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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 7  |  Issue : 3  |  Page : 100-107

Gastrointestinal stromal tumors: Do we follow the current guidelines? A self-critique


1 Department of Surgery, Armed Forces Hospital Southern Region, Khamis Mushait, Saudi Arabia
2 Department of Radiology, Armed Forces Hospital Southern Region, Khamis Mushait, Saudi Arabia

Date of Web Publication4-Nov-2019

Correspondence Address:
Mohammad Ezzedien Rabie
Department of Surgery, Armed Forces Hospital Southern Region, Khamis Mushait, PO Box 101
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ssj.ssj_7_19

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  Abstract 

Background: Despite its rarity, gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Several guidelines are currently present where, among other recommendations, mutational analysis and referral to specialized centers have been mentioned. However, this might be difficult to apply at times.
Aim: The aim of the study is to explore our experience in the management of GIST.
Patients and Methods: Histopathologically-proven GISTs, encountered in our hospital in the period from June 2012 to November 2018, were included in the study.
Results: We identified 14 patients, 8 males and 6 females, with a mean age of 58.6 years. Thirteen patients were sporadic GIST, while one was syndromic (associated with neurofibromatosis, multifocal, and arose from the small gut). Twelve patients presented in an emergency situation, while two presented in an elective setting. Thirteen cases were primary localized GISTs and one was metastatic. The organs involved were the stomach in five cases, ileum in four cases, jejunum in two cases, duodenum in two cases, and rectum in one case. In 13 cases, the patient's complaint led to the diagnosis, while in one case, it was discovered incidentally on investigations for another illness. The main clinical features were abdominal pain in five cases, melena and anemia in four cases, hematemesis and melena in one case, rectal bleeding in one case, abdominal pain and mass in one case, intestinal obstruction in one case, and urinary retention and constipation in one case. The mean diameter of the cyst on computed tomography was 8.7 cm. An endoscopic biopsy was performed in six occasions and missed the diagnosis in four of them, whereas percutaneous biopsy was performed in five occasions and was suggestive in two cases and diagnostic in the remaining three. According to a combination of stage, (primary, metastatic, or recurrent) size, risk stratification, mode of presentation, performance status, and comorbidities, treatment was planned. Five patients received surgery only, three patients received surgery followed by imatinib, one patient left to be treated elsewhere, and three patients received surgery to be followed by imatinib but did not show up, one patient received imatinib only, and one patient is still under evaluation. The mean duration of follow-up was 65.7 months, where the disease showed no recurrence in four cases, metastasized to the liver in two cases, and death occurred in two cases, while five cases were lost to follow-up. In this series, no mutational analysis was performed as imatinib was the only drug used, and no referral to specialized centers was done.
Conclusion: Surgical resection and kit inhibitors, either alone or in sequence, are the main pillars of treatment of GIST. Risk stratification, in addition to the mode of presentation, the presence or absence of metastasis and comorbidities, dictates which plan to follow. Except for mutational analysis, and referral to specialized centers, our practices are in line with the current guidelines to a reasonable extent.

Keywords: Gastrointestinal stromal tumor, imatinib, mutational analysis


How to cite this article:
Rabie ME, Hummadi A, Bazeed M, El Hakeem I, Al Qahtani AS, Haroon H, Al Zain A. Gastrointestinal stromal tumors: Do we follow the current guidelines? A self-critique. Saudi Surg J 2019;7:100-7

How to cite this URL:
Rabie ME, Hummadi A, Bazeed M, El Hakeem I, Al Qahtani AS, Haroon H, Al Zain A. Gastrointestinal stromal tumors: Do we follow the current guidelines? A self-critique. Saudi Surg J [serial online] 2019 [cited 2019 Dec 6];7:100-7. Available from: http://www.saudisurgj.org/text.asp?2019/7/3/100/270243


  Introduction Top


Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Nevertheless, they represent only 0.1%–3% of all its malignancies.[1] In the United States, an annual incidence of 3,300–6,000 new cases has been estimated.[2] In a study conducted in Memorial Sloan-Kettering Cancer Center, 200 cases were reported over the span of 16 years [3] reflecting the rarity of clinically manifest GIST. However, the true incidence may be much higher, as micro-GIST lesions (<1 cm) may be present without clinical evidence.[4],[5] This rarity of clinically manifest GISTs restricts the ability to gain wide local experience in any single institution. However, our understanding of GISTs has been rapidly evolving in the recent era, and this led to the development of guidelines from several specialized organizations which, though highly valuable, might be difficult to follow at times.

