Preoperative profiles of plasma amino acids and derivatives distinguish periampullary cancer and benign disease.

Periampullary cancers, including pancreatic ductal adenocarcinoma, ampullary-, cholangio-, and duodenal carcinoma, are frequently diagnosed in an advanced stage and are associated with poor overall survival. They are difficult to differentiate from each other and challenging to distinguish from benign periampullary disease preoperatively. To improve the preoperative diagnostics of periampullary neoplasms, clinical or biological markers are warranted.In this study, 28 blood plasma amino acids and derivatives from preoperative patients with benign (N = 45) and malignant (N = 72) periampullary disease were analyzed by LC-MS/MS.Principal component analysis and consensus clustering both separated the patients with cancer and the patients with benign disease. Glutamic acid had significantly higher plasma expression and 15 other metabolites significantly lower plasma expression in patients with malignant disease compared with patients having benign disease. Phenylalanine was the only metabolite associated with improved overall survival (HR = 0.50, CI 0.30-0.83, P < 0.01).Taken together, plasma metabolite profiles from patients with malignant and benign periampullary disease were significantly different and have the potential to distinguish malignant from benign disease preoperatively.

A Retrospective Study on the Clinical Characteristics and Computed Tomography, Biochemical, and Blood Parameters of Duodenal Papillary Diseases.

OBJECTIVE: This study was conducted to investigate the imaging information, laboratory data, and clinical characteristics of duodenal papillary malignancies, aiming to contribute to the early diagnosis of these diseases. METHODS: The clinical characteristics, laboratory data, and computed tomography (CT) findings of 17 patients with adenoma of the major duodenal papilla (the adenoma group) and 58 patients with cancer of the major duodenal papilla (the cancer group) were retrospectively analyzed. The measurement data were analyzed using t test and expressed as mean ± standard deviation. The counting data were analyzed using the χ2 test and expressed in n (%). Pearson correlation analysis was also conducted, and a scatter plot was drawn. RESULTS: There were significant differences in the diameter, shape, margin, and target sign of the major duodenal papilla, pancreatic duct diameter, common bile duct diameter, enhancement uniformity, fever, direct bilirubin, total bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9, and jaundice between the adenoma group and the cancer group (P < .01). The enhancement magnitude of the duodenal papilla was correlated with the lesion size, and the venous phase CT value of the enhanced scan was correlated with the duodenal papilla diameter (P < .05). Additionally, 12 patients in the cancer group suffered from malignant transformation of adenomas. CONCLUSION: Firstly, CT is of high value in the diagnosis of duodenal papilla diseases. Secondly, the enhancement magnitude of the duodenal papilla is correlated with the lesion size. Thirdly, patients with duodenal papilla adenomas have a risk of progression into adenocarcinoma, thereby requiring close follow-up.

A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. METHODS: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. RESULTS: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. CONCLUSION: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.

Management of cancer-associated venous thromboembolism - a case-based practical approach.

In patients with solid tumours or haematological malignancies, venous thromboembolism (VTE) is a leading cause of death and significantly contributes to morbidity and healthcare resource utilization. Current practice guidelines recommend long-term anticoagulation with low-molecular-weight heparin (LMWH) as the treatment of choice for cancer-associated VTE, based on clinical trial data showing an overall improved safety and efficacy profile of LMWH compared to vitamin K antagonists. However, several open questions remain, e. g. with regard to the intensity and duration of LMWH therapy; moreover, recent real-world evidence indicates that adherence to parenteral anticoagulation with LMWH over the course of treatment is poor in clinical practice. In this regard, the direct oral factor Xa or thrombin inhibitors (DOACs) have emerged as potential alternatives in the management of patients with cancer-associated VTE, albeit findings from randomized controlled studies with a direct head-to-head comparison of DOACs with LMWH, the current standard of care, are still lacking. Based on the case of a lymphoma patient experiencing symptomatic pulmonary embolism during immunochemotherapy, this article aims at both highlighting the current state-of-the-art approach to cancer-associated VTE and pointing out some of the unresolved, controversial issues clinicians have to face when taking care of haematology and oncology patients with already established or with high risk of developing VTE. These issues include the management of patients with incidental pulmonary embolism or thrombocytopenia, the use of DOACs, and the initiation of pharmacological thromboprophylaxis in non-surgical cancer patients.

Does blood group affect survival following pancreatoduodenectomy for periampullary malignancy?

