Osteoporos Int DOI 10.1007/s00198-017-3968-5

ORIGINAL ARTICLE

Bone texture analysis using CT-simulation scans to individuate risk parameters for radiation-induced insufficiency fractures V. Nardone 1 & P. Tini 1 & S. F. Carbone 2 & A. Grassi 2 & M. Biondi 3 & L. Sebaste 1 & T. Carfagno 1 & E. Vanzi 3 & G. De Otto 3 & G. Battaglia 1 & G. Rubino 1 & P. Pastina 1 & G. Belmonte 3 & L. N. Mazzoni 3 & F. Banci Buonamici 3 & M. A. Mazzei 2 & L. Pirtoli 1

Received: 10 August 2016 / Accepted: 13 February 2017 # International Osteoporosis Foundation and National Osteoporosis Foundation 2017

Abstract Summary This study deals with the role of texture analysis as a predictive factor of radiation-induced insufficiency fractures in patients undergoing pelvic radiation. Introduction This study aims to assess the texture analysis (TA) of computed tomography (CT) simulation scans as a predictive factor of insufficiency fractures (IFs) in patients with pelvic malignancies undergoing radiation therapy (RT). Methods We performed an analysis of patients undergoing pelvic RT from January 2010 to December 2014, 24 of whom had developed pelvic bone IFs. We analyzed CT-simulation images using ImageJ macro software and selected two regions of interest (ROIs), which are L5 body and the femoral head. TA parameters included mean (m), standard deviation (SD), skewness (sk), kurtosis (k), entropy (e), and uniformity (u). The IFs patients were compared (1:2 ratio) with controlled patients who had not developed IFs and matched for sex, age, menopausal status, type of tumor, use of chemotherapy, and RT dose. A reliability test of intra- and inter-reader ROI TA reproducibility with the intra-class correlation coefficient (ICC) was performed. Univariate and multivariate analyses (logistic regression) were applied for TA parameters observed both in the IFs and the controlled groups. Results Inter- and intra-reader ROI TA was highly reproducible (ICC > 0.90). Significant TA parameters on paired t test

* V. Nardone [email protected]

1

Unit of Radiation Oncology, University Hospital of Siena, Viale Bracci, 53100 Siena, Italy

2

Unit of Diagnostic Imaging, University Hospital of Siena, Siena, Italy

3

Unit of Medical Physics, University Hospital of Siena, Siena, Italy

included L5 m (p = 0.001), SD (p = 0.002), k (p = 0.006), e (p = 0.004), and u (p = 0.015) and femoral head m (p < 0.001) and SD (p = 0.001), whereas on logistic regression analysis, L5 e (p = 0.003) and u (p = 0.010) and femoral head m (p = 0.027), SD (p = 0.015), and sex (p = 0.044). Conclusions In our experience, bone CT TA could be correlated to the risk of radiation-induced IFs. Studies on a large patient series and methodological refinements are warranted. Keywords Insufficiency fractures . Radiation therapy . Side effects . Texture analysis

Introduction Insufficiency fractures (IFs) may occur after physiologic stress to the bones with a decreased mineralization and elastic resistance and are often associated with post-menopausal or corticosteroid-induced osteoporosis [1], although the related pathogenesis is not completely understood [2, 3]. Moreover, radiation therapy (RT) to the pelvis is a risk factor for IFs of the pelvic bones and has been described after RT for gynecological [4–6], anal [7], rectal [8], and prostate cancers [9]. The incidence of post-RT IFs, although generally considered low following modern RT, is currently reported with an increasing frequency, ranging from 8.2 to 45.2% in cervical [10–12], 9 to 11.2% in rectal [8], and up to 6.8% [9] in prostate cancers. This may be due to follow-up procedures and diagnostic tools becoming more and more reliable, which may also allow for the diagnosis in oligo-symptomatic patients. However, in some cases, IFs after RT may be severely painful and invalidating, grounding the suspect of bone metastases. Risk factors for RT-induced IFs are older age, post-menopausal state, female sex, and chemotherapy [6, 8, 11, 12].

