adults showed higher dual-task decrements than young adults but only when performing two tasks requiring similar responses.

Two recent studies [START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF][START_REF] Rapp | Adaptive task prioritization in aging: Selective resource allocation to postural control is preserved in Alzheimer disease[END_REF] examined age differences in concurrent posture-cognitive performance while controlling for concurrent response production and group differences in single-task cognitive performance levels. Young and older adults were asked to perform a working memory (WM) task and easy and difficult posture tasks both separately and concurrently. The WM task required verbal responding during (dual-task) posture data collection and the same number of items was verbalized in single-task posture assessments thereby equating concurrent response production across (single-, dual-) task contexts. Task difficulty was individually calibrated in order to equate cognitive challenge and single-task cognitive performance levels. Results showed that older but not young adults produced DTCs. These findings suggest that age differences in DTCs emerge even if response production in concurrent tasks do not use the same output modality and without group differences in single-task performance levels. In this respect, these studies already go beyond the Hartley findings [START_REF] Hartley | Age differences in dual-task interference are localized to responsegeneration processes[END_REF][START_REF] Hartley | Age-related differences and similarities in dual-task interference[END_REF]. However it remains possible that the combination of concurrent response production and cognitive load produced the observed dual-task decrements in older adults.

Altogether, the methodological considerations and empirical evidence summarized earlier suggest that verbal responding affects sensorimotor (e.g., tapping or posture) performance and that age differences in dual-task interference could be localized at the level of response generation or age differences in single-task performance levels. Consequently, age differences in dual-task performance could disappear when taking these methodological considerations into account.

Outline of the study

In the present study, we ask whether age differences in concurrent posture-cognitive performance emerge even in the absence of concurrent response production and group differences in single-task cognitive performance levels. To our knowledge, no previous dualtask study has taken these methodological considerations simultaneously into account when assessing concurrent posture and cognitive performance in different age groups. Young and older adults performed a WM task and two posture tasks (standing on a stable and moving platform) both separately and concurrently. The WM task required no verbal responding during posture data collection thereby eliminating concurrent response production. In addition, we individually calibrated WM task difficulty in order to equate cognitive challenge and single-task performance levels across age groups. This way, potential age differences in dual-task performance could not be attributed to concurrent response production or underlying single-task differences. Given evidence of sensorimotor and cognitive decline in the course of normal aging, we expected decreased WM capacity and posture performance in older adults. With respect to dual-task performance, we expected to observe pronounced dualtask decrements in older compared to young adults. Screening tests included two subtests from the Wechsler Adult Intelligence Scale [WAIS; Wechsler (1981)]: digit span and digit-symbol substitution. Exclusion criteria were the presence of medical conditions or intake of medication known to affect postural control [START_REF] Tillement | The risk of falling due to benzodiazepine administration, alone or in combination, in elderly subjects[END_REF]. None of the older adults showed impaired mental or general daily function as assessed by the Mini Mental State Examination [MMSE; [START_REF] Folstein | Mini-Mental State" a Practical Method for Grading the Cognitive Status of Patients for the Clinicial[END_REF]] and the Katz Basic Activities of Daily Living tests [ADL; [START_REF] Katz | Studies of illness in the aged. The index of ADL: A standardized measure of biological and psychosocial function[END_REF]] respectively. Prior to testing, participants signed an informed consent form approved by the Psychology Department's ethical committee.

Participants were paid 20 euro for their participation. Detailed sample characteristics are given in Table 2. -Insert Table 2 about here-

Apparatus and tasks

Posture performance was assessed using the NeuroCom Clinical Research System (NeuroCom International, Inc., Clackamas, OR, USA) consisting of a dynamic 18" dual force plate resting on five force transducers. Forces exerted on the support were recorded on a Pentium 4 PC at a sampling rate of 100 Hz over the course of the 24 s trial. Force recordings were used to derive anterior-posterior and medio-lateral position-time functions of the centre of pressure (COP) for each trial. Postural performance was assessed in two platform conditions: stable (involving a fixed support) and moving (involving platform rotations around the pitch axis, frequency: 0.3 Hz, amplitude: 3°). Each trial comprised a 4s stabilization period, after which presentation of the visual stimuli for the WM task started on a computer screen built into the system's three-sided surround.

The WM task was run on a Pentium D personal computer (Dell Optiplex GX 620, with a Planar monitor). Participants were asked to look at a screen displaying 12 squares organized in a 4 (columns)-by-3 (rows) grid. A number of red apple images appeared, one after the other, with a variable interstimulus interval and each for 400 ms, in a corresponding number of different squares for total trial duration of 20 s. Participants were asked to remember the apples' positions and order of appearance which was pseudo-random assuring that within a given trial the apple did not appear twice in the same square. Performance was expressed as a percentage correct. The number of apples was individually calibrated to equate performance levels at 80% correct.

The WM task and the two posture tasks were performed both separately (single-task context) and concurrently (dual-task context). In dual-task trials, participants performed the WM task while standing and in single-task assessment while sitting at a table. Single-task assessment of the posture tasks required participants to perform an adapted version of the WM task (which we will further refer to as the control task) while standing. The control task was similar to the WM task, included the same number of items, but one (at a random position in the series) or two of the apples (one at a random position and one at the end of the series) were yellow. Participants were asked to remember the position of the final yellow apple. The use of the control task guaranteed comparable visual input and eye-(and possible head-) movements in single-and dual-task contexts, thereby preventing these from artificially creating dual-task effects.

Procedure

Data were collected over the course of two sessions each taking 60 to 90 minutes. In the first session, the difficulty of the WM task was individually calibrated by means of an adaptive testing procedure. Adaptive testing started with 3 (older adults) or 4 (young adults) apples and this number was gradually increased until the target level of 80% correct performance was reached. In the second session, posture and cognitive performance was assessed in single-and dual-task contexts. Single-task WM performance was assessed at the beginning (four trials), the middle (three trials) and the end (three trials) of the session.

Posture performance was assessed in single-(A) and dual-task (B) contexts following an ABBA design where four dual-task trials were preceded and followed by 3 and 2 single-task posture trials respectively. The ABBA design was chosen in order to prevent potential practice or fatigue effects. The stable condition always preceded the moving condition, allowing participants to familiarize themselves with the equipment and preventing potential after effects following the moving platform.