We conducted this research to compare our practice to the guidelines of four major authoritative western organizations:

  • NCCN guidelines version 2.2018. GIST [6]
  • UK clinical practice guidelines for the management of GISTs. 2017[7]
  • GISTs: ESMO–EURACAN clinical practice. Guidelines for diagnosis, treatment, and follow-up [8]
  • National Cancer Institute. GISTs treatment (PDQ ®).[9]


These organizations endorse the following key recommendations:

  1. GIST should be managed by an experienced multidisciplinary team
  2. The diagnosis should be made by a pathologist experienced in the disease and includes the use of immunohistochemistry and mutational analysis
  3. Endoscopic ultrasound (US) and needle biopsy are invaluable tools, particularly if the lesion is in the stomach
  4. Percutaneous core needle biopsy may be performed if the tumor is inaccessible to endoscopic US-guided biopsy
  5. For localized GIST, surgery is the mainstay of treatment and R0 resection should be the aim, with no dissection of uninvolved lymph nodes
  6. Preoperative imatinib should be considered for large gastric or rectal primaries, where immediate resection is likely to be morbid, e.g., total gastrectomy or abdominoperineal resection
  7. Patients at high risk of recurrence or distant relapse after surgery should receive 3 years of adjuvant imatinib
  8. For unresectable, recurrent, and metastatic GIST, tyrosine kinase inhibitors (TKI) are the standard treatment, which should be continued indefinitely, as interruption of TKI in these situations leads to tumor flare up. In such cases, surgery may be occasionally performed in selected patients
  9. Imatinib is the first-line drug of TKI. If it fails, or the patient develops intolerance to it, the standard second-line treatment is sunitinib. After failure of both imatinib and sunitinib, the standard third-line treatment is regorafenib
  10. Mutational analysis should be performed before the introduction of imatinib
  11. GIST patients should be referred to specialized centers.


In addition, we reviewed the Asian Consensus guidelines for the diagnosis and management of GISTs.[10]


  Patients and Methods Top


GIST patients, who were encountered in our hospital in the period from June 2012 to November 2018, were included in the study. The patients' demographic data, mode of presentation, radiological studies, histopathological diagnosis, treatment provided and their condition on follow-up, were reviewed.


  Results Top


We identified 14 patients, 8 males and 6 females, with a mean age of 58.6 years (minimum 32, maximum 88, standard deviation [SD] 16.6). Thirteen patients were sporadic GIST, while one was syndromic (a small gut, multifocal lesion associated with neurofibromatosis in a young patient). Twelve patients presented in an emergency situation while two presented in an elective setting. Thirteen cases were primary GISTs and one was metastatic. The organs initially involved are shown in [Table 1]. In all cases, the patient's complaint led to the diagnosis, except in case where the disease was discovered incidentally upon investigations for another illness. The main presenting features are shown in [Table 2]. Patients' demographics, GIST location, and mode of presentation are shown in [Table 3]. Computed tomography (CT) scan was the radiologic modality used for diagnosis and follow-up, and the mean diameter of the cyst was 9.2 cm (minimum 2.7, maximum 21, SD 5.9) [Figure 1], [Figure 2], [Figure 3], [Figure 4].
Table 1: Site of lesion

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Table 2: Mode of presentation

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Table 3: Patients' demographics, gastrointestinal stromal tumors site, and mode of presentation

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Figure 1: Contrast-enhanced computed tomography scan shows a large, necrotic, exophytic mass arising from the stomach with heterogeneous enhancement and large central hypodense nonenhancing areas of necrosis (red arrow)

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Figure 2: Contrast-enhanced computed tomography scan shows a large, exophytic mass arising from the ileum with heterogeneously enhancing solid components and hypodense nonenhancing cystic components (red arrow)

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Figure 3: Contrast-enhanced computed tomography scan shows a large hepatic metastasis with heterogeneously enhancement solid peripheral components and central hypodense nonenhancing components (red arrow)

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Figure 4: Follow-up of imatinib treatment with contrast-enhanced computed tomography scan: (a) Soft-tissue density mass inseparable from the rectum with prominent intratumor vessels (red arrow). (b) Postimatinib treatment with reduced size and density along with disappearance of intratumor vessels (red arrow)