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CT-based texture analysis (TA) appreciates image heterogeneities that may not be appreciated with the naked eye, and preliminary evidence has suggested its potential value in imaging characterization for diagnostic purposes [13]. This method is based on mathematical approaches to the evaluation of gray-level intensity and position of the pixels within the image, providing the so-called Btexture features^ that represent a quantitative measure of heterogeneity [14]. To date, many studies have addressed TA in several areas of oncology, showing a potential improvement in diagnosis, characterization of images, and assessment of response to treatment [15–19]. Several investigations have dealt with bone TA, mainly for densitometry, leading to some important results, such as the development of the Trabecular Bone Score (TBS), an analytical tool for novel gray-level texture measurements on dual X-ray absorptiometry (DXA) of the lumbar spine, obtaining information related to trabecular microarchitecture [20–22]. With these premises, we investigated the potential role of a TA procedure based on CT-simulation images obtained for RT treatment planning, attempting to investigate if some of the TA results could be related to the increased risk of IFs in patients with pelvic malignancies undergoing RT.

Methods Patients Insufficiency fracture patient series From January 2010 to December 2014, 24 patients previously irradiated on pelvic content at our institution developed pelvis bone IFs during the follow-up, and their clinical, pathological, and dosimetry data is the investigation material for the present study. The insufficiency fracture patient (IF-p) series included 13 patients (54%) irradiated for anal or rectal cancer, 9 (38%) for endometrial or cervical cancer, and 2 (8%) for prostate or bladder cancer. In all cases, a CT simulation for treatment planning was obtained before RT. The presence of previous fractures of the pelvic bone was a cause of exclusion, as well as any kind of recurrence of the treated tumor in the follow-up period.

patients for sex, age, menopausal status, kind of tumor, chemotherapy administration, and RT tumor dose. The exclusion criteria were the same as for the IF-p series. In order to exclude biases due to factors not taken into account in the matched comparison, we also considered, for the comparison of the abovementioned series, the period of enrollment for RT (January 2010 to June 2012 vs. July 2012 to December 2014) and the applied RT technique (three-dimensional conformal RT (3D–CRT) vs. intensity-modulated RT (IMRT)). Radiotherapy and chemotherapy treatments RT was delivered with a linear accelerator, using 6- or 15MeV photon beams, with 3D–CRT or IMRT techniques. Target volumes and organs at risk were identified on CT simulation, with MRI image fusion if required. The mean RT doses delivered to the different pelvic bones were obtained from the dose-volume histograms resulting from treatment planning, both for IF-p and C-p groups. If deemed required according to international guidelines, chemotherapy was administered concurrently with, or sequentially to, RT, employing standard association of platinum, taxanes, mitomycin, and fluoro-pyrimidine compounds. The retrospective analysis of the data was authorized by the Internal Institutional Review Board. A signed informed consent was obtained both for any treatment and for the anonymous use of clinical data. All procedures were undertaken in compliance with the ethical statements of the Helsinki Declaration (1964, amended most recently in 2008) of the World Medical Association. Follow-up After completion of RT, all patients entered a scheduled follow-up program according to tumor type. In patients affected by gynecological, gastrointestinal, and bladder malignancies, a CT and/or MRI examination was obtained at 4 and 12– 16 weeks after RT, then every 6 months or in any case showing clinical signs suggesting tumor recurrence. In prostate cancer patients, diagnostic CT and/or MRI was obtained only if justified by a rise of the PSA value and/or by emerging symptoms (including pain) or physical signs of recurrence or complications. A physical examination, blood counts, and chemistry were obtained every 3 months.

Controlled patient series Assessment of IFs The above cohort of patients was evaluated through a matched analysis of the corresponding data of 48 patients who were also treated in our institution. The IF-p series was compared (1:2 ratio) with the controlled patient (C-p) series, composed of patients submitted to pelvic irradiation in our institution but without developing IFs, matching any IF-p with two C-p

The occurrence of IFs was confirmed at CT or MR examinations, performed during the follow-up, by a radiologist (SFC) with 14-year experience in the oncologic field. CT findings of IF were defined as fracture lines or sclerotic linear changes in the bones, and MRI findings of IFs were defined as signal

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intensity changes in the bones of >5 mm both on T1- and T2weighted images [6]. The simulation CT was reviewed for pre-existent fractures, and if a fracture was identified on the simulation CT, the patient was excluded from the study. Patients developing any kind of tumor recurrence were not included in the present evaluation, as previously stated.