Data-analysis

Postural performance was quantified through fitting an ellipse to the COP trajectory using principal component analysis. The lengths of the ellipse axes were equal to two standard deviations of the COP trajectory along each axis, fitting 88% of the COP trajectory within the ellipse [START_REF] Duarte | Effects of body lean and visual information on the equilibrium maintenance during stance[END_REF][START_REF] Oliveira | Calculation of area of stabilometric signals using principal component analysis[END_REF], thereby excluding outliers. The ellipse area was calculated using Matlab (Mathworks, Natick, Mass., USA) and represented the outcome measure. Individual trials were given a square-root transformation before averaging within conditions to control for single-trial outliers; means were squared back afterwards. Increases in the size of the area covered by the ellipse reflect an increase in postural instability, indicating decreased posture performance. Statistical analyses were performed using the 88% confidence ellipse as well as the full COP area; we report only results using the 88% confidence ellipse are since both measures yielded the same pattern of results.

Statistical analyses were conducted using SAS software, Version 9.1 (2002-2009 SAS Institute Inc., Cary, NC, USA). All reported effects are significant at p < .05. Eta square (ŋ 2 ) values are reported as measures of effect size.

Results

Single-task performance

To test our prediction of age related decline in WM capacity, we considered the number of items remembered at the target performance level. On average, young adults were able to recall 8.17 (SD = 1.66) items with 80% accuracy while older adults recalled 5.57 (SD = .84) items, F (1, 45) = 45.28, p < .01, ŋ 2 = .50, consistent with our prediction. Using the number of items determined during the adaptive testing procedure, WM performance was assessed three times over the course of the second session resulting in a total number of 10 trials, the first of which was considered as a warm-up trial and excluded from further analysis. Time of cognitive assessment did not affect performance so the average of nine trials was used to represent single-task WM performance. As intended by individually calibrating task difficulty, overall single-task performance was comparable across age groups (young adults: M = 82.23, SD = 6.63; older adults: M = 77.88, SD = 8.46), and did not reliably differ from 80%. These results emphasize the effectiveness of our adaptive testing procedure in equating cognitive challenge and single-task performance levels across age groups.

With respect to posture performance, we predicted an age related increase in ellipse areas reflecting decreased posture control. The first (single-task) trial in each platform condition (stable, moving) was considered a warm-up and was excluded from further analysis.

The remaining four single-and four dual-task trials for each participant were averaged separately for the two platform conditions. Posture performance is depicted in Figure 1. A mixed design repeated measures analysis of variance (ANOVA) using age group (young vs. old) as between-participants factor and platform condition (stable vs. moving) as withinparticipants factor conducted on ellipse area in single-task contexts showed main effects of platform condition, F (1, 45) = 153.30, p < .01, ŋ 2 = .77 and age, F (1, 45) = 11.51, p < .01, ŋ 2 =.20 and an age-by-platform interaction, F (1, 45)= 9.54 , p < .01, ŋ 2 =.17. In single-task contexts, posture performance for standing on a stable platform was similar in the two age groups. On the moving platform, single-task posture performance was better in young as compared with older adults, F (1, 45) = 13.86, p < .01, ŋ 2 = .24, consistent with our prediction.

Dual-task effects

We expected age related decline in dual-task performance. Two mixed design repeated measures ANOVAs were conducted to test the effects of the between-participants factor of age (young vs. older) and the within-participants factors of task context (single vs. dual task) and platform condition (stable vs. moving) on posture and cognitive performance. No reliable effects on cognitive performance were observed, indicating that task context (single vs. dual task) did not affect cognitive performance and this was the case for both age groups and platform conditions.

Posture performance is depicted in Figure 1. Greater ellipse areas were observed in dual-compared to single-task contexts, F (1, 45) = 7.66, p < .01, ŋ 2 = .15 and this effect was qualified through an interaction with age, F (1, 45) = 4.54, p <.05, ŋ 2 = .09, platform condition, F (1, 45) = 8.36, p < .01, ŋ 2 = .16, and a three-way interaction involving all three factors, F (1, 45) = 5.45, p < .05, ŋ 2 = .11. This three-way interaction was entirely attributable to the older age group showing decreased posture performance when performing the WM task on the moving platform, as indicated by post-hoc t tests, t (22) = 2.79, p < .05 (see Figure 1).

-Insert Figure 1 about here-Dual-task decrements were also expressed as proportional DTCs to account for individual differences in baseline performance. Proportional DTCs were computed for each participant by dividing the absolute difference in single-vs. dual-task performance with single-task performance and multiplying this outcome by 100 [for details on this procedure, see [START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF]]. Positive DTCs indicate declined performance in dual-compared to single-task contexts while negative DTCs indicate improved performance in dual-compared to single-task contexts. DTCs are depicted in Figure 2. A mixed design repeated measures ANOVA was conducted to test the effects of the between-participants factor of age group (young vs. older) and the two within-participants factors of platform condition (stable vs. moving) and modality (posture vs. cognition) on DTCs. There was a main effect of modality on DTCs, indicating that DTCs were higher in posture compared to the cognitive domain, F

(1, 45) = 6.66, p <.05, ŋ 2 = .13. No other effects reached significance. DTCs were only reliably different from zero in the posture domain for older adults in the moving platform condition, t (22) = 3.18, p < .01.

-Insert Figure 2 about here-

Discussion

In the present study, we asked whether age differences in dual-task performance emerge even in the absence of concurrent response production and after control of individual differences in single-task cognitive challenge. In line with our predictions, we found pronounced age differences in posture performance in the more difficult (i.e., moving) platform condition. These effects increased further in dual-task performance. Our findings extend results from previous dual-task studies, and by taking two key aspects of critique related to them into account, they lend further support to the claim that sensorimotor functions like postural control become more cognitively demanding in old age [START_REF] Doumas | Working memory and postural control: adult age differences in potential for improvement, task priority, and dual tasking[END_REF][START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF][START_REF] Huxhold | Dual-tasking postural control: aging and the effects of cognitive demand in conjunction with focus of attention[END_REF][START_REF] Maylor | Age differences in postural stability are increased by additional cognitive demands[END_REF][START_REF] Rapp | Adaptive task prioritization in aging: Selective resource allocation to postural control is preserved in Alzheimer disease[END_REF][START_REF] Shumway-Cook | Attentional demands and postural control: The effect of sensory context[END_REF][START_REF] Shumway-Cook | The effects of two types of cognitive tasks on postural stability in older adults with and without a history of falls[END_REF].