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The histopathologic diagnosis was based on endoscopic biopsy, percutaneous needle biopsy, or examination of the resected specimen. Endoscopic biopsy was performed in six occasions and missed the diagnosis in four of them, whereas percutaneous biopsy was performed in five occasions and was suggestive in two cases and diagnostic in the remaining three. Twelve cases were spindle cell GIST while in two, the type was not specified. GIST was high risk in three cases, intermediate risk in five cases, low risk in three cases, and the risk was not specified in three cases. The characteristic of GIST is shown in [Table 4]. According to a combination of stage, (primary, metastatic, or recurrent) size, risk stratification, mode of presentation, performance status and comorbidities, treatment was planned, but due to unavoidable reasons, was not always fully delivered [Table 5] and [Table 6]. On follow-up, two patients were died, five patients were lost, and seven patients were still under follow-up, out of them, the disease showed no recurrence in two cases, metastasized to the liver in two cases, two cases recently received treatment, and one case is still under evaluation. The mean duration of follow-up was 65.7 months (minimum 3, maximum 192, and SD 77.9). No mutational analysis was performed, and imatinib was the only drug used in this series. Imatinib therapy and follow-up status are shown in [Table 7] and [Figure 4].
Table 4: Gastrointestinal stromal tumors characteristics and patient's performance status

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Table 5: Initial treatment summary

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Table 6: Planned and received treatment for each individual patient

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Table 7: Imatinib therapy, its dose, and follow-up status

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  Discussion Top


In 1983, Mazur and Clark identified GIST as a distinct category of mesenchymal tumors of the gut,[11] arising from the myenteric nervous system, as opposed to the smooth muscle origin of leiomyoma and leiomyosarcoma. Several years later, Kindblom et al. pointed to the interstitial cells of Cajal as its possible precursor.[12]

These tumors have no sex predilection, and the majority of patients present between the age of 50 and 80 years.[13] They rarely affect the pediatric population, where they exhibit different characters from those of the adult variant.[14]

According to the site and size of the tumor as well as its aggressiveness, patients may have different manifestations.[15] Gastrointestinal bleeding, bowel obstruction, or acute abdominal pain consequent on tumor rupture, may be the presenting picture. However, the most common presentation is gastrointestinal bleeding, which may lead to anemia in chronic cases or hematemesis and melena in the acute setting.[16] Other symptoms may also exist, and small tumors may remain asymptomatic,[4],[5] to be discovered incidentally on radiology, endoscopy, or surgery. In this series, all tumors were clinically evident, and gastrointestinal bleeding was the most common presentation.

Up to 85% of cases have mutations in KIT or platelet-derived growth factor receptor alpha genes, which provide instructions for making receptor tyrosine kinases. On the other hand, <15% have no such mutations and are hence called wild-type GISTs. Other rarer variants may have mutations in succinate dehydrogenase, BRAF or RAS genes.[6],[7],[8],[17]

The stomach is the most common site affected (60%) to be followed by the small intestine (30%). Less frequently, the rectum (3%), colon (1%–2%), and esophagus (<1%), may be involved, and rarer still, the omentum and mesentery may be affected.[11] In our series, similar frequencies were observed, and the stomach was the most commonly affected organ.

The vast majority of GISTs are sporadic forms. However, syndromic forms may be rarely seen,[7],[8] an example is the association with neurofibromatosis type 1 (NF1).[18] This type usually occurs at a younger age, affects the small bowel and is a wild type, and multifocal variety. In our series, 11 cases were sporadic forms, while one was associated with neurofibromatosis.

Diagnostic tools for GIST include US, CT, magnetic resonance imaging (MRI), endoscopy, and positron emission tomography (PET). However, due to its universal availability, CT scan has been the modality of choice for both the diagnosis and follow-up of GIST, the CT features of which have been well documented.[7],[19] The most common CT appearance is a heterogeneously enhancing mass arising from the intestinal wall and protruding into the abdominal cavity,[20] with central hypodense nonenhancing areas of necrosis and cystic degeneration.[21] As for the follow-up, the main criteria of response to medical treatment are the decrease in tumor size and attenuation [Figure 4]. However, change in size usually takes longer than decreased attenuation.[22] On the other hand, detection of an enhancing nodule within a mass and the appearance of a new solid lesion are signs of recurrence. In equivocal cases, PET-CT is a highly sensitive modality.[23] In this series, although US has been occasionally utilized, CT was the primary diagnostic and follow-up tool.

