This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Boughanim, M. Articles by Morice, P. PubMed Articles by Boughanim, M. Articles by Morice, P.

Histologic Results of Para-Aortic Lymphadenectomy in Patients Treated for Stage IB2/II Cervical Cancer With Negative [¹⁸F]Fluorodeoxyglucose Positron Emission Tomography Scans in the Para-Aortic Area

Mathias Boughanim, Sophie Leboulleux, Annie Rey, Chi Tuan Pham, Yaelle Zafrani, Pierre Duvillard, Jean Lumbroso, Christine Haie-Meder, Martin Schlumberger, Philippe Morice

From the Departments of Surgery, Nuclear Medicine, Statistics, Pathology, and Radiation Therapy, Institut Gustave Roussy, and University Paris Sud, Villejuif, France

Corresponding author: Philippe Morice, MD, Service de Chirurgie, Institut Gustave Roussy and University Paris Sud, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: morice{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Purpose: Histologic results of complete para-aortic lymphadenectomy were studied in patients treated for stage IB2/II cervical carcinoma who had no para-aortic uptake on [¹⁸F]fluorodeoxyglucose positron emission tomography combined with integrated computed tomography (FDG-PET/CT).

Patients and Methods: Patients were treated between 2004 and 2006 for stage IB2/II cervical cancer. Magnetic resonance imaging of the abdomen and pelvis and FDG-PET/CT were initially performed. Patients with no para-aortic abnormalities were treated with external pelvic radiation therapy and concomitant chemotherapy followed by utero-vaginal brachytherapy. Para-aortic lymphadenectomy was then performed. FDG-PET/CT images were reviewed by two nuclear medicine specialists.

Results: Thirty-eight patients were studied. Three patients had histologically proven para-aortic involvement (metastatic nodes with capsular rupture in the para-aortic area), leading to a negative predictive value of 92% for para-aortic nodal involvement.

Conclusion: In this study, three of 38 patients with no para-aortic uptake on [¹⁸F]FDG-PET/CT imaging had histologically proven para-aortic node involvement. PET/CT imaging without histologic examination of the para-aortic area used to determine radiation therapy fields in stage IB2/II cervical cancer would overlook 8% of patients with histologic para-aortic nodal involvement.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Chemoradiotherapy (CRT) is considered as the standard treatment for bulky cervical cancer ( stage IB2 according to the International Federation of Gynecology and Obstetrics [FIGO] classification).¹ A major issue when defining the modalities of CRT and, in particular, fields of external radiation therapy (pelvis alone or pelvis and para-aortic area) is whether disease has spread beyond the pelvic cavity.

The para-aortic area is the first extra-pelvic site of spread in the natural history of the tumor and is involved in 12% to 25% of cases.^2,3 Determining such spread is a key to improving treatment efficacy for patients and can be researched by radiologic imaging or surgical lymphadenectomies. Magnetic resonance imaging (MRI) or computed tomography (CT) are, however, not sufficiently accurate for the adequate evaluation of nodal spread.⁴ Positron emission tomography (PET) scanning is a recent imaging modality that became a standard procedure in the management of several cancer types (lymphoma, lung cancer, and so on). Integrated PET-CT improves the diagnostic accuracy compared with PET alone.^5-7 In patients with cervical cancer, several recent reports focused on the interest of PET imaging for the evaluation of disease spread at extra-cervical sites and in particular in the para-aortic area. Most of these studies, however, did not include a histologic analysis of lymph nodes, and the accuracy of PET imaging was determined according to the clinical outcome of patients. Some studies included a histologic examination as standard but were performed with a PET without an integrated CT scan.^8-10 We thus decided to specifically correlate integrated [¹⁸F]fluorodeoxyglucose (FDG) -PET/CT imaging and histologic findings in the evaluation of para-aortic spread in stage IB2 and II cervical carcinoma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Data regarding women treated between January 2004 and December 2006 for stage IB2/II cervical cancer (according to the FIGO classification¹¹) were reviewed. An initial FDG-PET/CT imaging was performed before CRT, followed by surgery that included at least a para-aortic lymphadenectomy. The FIGO stage was determined by two physicians during a clinical examination. All patients underwent at least initial abdomino-pelvic MRI or pelvic MRI plus abdominal CT and FDG-PET combined with integrated CT (FDG-PET/CT). Patients with nodes in the para-aortic area that were suggestive of abnormality on abdominal MRI or conventional CT scan (defined as having nodes > 1 cm) and with significant uptake in para-aortic nodes on FDG-PET/CT imaging were treated with CRT with extended fields, including the pelvic and para-aortic areas, and did not undergo para-aortic surgery. They were excluded from the present study. During the period of study, six patients with stage IB2/II cervical cancer were excluded because their scan (or FDG-PET/CT imaging) suggested para-aortic node involvement.