BACKGROUND: Blood group is reported to have an effect upon survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma. The effect of blood group is not known, however, among patients with other periampullary cancers. This study sought to review this. METHODS: Data were collected for a range of factors and survival outcomes from patients treated at two centres. Those with blood groups B and AB were excluded, due to small numbers. Patient survival was compared between patients with blood groups O and A using multivariable analysis which accounted for confounding factors. RESULTS: Among 431 patients, 235 (54.5%) and 196 (45.5%) were of blood groups A and O respectively. Baseline comparisons found a significant difference in the distribution of tumour types (p = 0.011), with blood group O patients having more ampullary carcinomas (33.2% vs 23.4%) and less pancreatic ductal adenocarcinomas (45.4 vs 61.3%) than group A. On multivariable analysis, after accounting for confounding factors including pathologic variables, survival was found to be significantly shorter in those with blood group A than group O (p = 0.047, HR 1.30 [95%CI: 1.00-1.69]). CONCLUSIONS: There is a difference in the distribution of blood groups across the different types of periampullary cancers. Survival is shorter among blood group A patients.

Alkalin phosphatase is a predictive factor of unresecability in ampullary and periampullary tumors.

BACKGROUND: Patients with malignant obstructive jaundice should undergo surgery on the basis of results of preoperative imaging. However, about half of patients are found to be unsuitable forresection during surgical exploration. Our study aimed to determine the clinicobiologicalcharacteristics that predict the resecability of ampullary and periampullary tumors. METHODS: We retrospectively reviewed the medical records of 49 patients (45% men and 55% women) who had malignant obstructive jaundice collected in the Department B of generalsurgery, Charles Nicolle hospital between July 1, 2008 and December 31, 2013. Predictivevariables of unresecability in malignant obstructive jaundice were identified using univariate andmultivariate analysis. RESULTS: 49 patients were included in the study. The mean age was 66,3±12,9 years. Twenty patients underwent surgery. Radical resection was performed in 12 patients and surgical palliation by biliary bypass was performed in 8 patients. Twenty-nine patients unfit for surgery underwent endoscopic stenting and chemotherapy. At univariate analysis, age (p=0,016), body mass index (p=0,033), worse general health status (p=0,037), locally advanced disease (p<0,001), serum conjugated bilirubin level (p=0,055), and serum level alkaline phosphatase (ALP) (p=0,014) were associated with unresectableampullary and periampullary tumors. At multivariate analysis serum level ALP was identify as an independent factor of unresecability in malignant obstructive jaundice [OR=0,996; IC à 95% (0,992-1,000) ;p=0,048]. The area under the ROC curve was 0,745 (p=0,016). CONCLUSION: Serum level of ALP can predict resecability in malignant obstructive jaundice. Further studies are needed to identify other factors predicting resecability and prognosis of ampullary and periampullary tumors.

Microscopic polyangitis complicating double carcinoma of the stomach and duodenum: improvement after the resection of these carcinomas.

A 74-year-old woman developed fever, numbness of legs and glomerulonephritis. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase (MPO-ANCA) were positive in her serum, and she presented with acute renal failure. She was also simultaneously diagnosed as having both gastric and duodenal cancers. Complete resection of both cancers and renal biopsy was performed. Some glomeruli showed cellular crescentic changes, while submucosal necrotizing vasculitis of small vessels was noted adjacent to the gastric cancer. A diagnosis of microscopic polyangitis was made. After the operation, the patient's fever, renal failure and microscopic hematuria improved and obvious reductions in her serum soluble receptors of interleukin 2 values and MPO-ANCA titer were observed without any further treatment. However, the patient's proteinuria, cylinduria, and elevated C-reactive protein persisted; these findings eventually resolved after treatment with 30 mg of prednisolone daily. An immunohistochemical analysis showed that CD8 T lymphocytes had infiltrated both the carcinomas and the renal lesions. Our case suggests that CD8 T cells induced as part of an immune response against carcinoma may play a pathologic role in ANCA-positive paraneoplastic syndrome.

The prevalence of micronutrient deficiency in patients with suspected pancreatico-biliary malignancy: Results from a specialist Hepato-Biliary and Pancreatic unit.

