|Year : 2017 | Volume
| Issue : 6 | Page : 889-900
Diagnosis and management of gastrointestinal stromal tumors: An up-to-date literature review
Ayman El-Menyar1, Ahammed Mekkodathil2, Hassan Al-Thani3
1 Department of Surgery, Clinical Research, Trauma Surgery, Hamad General Hospital, Doha; Department of Clinical Medicine, Weill Cornell Medical College, Doha, Qatar
2 Department of Surgery, Clinical Research, Trauma Surgery, Hamad General Hospital, Doha, Qatar
3 Department of Surgery, Hamad General Hospital, Doha, Qatar
|Date of Web Publication||13-Dec-2017|
Prof. Ayman El-Menyar
Clinical Research, Trauma Surgery, Hamad General Hospital, P.O. Box 3050, Doha
Source of Support: None, Conflict of Interest: None
Gastrointestinal stromal tumors (GISTs) are rare life-threatening forms of cancer that may arise anywhere in the GI tract. Herein, we aimed to review the literature to describe the incidence, management, and outcomes of GISTs. We conducted a traditional narrative review using PubMed and EMBASE, searching for English-language publications for GISTs between January 2001 and January 2016 using keywords “”gastrointestinal” “stromal tumors.” Among 4582 retrieved articles, 50 articles were relevant over the last 15 years. Several risk stratification systems exist to predict the outcomes of GISTs based on certain criteria such as the primary site of occurrence, size of the tumor, mitotic activity, staining for proliferating cells, and tumor necrosis. Risk stratification is crucial in the management and outcomes of the disease. Surgical resection remains the gold standard option of GISTs treatment. Complete resection of the tumor is the main predictor of the postoperative patient's survival. Laparoscopic resections are associated with less intraoperative blood loss, early return of bowel function, early resumption of diet, and short hospital stay. However, laparoscopy is difficult to perform in large and unfavorably placed GISTs and may result in disease progression, recurrence, and poor survival. Robot-assisted laparoscopic resections provide instruments for surgeons to perform technically demanding operations. Moreover, extensive research work including large clinical trials is ongoing to establish promising role of the adjuvant and neo-adjuvant therapy for better disease- free survival in GIST patients.
Keywords: Gastrointestinal, stromal, tumors
|How to cite this article:|
El-Menyar A, Mekkodathil A, Al-Thani H. Diagnosis and management of gastrointestinal stromal tumors: An up-to-date literature review. J Can Res Ther 2017;13:889-900
|How to cite this URL:|
El-Menyar A, Mekkodathil A, Al-Thani H. Diagnosis and management of gastrointestinal stromal tumors: An up-to-date literature review. J Can Res Ther [serial online] 2017 [cited 2018 Jan 17];13:889-900. Available from: http://www.cancerjournal.net/text.asp?2017/13/6/889/177499
| > Introduction|| |
Gastrointestinal stromal tumors (GISTs) are rare life threatening forms of cancer representing 0.1–3% of all the GI malignancies. Moreover, GISTs account for 80% of the GI mesenchymal neoplasms. The major cause of GIST is the presence of an abnormal form of tyrosine protein kinase (KIT) protein also known as CD117, which causes uncontrollable growth of the GI cells. Population-based studies have shown that the annual incidence of GISTs is 11–20 per million population., GISTs may arise anywhere in the GI tract and are recognized as originating from gut pacemaker cells known as interstitial cells of Cajal (ICC) or their stem cell precursors that are distributed along the GI tract from the esophagus to the anus. Although it can appear at any age, advanced age is a risk factor for GISTs and the median age of onset reported in previous studies was about 60 years.,, The incidence of GISTs is much less in individuals below the age of 40 and GISTs are very rare in children and young adults. A slightly higher incidence rate was seen in males in some studies; the male to female ratio in incidence ranged from 1.02 to 1.7.,,,,, Herein, we aim to review the literature to describe the incidence, management, and outcomes of GISTs.
| > Literature Search Strategy|| |
A traditional narrative literature search was performed using the PubMed and EMBASE search engines. The search was limited to the duration from January 2001 to January 2016. We used the search terms in different combinations to enhance the retrieval of articles. In addition, Google Scholar searches were also carried out. Reference lists of appropriate studies were also hand-searched to include further studies for potential inclusion. A total of 4582 articles were retrieved from different search engines. We excluded videos, errata, letters, and corrections. Finally, 50 articles were deemed suitable for inclusion in the review after the exclusion of 4532 articles not relevant to the current review. Two relevant papers included from the reference lists were not within the limit of the duration in our search strategy.
Of 50 articles included, 23 were retrospective studies, 22 were prospective studies, two were case reports, two were meta-analyses, and one was randomized controlled trial. The sample size in retrospective population-based studies ranged from 22 to 6998 GIST patients whereas it was 5–2537 in prospective studies. [Table 1] shows sample size, type, year of publication, and origin of studies included in this review.
| > Trends in Incidence and Survival of Gastrointestinal Stromal Tumors|| |
GISTs are associated with a broad spectrum clinical behavior. Many patients are usually asymptomatic and incidentally found to have GIST during imaging or exploration. Metastatic GISTs often progress rapidly which account for 15–50% of cases. Nearly 70–90% of the GISTs are caused by c-KIT somatic gain-of-function mutations followed by similar mutations in platelet-derived growth factor receptor-alpha (PDGFRA). PDGFRA gain-of-function mutations account for approximately half of c-KIT-negative GISTs. Both c-KIT and PDGFRA genes are located in the fourth chromosome in humans which encodes tyrosine kinase receptors. The risk of GIST increases with the inheritance of the mutations and, in some instances, GISTs can be found in several members of the same family. Furthermore, GISTs being a part of genetic syndrome possibly linked with other syndromes such as neurofibromatosis type 1 and carney triad.