Although upper endoscopy can suggest the diagnosis in many cases, due to the presence of an intact mucosa over the intraluminal mass [Figure 5], biopsies taken are notoriously fallacious, as seen in our series, where it was performed in five occasions and picked the diagnosis only once.
Figure 5: Gastroscopic view. Intact mucosa overlying the intragastric mass

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It is obvious that the preoperative histologic diagnosis of a newly discovered intra-abdominal mass may change the treatment strategy. In this regard, CT-guided biopsy or endoscopic US-guided biopsy, preferably the later, has its definite role in the management of GIST.[6],[7],[8] In histologically proven GIST, clinically uninvolved lymph nodes need not be dissected,[6],[7],[8] in contrast to adenocarcinoma, where the lymphatic basin should be included in the resected specimen. Moreover, in unresectable or metastatic GISTs, histologic diagnosis should be obtained before starting molecular targeted therapy. In addition, certain malignancies such as lymphoma and germ cell tumors do not need surgery. In this regard, percutaneous CT-guided biopsy carries a negligible risk for peritoneal seedling if properly carried out.[8] However, extreme caution should be exercised in the case of cystic tumors, as the risk of spillage is higher. In our series, percutaneous CT-guided biopsy was carried in five occasions, with three positive and two equivocal results, whereas gastroscopic biopsy (without US guidance) was carried out in five occasions and came positive once. This disqualifies standard gastroscopic biopsy in this setting.

Histopathologically, the most commonly used marker for GIST is CD117 antigen, the epitope of KIT gene, a tyrosine kinase mast/stem cell growth factor receptor. However, CD117 is nonspecific and may be associated with other mesenchymal tumors.[24] Moreover, the test may be falsely positive under certain conditions.[8] For these reasons, testing for DOG1 and other immunohistochemistry techniques and genomic studies, including mutational analysis, may be needed [Figure 5]. In our hospital, the diagnosis of GIST depends on its morphology and the results of immunohistochemical techniques. However, genomic studies including mutational analysis are unavailable to us, and doubtful cases were sent to another higher facility for confirmation.

Morphologically, three types of GIST are recognized, spindle cell (70%), epitheloid cell (20%), and mixed (10%);[25] with the spindle cell having more aggressive behavior than the epitheloid type. In our series, 12 cases were spindle cell tumors, while the type was not specified in two.

Risk assessment is an important aspect of the management of GIST, for its prognostic and therapeutic implications, as the possibility of recurrence and the need for adjuvant therapy following surgery, could be calculated. According to the Armed Forces Institute of Pathology criteria,[17] the main factors involved are the anatomic site of the tumor, its size, and mitotic index.[7],[8],[17],[26],[27] Relatively recently, Joensuu added tumor rupture, either before, during, or after surgery, to these criteria.[28] In our series, the risk assessment was obtained to direct the management plan. However, it was not specified in two cases, due to the tiny size of the biopsy material, which was either a percutaneous or endoscopic biopsy, as the mitotic rate could not be calculated.

In the majority of cases, the treatment options are rather straightforward. For localized GIST, surgery is the mainstay of the treatment, with the utilization of TKIs as an adjuvant treatment in high-risk cases.[6],[7],[8] On the other hand, TKIs are the standard treatment for unresectable, recurrent, and metastatic GIST, with surgery utilized in selected cases.[6],[7],[8],[29] During surgery, clinically uninvolved lymph nodes need not be dissected, as GIST metastasizes mainly to the liver and intraperitoneum, and rarely to the lymph nodes.[3] In addition, R0 resection should be the aim [7],[8] to decrease the risk of recurrence. In this regard, although laparoscopic surgery may have a role in selected cases, tumor rupture, which tremendously increases the recurrence risk, should be avoided at all costs.[26] In this series, laparoscopic surgery was performed successfully in the fifth and sixth patients, while open surgery was the method utilized in the others.

Patients with large primary localized GIST, where the morbidity of resection is considered formidable, as in total gastrectomy or abdominoperineal resection, may benefit from neoadjuvant imatinib therapy. After maximum response and reduction of tumor size, usually in 6–12 months, surgery can be performed with reduced morbidity.[6],[7] This was planned in the fourth patient, an expatriate with very large gastric GIST, demanding total gastrectomy. However, the patient left to his country before the institution of treatment.

