Incidence, clinical management and prognosis of patients with small intestinal adenocarcinomas from 1999 through 2019: A nationwide Dutch cohort study.

BACKGROUND: Small intestinal adenocarcinomas (SIAs) are rare. Hence, randomized controlled trials are lacking and understanding of the disease features is limited. This nationwide cohort investigates incidence, treatment and prognosis of SIA patients, to improve disease outcome. PATIENTS AND METHODS: Data of 2697 SIA patients diagnosed from January 1999 through December 2019 were retrieved from the Netherlands Cancer Registry and Pathology Archive. Incidence was calculated using the revised European Standardized Rate. The influence of patient and tumor characteristics on overall survival (OS) was studied using survival analyses. RESULTS: The age-standardized incidence rate almost doubled from 0.58 to 1.06 per 100,000 person-years, exclusively caused by an increase in duodenal adenocarcinomas. OS did not improve over time. Independent factors for a better OS were a younger age, jejunal tumors, Lynch syndrome and systemic therapy. Only 13.8% of resected patients was treated with adjuvant chemotherapy, which improved OS compared to surgery alone in stage III disease (HR 0.47 (0.35-0.61)), but not in the limited group of deficient mismatch repair (MMR) patients (n = 53, HR 0.93 (0.25-3.47)). In the first-line setting, CAPOX was associated with improved OS compared to FOLFOX (HR 0.51 (0.36-0.72)). For oligometastatic patients, a metastasectomy significantly improved OS (HR 0.54 (0.36-0.80)). CONCLUSIONS: The incidence of SIAs almost doubled in the past 20 years, with no improvement in OS. This retrospective non-randomized study suggests the use of adjuvant chemotherapy for stage III disease and first-line CAPOX for metastatic patients. For selected oligometastatic patients, a metastasectomy may be considered. MMR-status testing could aid in clinical decision-making.

Immunotherapy in small bowel adenocarcinoma: a potential role?

Small bowel adenocarcinoma (SBA) is a rare tumor with an unfavorable prognosis, and due to its rarity, few studies on its treatment are available. Chemotherapy remains the standard of treatment in advanced disease. Recently immunotherapy has demonstrated to be a valid therapeutic option for many solid tumors. We reviewed the data published in literature to understand the impact of immunotherapy in this cancer.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Characteristics and prognosis of jejunoileal gastrointestinal stromal tumours (GISTs) in the era of imatinib: a comparative study with gastric GISTs

Backgroung Gastrointestinal stromal tumours (GISTs) located in the jejunum or ileum (JI-GIST) are considered worse prognosis compared to those of gastric (G-GIST) location. It has been suggested that this dogma should be revised. The aim of this study was to describe the characteristics of jejunoileal GISTs and its prognosis and to compare them with G-GISTs in the era of imatinib. Methods We retrospectively reviewed the clinical histories of all the patients diagnosed with GISTs between January 2000 and November 2016: Clinical and pathological data, as recurrence, metastatic state, disease-free survival (DFS) as well as overall survival (OS) rates of patients were reviewed. Results JI-GIST patients comprise 29 cases (37.7%). Compared to G-GIST, JI-GIST patients had undergone emergency surgery more frequently (37.9% vs. 10.4%, p = 0.007). According to the NIH-Fletcher classification, the low or very-low risk group represents 17.2% of JI-GISTs as opposed to 37.6% of G-GISTs (p < 0.005). When the AFIP-Miettinen system was used the low or very-low group represented 17.2% of JI-GISTs vs. 58.4% in the G-GISTs group (p < 0.001). Both local recurrence (24.1% vs. 12.5%, p < 0.05) and metastatic rate (34.5% vs. 22.9%, p < 0.05) were higher in the JI-GIST group than in G-GIST. 5- and 10-year DFS and 10-year OS rate were lower for JI-GIST (54.5% and 39.6% vs. 77.2% and 60.8%, and 57.9% vs. 65%, respectively, p < 0.05). Conclusions The observed differences between both groups in DFS and OS rates at long term could be attributed to the effect of imatinib (AU)

ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma.