GISTs were frequently misclassified as GI autonomic nerve tumor, leiomyoma, leiomyoblastoma, leiomyosarcoma, or schwannoma. However, a proper classification of GIST was established in 2002 based on the fact that KIT mutations are the major causes of GISTs. Over the years, advancements in immunohistochemical staining techniques, improvements in diagnosis, and improved registration led to increase in the incidence of GIST as reported in various population-based studies.
For example, a 25-fold increase in the rate of incidence was noted in the USA in 10 years since 1992. Similarly, the nationwide study in the Netherlands showed the annual incidence of GIST increased 6-fold in 8 years since 1995 whereas the incidence of GIST-like tumors decreased by 28%; however, the GIST incidence rate was stable from 2000 onward. In Japan, GISTs were registered in 1988 for the first time and found increased since 1999 whereas leiomyosarcomas have decreased. Nomura et al. concluded that GIST might have been diagnosed as leiomyosarcoma before using immunohistochemistry.
The trend in GIST survival rate was also found increased over the years, especially after the year 2000. Perez et al. attributed the increase in GIST survival rate found in the USA after 2000 to the launch of imatinib mesylate (imatinib), a KIT-selective tyrosine kinase inhibitor (TKI). The Taiwanese nationwide cancer registry-based study in 2986 GIST patients pointed out that the widespread use of imatinib resulted in better outcomes. The study showed that 5-year overall survival (OS) increased from 58.9% (1998–2001) to 70.2% (2005–2008). A recent trend analysis based on over 5000 GIST patients from the surveillance, epidemiology, and end results (SEER) registry revealed an increase in OS from 15% in 1998 to 55% in 2008 in metastatic GIST. However, the Spanish population-based study between 1994 and 2001 showed a favorable survival in preimatinib population. This improved survival in preimatinib era could be due to misclassification of very low-risk GIST as leiomyoma. Metastatic or recurrent GISTs are often associated with poor survival; however, patient outcomes improved significantly with the advent of imatinib and other KIT-selective TKIs.,
| > Sites of Occurrence and Clinical Presentation|| |
A population-based study in Western Sweden showed that 21% of GISTs were discovered incidentally during surgery for unrelated conditions including surgery for other intra-abdominal malignancies such as colorectal carcinoma or gastric carcinoma, and 10% were detected during autopsies. Kawanowa et al. revealed that most of the incidentally found tumors were microscopic GISTs and many of them were located in the stomach. Nearly 85% of the benign incidental tumors showed KIT mutations which were similar to the clinically significant GIST case series with larger size, suggested that KIT mutations occur very early in the GIST development. Many studies revealed that GISTs arise more commonly in the stomach (40–70%) followed by the small intestine (15–44%) and rarely seen in intra-abdominal sites (2–11%) such as omentum, mesentery, and retroperitoneum.,,,, Extra-GISTs may also present in organs such as liver, pancreas, prostate, ovaries, and uterus. Its occurrence was reported as nearly 10% in a Chinese survey. It has been reported that metastatic GISTs frequently occur at liver (65%) and peritoneum (21%).
GIST associated symptoms vary with the site and size of the lesion. Small-sized GISTs often do not have any symptoms. Increase in size may develop mass-related symptoms such as abdominal pain, digestive discomfort, and sensations of fullness of the abdomen. Caterino et al. studied the correlation between symptoms, location, and prognosis and reported that nearly 38% of the GIST patients were presented with epigastric or periumbilical abdominal pain. GISTs were located mainly (3 of 5) in the stomach. The most frequently noted clinical manifestation for GISTs was GI bleeding that resulted from mucosal ulceration which occurs in nearly half of the GIST cases., GI bleeding may change the texture of the stool to either dark-red or black. In addition, bleeding leads to occasional vomiting of blood. Chronic bleeding may lead to anemia which causes fatigue and in some cases tachycardia. Caterino et al. showed GI bleeding (58%) and abdominal pain (61%) were more frequent in gastric GISTs; however, other acute abdominal symptoms were more common in jejunal (40%) and ileal GISTs (60%).
Although it was not statistically significant, gastric GISTs showed abdominal pain as the main symptom was larger in size compared to gastric GISTs with bleeding as main symptom. Similarly, acute abdominal symptoms, which include appendicitis-like pain, GI obstruction, or tumor rupture, were frequent with larger jejunal/ileal GISTs. Acute abdomen symptoms require emergency medical attention. GIST rupture was very rare in previous reports. However, rupture and peritonitis were noted in 8% of GIST patients in GIST-related emergency study by Sorour et al.
| > Diagnosis and Immunohistochemistry|| |
Radiological examinations may not provide useful data on localization of GISTs. It can be achieved by the use of barium contrast studies, endoscopy, and computed tomography (CT) scan. CT scan also helps in determining size and presence of secondary localizations such as hepatic metastases. Positron emission tomography may be useful for secondary localization. However, histological and immunohistochemical confirmation are required. Immunohistologic features of GISTs differentiate it from other mesenchymal tumors such as leiomyomas, schwannomas, leiomyoblastomas, and leiomyosarcomas. Immunohistochemically, GISTs and ICC are KIT-positive, suggesting GISTs arise from ICC. However, GIST arises from the locations where ICC are absent such as mesentery or omentum suggests the origin of GISTs are from stem cell precursors of ICC.
Other important markers used in the diagnosis of GISTs include CD34, vimentin, keratin, smooth muscle actin (SMA), and S100. They are usually positive for vimentin and may be positive for SMA and keratin but often negative for desmin and protein S100. The National Comprehensive Cancer Network (NCCN) reported the proportion of positivity of GISTs toward various markers as KIT (95%), CD34 (60–70%), SMA (40%), S-100 (5%), desmin (1–2%), and keratin (1–2%).
