Clinical impact of tumor volume reduction in rectal cancer following preoperative chemoradiation

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Diagnostic and Interventional Imaging (2016) xxx, xxx—xxx

ORIGINAL ARTICLE /Gastrointestinal imaging

Clinical impact of tumor volume reduction in rectal cancer following preoperative chemoradiation Y.B. Han a, S.N. Oh a,f,∗, M.H. Choi a,f, S.H. Lee b,f, H.S. Jang c, M.A. Lee d,f, J.-G. Kim e a

Department of Radiology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea b Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea c Department of Radiation oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea d Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea e Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea f Cancer Research Institute in the Catholic University of Korea, Seoul, Republic of Korea

KEYWORDS Rectal cancer; Tumor volume reduction ratio; Chemoradiotherapy; Disease-free survival

∗

Abstract Purpose: The purpose of this study was to correlate tumor volumetric analysis obtained using magnetic resonance (MR) imaging with disease-free survival in patients with advanced rectal cancer who underwent preoperative chemoradiotherapy (CRT). Patients and methods: Institutional review board approval was obtained and patient informed consent was waived. This study included 74 patients (47 men, 27 women; mean age, 64 years ± 10 [SD] years) who underwent preoperative CRT and subsequent rectal surgery between January 2007 and December 2010. Two radiologists who were blinded to the clinical outcome measured tumor volume separately on two sets of MR images obtained before and after CRT. Patients were classified into two groups according to the episode of recurrence and recorded disease-free survival. To assess factors relevant to disease-free survival, univariate and multivariate Cox regression analysis were performed for tumor volume reduction ratio, circumferential resection margin, tumor regression grade, and pathologic staging.

Corresponding author. 222 Banpo-daero, Seocho-gu, Department of Radiology, Seoul St. Mary’s Hospital, Seoul 06591, Republic of Korea. E-mail addresses: [email protected], [email protected] (S.N. Oh).

http://dx.doi.org/10.1016/j.diii.2016.05.004 2211-5684/© 2016 Editions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Han YB, et al. Clinical impact of tumor volume reduction in rectal cancer following preoperative chemoradiation. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.05.004

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Y.B. Han et al. Results: Tumor volume reduction ratio (P = 0.009), circumferential resection margin (P = 0.008) and tumor regression grade (P = 0.002) were significantly associated with disease-free survival. At multivariate analysis, tumor volume reduction ratio was the single variable that was associated with disease-free survival (P = 0.003). Tumor volume reduction ratio was also a reliable parameter with an excellent interobserver correlation between two readers for pre-CRT volume (ICC = 0.939; 95%CI: 0.885—0.979; P < 0.001) and post-CRT volume (ICC = 0.889; 95%CI: 0.845—0.934; P < 0.001). Conclusions: MR volumetric measurement of rectal cancer helps predict disease-free survival in patients with rectal cancer who underwent preoperative CRT. © 2016 Editions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Chemoradiotherapy (CRT) before total mesorectal excision has been used for appropriate treatment of locally advanced rectal cancer due to its usefulness in anal sphincter preservation and reduced local recurrence [1—3]. Magnetic resonance (MR) imaging provides crucial information with respect to clinical prognosis as well as preoperative assessment [4,5], despite their uncertainties as a parameter to evaluate tumor response in rectal cancer after CRT. Post-CRT tumor pathologic staging is an important prognostic factor in rectal cancer after neoadjuvant CRT. However, estimations of restaging on post-CRT MR imaging are considered unsatisfactory due to low accuracy [6—13]. Many pathologic factors including post-CRT pathologic staging, tumor cellular differentiation, biological features have been studied to predict outcomes [14—21]. However, these parameters are obtained only after surgery and pathologic examination. More accurate tumor response assessments and reliable imaging parameters are required prior to surgery to evaluate clinical prognosis that could help clinicians determine an optimal treatment plan. Tumor volume reduction on MR imaging after neoadjuvant CRT has been previously studied [22—27]. Tumor volume reduction ratio (TVRR) also revealed a high correlation with pathologic parameters such as tumor regression grade (TRG) and pathologic staging, which are acknowledged prognostic factors for rectal cancer [23,24,26,27]. Prior studies reported a good correlation between these pathologic parameters and disease-free survival (DFS) [15—19]. However, few recent studies have evaluated the direct relationship between tumor volume reduction and clinical outcomes such as tumor recurrence and DFS [23,25]. The purpose of this study was to correlate tumor volumetric analysis obtained using MR imaging with DFS in patients with advanced rectal cancer who underwent preoperative chemoradiation therapy.