Despite general agreement about increased interference between sensorimotor and cognitive functions in later adulthood, one intriguing aspect varies unsystematically among earlier studies. This aspect relates to older adults' task prioritization, reflecting selective allocation of resources toward sensorimotor functioning at the expense of cognitive performance, when the sensorimotor task becomes very difficult. The typical prioritization pattern in older adults amounts to high DTCs in posture/low DTCs in cognition when the balance task is simple (e.g., stable platform) and the reverse pattern when the posture task is very challenging (e.g., tilting platform, sway-referencing, compromised vision). Task prioritization has been taken as evidence for older adults' efforts to protect their postural stability thereby adapting to their higher risk of falling and its negative consequences. The unsystematic nature of prioritization becomes evident when one considers recent studies demonstrating this effect [START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF][START_REF] Rapp | Adaptive task prioritization in aging: Selective resource allocation to postural control is preserved in Alzheimer disease[END_REF] and others [START_REF] Maylor | Effects of spatial and nonspatial cognitive activity on postural stability[END_REF][START_REF] Maylor | Age differences in postural stability are increased by additional cognitive demands[END_REF] including the present study, showing posture-cognition interference, but not prioritization.

Since the posture tasks used in the present study were identical to the ones used in the study by [START_REF] Rapp | Adaptive task prioritization in aging: Selective resource allocation to postural control is preserved in Alzheimer disease[END_REF], it seems reasonable to assume that WM task differences are responsible for these contradictory findings. The N-back task used by [START_REF] Rapp | Adaptive task prioritization in aging: Selective resource allocation to postural control is preserved in Alzheimer disease[END_REF] differs from the WM task in the present study not only with regard to concurrent response production, but also with respect to the pacing of stimulus presentation: in the N-back task stimuli are presented with a fixed interstimulus interval while in the WM task used in the present study stimuli are presented with a variable interstimulus interval, presumably allowing for self-paced processing and more flexible resource allocation. The absence of cognitive DTCs suggests that, overall, the WM task used in the present study is less challenging than the cognitive tasks used in previous studies [proportional DTCs in cognition in the most difficult sensorimotor condition: 39% in [START_REF] Lindenberger | Memorizing while walking: Increase in dual-task costs from young adulthood to old age[END_REF]; 25% in [START_REF] Li | Walking while memorizing: A SOC study of age-related differences in compensatory behavior under dual-task conditions[END_REF]; 12% in [START_REF] Doumas | Task prioritization in aging: effects of sensory information on concurrent posture and memory performance[END_REF]; 11% in [START_REF] Rapp | Adaptive task prioritization in aging: Selective resource allocation to postural control is preserved in Alzheimer disease[END_REF]]. Perhaps older adults felt safe and secure enough to allow a drop in posture performance in the most difficult posture condition in order to maintain cognitive performance at target level. Further research is needed to specify the role of posture and cognitive task difficulty in dual-task performance and age differences therein. Tapping (slow and fast tempos)

In slow but not fast tapping, especially in older adults OA, especially in slow tapping Note. Abbreviations (in alphabetical order): OA (older adults), Ref. (reference), RT (reaction time), YA (young adults). Digits behind author(s) refer to age groups included in the study (1= young, 2= middle-aged, 3= older), digits in italic refer to the mean ages of these groups. Digits behind cognitive tasks refer to response mode during sensorimotor data collection (0= no overt responding, 1= verbal responding, 1 * = verbal responding but controlled for, 2= button pressing).

  Twenty four young (M = 25.42 years, SD = 3.55, range 21-34 years) and 23 older (M = 68 years, SD = 4.46, range 60-78 years) adult volunteers participated in the present study.

Figure 1 .

 1 Figure 1. Posture performance expressed as the area of the fitted ellipse in the two platform

Figure 2 .

 2 Figure 2. Proportional DTCs for cognition and posture in the two platform conditions (stable,

Figure

  Figure(s)

Table 1A .

 1A Overview of studies assessing sensorimotor and cognitive performance in different adult age groups, using the same task difficulty for all age groups

	Ref.	Cognitive task	Sensorimotor task	Dual-task costs in cognitive task	Dual-task costs in sensorimotor task
	Maylor & Wing (1996) 2: 57; 3: 77 Lajoie et al. (1996) 1: 26; 3: 71	Random digit generation 1 , Brooks' spatial memory 1 , backward digit recall 1 , silent counting 0 , counting backward in threes 1 Auditory RT 1	Posture (stable support) narrow support) and walking Posture (broad support,	None walking, pronounced for OA in YA and OA in posture en	Increased age differences when performing visuo-spatial tasks OA in walking
				difficult posture condition
	Shumway-Cook et al. (1997) 1: 31; 3: 74	Sentence completion 1 , visual perception matching 1	support) Posture (stable vs. compliant	None	OA in difficult posture condition
	Brown et al. (1999) 1: 25; 3: 79 Lindenberger et 45; 3: 65 al. (2000) 1: 24; 2:	Counting backwards 1 Memorizing word lists 0	Posture (perturbations) walking track) Walking (oval vs. aperiodic	YA and OA, pronounced in OA OA in both walking conditions YA in difficult walking condition;	YA and OA, pronounced in OA YA and OA, pronounced in OA
	Shumway-Cook	Auditory choice RT 1	Posture, six sensory	OA in three most difficult posture	OA in two most difficult posture conditions
	& Woollacott (2000) 1: 35; 3: 75		conditions	conditions
	Maylor et al. (2001) 1: 22, 36, 44; 2: 54; 3: 65, 74	Brooks' spatial and non-spatial task 0	Posture	None	Increased age differences when performing spatial WM task
	Kemper et al. (2003) 1: 22; 3: 73 Heuninckx et al. (2004) 1: 25; 3: 64	Speech production 1 (fluency, complexity, content) Line figure judgement task 0	Walking, finger tapping, ignoring speech or noise Concurrent hand-foot movements	YA show DTCs in complexity, OA show DTCs in fluency None	-DTCs in tapping, DTC in walking, not age-differential Decreased accuracy and stability in OA, decreased stability in YA, age differences disappear after equating sensorimotor single-
	Huxhold et al. (2006) 1: 25; 3: 70	Choice RT 2 , 2-back 2 , spatial 2-back 2	Posture (stable support)	None	task performance level OA when performing difficult cognitive task. YA and OA show -DTCs when
	Voelcker-	N-back task 1	Force-tracking	OA	performing easy cognitive task OA
	Rehage et al. (2006) 1: 25; 3: 74

Table ( s)

 (

Table 1B .