CT simulation CT simulation was performed upon referral for RT, with a 16slice CT-simulation scanner (General Electric, Boston, USA, LightSpeed, RT16, slice thickness 2.5 mm, beam pitch of 1.375, reconstruction interval 2.5 mm, tube voltage of 120 kVp and reference mAs ranging from 100 to 440 mA, noise index 10). The stability of the CT to electron density table was annually validated with the CIRS Phantom model 62. The ICRP 162 tolerance was applied (<20 HU from the baseline), and in the time period considered (January 2010 to December 2014), the values were stable.

Image analysis We selected two regions of interest (ROIs) on CT simulation, being the vertebral body of L5 and the femoral head (Fig. 1). Each ROI was independently contoured by a radiation oncologist (VN) twice for each case with a 24–48-h interval and by a resident in radiology (AG), once for each case, keeping the contour as close as possible to the internal side of the compact bone. For the vertebral body of L5, the cranio-caudal anatomical landmark was the middle of the body, whereas for the femoral head, the cranio-caudal landmark was the fovea capitis (Fig. 1). The TA was accomplished using a homemade ImageJ macro, implementing a first-order, statistical-based method. With this kind of analysis, considering the gray-level frequency distribution obtained from the histogram of pixel intensities, it is possible to take into account the distribution of gray-level values in each ROI (Fig. 1). This approach is considered as the first order; in that, it is dependent on single-pixel values rather than pixel-topixel interactions. The following typical TA parameters were evaluated: mean (m), standard deviation (SD), skewness (sk), kurtosis (k), entropy (e), and uniformity (u). In Fig. 2, we report the mathematical functions implemented to calculate each parameter used in this study. In particular, m and SD refer to the mean intensity and the standard deviation of the values in the histogram of pixel intensities, sk to the asymmetry, and k to the flatness of the histogram, whereas u and e are, respectively, parameters of uniformity and of irregularity of gray-level distribution.

Fig. 1 Examples of ROI and histograms of the pixel distribution (CTsimulation DICOM images). a L5 ROI in a C-p patient. b L5 ROI in an IF-p patient. c Femoral head ROI in a C-p patient. d Femoral head ROI in an IF-p patient

Statistics Inter- and intra-reader reproducibility of the results were assessed using the intra-class correlation coefficient (ICC) method [23]. The TA parameters, also, were tested for co-correlation (Pearson’s correlation). The TA parameters were correlated with the development of IFs by paired t test (each patient in IF-p against his matched patients in C-p averaged). Binary logistic regression was tested with group as dependant variable and all the texture parameters plus all relevant confounding variables (sex, radiation doses, chemotherapy, RT technique, enrollment period), with forward conditional method, after standard deviation normalization of the TA parameters. The resulted odds ratio (OR) was then normalized. The mean doses delivered to the different pelvic bones in IF-p vs. C-p groups were compared using the Mann-Whitney test. We considered as significant a p value <0.005. The statistical analysis was performed using the SPSS software 17.0.

Osteoporos Int Fig. 2 Mathematical functions used for TA parameter calculations

Results The characteristics of IF-p and C-p series, as well as the localization of the Ifs, are reported in Table 1. IFs occurred in the sacroiliac joints, pubis, acetabulum, sacral body, and lumbar Table 1 Characteristics of patients in the insufficiency fracture (IF-p) and control (C-p) series

vertebrae. Fifteen patients (58%) developed multiple IFs. The median follow-up time was 47.34 months (mean 49.24 months, SD 22.12 months, range 14–76 months). Regarding the period of enrollment, 10 out of 24 patients (41%) in IF-p series and 22 out of 48 patients (46%) in C-p

Characteristics of patients

IF-p series

C-p series

Sex

6 (25%)

12 (25%)

18 (75%)

36 (75%)

66.5 years (±10.99 years)

63.5 years (±12.17 years)

Range 30–81 years

Range 32–78 years

5 (27%)

10 (27%)

13 (73%)

26 (73%)

Male Female Age Menopausal status

Pre-menopausal Post-menopausal Disease

9 (38%)

18 (38%)

Gynecological

13 (54%)

26 (54%)