Patients and methods Patients This study received study-specific institutional review board approval with a waiver of informed consent. We reviewed our electronic medical record databases from January 2007

to December 2010 for patients who satisfied the following inclusion criteria: • the patient had histopathologically confirmed rectal adenocarcinoma; • the patient received neoadjuvant CRT; • the patient had surgery at our institution; • the patient underwent pre-CRT and post-CRT rectal MR imaging; • the patient had non-metastatic disease at initial state. We selected 78 consecutive patients for our study. A total of 74 patients (47 men, 27 women) with a mean age of 64 ± 10 (SD) years; range, 37-84 years) were ultimately enrolled in our retrospective study after 4 patients were excluded due to severe MR metallic artifacts (n = 2) and immediate follow-up loss after surgery (n = 2).

MR imaging technique MR imaging studies were performed using a 1.5 T (Achieva® , Phillips, Best, The Netherlands) or a 3 T (Verio® , Siemens Healthcare, Erlangen, Germany) MR unit with a six-channel phased array surface coil. Before MR scanning, approximately 50-100 mL of sonography transmission gel was administered for adequate rectal luminal distention and to help delineate small rectal tumors. MR images were obtained using the following sequences. First, sagittal images were obtained with a T2-weighted fast spin-echo sequence. A plane perpendicular to the long axis of the rectal cancer was selected for axial scanning. Oblique axial diffusion-weighted echo planar images were acquired using the three b factors of 0, 500, and 1000 s/mm2 in a 3-T system and the two b factors of 0 and 1000 s/mm2 in an 1.5-T system. Gadolinium-chelate enhanced fat-suppressed T1-weighted sequences in the transverse and sagittal plane were obtained after an intravenous bolus injection of 0.1 mmol/kg of Gadobutrol (Gadovist® , Schering, Berlin, Germany) at a rate of 3 mL/s, followed by a 25 mL of saline flush. Table 1 summarizes the detail imaging parameters.

MR volume measurement and image interpretation Two radiologists with an experience of 11- and 2-years in abdominal imaging independently measured tumor volume

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Clinical impact of tumor volume reduction in rectal cancer Table 1

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MR sequences and parameters. 3-T

TR (ms) TE (ms) ETL Slice thickness (mm) Slice gap (mm) FOV Matrix size NEX b factor (s/mm2 )

1.5-T

T2WI TSE

T1WI

DWI

T2WI TSE

T1WI

DWI

3900 89 21 5 0 200 × 200 320 × 224 3

600 13 3 5 0 200 × 200 320 × 224 3

5100 90

3300 100 16 5 0 220 × 220 260 × 176 2

500 100 3 5 0 220 × 220 260 × 200 4

4200 73

5 0 200 × 200 132 × 92 5 0, 500, 1000

5 0 220 × 220 100 × 90 12 0, 1000

TR: repetition time; TE: echo time; ETL: echo train length; FOV: field of view; NEX: number of excitations; TSE: turbo spin-echo; DWI: diffusion-weighted image; T1WI: T1-weighted image: T2WI: T2-weighted image.

on MR images obtained before and after CRT. Observers were blinded to clinical information and patient outcomes. The two radiologists manually traced the tumor outer margin and placed free-hand regions-of-interest (ROIs) on each T2-weighted axial image after transferring the T2-weighted images of each patient to commercial software (TeraRecon Intuition® , version 4.4.7, TeraRecon Inc., Foster City, CA, USA). The software then automatically calculated the entire tumor volume by multiplying the sum of cross-sectional areas by section thickness (Fig. 1). The observers considered wall thickenings with intermediate to low signal intensity compared to adjacent normal rectal wall on T2-weighted images as tumors that showed a high signal intensity compared with the background low signal intensity of the normal rectal wall on the diffusion-weighted (DW) images with high b value (1000s/mm2 ) and a low signal intensity on the corresponding ADC map. TVRR was estimated by: [(pre-CRT tumor volume — post-CRT tumor volume)/pre-CRT tumor volume] × 100 (%). Two radiologists assessed tumor T-stage and CRM measurement in consensus and evaluated the presence or absence of CRM threatening on MR imaging. CRM threatening