Patients with no abnormalities in para-aortic nodes during abdominal MRI and FDG-PET/CT, underwent a complete para-aortic lymphadenectomy and were included in the present study. After initial FDG-PET/CT imaging, they received CRT that combined external radiation therapy at a dose of 45 Gy to the pelvic cavity and concomitant chemotherapy (cisplatin 40 mg/m²/wk) over 5 weeks. CRT was followed by low-dose-rate utero-vaginal brachytherapy to a dose of at least 15 Gy to the intermediate-risk clinical target volume. Some patients with large stage II disease and/or bulky pelvic nodes on initial imaging received a lateral pelvic boost of external radiation therapy to a total dose of 60 Gy (biologic effective dose calculation), integrating the contribution of the dose delivered by the brachytherapy. FDG-PET/CT was not repeated before surgery.

Surgical Procedure
All patients underwent completion surgery after radiation therapy that included at least a complete para-aortic lymphadenectomy up to the level of the left renal vein.¹² According to the presence or absence of residual disease in the cervix at the end of CRT, a laparoscopic or a laparotomic approach was used for the surgical management of the uterus and pelvic lymph nodes at the time of the para-aortic lymphadenectomy. Some patients did not undergo surgical removal of the uterus at the time of the para-aortic lymphadenectomy.

To decrease the rate of postoperative morbidity associated with complete lymphadenectomy of pelvic nodes that had been included in the radiotherapy fields, a pelvic lymphadenectomy was performed only in patients with residual lymphadenomegaly detected during the surgical procedure.

FDG-PET Imaging Technique
All imaging and data acquisitions were performed on an integrated FDG-PET/CT Biograph LSO system (Siemens Medical Solutions; Erlangen, Germany). After an intravenous injection of 4 to 5 MBq/kg of FDG followed by a 50- to 70-minute uptake phase, PET/CT imaging was performed. During image acquisition, patients maintained their arms above their head and no specific breathing instructions were given. The PET element of the system is based on a full ring tomograph (Siemens Medical Solutions; Erlangen, Germany). 3D mode was used for PET acquisition. PET data were reconstructed on a 128 x 128 matrix, using an iterative algorithm (FORE and AWOSEM) with two iterations, eight subsets, and a 5-mm full width at half maximum Gaussian postfilter. Reconstruction data were acquired using a single-slice spiral CT (Somatom Emotion, Siemens Medical Solutions; Erlangen, Germany). CT parameters were as follows: 80 mAs,120 kVp, 5-mm slice thickness every 2.5 mm and pitch 1.5. In the absence of renal obstruction or insufficiency, 10 to 20 mg of furosemide were administered intravenously to reduce ureteral artifacts.

Image Analysis
FDG-PET/CT images were analyzed by two nuclear physicians, blindly and independently. They were unaware of clinical and histologic findings or of any imaging studies concerning the patients. FDG-PET/CT analysis included quantitative assessment. On FDG-PET/CT images, nodes in the para-aortic area were considered suggestive of abnormality if, during the visual interpretation, they exhibited FDG uptake above background uptake.

Statistical Analysis
Positive lymph nodes on the histologic analysis were correlated with the results of FDG-PET/CT imaging. The number of false-negative cases and the negative predictive value were determined using the total number of patients with negative FDG-PET/CT imaging as the study group.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Thirty-eight patients were included. The median age of patients was 42 years (range, 19 to 69 years). The disease stage was as follows: IB2 (n = 17; 44%) and IIB (n = 21; 56%). There were 28 cases of squamous cell carcinoma (75%), nine cases of adenocarcinomas (23%), and one case of small-cell carcinoma (2%). No patient had para-aortic lymph nodes suggestive of abnormality during conventional imaging (MRI or CT scan) and FDG-PET/CT imaging in the study group.

The median time between FDG-PET/CT imaging and the surgical procedure was 123 days (range, 31 to 196 days). Thirty patients underwent a hysterectomy (extra-fascial in 22% to 56% and radical in 8% to 21%), of whom 16 patients had residual disease in the cervix. Of the nine patients who underwent a pelvic lymphadenectomy, four patients had metastatic pelvic nodes at histologic analysis, among whom the initial FDG-PET/CT imaging had shown pelvic nodes suggestive of abnormality in two patients and a node suggestive of abnormality in the parametria in one patient (node was not suggestive of abnormality on MRI); the remaining patient had no pelvic lymph node suggestive of abnormality during initial FDG-PET/CT imaging.