Other markers currently explored include protein kinase C-theta and carbonic anhydrase II (CAII), nestin, and Discovered on GIST-1 (DOG1). DOG1, also known as TMEM16A and ANO, is a promising biomarker with high sensitivity and specificity. Wong reported that one-thirds of KIT-negative GISTs were positive for the antibody DOG1. According to Lee et al., DOG1 antibodies are more sensitive than KIT in detecting gastric GISTs, tumors with epithelioid morphology, and tumors with PDGFRA mutation. Moreover, DOG1 immunoreactivity is virtually absent in other mesenchymal and nonmesenchymal tumor types and its use in combination with KIT will be beneficial in identifying the patients for targeted therapies. However, the role of DOG1 is uncertain especially when KIT and PDGFRA mutation analysis by polymerase chain reaction and gene sequencing of tumor biopsy specimens is available. Kakkar et al. recently studied the utility of DOG1 immunocytochemistry and reported DOG1 immunopositivity in 57% of the cases examined. The authors concluded that DOG1 immunocytochemistry can serve as a valuable adjunct in ambiguous cases.
| > Prognostic Factors|| |
Variations in aggressiveness of GISTs are evident in the published literature. Studies have shown the occurrences of GISTs ranging from small benign nodules to malignant tumors in all sites. Many criteria exist to predict the biological behavior of GISTs, which include the primary site of occurrence, size of the tumor, mitotic activity, staining for proliferating cells, and tumor necrosis.
Emory et al. demonstrated the significant difference in site-specific survival for 10 years in 1004 GIST patients. The authors argued tumor size and mitotic activity alone was not sufficient to predict the long-term outcomes in any sites. Moreover, mitotic activity was found highly site dependent. For similar mitotic figures and size in 50 high-power fields (HPFs), gastric GISTs had shown better survival when compared to small bowel GISTs. Demetri et al. reported esophagus has the best prognosis whereas peritoneum has the worst.
DeMatteo et al. analyzed the outcomes of 200 patients with GISTs and predicted the survival by tumor size in patients with primary disease after complete resection of gross disease. Recurrence was predominantly intra-abdominal and noted in the original tumor site, peritoneum, and liver. Wu et al. showed that GIST size larger than 5 cm along with other factors predicted recurrence in patients after surgical treatment. Pierie et al. showed that GISTs with size more than 5 cm contributes to decrease in survival. Cao et al. confirmed that large tumor size is associated with worse prognosis in GIST patients undergoing surgical resection.
In addition, studies have concluded that a mitotic rate >5/10 HPFs is a predictive of the aggressive behavior of cells., Mitotic rate is a measure of tumor cell proliferation indicating the rate of growth of the tumor. Mitotic index can be considered as the most important single variable in prognosis of GIST. In short, tumor size, mitotic index, and tumor origin site are the important variables widely accepted in predicting the biological behavior of GISTs.
Other prognostic criteria include tumor necrosis, staining for proliferating cells (MIB-1 >10%), invasive character, presence of symptoms, and evidence of metastases, or lymph node invasion.
A recent study by Kargin et al. assessed the relationship of raised blood neutrophil-to- lymphocyte ratio with the prognosis in GIST patients. The authors found that this ratio significantly increased in the high-risk patients and was associated with short survival. Further, an increase in this ratio was associated with an increase in the mitotic activity of the tumor.
| > Gene Expression and Aggressive Behavior|| |
Studies identified that 60% of gain-of-function mutations occurs within the exon 11 of KIT which consists of 33 codons (codons-550-582). Deletions involving amino acids W557 and/or K558 (delWK) are more common (8–25% of KIT exon 11 mutations) which in fact are associated with higher rate of recurrence.,, Contrarily, Emile et al. found GISTs in which the last part of exon 11 (codons 562–579) frequently deleted and was associated with malignancy compared to GISTs with deletion of the first part (codons 550–561). However, several studies have shown that deletions at distal part of exon 11, particularly Tyr568 and/or Tyr570 (delTyr), are less common compared to delWK which accounts for 3–8% of exon 11 mutations. Bachet et al. showed that GISTs with delTyr and delWK mutations had similar prognosis after surgical resection and targeted therapy with imatinib. Mutations involving duplication or substitutions at KIT exon 11 showed better prognosis when compared to KIT exon 11 deletions.,, Similarly, KIT exon 9 mutations had unfavorable outcomes.
Evidence suggests that tumor site of origin is associated with mutations. Often, GISTs with KIT exon 9 mutations were located in the small intestine and with PDGFRA mutations in stomach. However, significant association between KIT exon 11 mutation status and tumor site of origin was not established., Bachet et al. analyzed a large series of patients and showed that GISTs with delWK were mainly gastric and with delTyr were mainly intestinal. Since both deletions lead to similar worse prognosis according to Bachet et al., the researchers concluded that gastric and small bowel GISTs are associated with same poor prognosis. However, Corless et al. argued that KIT mutation activation is acquired in the early stage of the development of most GISTs and are of little prognostic importance.
GISTs may show other gene abnormalities such as telomerase expression. Loss of expression of some genes may result in aggressive behavior. Sun et al. argued telomerase RNA can repress GIST growth which may be mediated by inhibition of telomerase activity and downregulation of Bcl-2 expression.
| > Risk Stratification Systems|| |
National Institutes of Health consensus criteria (Fletcher's criteria)
Malignant potential of GISTs varies ranging from small benign lesions to fatal sarcomas. GIST grading for malignant potential in the pre-KIT era was based on tumor size, mitotic count, and proliferative index and classified GISTs into low and high risks. The old grading system considered GISTs and true smooth muscle neoplasms together as stromal neoplasms.