was considered as a distance < 2 mm from the adjacent mesorectal fascia according to the results of Vliegen et al. [10]. A third radiologist reviewed pathologic reports to investigate tumor T-stage and the presence of pathologic CRM threatening and estimate the sensitivity, specificity, positive and negative predictive value of radiologic CRM threatening using the pathologic report as a standard reference.

Preoperative CRT and surgery All patients underwent preoperative planning CT simulation for three-dimensional conformal RT. Neoadjuvant radiation therapy was delivered to the pelvis with a dose of 45 Gy in 25 fractions for 5 weeks and followed by a boost of 5.4 Gy in 3 fractions to the primary tumor. Preoperative chemotherapy was concurrently performed on all patients with 5-fluorouracil (400-500 mg/m2 /day) and leucovorin (20 mg/m2 /day) regimens. Chemotherapy was administrated as split into two bolus doses, given at the start and end of the radiotherapy, usually in the first and fifth weeks (n = 54; 73%), or a continuous infusion

Figure 1. A 44-year-old man with rectal cancer with a 62% tumor volume decrease after chemoradiation therapy; a: T2-weighted MR image in the transverse plane obtained before chemoradiation therapy shows rectal tumor outlined by a manually traced white line; b: T2-weighted image in the transverse plane obtained after chemoradiation therapy shows rectal mass with low signal intensity, outlined by a manually traced white line. Software automatically calculates the rectal mass volume.

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Y.B. Han et al.

throughout the radiation treatment (n = 20; 27%). All patients received curative operations 6-8 weeks after the completion of neoadjuvant CRT, by three colorectal surgeons with 33, 25 and 14 years of experience. A total of 48 patients underwent lower anterior resection, 12 received abdominoperineal resection, 11 had laparoscopic abdominal transanal-rectosigmoidectomy and coloanal anastomosis and 3 Hartmann’s operation.

Kruskal-Wallis test and the relationships between TVRR and pathologic downstaging were analyzed with a Mann-Whitney U test. The reproducibility of the volumetric measurement of the two radiologists was analyzed by an interobserver correlation coefficient (ICC) test. Significant difference was set at a P value < 0.05.

Results Pathologic evaluation Pathologic tumor staging was performed with the specimen opened, according to the TNM classification system recommended by the American Joint Committee on Cancer, 7th edition, 2009. CRT response was evaluated with the TRG system proposed by Dworak et al. [28]. Tumor regression was graded as: • grade 0: no regression; • grade 1: dominant tumor mass with obvious fibrosis and/or vasculopathy (minimal regression); • grade 2: dominant fibrotic changes with some obvious tumor cells or groups of cells (moderate regression); • grade 3: fibrotic tissue with (or without) mucous substance containing few tumor cells and difficult to detect microscopically (near-complete regression); • grade 4: fibrotic mass or acellular mucin pools only, without detectable tumor cells (complete regression). Complete pathologic response is defined as the complete disappearance of tumor.

Follow-up for recurrence surveillance We retrospectively investigated local tumor recurrence or distant metastasis after surgery during the follow-up period. Total mean surveillance time was 39.8 ± 20.6 (SD) months (range: 6.2—81.6 months). DFS was obtained by the time interval from the date of tissue diagnosis of rectal cancer to first episode of locoregional/systemic recurrence or censored events. Patients underwent follow-up every 3 months for the 1st year, every 6 months for the next 2 years, and then yearly. Each follow-up evaluation included a digital rectal examination, chest radiography, and serum CEA test. Abdominal and pelvic CT was performed every 6 months for the first 2 years and then yearly. Local tumor recurrence and/or distant metastasis were determined by the results of biopsies obtained through colonoscopy and the results of imaging that included abdominopelvic CT, PET-CT, and chest CT. A target lesion biopsy was performed when pathological confirmation was required.