INTRODUCTION: There is a paucity of information on micronutrient status in patients with pancreatico-biliary malignancies referred for surgery. Deficiency states could impact recovery from surgery. The purpose of this study was to investigate the frequency of deficiency states in our specialist Hepato-Biliary and Pancreatic (HPB) unit. METHODS: Patients with suspected pancreatico-biliary malignancies referred to our surgical team between October 2019 and July 2020, and seen by a dietitian were included in the study. Serum levels of vitamins A, D, E, B12, and folate, and minerals zinc, selenium, copper and iron were obtained. RESULTS: Forty-eight patients were eligible for inclusion, 28 males and 20 females with a median age of 68 years. Pancreatic cancer was suspected in 40 patients, bile duct cancer in four patients, and duodenal cancer in four patients. Zinc, vitamin D, selenium and iron were the most frequently occurring micronutrient deficiencies. Zinc deficiency was found in 83% patients and vitamin D insufficiency in 57%. Selenium deficiency was less frequent but found in 24% cases, while iron deficiency suggested by low transferrin saturation was found in 23% patients. CONCLUSIONS: Micronutrient deficiencies and borderline status may be more frequent in this patient group than generally acknowledged. Routine analysis of specific vitamins and minerals may be useful to identify deficiency/sub-clinical deficiency states. Further more extensive studies are needed to inform practice and enable guideline development.

A Blood-based Polyamine Signature Associated With MEN1 Duodenopancreatic Neuroendocrine Tumor Progression.

CONTEXT: Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor-promoting roles in several cancer types. OBJECTIVE: We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines. METHODS: Through an international collaboration between The University of Texas MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht, plasma polyamine levels were assessed using mass spectrometry in 84 patients with MEN1 (20 with distant metastatic dpNETs [patients] and 64 with either indolent dpNETs or no dpNETs [controls]). A mouse model of MEN1-pNET, Men1fl/flPdx1-CreTg, was used to test time-dependent changes in plasma polyamines associated with disease progression. RESULTS: A 3-marker plasma polyamine signature (3MP: N-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the 3 participating centers. The fixed 3MP yielded an area under the curve of 0.84 (95% CI, 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing patients from controls in an independent test set from MDACC. In Men1fl/flPdx1-CreTg mice, the 3MP was elevated early and remained high during disease progression. CONCLUSION: Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.

Carcinoid tumors and morbid obesity.

Carcinoid is a rare gastrointestinal tumor, with an incidence varying from 1 to 2.5 per 100,000 in the general population. In this article, we report an elevated incidence of carcinoid tumor in an obese population, showing the importance of performing an endoscopic procedure before bariatric surgery.

[A case report of FOLFOX treatment for primary duodenal carcinoma with multiple liver metastases].

We report a case of a woman in her sixties having primary duodenal carcinoma with multiple liver metastases who was treated with oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin(FOLFOX regimen). After completing 2 courses of the chemotherapy, computed tomography showed a partial response without any severe adverse events. Now at 8 months, the PR stage has been maintained. So far, no standard therapeutic strategy for metastatic duodenal carcinoma has been developed. However, we suggest a FOLFOX regimen can be highly effective as a safe approach for continuously maintaining the quality of life of patients with this rare type of cancer.

[A case of long survival with unresectable duodenal papilla cancer treated with oral chemotherapy using combination UFT and cyclophosphamide].

A 69-year-old female patient underwent a choledochojejunostomy for unresectable duodenal papilla cancer with para-aortic lymph node metastases. Both tegafur-uracil(UFT) and cyclophosphamide were given orally every day after surgery. Twenty-eight months from the initiation of the chemotherapy the tumor had remarkably reduced and the objective response was evaluated as a PR. The patient is now doing well. Lymph node metastasis is considered an important prognostic factor of papilla Vater carcinoma, and especially with para-aortic lymph node metastases the long-term prognosis is poor. Combination chemotherapy using UFT and cyclophosphamide would be a therapeutic option for elderly or high-risk patients.

Favorable glycemic response after pancreatoduodenectomy in both patients with pancreatic cancer and patients with non-pancreatic cancer.

Diabetes mellitus (DM) is prevalent in patients with pancreatic cancer and tends to improve after tumor resection. However, the glycemic response of non-pancreatic cancer patients after surgery has not been examined in detail. We aimed to investigate the changes in glucose metabolism in patients with pancreatic cancer or non-pancreatic cancer after pancreatoduodenectomy (PD).We prospectively enrolled 48 patients with pancreatic cancer and 56 patients with non-pancreatic cancer, who underwent PD. Glucose metabolism was assessed with fasting glucose, glycated hemoglobin (HbA1c), plasma C-peptide and insulin, quantitative insulin check index (QUICKI), and a homeostatic model assessment of insulin resistance (HOMA-IR) and ß cell (HOMA-ß) before surgery and 6 months after surgery. Patients were divided into 2 groups: "improved" and "worsened" postoperative glycemic response, according to the changes in HbA1c and anti-diabetic medication. New-onset DM was defined as diagnosis of DM ≤ 2 years before PD, and cases with DM diagnosis >2 years preceding PD were described as long-standing DM.After PD, insulin resistance (IR), as measured by insulin, HOMA-IR and QUICKI, improved significantly, although C-peptide and HOMA-ß decreased. At 6 months after PD, new-onset DM patients showed improved glycemic control in both pancreatic cancer patients (75%) and non-pancreatic cancer patients (63%). Multivariate analysis showed that long-standing DM was a significant predictor for worsening glucose control (odds ratio = 4.01, P = .017).Favorable glycemic control was frequently observed in both pancreatic cancer and non-pancreatic cancer after PD. PD seems to contribute improved glucose control through the decreased IR. New-onset DM showed better glycemic control than long-standing DM.

Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors.

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.

Imaging of gastrinomas by nuclear medicine methods.

Somatostatin receptor scintigraphy (SRS) is a valuable method for the detection of somatostatin receptor-positive lesions. Most gastrinomas (over-)express the somatostatin receptor subtype 2 which can be targeted by In-111 labeled Octreotide. Different studies show a high sensitivity of SRS for the localization and staging of gastrinomas. SRS seems to be superior to other non-invasive imaging modalities and has been proven to significantly contribute to patient management. However, the sensitivity depends on the size and exact localization of the tumors. Smaller lesions and lesions located in the duodenum show a significantly lower sensitivity. In any case, SRS belongs to the routine imaging procedure for gastrinomas for localization and staging and can also be used for evaluation of the tumor progression.

Surgical aspects of gastrinoma in multiple endocrine neoplasia type 1.

Gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with multiple endocrine neoplasia type 1 (MEN1) and one major determinant of mortality in this syndrome. Whether routine surgical exploration should be performed in a patient with MEN1 associated Zollinger-Ellison syndrome (ZES) to possibly reduce the malignant spread and eventually increase survival still remains controversial. There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available. The article discusses the available data on treatment strategies of MEN1 associated ZES.

Surgical treatment of sporadic gastrinoma.

Surgical therapy for sporadic gastrinoma profits from innovative pre- and intraoperative diagnostics. Preoperative gastrinoma localization is enhanced by sophisticated endoscopic ultrasonography, scintigraphic and arteriographic studies with hormone sampling. Thereby a concise surgical approach is guided and additional intraoperative control of success may be gained by endoscopic transillumination and measurement of stimulated gastrin levels.

Medical treatment of gastrinomas.

Gastrinomas are functional neuroendocrine tumors of the gastroenteropancreatic system. Surgery is first line treatment in gastrinomas, however often fails to be curative. This manuscript reviews current strategies of medical treatment of surgically non-curable gastrinoma. Symptomatic treatment with H(+)-K(+)-ATPase proton-pump inhibitors suppresses hypersecretion of gastric acid and substantially improves quality of life in patients with Zollinger-Ellison syndrome. Further medical therapy is only recommended in cases of progressive metastatic gastrinoma. In well differentiated neuroendocrine carcinoma (G1 and G2) a so-called biotherapy with somatostatin analogues exists as first-line and chemotherapy with streptocotozin plus doxorubicine/5-FU as second-line medical treatment option. In poorly differentiated neuroendocrine carcinoma (G3) chemotherapy with etoposide plus cisplatin is possible. Prospective future therapeutic strategies may include treatment with novel somatostatin analogues as well as angiogenesis inhibitors and kinase inhibitors targeting tumor-specific signaling cascades.

Diagnosis and differential diagnosis of hypergastrinemia.

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.

Diagnosis and treatment of gastric neuroendocrine tumours.

Gastric neuroendocrine tumours (NET) are rare. Clinically they are classified in tumours type 1 to 3. The histological classification is according to the WHO 2000 classification for endocrine tumours. NET type 1 occur in coincidence with chronic atrophic gastritis, as single or multiple small tumours. The prognosis of type 1 tumours is excellent, with no tumour related death reported during follow-up. NET type 2 are part of the MEN-1 syndrome. These tumours may be more aggressive and even develop metastasis. However, in most patients with MEN-1 the prognosis is due to other manifestations of the disease as duodenal or pancreatic neuroendocrine tumours. Gastric neuroendocrine tumours type 3 are sporadic tumours without relationship to other gastric pathology. They tend to occur earlier, without sex preference. These tumours may develop an aggressive course, with metastatic disease and an overall poor prognosis. Thus, aggressive surgical therapy is recommended.