Risk stratification system has been further modified with the advent of KIT. The National Institutes of Health (NIH) consensus criteria, also known as Fletcher's criteria, was developed in the year 2002. Eight prognostic categories based on tumor size (≤2, >2–5, >5–10, and >10 cm) and mitotic activity (<5 vs. >5/50 HPFs) with four subdivisions of risk groups such as very low, low, intermediate, and high risk were followed to assess the malignant potential. Mitotic rate used in this system is an alternative to proliferative index followed in the old grading system. A size of 5 cm was fixed as the cut-off value to define low and nonlow risk tumors.,
Prediction of recurrence or metastasis based on the tumor size and mitotic rate that followed in NIH system was verified by several studies. Swedish, Icelandic, and Japanese studies showed high proportion of recurrences in patients classified as high-risk group according to NIH criteria. It was noted as 63%, 41%, and 39%, respectively.,, A slight male predominance in high-risk cases was evident in Jordanian population. In the Swedish study, none of the patients classified as very low-risk group had recurrent tumor disease or tumor-related deaths. In addition, the low- and intermediate-risk groups showed low proportion of tumor recurrence, i.e., 2.4% and 2%, respectively. Mortality associated with tumor collectively in very low-, low-, and intermediate-risk groups was shown as only 1.2%. Intermediate-risk groups showed a higher recurrence of 20% in Iceland-based study suggesting intermediate risk along with high-risk influences negatively on the survival rate. However, the recurrence proportion in these groups was lower in Japanese study which recorded as 4.5%. Iceland-based study concluded that the positive predictive value for aggressive behavior of the high-risk category was 46% whereas the negative predictive value of both low and very low risk was 100%.
Revised National Institutes of Health criteria
Modification of the NIH risk system was proposed by several authors and suggested inclusion of other prognostic factors. Although Rutkowski et al. validated the NIH system, they suggested addition of independent prognostic factors such as primary tumor location and sex. Notably, several studies showed the general tendency for the NIH system to overgrade gastric tumors and downgrade a subset of nongastric tumors when compared to other systems based on the tumor site of origin which developed later. Rutkowski et al. also showed that nonradical resection (R1) and tumor rupture were associated with adverse outcome. Takahashi et al. found “clinically malignant” factors such as peritoneal dissemination, metastasis, invasion, and tumor rupture affected disease-free survival and, therefore, suggested the modification of NIH system with addition of “clinically malignant” group to include patients presenting any of these factors.
However, the revised NIH criteria was based on Joensuu's proposal for modification based on two facts such as (1) nongastric tumors have high risk of recurrence compared to gastric GISTs of the same size and mitotic count and (2) tumor rupture contributes to the increased risk. Joensuu suggested the inclusion of patients with certain nongastric tumors (2.1–5 cm + >5 mitoses per 50 HPF or 5.1–10 cm + ≤5/50 HPF) and cases with tumor rupture in the NIH high-risk category. As mentioned earlier, several authors were in favor of prognosis based on anatomical sites. Moreover, tumor rupture was identified as a factor which negatively influences the survival. If the revised NIH system is applied, the disease recurrence in high-risk group category will increase by 15–20% and the positive predictive value for the aggressive behavior of high-risk category increases as well.
Armed Forces Institute of Pathology criteria (Miettinen's criteria)
Unlike Fletcher's criteria, Armed Forces Institute of Pathology (AFIP) criteria, known as Miettinen's criteria, considers the anatomic site of the tumor and included the risk group of “benign tumors” with no risk of malignancy., Miettinen's criteria was based on large series with nearly 1900 GIST cases having different sites of origin and with long-term follow-up. According to these criteria, gastric GISTs ≤10 cm and ≤5 mitoses per 50 HPFs possess a low risk for metastasis whereas >5 per 50 HPFs and >5 cm in diameter have a high-risk for metastasis. On the other hand, all intestinal GISTs >5 cm regardless mitotic rate have at least moderate risk for metastases and all >5 mitoses per 50 HPFs have a high-risk for metastases. Intestinal GISTs ≤5 cm with ≤5 mitoses per 50 HPFs has a low risk for metastases. Notably, nongastric tumors represented nearly 90% of all tumors which metastasized in the Icelandic population-based GIST study.
The positive sides of Mietttinen's criteria over NIH system are that NIH system was based on expert opinions whereas Miettinen system was based on study data in around 1900 GIST patients and a long-term follow-up based on tumor location, size, and mitotic rate. Goh et al. compared Miettinen's criteria with NIH criteria and confirmed the superiority of Miettinen's criteria in predicting the patient outcomes. The researchers observed that patients with mitotic counts >5/50 HPFs and tumor size 5–10 cm had fewer recurrences compared to tumor size >10 cm which resulted in a suggestion of modification of AFIP system with addition of “very high-risk” group with tumor size >10 cm and mitotic count >5/50 HPFs.
The major shortfall of Miettinen's criteria is the complexity of the system by having excessive prognostic subgroups, which might reduce the prognostic sensitivity and specificity of recurrence. The total area used for mitotic count varied in different studies; however, AFIP suggested an area of 5 mm 2. Counting remains as an issue when irregular-shaped lymphocytes and other inflammatory cells between tumor cells and presence of apoptotic bodies in GIST are considered.,
Memorial Sloan-Kettering Cancer Center nomogram
In 2009, Gold et al. (Memorial Sloan-Kettering Cancer Center sarcoma team) developed a nomogram to predict recurrence-free survival (RFS) after surgery in GIST patients. The risk of tumor progression was estimated using a point system based on tumor site (gastric, small intestine, colon/rectum, extra-GI), size, and mitotic activity. The probabilities of RFS at 2 and 5 years were predicted by the nomogram and calculated as 100% minus the predicted probability of RFS.
The Surveillance, Epidemiology, and End Results-based tumor-grade-metastasis system
Woodall et al., based on SEER, proposed a system for GIST staging based on a tumor-grade-metastasis (TGM) system. The system follows a cut-off point for tumor size 70 mm in defining clinical behavior in GISTs in place of tumor sizes (2, 5, and 10 cm) used in previous risk stratification systems. The presence of nodal and distant metastasis was regarded as advanced stage in this system. Tumor size (T1, ≤70 mm; T2, >70 mm; P < 0.001), grade (G1, Grades I and II; G2, Grades III and IV; P < 0.001), and presence of metastases (M0, no; M1, yes; P < 0.001) affected OS. Grade and metastasis were the factors most predictive of survival when combined in a TGM staging system.
