Progress in the Treatment of Small Intestine Cancer.

OPINION STATEMENT: Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs.

Gastrointestinal Stromal Tumors: What Is the Best Sequence of TKIs?

OPINION STATEMENT: In our practice, we evaluate the mutation status of advanced unresectable disease to guide decisions on use of tyrosine kinase inhibitor (TKI) therapy. This review focuses on management of GIST with KIT and PDGFRA mutations. Imatinib is first-line treatment for unresectable gastrointestinal stromal tumors (GISTs) unless they harbor a PDGFRA D842V mutation; it is recommended to escalate imatinib to twice daily dosing for KIT exon 9 mutant tumors. When patients progress on first-line treatment, treatment is changed to sunitinib followed by regorafenib; while the spectrum of activity against resistance mutations varies with these agents, routine biopsies provide data on one area of disease and ctDNA has not been validated prospectively. For those with a PDGFRA D842V mutation, avapritinib is the first TKI to lead to tumor response and disease control. Ripretinib is approved in the 4th line setting, with limited data on its benefit for PDGFRA D842V GIST. Avapritinib can be considered for treatment beyond ripretinib for KIT mutant disease. The efficacy of other TKIs tested in GIST is reviewed. Ongoing therapy provides palliative benefit and should be continued given rapid decline observed off of treatment.

Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are a subtype of soft tissue sarcoma (STS), and have become a concept of oncogenic addiction and targeted therapies.The large majority of these tumors develop after a mutation in KIT or platelet derived growth factor receptor α (PDGFRα), resulting in uncontrolled proliferation. GISTs are highly sensitive to imatinib. GISTs are immune infiltrated tumors with a predominance of tumor-associated macrophages (TAMs) and T-cells, including many CD8+ T-cells, whose numbers are prognostic. The genomic expression profile is that of an inhibited Th1 response and the presence of tertiary lymphoid structures and B cell signatures, which are known as predictive to response to ICI. However, the microtumoral environment has immunosuppressive attributes, with immunosuppressive M2 macrophages, overexpression of indoleamine 2,3-dioxygenase (IDO) or PD-L1, and loss of major histocompatibility complex type 1. In addition to inhibiting the KIT oncogene, imatinib appears to act by promoting cytotoxic T-cell activity, interacting with natural killer cells, and inhibiting the expression of PD-L1. Paradoxically, imatinib also appears to induce M2 polarization of macrophages. There have been few immunotherapy trials with anti-CTLA-4 or anti-PD-L1drugs and available clinical data are not very promising. Based on this comprehensive analysis of TME, we believe three immunotherapeutic strategies must be underlined in GIST. First, patients included in clinical trials must be better selected, based on the identified driver mutation (such as PDGFRα D842V mutation), the presence of tertiary lymphoid structures (TLS) or PD-L1 expression. Moreover, innovative immunotherapeutic agents also provide great interest in GIST, and there is a strong rationale for exploring IDO targeting after disease progression during imatinib therapy. Finally and most importantly, there is a strong rationale to combine of c-kit inhibition with immune checkpoint inhibitors.

Malignant gastrointestinal stromal tumor in association with Russell body gastritis-A case report.

Russell body gastritis (RBG) is an unusual form of chronic inflammation characterized by accumulation of plasma cells containing Russell bodies (RB) in the gastric mucosa. Although its pathogenesis has not been fully evaluated, there is evidence to support a strong association with Helicobacter pylori infection. Only four cases of RBG in association with malignant epithelial gastric tumors were reported. We report the first case of RBG in peritumoral mucosa of a malignant gastrointestinal stromal tumor in association with coccoid form of Helicobacter pylori and a follow-up.

Ripretinib and MEK Inhibitors Synergize to Induce Apoptosis in Preclinical Models of GIST and Systemic Mastocytosis.