The 38 patients underwent a complete para-aortic lymphadenectomy (by laparoscopy in 21 patients). The median number of para-aortic nodes removed was 16 (range, five to 42 nodes). Three patients (8%) had positive para-aortic lymph nodes, and FDG-PET/CT imaging was considered falsely negative. The negative predictive value for para-aortic involvement was 92% (95% CI, 79% to 98%). Characteristics of three patients with false-negative results are listed in Tables 1 and 2.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
PET imaging is a promising procedure for the management of cervical cancer^13-15 and is used for the management of recurrent disease.¹³ During initial management, its accuracy for disease staging is excellent,^13,15 but it seems to be more limited for evaluating pelvic nodal spread in patients with early-stage disease (tumor size < 4 cm).^16,17 In such patients, PET/CT imaging cannot replace lymphadenectomy for pathologic examination of lymph nodes.

In patients with more advanced-stage diseases (stage IB2), PET/CT is potentially interesting because extra-pelvic (particularly in the para-aortic area) spread is frequent.^18,19 This is why para-aortic lymphadenectomy has long been part of the surgical staging of advanced-stage cervical cancer.^2,3,12 This procedure was conventionally performed in our institution at the end of the treatment procedure during completion surgery.²⁰ However, our recent results showed that the prognosis of patients with para-aortic nodal involvement at the time of completion surgery remains poor.²⁰ If a para-aortic lymphadenectomy is to be considered, it may be done during the initial management (before the chemoradiotherapy).^3,21,22 The interest of such staging surgery, in terms of optimizing the survival of patients, is, however, still debated.²³

PET/CT seems to be an accurate procedure for the staging of para-aortic nodes in advanced-stage cervical cancer and may potentially replace the surgical procedure.^13-15,24 However, only few studies have correlated the results of PET imaging with routine para-aortic lymphadenectomy for the histologic analysis.^8-10,25 Furthermore, three studies reported results using PET alone without an integrated CT scan.^8-10 Only one recent study compared the histologic analysis of pelvic and para-aortic nodes from 22 patients with results of preoperative PET/CT imaging.²⁵ Thirteen patients had 33 metastatic lymph nodes in the pelvic or para-aortic areas. Two of the four para-aortic metastatic nodes were missed by PET/CT imaging.²⁵ However, no patient characteristics were provided, nor did the authors mention the total number of patients with para-aortic nodal involvement. In addition, patients with stage IB1 were mixed with those with more advanced disease stages.²⁵

In our study of patients with stage IB2/II cervical cancer, we correlated the histologic analysis of completion lymphadenectomy specimens with FDG-PET/CT findings. The evaluation of pelvic lymph nodes by PET scanning would not modify deeply the therapeutic strategy for the pelvic cavity because it was submitted to external radiation exposure during CRT. In contrast, uptake foci in the para-aortic area suggestive of abnormality raise the question of whether this area should be included in conventional radiation therapy fields. This is the policy in our institution. When there are no bulky nodes on conventional imaging but uptake foci suggestive of abnormality in the para-aortic area on FDG-PET scan, we consider that the rate of false-positive of FDG-PET/CT imaging is low in this context,¹⁵ so such patients will receive pelvic and para-aortic CRT, without any histologic confirmation. This is why we analyzed our results as per patient and not as per nodal group in the para-aortic area, because extended-field radiation therapy is given during CRT for any para-aortic uptake.

This policy also explains why patients with positive FDG-PET/CT findings in the para-aortic nodes were excluded, because we treated them without any histologic confirmation of their lymph node involvement, and thus sensitivity, specificity, and positive predictive values could not be evaluated.

The most important finding in our study is that 8% of patients had false-negative results, which would lead to undertreatment of these patients if FDG-PET/CT were used alone, without histologic confirmation of the para-aortic lymph node status. These false-negative results were not related to a small size of lymph node metastases, because all these patients with positive nodes had macroscopic nodal involvement with capsular rupture, and two of three patients had metastatic size more than 5 mm.

Different mechanisms could explain the nonvisualization of the nodal disease in present study. First, the PET/CT imaging could have been initially misdiagnosed. This potential bias is present in all series, including an interpretative examination. But in the present study, all PET/CT images were blindly and independently reviewed by two nuclear physicians to ensure the absence of uptake in para-aortic area.