American Joint Committee on Cancer staging for gastrointestinal stromal tumor
In 2010, Edge and Compton, on behalf of the American Joint Committee on Cancer, introduced a staging system for GISTs, by adopting the Miettinen's criteria and incorporating tumor (T) node (N) metastasis (M) status. In addition, a grade category was assigned to tumors based on mitotic rate. A “low grade” was assigned for 5 or fewer mitoses per 50 HPF and “high grade” for 6 or more mitoses per 50 HPF. The most remarkable aspect of TNM classification is the subdivisions of high-risk category into substages (II, IIIA, or 1MB). However, further studies are required to validate this subclassification.
| > Surgical Treatment|| |
Currently, surgical resection remains as the gold standard in the treatment for GISTs. The clinical practice guideline by European Society for Medical Oncology considers every GIST as potentially malignant and recommends surgical management of all GISTs without metastasis. Resectability depends on the tumor dimension and localization. Complete removal (R0) of the tumor and the surrounding tissue is the goal of the surgery as completeness was found related to postoperative survival in patients with GISTs localized to primary organ sites. Surgical resections were indicated even if it was incomplete, aimed at palliation of symptoms related to mass effect and the risk of bleeding. Unresectable GISTs should undergo molecularly targeted intervention with imatinib mesylate, and complementary resection should be considered if GISTs responds to the medication. In patients with primary GISTs, surgical resection offers a 5-year survival rate of 48–70%.,, Studies revealed the prognosis of low-risk GIST after complete resection was excellent while high risk has a high rate of recurrence. Unresectable patients normally have short survival and frequent recurrence. Sorour et al. showed that median survival among unresectable GIST patients was nearly12 months.
Surgical management of gastrointestinal stromal tumors including open surgeries, laparoscopic method, and robot assisted surgeries are the commonly used methods in the resection of GISTs.,,,, Laparoscopic resections had shown advantages over traditional open surgeries. Postoperative pains, infections, hernia, dehiscence associated with longer incisions in traditional open resections are less likely to occur in laparoscopic resections. In addition, laparoscopy provides clear view of intraoperative field and helps in minimizing the damage caused by hands and instruments during the procedure, enhances postoperative recovery, and results in short hospital stay. Furthermore, diagnosis and treatment of GISTs can be done while performing laparoscopic resection. Karakousis et al. demonstrated that laparoscopic resection of primary gastric GISTs ≤8 cm resulted in shorter hospital stays and associated with better oncologic outcomes compared with open resection.
A recent meta-analysis on laparoscopic versus open gastric resections for gastric GISTs, which included 17 studies involving 776 participants showed laparoscopic resections were associated with favorable outcomes such as less intraoperative blood loss, early return of bowel function, early resumption of diet, and short hospital stay. However, there were no differences in terms of recurrence, operative time, and overall complications. Laparoscopic resection was shown as a strategy with higher overall success (93%) compared with open surgeries (88%) by the decision analysis. Koh et al. also confirmed that laparoscopic resections result in better short-term postoperative outcomes and long-term outcomes without compromising oncological safety compared with open resections.
However, the two-dimensional visualization, counterintuitive instrument movement, limited instrument mobility, and surgeon fatigue due to abdominal wall torque limit the use of conventional laparoscopic equipment. Therefore, the use of the laparoscopic technique in large and unfavorably located GISTs is limited. The NCCN restricts the use of laparoscopy for tumors <2 cm in dimension. In unfavorably placed GISTs, instrument mobility is affected and suturing becomes difficult while performing laparoscopic resection. It can also result in inadequate resection margins or tumor spillage and consequently end in disease progression, recurrence, and poor survival.
Robot-assisted laparoscopic resections are in place to address the shortfalls with laparoscopic resections by providing instruments for surgeons to perform technically demanding operations.,, It may be advantageous in surgical resection of large and unfavorably located GISTs, especially placed at pylorus or cardia. Da Vinci surgical system offers superior ergonomics, enhanced vision, precision, dexterity, and control for surgeons to operate., The three-dimensional high definition images can be magnified up to 10 times so that surgeons have a close view of the operating area. The mechanical wrists that bend and rotate resemble the movements of the human wrist and, therefore, allow surgeons to make small and precise movements. In addition, the software incorporated with da Vinci minimizes the effects of a surgeon's hand tremors on instrument movements. Recent studies also found that the minimally invasive robotic resection was oncologically safe and resulted in favorable outcomes such as earlier return of bowel function, earlier resumption of diet, decreased duration of the use of analgesia, and shorter postoperative hospitalization.,,,
Hashizume and Sugimachi in 2003 reported the first robot-assisted gastrectomy in10 patients in South Korea. Since then, it was proven safe and feasible by many researchers particularly in lymph node dissection for gastric cancer and adenocarcinoma., Song et al. series was the largest in this regard which comprised 100 patients with gastric adenocarcinoma. However, only a few studies were published regarding the use of da Vinci system in oncologic resection for gastric GISTs. Buchs et al. performed esogastric or duodenogastric junction preservation in five GIST cases located at cardia or antrum and found oncologically safe resection was possible with the robotic system. Similarly, Desiderio et al. series of five GIST cases underwent robotic gastric resection of tumors located at unfavorable positions, i.e., cardia or antrum.
| > Targeted Therapy with Imatinib|| |
Identification of the fact that oncogenic mutations in tyrosine kinases such as KIT or PDGFRA stimulated the growth of the cancer cells resulted in the development of TKIs such as imatinib aimed at inhibition of tumor proliferation. The US Food and Drug Administration granted accelerated approval for the use of imatinib for patients with advanced or metastatic GIST in 2002. In 2008, the approval included patients at an increased risk for recurrence after surgical removal of the GIST and regular approval was granted for patients with metastatic GIST.