The majority of gastrointestinal stromal tumors (GIST) harbor constitutively activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and regorafenib are available as first-, second-, and third-line targeted therapies, respectively, for metastatic or unresectable KIT-driven GIST. Treatment of patients with GIST with KIT kinase inhibitors generally leads to a partial response or stable disease but most patients eventually progress by developing secondary resistance mutations in KIT. Tumor heterogeneity for secondary resistant KIT mutations within the same patient adds further complexity to GIST treatment. Several other mechanisms converge and reactivate the MAPK pathway upon KIT/PDGFRA-targeted inhibition, generating treatment adaptation and impairing cytotoxicity. To address the multiple potential pathways of drug resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the FDA for the treatment of adult patients with advanced GIST who have received previous treatment with 3 or more kinase inhibitors, including imatinib. Here we show that ripretinib treatment in combination with MEK inhibitors is effective at inducing and enhancing the apoptotic response and preventing growth of resistant colonies in both imatinib-sensitive and -resistant GIST cell lines, even after long-term removal of drugs. The effect was also observed in systemic mastocytosis (SM) cells, wherein the primary drug-resistant KIT D816V is the driver mutation. Our results show that the combination of KIT and MEK inhibition has the potential to induce cytocidal responses in GIST and SM cells.

Low Distribution of TIM-3+ Cytotoxic Tumor-Infiltrating Lymphocytes Predicts Poor Outcomes in Gastrointestinal Stromal Tumors.

There are multiple tumor-infiltrating lymphocytes (TILs) and relevant immune checkpoints existing in gastrointestinal stromal tumor (GIST), which provides opportunities and rationales for developing effective immunotherapies. Recent studies have suggested that checkpoint TIM-3/Gal-9 plays a pivotal role on immune response in multiple tumors, similar to the PD-1/PD-L1, emerging as a potential therapeutic target. However, their functions in GIST are unrevealed. Hence, the expression of immune checkpoints TIM-3 and Gal-9, as well as the infiltration of CD8+ T cells and NK cells, is described in 299 cases of GIST specimens. The results showed that TIM-3 and Gal-9 are mainly expressed in TILs, rarely in tumor cells. Expression levels of TIM-3 and Gal-9 significantly differ in varying risks of GIST and exert opposite distribution trends. Indicated by prognosis analysis, high TIM-3 expression of TILs was associated with improved outcome, while low expression levels of TIM-3 in combination with low amounts of CD8+ and CD56+ TILs predict extremely poor survival. The integrated analysis of TIM-3+, CD8+, and CD56+ TILs as one biomarker is a reliable independent predictor of prognosis. In conclusion, low densities of TIM-3+ TILs are associated with poor survival, and integrated immune biomarkers lead to superior predictors of GIST prognosis.

Synchronous occurrence of myelodysplastic syndrome and a bleeding jejunal gastrointestinal stromal tumor in a patient with obscure gastrointestinal bleed.

The coexistence of gastrointestinal (GI) stromal tumors (GISTs) and other malignancies, both synchronous or metachronous, has been discussed extensively in literature. It has also been described that the frequency of malignancies among patients with GIST is significantly higher than that in the general population. We present a case report of a patient with synchronous occurrence of myelodysplastic syndrome (MDS) and a GIST who presented with chronic fatigue and an episode of syncope and was found to have obscure GI bleed. Laboratory investigations revealed severe anemia, marrow picture was suggestive of MDS, and magnetic resonance imaging of the abdomen revealed a proximal small bowel neoplasm. She underwent resection of the diseased segment and anastomosis. The histopathology of the specimen confirmed the diagnosis of a GIST arising from the jejunum. She was started on imatinib on postoperative day 21 and is presently well preserved and on regular follow-up. The possibility of small bowel neoplasm, especially GIST, must be considered in patients diagnosed with chronic anemia secondary to obscure GI bleed and the possibility of a synchronous GIST, although uncommon must be considered in patients with myeloproliferative disorders and leukemia.

Liquid Biopsy in Gastrointestinal Stromal Tumors: Ready for Prime Time?