 1B Overview of studies assessing sensorimotor and cognitive performance in different adult age groups, equating task difficulty across age groups

	Lovden et al. (2008) 1: 25; 3: 74	N-back task 1	Walking	None	-DTCs for YA and OA when performing easy cognitive task, -DTCs for YA when
	Ref.	Cognitive task	Sensorimotor task	Dual-task costs in cognitive task	performing difficult cognitive task Dual-task costs in sensorimotor task
	Note. Abbreviations (in alphabetical order): OA (older adults), Ref. (reference), RT (reaction time), YA (young adults). Digits behind author(s) refer to age groups included in the study (1= young, 2= middle-aged, 3= older), digits in italic refer to the mean ages of these groups. Digits behind cognitive tasks refer to response mode during sensorimotor data Li et al. (2001) Episodic WM 0 Walking (with or without OA in both walking conditions, YO & OA, pronounced in OA and difficult 1: 25; 3: 66 obstacles) pronounced in difficult walking walking condition collection (0= no overt responding, 1= verbal responding, 1 * = verbal responding but controlled for, 2= button pressing). condition Rapp et al. platform) (2006) 1: 24; 3: 69 N-back task 1* Posture (stable vs. moving OA in easy posture condition OA in difficult posture condition
	Doumas et al. (2008) 1: 22; 3: 71	N-back task 1*	conditions Posture, three sensory	OA in easy posture condition	OA, -DTCs in difficult P condition
	Doumas et al. (2009) 1: 27; 3: 67 Krampe et al. (under review) 1:24; 3:67	N-back task 1* Digit monitoring 0 , 0-back 1 , N-back 1	Posture, moving platform	None	None

Table 2 .

 2 Sample characteristics, group means (standard deviations in parentheses); * denotes significant age difference at .05-level

	Young adults	Older adults

The authors acknowledge financial support through BOF grant OT25/05 from the Research Council of KU Leuven and FWO grant G.0379.06 awarded to RK. MD is a postdoctoral fellow of the Fund for Scientific Research -Flanders. We thank Jessie Van den Eynde for help with data collection.

Abstract

We investigated adult age differences in dual-task costs in cognitive-sensorimotor settings without concurrent response production and with individually adjusted resource demands for the cognitive task. Twenty-four young adults (M = 25.42 years, SD = 3.55) 23 older adults (M = 68 years, SD = 4.46) performed a cognitive task and two postural control tasks (standing on a stable and moving platform) both separately (single-task context) and concurrently (dual-task context). The cognitive task did not require response production during posture data collection and its difficulty was individually adjusted to 80% correct performance under single-task conditions. Results showed pronounced age differences in postural control in the moving platform condition, which increased further under dual-task conditions. Our findings support the assumption of increased cognitive resource demands for postural control in older adults. They extend existing work by taking two shortcomings of previous studies into account. We discuss cognitive and posture task constraints in this and previous studies as factors determining multi-tasking and its changes in later adulthood.


PhD E Vizza

MD b , R A Pellegrino

MD R Milani

MD R Fruscio

MD a , F E Baiocco

MD F Cognetti

MD A Savarese

MD a , F Tomao

MD C Chen

PhD G Corrado

MD c , R Milani

MD Fruscio

MD Cognetti

Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in locally advanced stage ib2-iib cervical cancer patients after neoadjuvant

Keywords: total laparoscopic radical hysterectomy, cervical cancer, neoadjuvant chemotherapy

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INTRODUCTION

In the recent years, locally advanced cervical cancer treatment has changed from single radiation therapy [START_REF] Kesic | Management of cervical cancer[END_REF] to concurrent chemo-radiotherapy, since the 1999 National Cancer Institute Alert strongly supported its use in all patients with cancer requiring radiation, based on results of five large randomized trial [START_REF] Green | Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis[END_REF][START_REF] Eifel | Concurrent chemotherapy and radiation therapy as the standard of care for cervical cancer[END_REF]. Neoadjuvant chemotherapy followed by surgery is a completely different therapeutic approach that seems to offer some specific advantages over chemoradiation, such as a potential higher activity against micrometastastic disease, a debulking effect improving subsequent surgical outcome, less toxicity, and an easier management of salvage therapy [START_REF] Lissoni | A phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study[END_REF].

Laparoscopic assisted vaginal radical hysterectomy and total laparoscopic radical hysterectomy (TLRH), and, more recently, robotic surgery, have been performed in early stage cervical cancer, with no adverse effect in patient's overall prognosis and survival [START_REF] Zakashansky | New techniques in radical hysterectomy[END_REF]. This data has also been confirmed by our recent experience [START_REF] Pellegrino | Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in patients with Ib1 stage cervical cancer: Analysis of surgical and oncological outcome[END_REF]. The feasibility of this procedure in locally advanced cervical cancer, especially in patients treated with neoadjuvant chemotherapy, has not been investigated.

The purpose of the present study was to evaluate the feasibility and morbidity of total laparoscopic radical hysterectomy (type C 2 according to Querleu and Morrow classification [START_REF] Querleu | Classification of radical hysterectomy[END_REF]) with pelvic lymphadenectomy in stage IB2-IIB cervical cancer patients after neoadjuvant chemotherapy.