Wu et al. studied imatinib-targeted therapy in the treatment of GIST and showed that use of drug in metastatic disease yields promising clinical responses. Blanke et al. showed the improved survival of patients with advanced GISTs with imatinib treatment and reported that median survival increased approximately from 20 to 60 months. This study among 147 patients showed that nearly half of patients with advanced GIST, when treated with imatinib mesylate, survived for more than 5 years, regardless of starting dose. Wu et al. reported disease stabilization or tumor regression in 39% of patients in a median duration of response of 19 months, in their study. Taiwanese population-based study noted the OS in preimatinib period (1998–2001) and imatinib period (2005–2008) and found the significant improvement with the use of imatinib as OS increased from 58.9% (preimatinib) to 70.2% (imatinib). Perez et al. showed the marked improvement in GIST survival in the US since 2000 paralleled the introduction of imatinib into clinical practice.
The effectiveness experienced in unresectable GISTs led their use in both preoperative and adjuvant therapy. Preoperative treatment with imatinib improves the resectability by reducing the size of the tumors (neoadjuvant therapy) which were initially inoperable. This was found safe, reducing surgical morbidity lowers the risk of bleeding and ruptures and may reduce the extent of the operation. The drug was also indicated after complete resection of primary GIST with higher risk of recurrence as adjuvant therapy (preventive). Takahashi et al. suggested the use of imatinib as an adjuvant therapy in patients with peritoneal dissemination, metastasis, invasion, or tumor rupture where the disease-free survival is largely affected. A phase 3 trial in patients with moderate to high risk of recurrence, adjuvant imatinib therapy significantly improved RFS at 1 year; however, there was no difference in OS. However, adjuvant therapy was highly benefited in high-risk GISTs classified according to the AFIP risk score or revised NIH criteria. Based on various trials and treatment recommendations, Yip et al. concluded that imatinib adjuvant therapy is indicated in high-risk patients for the duration of 3 years. Al-Thani et al. described all the GIST cases in a small country from the Middle East, in which imatinib was found in one case only. This patient showed a 10-cm lesion with an intermediate risk received adjuvant imatinib therapy and showed a favorable long-term outcome.
Clinical trials for GIST cancer are summarized in [Table 2].
| > Conclusion|| |
Although GIST is not common, it represents the majority of the GI mesenchymal neoplasms. Risk stratification is crucial in the management and outcomes of the disease. Surgical resection remains as the gold standard in the treatment. Complete resection is related to the postoperative survival in patients. Laparoscopic resections are associated with less intraoperative blood loss, early return of bowel function, early resumption of diet, and short hospital stay. However, laparoscopy is difficult to perform in large and unfavorably placed GISTs and may result in disease progression, recurrence, and poor survival. Robot-assisted laparoscopic resections provide instruments for surgeons to perform technically demanding operations. Moreover, extensive research work including large clinical trials is ongoing to establish promising role of the adjuvant and neo-adjuvant therapy for better disease- free survival in GIST patients
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Raut CP, Morgan JA, Ashley SW. Current issues in gastrointestinal stromal tumors: Incidence, molecular biology, and contemporary treatment of localized and advanced disease. Curr Opin Gastroenterol 2007;23:149-58.
Ducimetière F, Lurkin A, Ranchère-Vince D, Decouvelaere AV, Péoc'h M, Istier L, et al.
Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One 2011;6:e20294.
Mazzola P, Spitale A, Banfi S, Mazzucchelli L, Frattini M, Bordoni A. Epidemiology and molecular biology of gastrointestinal stromal tumors (GISTs): A population-based study in the South of Switzerland, 1999-2005. Histol Histopathol 2008;23:1379-86.
Min KW, Leabu M. Interstitial cells of Cajal (ICC) and gastrointestinal stromal tumor (GIST): Facts, speculations, and myths. J Cell Mol Med 2006;10:995-1013.
Wang ZH, Liang XB, Wang Y, Ma GL, Qu YQ, Tian XW. Epidemiology survey of gastrointestinal stromal tumor in Shanxi Province in 2011. Zhonghua Yi Xue Za Zhi 2013;93:2541-4.
Yan BM, Kaplan GG, Urbanski S, Nash CL, Beck PL. Epidemiology of gastrointestinal stromal tumors in a defined Canadian Health Region: A population-based study. Int J Surg Pathol 2008;16:241-50.
Mucciarini C, Rossi G, Bertolini F, Valli R, Cirilli C, Rashid I, et al.
Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. BMC Cancer 2007;7:230.
Miettinen M, Majidi M, Lasota J. Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): A review. Eur J Cancer 2002;38 Suppl 5:S39-51.
Chiang NJ, Chen LT, Tsai CR, Chang JS. The epidemiology of gastrointestinal stromal tumors in Taiwan, 1998-2008: A nation-wide cancer registry-based study. BMC Cancer 2014;14:102.
Nomura E, Ioka A, Tsukuma H. Incidence of soft tissue sarcoma focusing on gastrointestinal stromal sarcoma in Osaka, Japan, during 1978-2007. Jpn J Clin Oncol 2013;43:841-5.
Bokhary RY, Al-Maghrabi JA. Gastrointestinal stromal tumors in Western Saudi Arabia. Saudi Med J 2010;31:437-41.
Barakat FH, Haddad HA, Matalka II, Al-Orjani MS, Al-Masri MM, Sughayer MA. Characteristics of gastrointestinal stromal tumors in a Middle Eastern population. Saudi Med J 2010;31:797-802.
Hirota S, Isozaki K. Pathology of gastrointestinal stromal tumors. Pathol Int 2006;56:1-9.
Agarwal R, Robson M. Inherited predisposition to gastrointestinal stromal tumor. Hematol Oncol Clin North Am 2009;23:1-13, vii.