OPINION STATEMENT: Gastrointestinal stromal tumor (GIST) constitutes a paradigm for clinically effective targeted inhibition of oncogenic driver mutations. Therefore, GIST has emerged as a compelling clinical and biological model to study oncogene addiction and to validate preclinical concepts for drug response and drug resistance. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the essential drivers of GIST progression throughout all stages of the disease. Interestingly, KIT/PDGFRA genotype predicts the response to first-line imatinib and to all tyrosine kinase inhibitors (TKIs) approved or in investigation after imatinib failure. Considering that TKIs are effective only against a subset of KIT or PDGFRA resistance mutations, close monitoring of tumor dynamics with non-invasive methods such as liquid biopsy emerges as a necessary step forward in the field. Liquid biopsy, in contrast to solid tumor biopsy, aims to characterize tumors irrespective of heterogeneity. Although there are several components in the peripheral blood, most recent studies have been focused on circulating tumor (ct)DNA, due to the technological feasibility, the stability of DNA itself and DNA alterations, and the therapeutic development in precision oncology largely based on the identification of genetic driver mutations. In the present review, we systematically dissect the current wealth of data of ctDNA in GIST. To do so, a critical understanding of the promises and limitations of the current technologies will be followed by an exposition of the knowledge gathered with such studies in GIST. Collectively, our goal is to establish clear premises that can be used as the foundations to build future studies towards the clinical implementation of ctDNA evaluation in GIST patients.

Rapid Flow Cytometry of Gastrointestinal Stromal Tumours Closely Matches the Modified Fletcher Classification.

AIM: We aimed to develop a rapid, simple procedure and an algorithm for quantitative analysis and classification of the metastatic risk of gastrointestinal stromal tumours (GIST) for clinical use. MATERIALS AND METHODS: Eighteen specimens from laparoscopic local gastrectomy were assessed by flow cytometry. We devised a new risk classification for GIST by combining flow cytometry parameters with tumour size and evaluated whether the combined parameters correlated with the modified Fletcher risk classification. RESULTS: We found a significant correlation between clinical prognostic factors (mitotic count and Ki-67 labelling index) and the flow cytometry parameters DNA ploidy, DNA index and S-phase fraction. The combined parameters established from tumour size and the flow cytometry parameters showed a high correlation with the modified Fletcher risk classification (p=0.0064). Flow cytometry had to be performed for approximately 10 minutes to determine the metastatic risk. CONCLUSION: Rapid flow cytometry parameters can classify risk without the need for histological analysis.

Cross-testing of major molecular markers indicates distinct pathways of tumorigenesis in gastric adenocarcinomas and synchronous gastrointestinal stromal tumors.

Small subtype of the gastrointestinal stromal tumor (micro-GIST, MG) is usually asymptomatic and is frequently found incidentally in association with gastric adenocarcinoma (GAC). The background of this coincidence is still an open question. This study comprehensively characterized nine MGs and GACs present in the same surgical specimen by cross-testing the markers of the major pathogenetic pathways of both tumor types. All of the MGs were immunohistochemically positive for CD117/KIT, CD34, and DOG1. DOG1 was also detected in four GACs. Four MGs carried mutations in c-KIT (exons 9, 11, and 13) and two cases in PDGFRα (exon 18). None of the GACs carried activating mutations in c-KIT or PDGFRα. MMR immunopanel identified one GAC as microsatellite unstable tumor. No EBV-positive tumor was found. According to the TCGA molecular classification, one GAC was categorized in the MSI subgroup, three GACs in the genomically stable subgroup, and the rest into the chromosomal instability subgroup. Although a common carcinogenic effect cannot be ruled out, our data suggest a distinct molecular background in the evolvement of the synchronous MGs and GACs. The presence of a MG in gastric resection specimens may be indicative of the development of synchronous malignant tumors in or outside the stomach.

Small Cell Lung Carcinoma and Synchronous Rectal Adenocarcinoma and Jejunal Gastrointestinal Stromal Tumor Present in a Patient With History of Laryngeal Squamous Cell Carcinoma.