PURPOSE: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. PATIENTS AND METHODS: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. RESULTS: Forty patients were treated for a median duration of four cycles (range, 1-35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2-20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1-17.1) and median PFS (2.8 months; 95% CI, 2.7-4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. CONCLUSIONS: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Characteristics and prognosis of jejunoileal gastrointestinal stromal tumours (GISTs) in the era of imatinib: a comparative study with gastric GISTs.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) located in the jejunum or ileum (JI-GIST) are considered worse prognosis compared to those of gastric (G-GIST) location. It has been suggested that this dogma should be revised. The aim of this study was to describe the characteristics of jejunoileal GISTs and its prognosis and to compare them with G-GISTs in the era of imatinib. METHODS: We retrospectively reviewed the clinical histories of all the patients diagnosed with GISTs between January 2000 and November 2016: Clinical and pathological data, as recurrence, metastatic state, disease-free survival (DFS) as well as overall survival (OS) rates of patients were reviewed. RESULTS: JI-GIST patients comprise 29 cases (37.7%). Compared to G-GIST, JI-GIST patients had undergone emergency surgery more frequently (37.9% vs. 10.4%, p = 0.007). According to the NIH-Fletcher classification, the low or very-low risk group represents 17.2% of JI-GISTs as opposed to 37.6% of G-GISTs (p < 0.005). When the AFIP-Miettinen system was used the low or very-low group represented 17.2% of JI-GISTs vs. 58.4% in the G-GISTs group (p < 0.001). Both local recurrence (24.1% vs. 12.5%, p < 0.05) and metastatic rate (34.5% vs. 22.9%, p < 0.05) were higher in the JI-GIST group than in G-GIST. 5- and 10-year DFS and 10-year OS rate were lower for JI-GIST (54.5% and 39.6% vs. 77.2% and 60.8%, and 57.9% vs. 65%, respectively, p < 0.05). CONCLUSIONS: The observed differences between both groups in DFS and OS rates at long term could be attributed to the effect of imatinib.

[Case of Peritoneal Dissemination from Gastrointestinal Stromal Tumor of Jejunum Treated with Repeated Non-Curative Surgery].

A 71-year-old male presented with abdominal distension and fever to our hospital. Abdominal CT revealed a huge tumor in abdomen, and non-curative surgery was performed. Peritoneal dissemination was widespread and the tumor invaded the bladder and sigmoid-colon mesenterium. Two months after the initial surgery, CT showed liver metastasis, and oral administration of imatinib mesylate was started. The peritoneal dissemination and liver metastasis showed a decrease, and this was well controlled for 45 months without severe side effects. Abdominal CT revealed peritoneal dissemination in the ileocecum after 43 months since the administration of imatinib. Therefore, sunitinib treatment was initiated. After 3 months of sunitinib administration, the tumor perforated. Emergency operation was performed to resect the ileocecum, and sunitinib was continued for 1 year. In GIST with liver metastasis and peritoneal dissemination, repeated surgical resection combined with chemotherapy is important to improve the patient's survival.

A patient-derived xenograft and a cell line derived from it form a useful preclinical model for small bowel adenocarcinoma.

Basic and clinical studies on small bowel adenocarcinoma (SBA) are limited due to the rare nature of this cancer. We established a patient-derived xenograft (PDX) model from the tumor tissue of an advanced SBA patient with liver and peritoneal metastasis, and a cell line from the PDX. In the PDX model, compared to the control group, 5-fluorouracil (5-FU) treatment resulted in statistically significant tumor growth inhibition (TGI), while oxaliplatin (OHP) and irinotecan had no significant inhibitory effects. In combination with 5-FU, OHP showed the highest rate of TGI. The IC50 for OHP was significantly lower than those for paclitaxel, gemcitabine, and trifluorothymidine in the PDX-derived cell line when compared to in HT29, a colon cancer cell line. Genetic analysis of the patient tumor, PDX tumor, and the cell line demonstrated consistency in the microsatellite status and mutations in TP53, APC, HRAS, CSF1R, FGFR3, FLT3, PDGFRA, and RET genes. However, the PDX tumor alone had additional mutations, indicating that the PDX-derived cell line may support the unstable genetic status of the PDX. Our findings confirmed the effectiveness of the combination of OHP and 5-FU, which is a common treatment for advanced SBA and advanced colorectal cancer, in a preclinical model. This preclinical model of SBA can help in further understanding the biology of SBA.

[Clinical Experience with 13 Cases of Primary Small Bowel Adenocarcinoma].

Between 2003 and 2017, 13 patients with primary small bowel adenocarcinoma(SBA)were treated at our hospital. Tumors developed in the duodenum in 6 patients and in the jejunum in 7 patients. The median age of the patients was 62 (range: 31-83)years and male/female ratio was 10/3. Initial symptoms were obstruction in 5 patients, bleeding in 3 patients, and abdominal pain in 1 patient. The median diameter of tumor was 50(range: 23-100)mm. Concerning surgical margin, R0 resection was in 8 patients, R1 resection in 3 patients, and R2 resection in 2 patients. The number of patients with stage 0 disease was 1, stage Ⅱ was 2, stage Ⅲ was 6, and stage Ⅳ was 4. Chemotherapy was provided to 8 patients. The median survival time was 31.6(range: 1-118)months and 5-year survival rate were 26.9%. Four patients survived longer than 4 years without recurrence. Although there is no treatment established for SBA, it was thought that proactive resection and chemotherapy can be anticipated in these patients to bring about an improved survival.