Miettinen M, Lasota J. Gastrointestinal stromal tumors (GISTs): Definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol 2003;54:3-24.
Perez EA, Livingstone AS, Franceschi D, Rocha-Lima C, Lee DJ, Hodgson N, et al.
Current incidence and outcomes of gastrointestinal mesenchymal tumors including gastrointestinal stromal tumors. J Am Coll Surg 2006;202:623-9.
Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: Results of a nation-wide study. Eur J Cancer 2005;41:2868-72.
Güller U, Tarantino I, Cerny T, Schmied BM, Warschkow R. Population-based SEER trend analysis of overall and cancer-specific survival in 5138 patients with gastrointestinal stromal tumor. BMC Cancer 2015;15:557.
Rubió J, Marcos-Gragera R, Ortiz MR, Miró J, Vilardell L, Gironès J, et al.
Population-based incidence and survival of gastrointestinal stromal tumours (GIST) in Girona, Spain. Eur J Cancer 2007;43:144-8.
Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, et al.
Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era – A population-based study in Western Sweden. Cancer 2005;103:821-9.
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.
Corless CL, McGreevey L, Haley A, Town A, Heinrich MC. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 2002;160:1567-72.
Caterino S, Lorenzon L, Petrucciani N, Iannicelli E, Pilozzi E, Romiti A, et al
. Gastrointestinal stromal tumors: Correlation between symptoms at presentation, tumor location and prognostic factors in 47 consecutive patients. World J Surg Oncol 2011;9:13.
DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-8.
Sorour MA, Kassem MI, Ghazal Ael-H, El-Riwini MT, Abu Nasr A. Gastrointestinal stromal tumors (GIST) related emergencies. Int J Surg 2014;12:269-80.
Bucher P, Villiger P, Egger JF, Buhler LH, Morel P. Management of gastrointestinal stromal tumors: From diagnosis to treatment. Swiss Med Wkly 2004;134:145-53.
Graadt van Roggen JF, van Velthuysen ML, Hogendoorn PC. The histopathological differential diagnosis of gastrointestinal stromal tumours. J Clin Pathol 2001;54:96-102.
Wang L, Vargas H, French SW. Cellular origin of gastrointestinal stromal tumors: A study of 27 cases. Arch Pathol Lab Med 2000;124:1471-5.
Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, et al.
NCCN Task Force report: Management of patients with gastrointestinal stromal tumor (GIST) – Update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2007;5 Suppl 2:S1-29.
Wong NA. Gastrointestinal stromal tumours – An update for histopathologists. Histopathology 2011;59:807-21.
Lee CH, Liang CW, Espinosa I. The utility of discovered on gastrointestinal stromal tumor 1 (DOG1) antibody in surgical pathology-the GIST of it. Adv Anat Pathol 2010;17:222-32.
ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii49-55.
Kakkar A, Mathur SR, Jain D, Iyer VK, Nalwa A, Sharma MC. Utility of DOG1 immunomarker in fine needle aspirates of gastrointestinal stromal tumor. Acta Cytol 2015;59:61-7.
Emory TS, Sobin LH, Lukes L, Lee DH, O'Leary TJ. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: Dependence on anatomic site. Am J Surg Pathol 1999;23:82-7.
Wu PC, Langerman A, Ryan CW, Hart J, Swiger S, Posner MC. Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era. Surgery 2003;134:656-65.
Pierie JP, Choudry U, Muzikansky A, Yeap BY, Souba WW, Ott MJ. The effect of surgery and grade on outcome of gastrointestinal stromal tumors. Arch Surg 2001;136:383-9.
Cao H, Zhang Y, Wang M, Shen DP, Sheng ZY, Ni XZ, et al.
Prognostic analysis of patients with gastrointestinal stromal tumors: A single unit experience with surgical treatment of primary disease. Chin Med J (Engl) 2010;123:131-6.
Dematteo RP, Gold JS, Saran L, Gönen M, Liau KH, Maki RG, et al.
Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008;112:608-15.
Kargin S, Çakir M, Gündes E, Yavuz Y, Esen HH, Sinan Iyisoy M, et al.
Relationship of preoperative neutrophil lymphocyte ratio with prognosis in gastrointestinal stromal tumors. Ulus Cerrahi Derg 2015;31:61-4.
Emile JF, Théou N, Tabone S, Cortez A, Terrier P, Chaumette MT, et al.
Clinicopathologic, phenotypic, and genotypic characteristics of gastrointestinal mesenchymal tumors. Clin Gastroenterol Hepatol 2004;2:597-605.
Martín J, Poveda A, Llombart-Bosch A, Ramos R, López-Guerrero JA, García del Muro J. Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: A study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol2005;23:6190-8.
Bachet JB, Hostein I, Le Cesne A, Brahimi S, Beauchet A, Tabone-Eglinger S, et al.
Prognosis and predictive value of KIT exon 11 deletion in GISTs. Br J Cancer 2009;101:7-11.
Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, et al.
Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 2006;130:1573-81.
Cho S, Kitadai Y, Yoshida S, Tanaka S, Yoshihara M, Yoshida K, et al.
Deletion of the KIT gene is associated with liver metastasis and poor prognosis in patients with gastrointestinal stromal tumor in the stomach. Int J Oncol 2006;28:1361-7.
Rubin BP. Gastrointestinal stromal tumours: An update. Histopathology 2006;48:83-96.
Tornillo L, Terracciano LM. An update on molecular genetics of gastrointestinal stromal tumours. J Clin Pathol 2006;59:557-63.
Antonescu CR, Viale A, Sarran L, Tschernyavsky SJ, Gonen M, Segal NH, et al.
Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res 2004;10:3282-90.
Sun XC, Yan JY, Chen XL, Huang YP, Shen X, Ye XH. Depletion of telomerase RNA inhibits growth of gastrointestinal tumors transplanted in mice. World J Gastroenterol 2013;19:2340-7.