BACKGROUND: The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. CASE REPORT: We report such a case of a 67-year-old male smoker with a history of laryngeal squamous cell carcinoma. He was incidentally identified through follow up computed tomography to have three masses in the lung, rectum and jejunum, respectively. Biopsies were performed and demonstrated synchronous lung small cell carcinoma (pT1bN0) and rectal adenocarcinoma. The patient underwent fractionated stereotactic radiation (FSRT) to the pulmonary tumor and chemotherapy with cisplatin and etoposide followed by laparoscopic rectum low anterior resection and small bowel segmental resection. Final pathology diagnoses confirmed synchronous microsatellite stable (MMS) moderately differentiated adenocarcinoma of the rectum (pT3N1b) and jejunal gastrointestinal stromal tumor (GIST), spindle cell type (pT2N0). At 8 months follow up postsurgery, the patient was doing well and no tumor recurrences were identified. CONCLUSION: To the best of our knowledge, this is the first documented case of synchronous primary small cell lung carcinoma, rectal adenocarcinoma, and GIST in the English literature. The rarity, diagnosis and treatment challenges of these entities are discussed.

Malignant Prolactinoma With Liver Metastases Masquerading as Metastatic Gastrointestinal Stromal Tumor: A Case Report and Literature Review.

Pituitary carcinomas are rare diseases defined as pituitary tumors with metastases. In this report, we describe a case of malignant prolactinoma with liver metastases masquerading as metastatic gastrointestinal stromal tumor (GIST). A 54-years-old woman received dopamine agonists for macroprolactinoma for 2 years, followed by transsphenoidal surgery due to a poor response to medical therapy. Despite the continuation of dopamine agonist after surgery, serum prolactin level progressively increased to above 8,000 ng/ml in 5 years. There was no evidence of disease recurrence on sella magnetic resonance imaging (MRI). She stopped medical therapy. Meanwhile, she was diagnosed with GIST accompanied by liver and peritoneal metastases. After a 2-months treatment with imatinib, she suddenly presented with headache and visual impairment. Sella MRI showed a 3.3-cm sized pituitary mass, and serum prolactin levels were still high. For the recurred mass, she underwent a second surgery followed by radiation therapy. During the imatinib treatment for GIST, main mass and peritoneal metastases were dramatically decreased, but liver metastases were markedly aggravated. Liver masses were eventually confirmed as metastases from prolactin-producing pituitary carcinoma and not from GIST by percutaneous biopsy. Unfortunately, she died 6 months after the second surgery due to acute renal failure and sepsis. This case suggests that highly sustained serum prolactin levels during the dopamine agonist may indicate prolactin-producing pituitary carcinomas with hidden metastases.

Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates

OPINION STATEMENT: The treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup. For second- and third-line treatment, results are awaited of a number of clinical trials. However, second-line and further treatment could potentially be tailored depending on secondary mutations found in imatinib-resistant GISTs. As secondary resistance to TKIs remains the biggest challenge in the treatment of GIST and despite negative results with alternating regimens in phase II, combination treatments should be further evaluated to tackle this issue. Moreover, the favourable safety profiles observed with avapritinib and ripretinib suggest that combination treatments are feasible, for instance, combining two TKIs or a TKI with drugs targeting downstream signalling pathways, such as PI3K inhibitors or MEK inhibitors. Finally, in line with further personalisation of treatment in GIST, a multidisciplinary approach is essential, and local treatment options, such as RFA, resection in case of unifocal progression, and radiotherapy, should be considered.

Identification of gastrointestinal stromal tumors from leiomyomas in the esophagogastric junction: A single-center review of 136 cases.

To identify significant clinical and CT features for the differentiation of gastrointestinal stromal tumors (GISTs) from leiomyomas in the esophagogastric junction (EGJ).One hundred thirty six patients with pathologically proven GISTs (n = 87) and leiomyomas (n = 49) in the EGJ were enrolled. And preoperative CT images were available in 73 GISTs cases and 34 leiomyoma cases. Two radiologists reviewed the CT images by consensus with regard to tumor size, shape, growth pattern, surface, enhancement pattern, enhancement degree, attention at each phasic image and the presence of surface ulcer, calcification, and intralesional low attention.Eight significant clinical and CT features were identified for differentiating GISTs from leiomyomas: older age (>46.5 years), tumor long diameter >4.5 cm, heterogeneous enhancement, high degree enhancement, mean CT attenuation >69.2 HU, presences of intralesional low attenuation and surface ulcer, absences of calcification (P < .05). On the receiver operating characteristic curve analysis, an optimal cutoff score of 3.5 was achieved for differentiating GISTs from leiomyomas with an AUC of 0.844 (sensitivity: 76.7%, specificity: 76.5%).older age (>46.5 years), tumor long diameter >4.5 cm, heterogeneous enhancement, high degree enhancement, mean CT attenuation >69.2 HU, presences of intralesional low attenuation and surface ulcer, absence of calcification are significant features highly suggestive of GISTs in differentiation from leiomyomas in the EGJ.