Statistical analysis A univariate Cox proportional hazard model was used to analyze the correlation between DFS and potentially related factors: TVRR, TRG, occurrence of downstaging, CRM threatening, clinical, and pathologic T stage. We used a multivariate Cox proportional hazard model to investigate independent predictable factors for DFS among potential parameters. The optimal cutoff value of TVRR to predict DFS was calculated by a maximal chi-square method. The relationships between TVRR and TRG were analyzed with a

Baseline characteristics Table 2 summarizes the clinical characteristics of 74 patients included in our study. Among 74 patients, 23 (31%) patients developed tumor recurrence after 21.2 ± 19.9 (SD) months. The most common site for recurrence was the lung as noted in 12 patients (16%). Other recurrence sites were liver (n = 5), anastomosis sites (n = 4), lymph nodes (n = 4), vagina (n = 1), and bone (n = 1). In addition, 4 patients had tumor recurrence in two other sites synchronously. Table 3 demonstrates the correlation of post-CRT restaging and histologic staging. Overall accuracy of the restaging on post-CRT MR imaging was 57% in all rectal cancers (42/74). Table 4 shows the results of radiologic CRM threatening and correlation with pathologic CRM involvement. Table 2 Baseline characteristics of 74 patients with rectal cancer. Parameters Gender Men Women

47 (64) 27 (36)

Age (years) All Men Women

64 ± 10 (SD) [37—84] 64 [47—84] 64 [37—81]

Tumor site Distal (AV < 5 cm) Middle (5 ≤ AV < 10 cm) Proximal (AV ≥ 10 cm)

38 (51) 31 (42) 5 (7)

Clinical outcome Recurrence No recurrence

23 (31) 51 (69)

Pathologic tumor T stage ypT0 ypT1 ypT2 ypT3 ypT4

9 (12) 2 (2.7) 25 (33.8) 36 (48.6) 2 (2.7)

Tumor regression grade 1 (minimal regression) 2 (moderate regression) 3 (near-complete regression) 4 (complete regression)

31 (42) 22 (30) 12 (16) 9 (12)

AV: anal verge; TRG: tumor regression grade; SD: standard deviation. Numbers in parentheses are percentages; numbers in brackets are ranges.

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Clinical impact of tumor volume reduction in rectal cancer Table 3

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Correlation between clinical and pathological staginga .

T stage at post-CRT MRI

Pathological stage ypT0

ypT1-2

ypT3

ypT4

All rectal cancers (n = 74) ycT0 ycT1-2 ycT3 ycT4

2 3 4 0

0 12 11 4

0 8 27 1

0 0 1 1

Lower rectal cancers (n = 38) ycT0 ycT1-2 ycT3 ycT4

1 4 2 0

0 8 4 1

0 5 12 0

0 0 1 0

a

Overall accuracy of restaging on post-CRT MR imaging was 57% for all rectal cancers (42/74) and 55% (21/38) in lower rectal cancers.

Table 4

CRM measurement on MR imaging with histopathological correlation in the study population.

CRM on post-CRT MRI

Recurrence (n = 23, 31%)

No recurrence (n = 51, 69%)

Mean CRM Radiologic CRM threatening (n = 21, 21/74, 28%)

3.24 mm 12 (12/23, 52.2%)

4.14 mm 9 (9/51, 17.6%)

Tumor location

Correlation of radiologic CRM with pathologic CRM threatening (n = 11, 11/53, 21%a )

Lower(n = 9, 82%)

Mid(n = 2, 18%)

Totalb (n = 11)

Sensitivity Specificity Positive predictive value Negative predictive value

8/9 16/20 8/12 16/17

1/2 18/19 1/5 18/19

82% 81% 53% 94%

(9/11) (34/42) (9/17) (34/36)

MRI: magnetic resonance imaging. a Pathologic CRM involvement was not mentioned on early pathologic reports, so available pathologic CRM threatening was surveyed only 53 patients (53/74, 72%). Pathologic CRM threatening was seen in 11 (11/53, 21%). b Among 21 patients suspicious for CRM threatening on MRI, only 17 had histopathological correlation, because of lack of pathologic data.