Gastrointestinal

2 (8%)

4 (8%)

Yes 16 (66%)

Yes 32 (66%)

No 8 (34%)

No 16 (34%)

Mean 5030 cGy (±480 cGy)

Mean 5060 cGy (±530 cGy)

Range 4500–5940 cGy

Range 4500–5940 cGy

Urological Chemotherapy RT target dose (PTV) Localization of the IFs

14 (58%)

Sacroiliac joints

7 (29%)

Pubis

2 (8%)

Acetabulum

5 (20%)

Sacral body

4 (16%)

Lumbar vertebrae Enrollment period

14/24 (59%)

26/48 (54%)

10/24 (41%)

22/48 (46%)

RT technique

13/24 (54%)

28/48 (58%)

IMRT

11/24 (46%)

20/48 (42%)

January 2010 to June 2012 July 2012 to December 2014

3D–CRT

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IF-p

Fig. 3 Analysis of mean RT doses delivered to pelvic bones (Mann-Whitney test) in IF-p and C-p patients

C-p

p-value

0,718

L5 10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

0,198

Sacrum 10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

0,355

Ilium

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

Ischium

0,588 10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

0,924

Pubis

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

Femoral Head

0,456

10 Gy

series were enrolled from January 2010 to June 2012, whereas 14 out of 24 patients (59%) in IF-p series and 26 out of 48 patients (54%) in C-p series were enrolled from July 2012 to December 2014. Regarding the RT technique, 13 out of 24 patients (54%) in IF-p series and 28 out of 48 patients (58%) in C-p series underwent 3D–CRT, whereas 11 out of 24 patients (46%) in IF-p series and 20 out of 48 patients (42%) in C-p series underwent IMRT. As resulting in dose-volume

20 Gy

30 Gy

40 Gy

50 Gy

10 Gy

20 Gy

30 Gy

40 Gy

50 Gy

histograms (p values in the 0.198–0.924 range), the doses on the pelvic bones between IF-p and C-p were well balanced between the groups (see the results reported in Fig. 3). Test reproducibility After the definition of the window level in Hounsfield unit (level 200, window 1000) and of the spatial definition of the

Osteoporos Int Table 2 Reproducibility (statistical analysis, ICC; see text) of TA parameters between the IF-p and C-p series Texture analysis parameter

Intra-reader ICC

Inter-reader ICC

L5 mean

0.924

0.923

L5 standard deviation

0.936

0.918

L5 skewness L5 kurtosis

0.942 0.921

0.874 0.894

L5 entropy

0.907

0.854

L5 uniformity Femoral head mean

0.901 0.945

0.864 0.974

Femoral head standard deviation Femoral head skewness

0.942 0.938

0.938 0.981

Femoral head kurtosis

0.952

0.948

Femoral head entropy

0.932

0.912

Femoral head uniformity

0.913

0.923

ROI (the inner aspect of the cortical bone at middle L5 and at the level of fovea in femoral head), we obtained a high reproducibility of the method, with an inter- and intra-reader ICC > 85% for each evaluated parameter (Table 2). Texture analysis parameters related to the development of IFs after matched comparison The TA parameters that resulted significant at the paired t test analysis were L5 m (p = 0.001), SD (p = 0.002), k (p = 0.006), e (p = 0.004), and u (p = 0.015) and femoral head m (p < 0.001) and SD (p = 0.001) (Table 3). On binary logistic regression analysis with group as dependant variable and all the texture parameters plus all relevant confounding variables (sex, radiation doses, chemotherapy, RT technique, enrollment period), the variables that resulted significant were L5 e (p = 0.003, OR 1.24) and u (p = 0.010, OR 1.87) and femoral head m (p = 0.027, OR 1.23), SD (p = 0.015, OR 1.24), and the sex (p = 0.044, OR 2.81), with a R2 0.672 (Table 3). The TA parameters, finally, were tested for co-correlation with Pearson’s correlation analysis (Table 4).