MATERIALS AND METHODS

Study design and data collection

Patients with histological confirmed locally advanced cervical carcinoma (International Federation of Gynaecology and Obstetrics (FIGO) stages IB2-IIB) [START_REF] Figo Committee On | Staging classifications and clinical practice guidelines of gynaecologic cancers[END_REF] were eligible for the study; from October 2004 to September 2009 patients received 3 courses of neoadjuvant chemotherapy, and were then evaluated under anaesthesia in combination with MRI, before and after chemotherapy. Further eligibility criteria included: ECOG performance status of 2 or less, adequate bone marrow reserve (absolute granulocyte count ≥2000/ml, platelet count ≥100 000/ml); and adequate renal, hepatic, and cardiac function. Patients who showed clinical response to NACT were eligible for TLRH with pelvic lymphadenectomy. Patients that were not considered candidates for the laparoscopic approach underwent abdominal radical hysterectomy (ARH). Previous abdominal surgery was not considered a contraindication for the laparoscopic approach.

Approval to conduct the study was obtained independently from an internal review board at each participating institution. Informed consent, including to neoadjuvant chemotherapy, clinical evaluation and laparoscopic surgery, was obtained from all patients in accordance with local and international legislation (declaration of Helsinki). All the patients who underwent TLRH were informed that ARH would be carried out if difficulties were encountered with the laparoscopic approach.

Surgery was performed at the department of surgical gynaecologic oncology of two Italian hospitals, the San Gerardo Hospital, Monza (16 patients), and National Cancer Institute "Regina Elena" of Rome (24 patients). Clinical patient characteristics including age, body mass index (BMI), clinical stage according to FIGO, histopathologic subtype, and tumour grade were recorded. Intraoperative parameters evaluation included complications, blood loss and haemoglobin (Hb) drop. Blood transfusions were administrated if Hb value was ≤ 7 g/L. Postoperative parameters included short-term (within 30 days of the procedure), and long-term complications (more than 30 days after the procedure); moreover, status of the surgical margins, status and number of pelvic lymph nodes removed, length of dissected vagina, width of bilateral parametrium were evaluated, along with pathological response evaluation, length of hospitalization, time to recovery of normal bladder function, median follow-up duration, recurrence, and disease-free interval (DFI).

Neoadjuvant chemotherapy and evaluation of clinical response

Neoadjuvant chemotherapy was chosen according to the regimen of the European study SNAP01 [START_REF] Buda | Randomized Trial of Neoadjuvant Chemotherapy Comparing Paclitaxel, Ifosfamide, and Cisplatin With Ifosfamide and Cisplatin Followed by Radical Surgery in Patients With Locally Advanced Squamous Cell Cervical Carcinoma: The SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study[END_REF]. Clinical objective tumour responses were evaluated according to the Response Evaluation Criteria in Solid Tumours criteria [START_REF] Therasse | New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada[END_REF]. Pathological responses were defined as follows: optimal response (OPR) included complete pathologic response (PRC) with complete disappearance of tumour in the cervix and negative nodes, or a residual disease with <3mm stromal invasion including in situ carcinoma (pPR1); suboptimal response (SOR) consisted of persistent residual disease with >3 mm stromal invasion on surgical specimen (pPR2). After clinical evaluation of response, before and after NACT, all patients deemed operable underwent total laparoscopic radical hysterectomy (type C 2 ) with pelvic lymphadenectomy within 4 weeks from the last chemotherapy cycle.

Women with positive nodes, parametrial involvement, cut-through or SOR or OPR but with positive nodes underwent further treatment (chemotherapy, external beam irradiation plus brachytherapy or chemoradiation). Patients with inoperable tumours because of lack of response, defined as <50% decrease or <25% increase in the product of the two largest perpendicular diameters of the measurable lesion, or patients progressive after neoadjuvant chemotherapy, defined as >25% increase in the product of the two largest perpendicular diameters of one measurable lesion or the appearance of new ones, were offered radiotherapy.

Surgical procedure and characteristics

No uterus manipulator devices were used, but the cervix were grasped with a tenaculum and a medical grade silicone balloon, named colpo-pneumo occluder (Cooper Surgical) were emplaced in vagina in order to preserve an adequate pneumoperitoneum during colpotomy.

The first step of our technique consist in opening the retroperitoneal spaces according to the following sequence: paravescical space, pararectal lateral space (Latzko), pararectal medial space (Okabayashi), rectovaginal space and vescicovaginal space.

The second step is the "en bloc" level 1 and level 2 pelvic lymphadenectomy according to Querleu and Morrow classification [START_REF] Querleu | Classification of radical hysterectomy[END_REF]. Para-aortic lymphadenectomy is not routinely performed unless suspicious pelvic lymph nodes are confirmed to have metastatic disease on frozen section evaluation in order to determine the field of postoperative radiation.

Afterwards, type C2 radical hysterectomy is performed as described by Querleu and Morrow [START_REF] Querleu | Classification of radical hysterectomy[END_REF]. The uterosacral ligment is isolated into two parts according to Yabuki [START_REF] Yabuki | A New Proposal for Radical Hysterectomy[END_REF], the middle part and the lateral part, which can be coagulated and then dissected by scissors, respectively from the shallow layer to the deep layer close to the pelvic sidewall. The ureter is dissected free from the overlying uterine artery and vesicouterine ligament using the curved tip of the gyrus shears and the anterior parametrium is coagulated laterally so that the ureter can be completely unroofed to the point of insertion into the bladder according to Tokyo technique [START_REF] Yabuki | A New Proposal for Radical Hysterectomy[END_REF][START_REF] Yabuki | Radical Hysterectomy: An Anatomic Evaluation of Parametrial Dissection[END_REF]. To prevent heat damage to the ureter, saline irrigation is performed during Gyrus coagulation. Finally uterosacral ligament is transacted close to the rectum, vescicouterine ligament close to the bladder. Paracervical tissue is also completely removed, including the part caudal to the deep uterine vein.

In young patients whose ovarian function needs to be preserved, the ovaries are transposed laterally to the para-colic gutters and fixed securely to the abdominal wall.

After a careful control of blood loss, to minimize the risk of port site metastases, the vagina and all the ports sites are irrigated with 5% povidine-iodine solution before completion of the surgery.

In all patients the urine catheter is removed 3 days after operation and an intermittent self catheter is used for voiding until the residual urine volume is less than 100 ml.