Agaimy A. Gastrointestinal stromal tumors (GIST) from risk stratification systems to the new TNM proposal: More questions than answers? A review emphasizing the need for a standardized GIST reporting. Int J Clin Exp Pathol 2010;3:461-71.
Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al.
Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002;33:459-65.
Tryggvason G, Gíslason HG, Magnússon MK, Jónasson JG. Gastrointestinal stromal tumors in Iceland, 1990-2003: The Icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer 2005;117:289-93.
Nakamura N, Yamamoto H, Yao T, Oda Y, Nishiyama K, Imamura M, et al.
Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. Hum Pathol 2005;36:828-37.
Rutkowski P, Nowecki ZI, Michej W, Debiec-Rychter M, Wozniak A, Limon J, et al.
Risk criteria and prognostic factors for predicting recurrences after resection of primary gastrointestinal stromal tumor. Ann Surg Oncol 2007;14:2018-27.
Takahashi T, Nakajima K, Nishitani A, Souma Y, Hirota S, Sawa Y, et al.
An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. Int J Clin Oncol 2007;12:369-74.
Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008;39:1411-9.
Miettinen M, Lasota J. Gastrointestinal stromal tumors: Pathology and prognosis at different sites. Semin Diagn Pathol 2006;23:70-83.
Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: A clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005;29:52-68.
Goh BK, Chow PK, Yap WM, Kesavan SM, Song IC, Paul PG, et al.
Which is the optimal risk stratification system for surgically treated localized primary GIST? Comparison of three contemporary prognostic criteria in 171 tumors and a proposal for a modified Armed Forces Institute of Pathology risk criteria. Ann Surg Oncol 2008;15:2153-63.
Sanchez Hidalgo JM, Rufian Peña S, Ciria Bru R, Naranjo Torres A, Muñoz Casares C, Ruiz Rabelo J, et al.
Gastrointestinal stromal tumors (GIST): A prospective evaluation of risk factors and prognostic scores. J Gastrointest Cancer 2010;41:27-37.
Gold JS, Gönen M, Gutiérrez A, Broto JM, García-del-Muro X, Smyrk TC, et al.
Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: A retrospective analysis. Lancet Oncol 2009;10:1045-52.
Woodall CE 3rd
, Brock GN, Fan J, Byam JA, Scoggins CR, McMasters KM, et al.
An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical staging system. Arch Surg 2009;144:670-8.
Edge SB, Compton CC. The American joint committee on cancer: The 7th
edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.
Casali PG, Jost L, Reichardt P, Schlemmer M, Blay JY; ESMO Guidelines Working Group. Gastrointestinal stromal tumours: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20 Suppl 4:64-7.
Gervaz P, Huber O, Morel P. Surgical management of gastrointestinal stromal tumours. Br J Surg 2009;96:567-78.
Karakousis GC, Singer S, Zheng J, Gonen M, Coit D, DeMatteo RP, et al.
Laparoscopic versus open gastric resections for primary gastrointestinal stromal tumors (GISTs): A size-matched comparison. Ann Surg Oncol 2011;18:1599-605.
Liang JW, Zheng ZC, Zhang JJ, Zhang T, Zhao Y, Yang W, et al.
Laparoscopic versus open gastric resections for gastric gastrointestinal stromal tumors: A meta-analysis. Surg Laparosc Endosc Percutan Tech 2013;23:378-87.
Koh YX, Chok AY, Zheng HL, Tan CS, Chow PK, Wong WK, et al.
A systematic review and meta-analysis comparing laparoscopic versus open gastric resections for gastrointestinal stromal tumors of the stomach. Ann Surg Oncol 2013;20:3549-60.
Buchs NC, Bucher P, Pugin F, Hagen ME, Morel P. Robot-assisted oncologic resection for large gastric gastrointestinal stromal tumor: A preliminary case series. J Laparoendosc Adv Surg Tech A 2010;20:411-5.
Desiderio J, Trastulli S, Cirocchi R, Boselli C, Noya G, Parisi A, et al.
Robotic gastric resection of large gastrointestinal stromal tumors. Int J Surg 2013;11:191-6.
Ortiz-Oshiro E, Exposito PB, Sierra JM, Gonzalez JD, Barbosa DS, Fernandez-Represa JA. Laparoscopic and robotic distal gastrectomy for gastrointestinal stromal tumour: Case report. Int J Med Robot 2012;8:491-5.
Moriyama H, Ishikawa N, Kawaguchi M, Hirose K, Watanabe G. Robot-assisted laparoscopic resection for gastric gastrointestinal stromal tumor. Surg Laparosc Endosc Percutan Tech 2012;22:e155-6.
Hashizume M, Sugimachi K. Robot-assisted gastric surgery. Surg Clin North Am 2003;83:1429-44.
Song J, Oh SJ, Kang WH, Hyung WJ, Choi SH, Noh SH. Robot-assisted gastrectomy with lymph node dissection for gastric cancer: Lessons learned from an initial 100 consecutive procedures. Ann Surg 2009;249:927-32.
Patriti A, Ceccarelli G, Bellochi R, Bartoli A, Spaziani A, Di Zitti L, et al.
Robot-assisted laparoscopic total and partial gastric resection with D2 lymph node dissection for adenocarcinoma. Surg Endosc 2008;22:2753-60.
Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, et al.
Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008;26:620-5.
Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, et al.
Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial. Lancet 2009;373:1097-104.
Yip D, Zalcberg J, Ackland S, Barbour AP, Desai J, Fox S, et al.
Controversies in the management of gastrointestinal stromal tumors. Asia Pac J Clin Oncol 2014;10:216-27.
Al-Thani H, El-Menyar A, Rasul KI, Al-Sulaiti M, El-Mabrok J, Hajaji K, et al.
Clinical presentation, management and outcomes of gastrointestinal stromal tumors. Int J Surg 2014;12:1127-33.
[Table 1], [Table 2]