Predictive factors for DFS We surveyed DFS in all 74 patients. The mean DFS was 53.1 ± 17.2 (SD) months in the non-recurrent group and 21.2 ± 14.9 (SD) months in the recurrence group (P < 0.001). At univariate Cox proportional hazard statistics, TVRR, TRG, and CRM threatening were significant factors to predict DFS. However, post-CRT MR stage, pathologic stage, and MR downstaging were not significant factors. In addition, TVRR was the single significant variable at multivariate Cox regression analysis for DFS (Table 5).

Tumor volume regression and DFS A significant correlation was found between TVRR and DFS. We estimated the cutoff value of TVRR using the maximal chi-square method, which determined 61.38% of TVRR

as the cutoff value. When we use this cutoff value, 50 patients (50/74, 68%) had a TVRR greater than 61.38%, and 24 (24/74, 32%) had a TVRR smaller than 61.38%. The high TVRR group (≥ 61.4%) showed longer DFS than the low TVRR group (< 61.38%) in the Kaplan-Meier analysis and log rank test (P = 0.011) (Fig. 2). The recurrence rate (8/50, 16%) of the high TVRR group (≥ 61.38%) was also lower than the low TVRR group (15/24, 63%, P = 0.01).

Relationship between TVRR and TRG, ypTdownstaging We estimated the relationship between TVRR with pathologic parameters that included TRG and ypTdownstaging. TVRR was significantly different between each TRG subgroup and significantly different according to the presence or absence of ypTdownstaging after CRT (Table 6).

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Y.B. Han et al. Table 5

A comparison of prognostic variables to predict DFS.

Parameters

TVRR (%) ≥ 61.38% vs < 61.38% TRG 3—4 vs 0—2 CRM threatening MR downstaging Clinical stage Tx, 1, 2 vs ycT3—4 Pathologic stageypT0—2 vs T3—4

Univariate analysis

Multivariate analysis

HR

95% CI

P*

HR

95% CI

P*

5.75

2.51—13.22

< 0.01

6.42 6.78

1.82—9.92 0.90—50.82

< 0.01 0.065

8.95 3.38 1.32 1.26 2.38

1.21—66.4 1.49—7.69 0.54—3.22 0.42—2.67 0.97—5.78

< 0.01 < 0.01 0.539 0.985 0.057

1.75

0.70—4.25

0.303

DFS: disease-free survival; CRM: circumferential resection margin; TVRR: tumor volume reduction rate; TRG: tumor regression grade. * Estimated by Cox proportional hazard analysis.

Table 6 Relationships between downstaging and TVRR and TRG. Parameters TRG 1 2 3 4 ypT downstaging No Yes * a

Patients (n)

Mean TVRR (%)

P < 0.01*

31 22 12 9

(42%) (30%) (16%) (12%)

58.12 66.41 71.8 86.4

± ± ± ±

17.1 24.5 12.5 8.0 < 0.01a

40 (54%) 34 (46%)

60.5 ± 15.5 74.8 ± 20.3

Estimated by Kruskal-Wallis test. Mann-Whitney U test.

Discussion

Figure 2. Graph shows significant disease-free survival (DFS) difference according to TVRR. A TVRR greater than 61.38% was associated with a higher DFS rate (P = .011*). TVRR indicates tumor volume reduction rate (%); DFS indicates disease-free survival (month). * Kaplan-Meier analysis and log rank test.

Reproducibility of the volumetry Pre-CRT tumor volumes measured by reader 1 and 2 were 24 ± 22 (SD) cm3 and 27 ± 32 (SD) cm3 , respectively. PostCRT tumor volumes measured by reader 1 and reader 2 were 7.05 ± 6.9 (SD) cm3 and 8.82 ± 10.2 (SD) cm3 , respectively. ICC value between the two radiologists was 0.939 (95%CI: 0.885-0.979; P < 0.001) for pre-CRT volumetry and 0.889 (95%CI: 0.845—0.934; P < 0.001) for post-CRT volumetry.