RESULTS

Patient characteristics (Table 1)

From October 2004 to September 2009, forty patients were included into the study. The median age was 46 years (range 25 -65), median BMI was 24 kg/m 2 (range 15 -49 kg/m 2 ). Four patients converted to laparotomy for the following reasons: one was found with a diaphragm hernia, one was diagnosed as pneumoderma, one was found with a rupture of the uterus at the isthmus due to cancer and the remaining patient was diagnosed with a bulky pelvic lymph node metastasis of about 1.5 cm of diameter not evidenced by MRI and strongly adherent to the left iliac vein. A total of 36 patients underwent total laparoscopic radical hysterectomy (type C 2 ) and pelvic lymphadenectomy. All patients were evaluated for toxicity and response to chemotherapy.

Toxicity and response to chemotherapy

A total of 90 courses of chemotherapy were administered. Toxicity is shown in table 2. Thirty seven out of 40 patients had good clinical response to NACT. The median diameter of tumour evaluated before chemotherapy administration was 43 mm (range, 30 -70 mm), while it was 14 mm (range, 0 -40 mm) after chemotherapy (evaluated under anesthesia and MRI) and 11mm (range, 0 -33 mm) by final pathological evaluation after surgery. Eighteen patients had an optimal response (pCR, pPR1) to chemotherapy, 15 patients had a pPR2 and 3 patients showed no response with parametrial invasion.

Perioperative parameters (Table 3)

Median ooperative time was 305 min (range, 215 -430) and it was strongly correlated with patients BMI. In two patients with high BMI (49 and 43 kg/m 2 ), the operative time was longer than 400 min, and in 5 patients with BMI less than 25 kg/m 2 , the median operative time was 270 min (range, 215 -300). The median blood loss was 250 ml (range, 100 -400 ml); none of the patients required intraoperative blood transfusion, while four patients had a postoperative blood transfusion. The median Hb drop was 2 g/L (range, 0.3 -4.8 g/L) before and 24 hours after operation.

The median number of removed pelvic lymph nodes was 24 (range, 10 -64). Eight squamous cell carcinoma and one adenocarcinoma patients had a total of 9 positive pelvic nodes at frozen section. In these nine patients, lymphadenectomy was extended to the para-aortic nodes, with negative specimens.

The superior border of the dissection in the para-aortic lymphadenectomy was the inferior mesenteric artery and the median number of removed para-aortic lymph nodes was 7 (range, 5 -11).

The median length of dissected vagina was 21 mm (range, 15 -45 mm). The median width of parametrium was 30 mm on the right side (range, 15 -50 mm) and 30 mm on the left side (range, 15 -60). The surgical margins were free of disease in all cases.

There was 1 intraoperative complication: one patient had injury of the left hypogastric vein and promptly repaired during the same laparoscopic surgery with a total blood loss of 300 ml without need of blood transfusion.

Postoperative parameters

There were 2 postoperative short term complications: in one case postoperative pelvic bleeding was successfully recovered by drainage; a second patient suffered from lymphocyst on the 10 th day post-operation.

Long term complications were: bladder symptoms in 16 patients, reduction in bladder sensitivity in 8, recurrent urinary tract infection in 2 and urinary incontinence in 6. Moreover one patient had a left ureteral fistula that was diagnosed 3 month later by urography. This patient underwent placement of a nephrostomy for 5 months and then an ureteral stent that was removed after 3 months with no sequelae.

Eleven patients had bowel symptoms: 9 constipation and 2 a reduction of sensitivity. Other 8 patients had symptoms relating to vaginal and sexual function: 3 a reduction of sensitivity, 3 a vaginal pain during sexual intercourse and 2 complaining of vaginal dryness. In contrast, 5 patients, of age less than 45 years who had kept their ovaries, had no change in sexual activity, except for one patient who underwent further radiotherapy. Self catheterization was started on day 3 from the intervention. The time to resumption of normal bladder function ranged from 10 days to 3 months. Four patients treated with radiation therapy and three with chemoradiation plus brachytherapy showed a worsening in condition. The median length of hospital stay was 6 days (range 3 -12 days).

Further management and long term follow up

Three patients with parametrial invasion underwent further adjuvant concomitant radiochemotherapy. Nine patients with positive nodes underwent 3 further cycles of chemotherapy with TIP regimen, and five patients received adjuvant radiation therapy due to the coexistence of lymphovascular space involvement (LVSI).

The median follow-up was 37 months (range, 10 -69 months). Thirty-three patients are free from recurrence at the time of this report. One patient, who had no pathological response with parametrial invasion, suffered from a central pelvic recurrence, with a DFI of 9 months, and died of disease after 12 months. Another patient, who obtained a partial response, demonstrated pelvic lymph node involvement after neoadjuvant chemotherapy, and treated with adjuvant chemotherapy, showed lung metastasis, with a DFI of 19 months; she underwent removal of metastases and is currently disease free after 56 months. Other two patients, who obtained a partial response, suffered from a pelvic lymph node and lung plus liver recurrence, with a DFI of 5 and 22 months respectively. They underwent chemotherapy and are currently alive with disease after 21 and 34 months respectively.

DISCUSSION

From a recent report, in locally advanced stages cervical cancer, NACT followed by radical hysterectomy showed an absolute benefit of 15% at 5-year survival [START_REF] Buda | Randomized Trial of Neoadjuvant Chemotherapy Comparing Paclitaxel, Ifosfamide, and Cisplatin With Ifosfamide and Cisplatin Followed by Radical Surgery in Patients With Locally Advanced Squamous Cell Cervical Carcinoma: The SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study[END_REF]. Therefore we started the present study with totally laparoscopic radical hysterectomy and lymphadenectomy after NACT based on our previous experience of laparoscopic type III radical hysterectomy in early stage cervical cancer [START_REF] Zakashansky | New techniques in radical hysterectomy[END_REF].