Discussion Radiation-induced bone damage (and in particular IFs) has been described since the beginning of the twentieth century, and moreover, the incidence of IFs has apparently increased in recent observations, probably due to more thorough follow-up policies including sophisticated imaging resources, although there remain many discrepancies in various studies [8–12]. One MRI study reported an

impressive (89%) incidence of findings compatible with IFs from patients who had previously undergone pelvic RT [24], while a bone nuclide scan could detect a 34% incidence [25]. Although the majority of the IFs develop within 1 year after the RT [24], the temporal limit is not defined [26]. Therefore, our follow-up, with a median value of nearly 4 years, can be adequate. Several authors have recently addressed the importance of high RT doses to bone, advanced age, BMD loss, and chemotherapy [27–30], even with the development of a post-RT, BMD-based predictive model for IFs [29]. Very recently [20–22], the TBS measurement of gray-level texture on DXA images provided information on trabecular microarchitecture of the bone, and this seems consistently associated with both prevalent and incident fractures, partially independent from both clinical risk factors and BMD. At this regard, patients undergoing RT usually do not undergo DXA, so we chose to apply a similar method of imaging analysis to the simulation CT. We chose to apply a Bsingle-slice^ analysis and to focalize on the parameters known to be correlated with the bone density and microarchitecture; therefore, we chose a limited number of texture parameters, as previously published in a short version of this work [31]. Only Uezono et al. [32] have taken into account pre-RT, CT imaging-detectable parameters (i.e., low bone density) as predictive factors for IFs, but their data are not robust. Our method of analysis, using a matched comparison, allows to focalize on the texture parameters and does not take into account the radiation therapy doses, or the other parameters known to be related to IFs (i.e., age, chemotherapy, sex), and this is demonstrated by their non-significance in logistic regression analysis, except for the sex, whose significance is due to the ratio between male and females in the patients series. In fact, a significant characterization was shown in terms of TA parameters of L5 and femoral heads upon the univariate and multivariate analyses. The femoral head TA parameters m and SD, as well as the L5 TA parameters SD and e, were significantly lower in the IFp series than in C-p series, whereas the L5 TA parameters k and u were significantly higher in the IF-p series than in C-p series. We can speculate, at this regard, that the lower m reflects a lower density and a lower mineralization of the bone, in accordance to other works in the literature [20, 33]. The lower SD and the higher k, as well as the lower e and the higher u, at the same time, are correlated to the trabecular microarchitecture, in accordance with the work of Rachidi et al. [34] and Thevenot et al. [35]. In their studies, patients with IFs had lower entropy than the C-p, and this might be

Osteoporos Int Table 3 Paired t test analysis and binary logistic regression analysis

Paired t test analysis Paired differences (IF-p) − (C-p) TA parameters Mean

L5

Mean −42.53 ± 44.62

95% CI −61.37/−23.68

p value 0.001

−71.13 ± 64.55

−98.39/−43.88

<0.001

Femoral head Standard deviation

L5

−23.86 ± 32.96

−37.78/−9.94

0.002

−16.76 ± 20.93

−25.61/−7.92

0.001

Femoral head Skewness

0.26 ± 0.78

−0.068/0.595

0.115

L5

−0.05 ± 0.73

−0.367/0.254

0.710

Femoral head Kurtosis

2.21 ± 3.60

0.69/3.73

0.006

L5

−0.61 ± 3.48

−2.08/0.85

0.393

Entropy

−0.21 ± 0.34

−0.363/−0.075

0.004

L5

0.101 ± 0.309

−0.029/0.232

0.121

0.0018 ± 0.0034

0.00038/0.00328

0.015

−0.00062 ± 0.00229

−0.0015/0.00034

0.194

Femoral head

Femoral head Uniformity

L5 Femoral head

Logistic regression analysis (normalized odds ratio) Parameter p value Entropy (L5) 0.003 Uniformity (L5) 0.010 Mean (FH) 0.027 Standard deviation (FH) 0.015 Sex 0.044

Odds ratio 1.24 (protection) 1.87 (risk) 1.23 (protection) 1.24 (protection) 2.81 (risk for F)

95% CI 1.08–1.35 1.34–2.64 1.02–1.49 1.04–1.48 1.06–7.48

The normalized odds ratios were divided in Bprotection^ and Brisk^ according to their positive or negative correlation with the outcome

explained by the fibers being more marked in the control group, with an increase in the randomness of the pixel values, and eventually an increase in the entropy and a decrease in uniformity. Table 4

However, some aspects are worthy of consideration. This analysis intended to provide a reliable and reproducible method, suitable for identifying patients who are prone to develop pelvic RT-induced IFs prior to treatment.