The introduction of TKI has revolutionized the management of GIST. In the setting of localized primary GISTs, they may be used as a neoadjuvant or adjuvant therapy in conjunction with surgery. For unresectable, recurrent, or metastatic GIST, they are used as a palliative therapy.[6],[7],[8] These agents should be instituted in a step-wise fashion, starting with imatinib as the first-line drug. As resistance or intolerance develops, the second-line drug, sunitinib, should be utilized. Finally, the third-line drug, regorafenib, may be introduced.[6],[7],[8],[29] Currently, the recommended duration for adjuvant imatinib is 3 years, whereas palliative imatinib therapy should be used indefinitely to avoid tumor flare up if the treatment is interrupted (ESMO),[8] the UK,[7] (NCCN).[6] In accordance with these recommendations,[6],[7],[8] following resection of localized GIST, we utilize adjuvant imatinib for 3 years in high-risk cases. On the other hand, for inoperable, unresectable, and metastatic disease, we continue on palliative imatinib indefinitely. In this context, although radiofrequency ablation and similar palliative procedures have its role in selected cases with liver metastasis,[7] this was not reported in our series.

An important recommendation in the management of GIST is mutational analysis,[6],[7],[8] for its diagnostic and therapeutic implications. From the diagnostic side, cases negative for both CD117 and DOG1, may be subjected to mutational analysis, to identify the mutant gene [Figure 5]. As for the therapeutic side, mutational analysis can guide TKI therapy. While KIT exon 11 mutation shows favorable response to the standard dose of imatinib, which is 400 mg; GIST with exon 9 mutation has less favorable response, and a higher starting dose of 800 mg has been recommended. In addition, GIST with PDGEFRA D842V (exon 18 mutation) and NF1-related GIST are not sensitive to imatinib, which should not be used in these cases.[6],[7],[8] Certainly, this is not a part of our practice as, to our knowledge, mutational analysis is not readily available in the kingdom. However, this is also the case in several Asian countries, as reported in the Asian consensus on the management of GIST, where a diagnostic algorithm has been suggested ([Figure 6], with permission).[10] However, in the absence of mutational analysis, early assessment of the response to neoadjuvant imatinib therapy, is particularly crucial, to avoid unnecessary delay of surgery in unresponsive cases.[10] However, mutational analysis should be considered in our future cases and ties with centers, where this facility is available should be established.
Figure 6: Diagnostic algorithm for gastrointestinal stromal tumor.[10] IHC: immunohistochemistry

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Another recommendation which was not followed in this series, is to refer cases to pathology centers with special experience in the field.[6],[7],[8] The reason is our unawareness of the existence of such centers in the kingdom. However, all pathology works were done by our pathologists, with a second opinion being sought from a higher center in ambiguous cases. In this regard, the management of GIST in our center is carried out by a multidisciplinary team, formed by surgeons, radiologists, pathologists, and medical oncologists, forming a tumor board. All our oncology decisions, for GIST and other malignancies, are taken after group discussions in weekly meetings. We also seek a second opinion from a higher center when needed. This might be a partial answer for the call to centralize the management of GIST by a multidisciplinary team in specialized centers.

Regarding follow-up, no consensus exists. However, this should be tailored according to the institutional local experience and estimated the risk of recurrence. A 3–6 months interval with CT assessment is generally appropriate with the understanding that short intervals are needed early in the course of the disease and in high-risk patients. In addition, high-risk patients need a longer duration of follow-up than low-risk patients (up to 13 years vs. 5 years).[6],[7],[8] In our series, the mean duration of follow-up was 64.8 months, and the longest period was 192 months. Other radiology methods include MRI, US, and PET-CT scan, with the latter being particularly useful in the early assessment of tumor response.[15] With this modality, response to therapy may be detected much earlier than CT. However, the CT scan was the only radiologic method used for follow-up in our series.


  Conclusion Top


Surgical resection and KIT inhibitors, either alone or in sequence, are the main pillars of treatment of GIST. Risk stratification, in addition to mode of presentation, the presence or absence of metastasis and comorbidities, should dictate the management plan. Except for mutational analysis, and referral to specialized centers, our practice is in line with the current guidelines to a reasonable extent. However, mutational analysis should be incorporated in the care of our future patients'.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Zhang L, Smyrk TC, Young WF Jr., Stratakis CA, Carney JA. Gastric stromal tumors in carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: Findings in 104 cases. Am J Surg Pathol 2010;34:53-64.  Back to cited text no. 1
    
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Agaimy A, Wünsch PH, Hofstaedter F, Blaszyk H, Rümmele P, Gaumann A, et al. Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations. Am J Surg Pathol 2007;31:113-20.  Back to cited text no. 4
    
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Kawanowa K, Sakuma Y, Sakurai S, Hishima T, Iwasaki Y, Saito K, et al. High incidence of microscopic gastrointestinal stromal tumors in the stomach. Hum Pathol 2006;37:1527-35.  Back to cited text no. 5
    
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Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): Gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998;152:1259-69.  Back to cited text no. 12
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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