In our study, CRM threatening, TRG and TVRR show a significant correlation with DFS in univariate analysis. However, multivariate Cox-regression analysis revealed that TVRR was the only constant parameter to predict DFS and was similar to the results of a prior study [27]. TVRR also shows a good correlation with two pathologic parameters, TRG and ypTdownstaging. CRM threatening and TRG are important prognostic factors [10,29—31] obtained only after surgery. TVRR is a non-invasive imaging parameter obtainable prior to surgery; consequently, it is possible for radiologists to provide prognostic information and treatment options to clinicians prior to surgery. For example, a watch and wait approach is now carefully considered for selected patients with a complete response after CRT [32]. MR volumetric measurement has several advantages compared to clinical restaging. It is a quantitative parameter that directly reflects the tumor burden. However, post-CRT restaging is a categorical and subjective parameter that did not show satisfactory accuracy in our study (57%) and was similar to those reported in several studies (47—53%) [6,8]. It can be difficult to determine restaging on post-CRT MR images because of edema, fibrosis, desmoplastic reaction,

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and inflammatory changes. In particular, it is hard to detect remnant viable tumor within fibrosis when it is small. One limitation of MR volumetry is that it is timeconsuming. Another limitation is that no standardized data exist for an optimal TVRR cutoff value. Prior studies showed various tumor volumes and TVRR cutoff values. In our study, the pre-CRT tumor volume was relatively small; it may be due to a trend at our institution to stratify an increasing number of small rectal cancers into the pre-CRT regimen. Small T2- or T3-cancers with suspected nodal metastasis are also candidates for pre-CRT. This tendency follows previous studies [33—35]. The cutoff values of TVRR to predict clinical outcome varied in prior studies [23,25]. Yeo et al. [25] recently reported that a TVRR > 45% significantly correlated with prolonged DFS and Nougaret et al. [23] estimated the optimal cutoff as 70%. The optimal cutoff value of TVRR in our study was 61.38%. Factors thought to influence the TVRR cutoff value include radiation or chemotherapeutic methods, surveillance periods, patient or tumor characteristics and statistical analyses. Further investigations with a larger cohort are required because differences in the TVRR cutoff value to predict good prognosis seem inevitable across institutions or patient groups. The high diagnostic performance of the DW (diffusionweighted) MR image provides additional benefits in regards to prediction of treatment responses [33—35]. Viable tumor detection, characterization, and evaluation of treatment response is more accurate compared to conventional MR images because the DWMR image is a functional imaging modality that provides information on tumor cellularity [33—37]. Especially after CRT, assessing the remnant viable tumor is hindered by the mixed heterogeneous signal intensity that results from radiation-induced fibrosis and inflammation on conventional T2-weighted images. The DWMR image can efficiently enable the detection and localization of the viable tumor focus. However, the DWMR image has several limitations of low spatial resolution with poor anatomical detail, low signal to noise ratio, and vulnerability to variable artifacts. Conversely, conventional T2-weighted MR image reveals a high resolution of tumor configuration. Therefore, the combined interpretation of DW- with T2weighted MR image is essential, especially after treatment. Our study has several limitations. First, this study was performed in a single center with a relatively small sample size. Second, the retrospective design might have resulted in selection bias. A prospective study with a larger cohort would be required to validate our results. Third, our study group included a small proportion of patients with upper rectal cancers on which the effect of radiation therapy is still inconclusive. The improved final survival of upper rectal cancer treated by radiation therapy was unproven; however, a lower local recurrence rate was already proven for upper rectal cancers treated by CRT. Accordingly, the CRT for upper rectal cancers was performed based on the preference of clinicians. Fourth, the imaging slice thickness was 5 mm because imaging data was obtained earlier than 2011. However, the measurement of volumetric change would be unaffected because the MR scan protocol was identical before and after CRT. Finally, a prolonged surveillance time would be required for the validation of our results since the follow-up time was relatively short.

In conclusion, MR volumetric measurement of rectal cancer helps predict DFS and correlates with pathologic tumor responses.

Disclosure of interest The authors declare that they have no competing interest.

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Please cite this article in press as: Han YB, et al. Clinical impact of tumor volume reduction in rectal cancer following preoperative chemoradiation. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.05.004