Co-correlation between TA parameters (Pearson’s correlation analysis)

L5 mean L5 standard deviation L5 skewness L5 kurtosis L5 entropy L5 uniformity FH mean FH standard deviation FH skewness FH kurtosis FH entropy FH uniformity

L5 L5 standard mean deviation

L5 L5 L5 L5 FH skewness kurtosis entropy uniformity mean

FH standard deviation

FH FH FH FH skewness kurtosis entropy uniformity

1 0.776 0.776 1

0.238 0.059

0.367 0.167

0.248 0.172

0.221 0.087

0.544 0.021 0.422 0.002

0.039 0.056

0.038 0.080

0.398 0.339

0.348 0.306

0.248 0.059 0.367 0.167

1 0.917

0.917 1

0.837 0.900

0.893 0.906

0.194 0.032 0.273 0.067

0.181 0.135

0.131 0.060

0.013 0.074

0.018 0.061

0.248 0.221 0.544 0.021

0.172 0.087 0.422 0.002

0.837 0.893 0.194 0.032

0.900 0.906 0.273 0.067

1 0.974 0.120 0.020

0.974 1 0.106 0.008

0.120 0.106 1 0.464

0.020 0.008 0.464 1

0.063 0.089 0.332 0.078

0.012 0.017 0.177 0.214

0.066 0.022 0.084 0.036

0.067 0.033 0.045 0.001

0.039 0.038 0.398 0.348

0.056 0.080 0.339 0.306

0.181 0.131 0.013 0.018

0.135 0.060 0.074 0.061

0.063 0.012 0.066 0.067

0.089 0.017 0.022 0.033

0.332 0.177 0.084 0.045

0.078 0.214 0.036 0.001

1 0.898 0.723 0.779

0.898 1 0.804 0.871

0.723 0.804 1 0.986

0.779 0.871 0.986 1

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The ROI contouring was done by a radiation oncologist and by a radiologist, and the learning curve was minimum, due to their knowledge of this kind of analysis. The definition of the ROI (window level, anatomical landmark, and contouring as close as possible to the internal side of the compact bone) was critical to achieve the reliability results, but at the same time, we did not get information regarding the cortical part of the bones, whose contouring was not reproducible. We chose the CT simulation due to the uniformity of the scanner parameters in the patient series, as well as for the phantom-based calibration, regularly performed. Finally, the interpretation of TA parameters on the grounds of bone pathophysiology is incomplete, also, resulting at present by related literature [33–35]; thus, our study and other similar ones are still awaiting an exhaustive scientific background.

anonymous use of clinical data. All procedures were undertaken in compliance with the ethical statements of the Helsinki Declaration (1964, amended most recently in 2008) of the World Medical Association. Conflicts of interest None.

References 1.

2.

3.

4.

Limitations of the study 5.

Our results may be worthy of critical consideration for possible methodological and technical refinements and a desirable more fitting correlation with post-RT IFs. In particular, the single-slice analysis, in respect of the volumetric analysis, is more prone to errors due to the operator and, at the same time, can produce only a limited number of texture parameters [36–38]. At this regard, our choice of the TA parameters could be complemented by other TA parameters, such as the TBS and its precursor variogram slope that has been successfully used for TA [20, 22]. The choice of the matched comparison, also, can overestimate the effects of the TA parameters in respect of the other known variables (i.e., radiation doses, sex, age, menopausal state), so the effective value of the TA parameters needs to be investigated in a prospective study to substantiate this field of investigation. Further, we need to investigate the real reproducibility and the reliability of this kind of analysis in other departments and hospitals, with different parameters of CT acquisitions and different specialists.

Conclusions Despite the limitations of the study, the reported data are nevertheless worthy of attention. At our knowledge, these data are original, as no one correlated bone CT TA to the risk of radiation-induced IFs. A prospective analysis is needed to validate and estimate the reliability of this kind of approach. Compliance with ethical standards The retrospective analysis of the data was authorized by the Internal Institutional Review Board. A signed informed consent was obtained both for any treatment and for the

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10.

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