Aberrant accumulation of Dickkopf 4 promotes tumor progression via forming the immune suppressive microenvironment in gastrointestinal stromal tumor.

BACKGROUND: Drug resistance and tumor recurrence are the major concerns in clinical practices of gastrointestinal stromal tumor (GIST), with the urgent requirement for exploring undiscovered pathways driving malignancy. To deal with these, recent studies have made many efforts to explore prognosis indicators and establish potential therapeutic targets. METHODS: Expression profiles of different risks of GISTs were described and abundant clinical evidences supported our findings in this study. Following exploration in vitro by cell experiments and verification in vivo using tumor microarray were taken to elucidate the underlying mechanism, which drove the malignancy in GIST. RESULTS: Dickkopf 4 (DKK4), as the canonical Wnt pathway antagonist, was unexpectedly and universally upregulated in high-risk GISTs, and aberrant accumulation of DKK4 was closely correlated with poor prognosis. In addition, tumor-derived DKK4 could decrease immune cells infiltration and activation in the tumor microenvironment, which decreased the antitumor effects in return. And this phenomenon was recurrent in human tumor specimens. CONCLUSIONS: Our findings identified DKK4 as a proper tumor biomarker for prognosis predicting and recurrence monitoring, and suggested a novel immune-escape mechanism driving malignancy in GIST, which might be a potential therapeutic target to improve the effects of canonical RTK therapy and combined immunotherapy.

Esophagogastric Neoplasms Following Bariatric Surgery: an Updated Systematic Review.

The risk of gastric and/or esophageal cancers after bariatric surgery has been previously discussed in literature. A systematic review was performed to identify articles published between June 2012 and December 2018 reporting new cases of esophageal or gastric cancer not included in previous systematic reviews. Ten gastric malignancies, 28 esophageal cancers, and 2 gastro-intestinal stromal tumors (GIST) were identified. Primary bariatric surgery was a restrictive procedure in 26 cases, a purely malabsorptive procedure in 1 subject, and a gastric bypass in 13 patients. Although the vast majority of bariatric procedures seem to present a negligible relationship with any esophagogastric (EG) malignancy, published data remain incomplete. It was however considered of interest to update the number of EG neoplasms arisen following bariatric surgery.

Defining Tumor Rupture in Gastrointestinal Stromal Tumor.

Tumor rupture is an important risk factor predictive of recurrence after macroscopically complete resection of gastrointestinal stromal tumors (GISTs), and an indication for defined interval or even lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of the term 'tumor rupture', and, consequently, its incidence varies greatly across reported series. Without predefined criteria, the clinical significance of rupture has also been difficult to assess on multivariate analysis of retrospective data. We reviewed the relevant literature and international guidelines, and, based on the Oslo criteria, proposed the following six definitions for 'tumor rupture': (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; or (6) incisional biopsy. Not all minor defects of tumor integrity should not be classified as rupture, i.e. mucosal defects or spillage contained within the gastrointestinal lumen, microscopic tumor penetration of the peritoneum or iatrogenic damage only to the peritoneal lining, uncomplicated transperitoneal needle biopsy, and R1 resection. This broad definition identifies GIST patients at particularly high risk of recurrence in population-based cohorts; however, its applicability in other sarcomas has not been investigated. As the proposed definition of tumor rupture in GIST has limited evidence based on the small number of patients with rupture in each retrospective study, we recommend validating the proposed definition of tumor rupture in GIST in prospective studies and considering it in clinical practice.