[A Case of Small Intestinal Cancer Resected by Laparoscopic Surgery].

We report a case of laparoscopic surgical resection of a small intestinal cancer. A woman in her 40s was referred to our department for prolonged abdominal problems(epigastralgia, nausea, diarrhea, and constipation). CT scan revealed a small intestinal tumor with dilatation of the oral side of the intestine. She was admitted to our hospital, and an ileus tube was introduced. One week after admission, she experienced laparoscopic partial resection of the small intestine. She was soon discharged without any problems and has had no recurrence of small intestinal cancer after 8 months of surgery without any adjuvant chemotherapy. Small intestinal cancer is frequently detected in an advanced stage, resulting in poor prognosis, but curative surgery can improve the prognosis. Optimal therapy for small intestinal cancer has not been established yet because it is rare. A multi-centered study of small intestinal cancer for the establishment of its diagnosis and therapy needs to be conducted.

A case of small bowel adenocarcinoma wherein nivolumab conferred temporary benefit in disease control.

Small bowel adenocarcinomas are rare. There is no definite consensus as to whether they should be treated in a manner similar to gastric or to colon cancer. We report the case of a young woman with a primary jejunal adenocarcinoma, bilateral ovary metastases, and peritoneal dissemination. First- and second-line chemotherapy for the gastric cancer failed. She was then treated with the immune checkpoint inhibitor nivolumab and had temporary improvement in her condition. To the best of our knowledge, this is the first case wherein nivolumab has been used to treat small bowel adenocarcinoma.

Preoperative therapy with sunitinib malate in a patient with a gastrointestinal stromal tumor and liver metastases: A case report.

RATIONALE: Patients with gastrointestinal stromal tumors (GISTs) are often found to have liver metastases at their 1st presentation. Most patients need preoperative treatment to reduce the size of the liver metastases to increase the possibility of surgical resection. Currently, imatinib mesylate is the drug of 1st choice for preoperative treatment and sunitinib malate (SM) is seldom used. Here we report a case of GIST with liver metastases where SM was used as a preoperative treatment. PATIENT CONCERNS: A 56-year-old worker presented with intermittent abdominal pain and eating difficulties. DIAGNOSES: An enhanced computed tomography scan showed a 15 × 15 × 10 cm malignant mass in the upper abdomen, and 2 metastases (15.1 × 13.1 cm and 14.8 × 8.8 cm) in the liver. The postcaval and middle hepatic veins were compressed by the liver metastases, making radical resection very difficult. INTERVENTIONS: First the primary tumor in the jejunum was resected, and then SM was used as a preoperative treatment to reduce the size of the liver metastases to improve the possibility of surgical resection. OUTCOMES: Both liver metastases regressed considerably in size and it was then possible to perform a radical resection. LESSONS: The SM has the potential to be used as preoperative therapy for GIST with large liver metastases. This method provides a new option for the preoperative treatment of GIST with liver metastases.

Complete response to sunitinib for more than three years in a patient with a jejunum gastrointestinal stromal tumor: A case report.

RATIONALE: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is characterized by KIT mutations. Patientsresistant to 1st-line imatinib therapy are usually given sunitinib assecond-line treatment, which provides a median progression-free survival of 8 to 12 months. We report the 1st case of metastatic jejunum GIST with a KIT exon 11 deletion that showed complete response (CR) to sunitinib for more than 3 years. PATIENT CONCERNS: A 34-year-old man with advanced jejunum GIST was surgically treated upon initial diagnosis, and was histologically found to carry a high recurrence risk. Genetic testing revealed a KIT exon 11 deletion, and adjuvant therapy with imatinib was administered. The imatinib dose was escalated following recurrence in the abdomen, but the mass continued to grow. DIAGNOSIS: He was diagnosed with abdominal recurrence of GIST based on his medical history and histopathological results. INTERVENTION: Second-line sunitinib therapy was given. OUTCOMES: The mass disappeared, and CR was seen following 7 months of sunitinib therapy; this CR was sustained for more than 45 months. LESSONS: In cases of metastatic jejunum GIST with a KIT exon 11 deletion, sunitinib as second-line therapy can be used to achieve CR for more than 3 years.

Randomized phase III trial of post-operative chemotherapy for patients with stage I/II/III small bowel adenocarcinoma (JCOG1502C, J-BALLAD).