Second, metastases could have occurred during the interval between PET/CT imaging and the histologic control during lymphadenectomy. This is a potential bias in this study related to the long delay between PET/CT imaging and the lymphadenectomy in the majority of patients. During the interval between both procedures, there was a potential growth in tumor volume and so a spread in para-aortic area. Therefore, it could be theoretically argued that this nodal involvement may have been absent initially but was observed because the disease had time to spread during treatment of the pelvic cavity. But this seems to be unlikely, because two of the three patients with apparent false-negative results had massive involvement (size 10 mm) in the para-aortic area (with several nodes involved), and two of these patients had no residual disease in the cervix at histologic examination of the specimen removed at the time of completion surgery. This suggests that these patients had extremely radiosensitive tumors. Therefore, the nodal spread in para-aortic area was likely present at the time of initial management in these patients.

Third, at least the last explanation could be related to the difference of uptake between pelvic and para-aortic metastatic nodes. Perhaps biologic characteristics of pelvic and para-aortic metastasis were different and could explain a discrepancy in terms of uptake. But further studies are needed to explore such a hypothesis.

In conclusion, FDG-PET/CT imaging is a key examination because CRT modalities should be adapted in patients with uptake foci in the para-aortic area. However, in patients with stage IB2/II cervical cancer without uptake in this area, initial PET-CT imaging seems to overlook 8% of patients who have histologic para-aortic nodal involvement, with a risk of undertreatment. These results suggest that selected patients with stage IB2/II cervical cancer who have negative FDG-PET scan might still be appropriate candidates for a diagnostic lymphadenectomy. However, the effect of this management strategy on improving the survival of patients with stage IB2/II cervical cancer remains unclear and will require further evaluation in prospective clinical trials.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Christine Haie-Meder, Martin Schlumberger, Philippe Morice

Provision of study materials or patients: Mathias Boughanim, Sophie Leboulleux, Yaelle Zafrani, Pierre Duvillard, Jean Lumbroso, Christine Haie-Meder, Martin Schlumberger, Philippe Morice

Collection and assembly of data: Mathias Boughanim, Sophie Leboulleux, Annie Rey, Chi Tuan Pham, Yaelle Zafrani, Pierre Duvillard, Christine Haie-Meder, Martin Schlumberger, Philippe Morice

Data analysis and interpretation: Mathias Boughanim, Sophie Leboulleux, Annie Rey, Chi Tuan Pham, Pierre Duvillard, Jean Lumbroso, Christine Haie-Meder, Martin Schlumberger, Philippe Morice

Manuscript writing: Sophie Leboulleux, Jean Lumbroso, Christine Haie-Meder, Martin Schlumberger, Philippe Morice

Final approval of manuscript: Mathias Boughanim, Sophie Leboulleux, Annie Rey, Jean Lumbroso, Christine Haie-Meder, Martin Schlumberger, Philippe Morice

	ACKNOWLEDGMENTS

 
We thank Lorna Saint Ange for editing.

	NOTES

 
Presented at the 39th Annual Meeting of the Society of Gynecologic Oncology, March 9-12, 2008, Tampa, FL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Green JA, Kirwan JM, Tierney JF, et al: Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 358:781-786, 2001[CrossRef][Medline]

2. Morice P, Castaigne D, Pautier P, et al: Interest of pelvic and paraaortic lymphadenectomy in patients with stage IB and II cervical carcinoma. Gynecol Oncol 73:106-110, 1999[CrossRef][Medline]

3. Leblanc E, Narducci F, Frumovitz M, et al: Therapeutic value of pretherapeutic extraperitoneal laparoscopic staging in locally advanced cervical carcinoma. Gynecol Oncol 105:304-311, 2007[CrossRef][Medline]

4. Scheidler J, Hricak H, Yu KK, et al: Radiological evaluation of lymph node metastases in patients with cervical cancer: A meta-analysis. JAMA 278:1096-1101, 1997[Abstract]

5. Antoch G, Saoudi N, Kuehl H, et al: Accuracy of whole-body dual-modality fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: Comparison with CT and PET. J Clin Oncol 22:4357-4368, 2004[Abstract/Free Full Text]

6. Branstetter BF, Blodgett TM, Zimmer LA, et al: Head and neck malignancy: Is PET/CT more accurate than PET or CT alone? Radiology 235:580-586, 2005[Abstract/Free Full Text]