Response to neoadjuvant chemotherapy

We achieved a good clinical response after NACT by combined evaluation under anaesthesia and MRI. Pathological evaluation showed 9 pCR, 9 pPR1 and 15 pPR2. Notwithstanding the combined evaluation (anaesthesia and MRI) of the cervix size, three patients had no pathological response, with the invasion of parametrium, and one of them had a recurrence after 9 months after the operation and died of disease after 12 months. Therefore the importance of an accurate clinical evaluation after NACT is mandatory. In our study the TIP regimen as NACT has been confirmed to be effective and tolerable, as reported by other recent published trials [START_REF] Buda | Randomized Trial of Neoadjuvant Chemotherapy Comparing Paclitaxel, Ifosfamide, and Cisplatin With Ifosfamide and Cisplatin Followed by Radical Surgery in Patients With Locally Advanced Squamous Cell Cervical Carcinoma: The SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study[END_REF][START_REF]Neoadjuvant chemotherapy for cervical cancer meta-analysis collaboration: Neoadjuvant chemotherapy for locally advanced cervix cancer: a systematic review and meta-analysis of individual patient data from 21 randomized controlled trials[END_REF].

Surgical procedure

Regarding the surgical procedure, we achieved 90% success rate of laparoscopic surgery with only 4 conversions. There was no limitation of BMI (range, 15-49 kg/m 2 ). Using this technique, we performed total laparoscopic radical hysterectomy in early stage cervical cancer [START_REF] Querleu | Classification of radical hysterectomy[END_REF], extended to the locally advanced cervical cancer after NACT. To overcome the debate on the shortage of uterosacral ligament and length of vagina resection, several modifications were made in the laparoscopic procedure compared with laparotomy.

First we used the special colpo-pneumo occluder instead of uterus manipulator leading to a better direction of the vagina and sufficient vaginal resection.

Moreover changing the order of dissection in the laparoscopic procedure lead to several advantages. In fact, starting the dissection from the lateral parametrium resulted in significant uterus uplift, thus making the dissection of the uterosacral ligament easier. In fact, the section of the lateral parametrial just after the section of the upper part of the posterior pillar allows lifting up the lower part of the posterior pillar leading to its better exposure.

The third characteristic of our procedure is the "en bloc" lymphadenectomy. The key point of this procedure is to make an advanced separation of the paravescical and the pararectal space laterally and medially, respectively, then remove pelvic lymph nodes around the vein, artery and nerves completely including the common iliac node pushing the nodes laterally or medially until all the nodes are removed together. So, we emphasize the step by step techniques. Never start the next procedure before you complete the previous one.

Finally when all the lymph nodes were well separated, they can be moved in the 'En bloc' way. Using this technique, an average of 24 lymph nodes were removed in both sides, and there were no significant complications except in one patient with lymphocyst.

Median length of hospital stay was 6 days (range, 3 -12). The reason for this prolonged hospitalization was due to postoperative short term complications that requires a total of 12 days of hospitalisations. Indeed, without these three complications, the median hospital stay was 4 days (range, 3 -7).

Oncological results

No large series are available thus far to analyze the surgical and oncological results of this approach. The effects of NACT on pelvic tissues are thought to increase the difficulties of surgical dissection, in particular on pelvic structures such as the bladder and ureters. Due to these difficulties, laparoscopic techniques are generally not used to perform radical hysterectomy after NACT. In our study, we demonstrated the feasibility of a laparoscopic approach in this setting in 90% of the cases.

The low surgical difficulties of surgery on pretreated tissues were evidenced in our experience by the low rate of conversion to laparotomy. Moreover, we showed that surgical outcomes were similar to others reports on laparoscopic radical hysterectomy and pelvic lymphadenectomy in early cervical cancer without NACT [START_REF] Spirtos | Laparoscopic radical hysterectomy (type III) with aortic and pelvic lymphadenectomy[END_REF][START_REF] Kim | Laparoscopic radical hysterectomy with pelvic lymphadenectomy for early, invasive cervical carcinoma[END_REF][START_REF] Hsieh | Laparoscopic radical hysterectomy with low paraaortic, subaortic and pelvic lymphadenectomy. Results of short-term follow-up[END_REF][START_REF] Spirtos | Laparoscopic radical hysterectomy (type III) with aortic and pelvic lymphadenectomy in patients with stage I cervical cancer: surgical morbidity and intermediate follow up[END_REF][START_REF] Lee | Comparison of laparoscopic and conventional surgery in the treatment of early cervical cancer[END_REF][START_REF] Lin | Preliminary results of laparoscopic modified radical hysterectomy in early invasive cervical cancer[END_REF][START_REF] Pomel | Laparoscopic radical hysterectomy for invasive cervical cancer: 8-year experience of a pilot study[END_REF][START_REF] Abu-Rustum | Total laparoscopic radical hysterectomy with pelvic lymphadenectomy using the argon-beam coagulator: pilot data and comparison to laparotomy[END_REF][START_REF] Gil-Moreno | Total laparoscopic radical hysterectomy (type II-III) with pelvic lymphadenectomy in early invasive cervical cancer[END_REF][START_REF] Nezhat | Total laparoscopic radical hysterectomy and pelvic lymphadenectomy using harmonic shears[END_REF][START_REF] Ramirez | Total laparoscopic radical hysterectomy and lymphadenectomy: the M. D. Anderson Cancer Center experience[END_REF][START_REF] Li | A comparison of laparoscopic radical hysterectomy and pelvic lymphadenectomy and laparotomy in the treatment of Ib-IIa cervical cancer[END_REF][START_REF] Frumovitz | Comparison of total laparoscopic and abdominal radical hysterectomy for patients with early-stage cervical cancer[END_REF][START_REF] Ghezzi | Surgicopathologic outcome of laparoscopic versus open radical hysterectomy[END_REF][28][29][START_REF] Pellegrino | Total laparoscopic radical hysterectomy and pelvic lymphadenectomy in patients with Ib1 stage cervical cancer: Analysis of surgical and oncological outcome[END_REF].

Recently, Colombo et al. [30] has described the first experience of TLRH for locally advanced cervical carcinoma after concurrent chemoradiation therapy in which he reviewed 102 patients treated 46 with TLRH and 56 with ARH. In the laparoscopic group the intraoperative and postoperative complications were 10.9% and 28.3% respectively, while incomplete resection, that was associated with microscopic or macroscopic residual disease, in 8.7%. The OS and the DFS were 82% and 81% respectevely.

Although the two studies are hardly comparable, we had less intraoperative complications and free surgical margins compared to this study, probably reflecting the different anatomical alterations induced by chemoradiation.