A randomized phase III trial was initiated in May 2017 to confirm the superiority of post-operative therapy with capecitabine and oxaliplatin over observation in terms of relapse-free survival in patients with curatively resected small bowel adenocarcinoma. Total 150 patients will be enrolled from 20 Japanese institutions over a period of 6.5 years. Relapse-free survival is the primary endpoint, while the secondary endpoints are overall survival, disease-free survival as defined by the Japan Clinical Oncology Group (JCOG), disease-free survival as defined by the International Rare Cancer Initiative (IRCI), and adverse events. Global phase III trial of IRCI to confirm the superiority of post-operative chemotherapy for small bowel adenocarcinoma was started in the UK in August 2015 (ClinicalTrials.gov Identifier: NCT02502370). An integrated analysis of the IRCI trial and our study are planned. Our trial has been registered in the UMIN Clinical Trials Registry as UMIN000027280 (http://www.umin.ac.jp/ctr/index.htm).

[Lung Adenosquamous Cell Carcinoma in which the Administration of Nivolumab Became Untenable due to Bleeding from Small Intestine Metastasis].

A 59-year-old man who had postoperative recurrence of lung adenosquamous cell carcinoma was administered nivolumab as 3rd-line chemotherapy. Although nivolumab was considered effective, bleeding from a metastatic lesion at the jejunum was recognized by double-balloon enteroscopy, and partial resection was performed. Although the re-administration of nivolumab was planned, the patient died of acute respiratory failure 6 days postoperatively.

[A Case of Intussusception in the Jejunum Due to Small Intestinal Adenocarcinoma].

The patient was a woman in her 60's with an 11-month history ofpersistent epigastralgia and abdominal distension, without abnormal findings on upper endoscopy, abdominal ultrasonography, and abdominal computed tomography in other hospitals. She presented to our hospital with a complaint off requent vomiting; abdominal CT indicated intussusception in the jejunum due to a small intestinal tumor, and laparoscopic exploration and partial jejunectomy were performed. The histopathological diagnosis was tub1>tub2>pap, pT4(SE), pN1, pPM0, pDM0, pStage III A. She was treated with oral chemotherapy( S-1)and developed no recurrence 7 months after surgery. Laparoscopic exploration was useful to detect intussusception in the jejunum due to small intestinal adenocarcinoma.

Anti epidermal growth factor receptor therapy in small bowel adenocarcinoma: Case report and literature review.

RATIONALE: Small bowel adenocarcinoma (SBA) is an uncommon gastrointestinal cancer, thus limited data about treatment for advanced disease are available. The lack of specific guidelines has justified the use of therapeutic protocols usually applied in advanced colorectal cancer. Few and preliminary data have suggested possible clinical benefit from the use of target therapy such as bevacizumab and cetuximab. PATIENT CONCERNS: We present the case of a young woman who was admitted to the emergency department for acute abdominal pain, nausea, and vomiting related to a jejunal stenosis. DIAGNOSES: An enteroscopy with jejunal biopsy showed poorly differentiated cancerous cells suggestive for primary intestinal cancer. There were no signs of metastatic disease at radiological evaluation. A jejunal resection was subsequently carried out and the diagnosis of mucinous adenocarcinoma of the jejunum was confirmed. INTERVENTIONS: The computed tomography scan performed 1 month after surgery showed metastatic disease. Therefore, the patient received combined protocols of chemotherapy and either bevacizumab or the anti-epidermal growth factor receptor (EGFR) panitumumab. OUTCOMES: A partial response (PR) was achieved with Folfox plus panitumumab and a maintenance therapy with panitumumab is being conducted with a mild toxicity and a progression free survival of 19 months since the beginning of panitumumab. LESSONS: This is, to the best of our knowledge, the first report in the literature of a patient with SBA who has benefitted from panitumumab with an overall survival of 83 months.

A case of small intestinal neuroendocrine carcinoma diagnosed using double-balloon endoscopy with long-term survival.

Neuroendocrine neoplasms, including neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), are rare epithelial tumors with a predominant neuroendocrine differentiation. Compared with NETs, NECs have been reported to be rarer and have a poorer prognosis. We present a rare case of small bowel NEC diagnosed using double-balloon endoscopy (DBE) and the long-term survival accomplished via intensive therapy. DBE revealed an ulcerative tumor in the deep jejunum, and biopsy specimens showed large and highly dysplastic tumor cells; immuno-histological synaptophysin and chromogranin A tests were positive, and the Ki-67 index was more than 90%. Partial intestinal resection without complete lymph node dissection was performed and, postoperatively, chemotherapy was administered. The patient was observed for 3 years after chemotherapy, and complete remission was maintained.