7. Lardinois D, Weder W, Hany TF, et al: Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 348:2500-2507, 2003[Abstract/Free Full Text]

8. Roh JW, Seo SS, Lee S, et al: Role of positron emission tomography in pretreatment lymph node staging of uterine cervical cancer: A prospective surgicopathologic correlation study. Eur J Cancer 41:2086-2092, 2005[CrossRef][Medline]

9. Lin WC, Hung YC, Yeh LS, et al: Usefulness of (18)F-fluorodeoxyglucose positron emission tomography to detect para-aortic lymph nodal metastasis in advanced cervical cancer with negative computed tomography findings. Gynecol Oncol 89:73-76, 2003[CrossRef][Medline]

10. Rose PG, Adler LP, Rodriguez M, et al: Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: A surgicopathologic study. J Clin Oncol 17:41-45, 1999[Abstract/Free Full Text]

11. International Federation of Gynecology and Obstetrics: Modifications in the staging for stage I vulvar and stage I cervical cancer. Int J Gynaecol Obstet 50:215-216, 1995[CrossRef][Medline]

12. Michel G, Morice P, Castaigne D, et al: Lymphatic spread of stage IB/II cervical carcinoma: Anatomy and surgical implications. Obstet Gynecol 91:360-363, 1998[Abstract]

13. Lai CH, Yen TC, Chang TC: Positron emission tomography imaging for gynecologic malignancy. Curr Opin Obstet Gynecol 19:37-41, 2007[Medline]

14. Loft A, Berthelsen AK, Roed H, et al: The diagnostic value of PET/CT scanning in patients with cervical cancer: A prospective study. Gynecol Oncol 106:29-34, 2007[CrossRef][Medline]

15. Grigsby PW, Siegel BA, Dehdashti F: Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 19:3745-3749, 2001[Abstract/Free Full Text]

16. Sironi S, Buda A, Picchio M, et al: Lymph node metastasis in patients with clinical early-stage cervical cancer: Detection with integrated FDG PET/CT. Radiology 238:272-279, 2006[CrossRef][Medline]

17. Wright JD, Dehdashti F, Herzog T, et al: Preoperative lymph node staging of early-stage cervical carcinoma by [18F]-fluoro-2-deoxy-D-glucose-positron emission tomography. Cancer 104:2484-2491, 2005[CrossRef][Medline]

18. Grigsby PW, Singh AK, Siegel BA, et al: Lymph node control in cervical cancer. Int J Radiat Oncol Biol Phys 59:706-712, 2004[CrossRef][Medline]

19. Tran BN, Grigsby PW, Dehdashti F, et al: Occult supraclavicular lymph node metastasis identified by FDG-PET in patients with carcinoma of the uterine cervix. Gynecol Oncol 90:572-576, 2003[CrossRef][Medline]

20. Delpech Y, Haie-Meder C, Rey A, et al: Para-aortic involvement in stage IB 2/II cervical carcinoma confined radiologically to the pelvic cavity treated using pelvic radiotherapy and concomitant chemotherapy. Ann Surg Oncol 14:3223-3231, 2007[Abstract/Free Full Text]

21. Holcomb K, Abulafia O, Matthews RP, et al: The impact of pretreatment staging laparotomy on survival in locally advanced cervical carcinoma. Eur J Gynaecol Oncol 20:90-93, 1999[Medline]

22. Goff BA, Muntz HG, Paley PJ, et al: Impact of surgical staging in women with locally advanced cervical cancer. Gynecol Oncol 74:436-442, 1999[CrossRef][Medline]

23. Lai CH, Huang KG, Hong JH, et al: Randomized trial of surgical staging (extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer. Gynecol Oncol 89:160-167, 2003[CrossRef][Medline]

24. Nakamoto Y, Eisbruch A, Achtyes ED, et al: Prognostic value of positron emission tomography using F-18-fluorodeoxyglucose in patients with cervical cancer undergoing radiotherapy. Gynecol Oncol 84:289-295, 2002[CrossRef][Medline]

25. Choi HJ, Roh JW, Seo SS, et al: Comparison of the accuracy of magnetic resonance imaging and positron emission tomography/computed tomography in the presurgical detection of lymph node metastases in patients with uterine cervical carcinoma: A prospective study. Cancer 106:914-922, 2006[CrossRef][Medline]

Submitted September 10, 2007; accepted January 28, 2008.

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Boughanim, M. Articles by Morice, P. PubMed Articles by Boughanim, M. Articles by Morice, P.