In the present initial experience a radical excisions of paracervix has been performed in all cases because in the letterature there is not agreement on which radicality should be done after neoadiuvant treatment. After the present results, to reduce postoperative long-term complications, in our istitution we start to use of nerve sparing laparoscopic radical hysterectomy (type C 1 ) in patients with locally advanced cervical cancer after clinical complete response to neoadjuvant chemotherapy.

The status of the pelvic lymph nodes and response to neoadjuvant chemotherapy were found to be two major prognostic factors in our cohort of 40 patients operated on after NACT. Disease-free and overall survivals with low local and distant recurrence rates were higher for patients with complete histological response or microscopic residual disease on histopathologic examination. For patients with partial response with significant residual disease after NACT, survival was poor with a high risk of local and systemic relapse. This identified subgroup of patients could be submitted to adjuvant therapies.

The present study indicates that totally laparoscopic radical hysterectomy can be performed not only in early stage cervical cancer but also in locally advanced stage cervical cancer after neoadjuvant chemotherapy; this technique is feasible and safe, with less blood loss and less intraoperative and postoperative short term complications. The key point is to make an accurate evaluation and restaging of the patients after neoadjuvant chemotherapy.

TABLES LEGENDS

[ 28 ]

 28 Malzoni M, Tinelli R, Cosentino F, Perone C, Iuzzolino D, Rasile M, Tinelli A. Laparoscopic radical hysterectomy with lymphadenectomy in patients with early cervical cancer: Our instruments and technique. Surg Oncol. 2009; 18(4): 289-97 [29] Chen Y, Xu H, Li Y, Wang D, Li J, Yuan J, Liang Z. The outcome of laparoscopic radical hysterectomy and lymphadenectomy for cervical cancer: a prospective analysis of 295 patients. Ann Surg Oncol. 2008; 15(10): 2847-55. [30] Colombo PE, Bertrand MM, Gutowski M, Mourregot A, Fabbro M, Saint-Aubert B, Quenet F, Gourgou S, Kerr C, Rouanet P. Total laparoscopic radical hysterectomy for locally advanced cervical carcinoma (stages IIB, IIA and bulky stages IB) after concurrent chemoradiation therapy: surgical morbidity and oncological results. Gynecol Oncol. 2009; 114(3): 404-9.

Table 1 :

 1 Clinical characteristics of the 40 women with cervical cancer operated by total laparoscopic type C2 radical hysterectomy (TLRH) with pelvic lymphadenectomy after neoadjuvant chemotherapy (NACT)

Table 2 :

 2 Maximum grade of toxicity observed during neoadjuvant chemotherapy

Table 3 :

 3 Surgical outcome of patients with cervical cancer operated by total laparoscopic type C 2

	radical hysterectomy (TLRH) with pelvic lymphadenectomy after neoadjuvant chemotherapy (NACT)

Table 1 : Clinical characteristics of the 40 women with cervical cancer operated by total laparoscopic type C 2 radical hysterectomy (TLRH) with pelvic lymphadenectomy after neoadjuvant chemotherapy (NACT)

 1

	Characteristics	Patients (n° = 40)
	Mean Age	46 (25-65)
	Mean BMI (Kg/m 2 )	24 (15-49)
	Mean tumour size (mm)	43 (30-70mm)
	Histology
	Squamous	33
	Adenosquamous	2
	Adenocarcinoma	5
	FIGO stage
	IB 2	23
	IIA	6
	IIB	11
	Grading
	G1	2
	G2	16
	G3	22

Table 3 : Observed responses after neoadjuvant chemotherapy (NACT) and total laparoscopic type C 2 radical hysterectomy (TLRH) with pelvic lymphadenectomy

 3 Pathological complete response; pPR1: Pathological partial response with microscopic tumour; pPR2:Pathological partial response with macroscopic tumour; SD: Stable of disease; PD: Progression of disease

	Response	N° of patients (%)
	pCR	9 (25)
	pPR1	9 (35)
	pPR2	15 (42)
	SD	3 (8)
	PD	0
	pCR:

Table 4 : Surgical outcome of patients with cervical cancer operated by total laparoscopic type C 2 radical hysterectomy (TLRH) with pelvic lymphadenectomy after neoadjuvant chemotherapy (NACT) Characteristics LRH type C 2

 4

	Mean operative time (min.)	305 (215 -430)
	Mean blood loss (cc.)	250 (100 -400)
	Mean Hb drop (gr/dl)	2 (0.3 -4.8)
	Mean pelvic lymph nodes	24 (11 -52)
	Mean para-aortic lymph nodes	7 (5 -11)
	Mean length right parametrium (mm.)	30 (15 -50)
	Mean length left parametrium (mm.)	30 (15 -60)
	Mean length vaginal cuff (mm.)	21 (15 -45)
	Major intraoperative complications	1
	Major postoperative complications	2
	Blood transfusion	4
	Convertion to laparotomy	4
	Reoperation	0
	Mean hospital stay (day)	6 (3 -12)

Table 5 : Intraoperative and postoperative complications after neoadjuvant chemotherapy (NACT) and total laparoscopic type C 2 radical hysterectomy (TLRH) with pelvic lymphadenectomy Type of complication Patients (n° 36)

 5

	Intraoperative
	Vascular injury	1 (2.7%)
	Postoperative short-term (≤ 30 days)
	Pelvic bleeding	1 (2.7%)
	Symptomatic lymphocysts	1 (2.7%)
	Postoperative long-term (> 30 days)
	Urinary dysfunctions	16 (44.4%)
	Bowel dysfunctions	11 (30.5%)
	Vaginal and sexual dysfunctions	8 (22.2%)

Table 6 : Adjuvant therapy and long term follow-up Adjuvant therapy Patients (n° 36)

 6

	None	19
	CT	9
	RT	5
	RT + CT	3
	Mean Follow-up (months)	37 (10 -69)
	NED	33
	AWD	2
	DOD	1

CT: chemotherapy; RT: radiotherapy; NED: no evidence of disease; AWD: alive with disease; DOD: died of disease

ACKNOWELEDGEMENTS

We gratefully acknowledge Prof. Costantino Mangioni, Dr. Alessandro Buda and Dr. Luciano Mariani.

for their outstanding technical help and valuable advice.

COMPETING INTERESTS

The authors declare that they have no competing interests.