A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

Outcome of pancreaticoduodenectomy in octogenarians: Single institution's experience and review of the literature.

INTRODUCTION: Pancreatic and perampullary neoplasms in patients aged 80 or older trouble the surgeons because of the risk of surgical treatment. We have reviewed our experience and literature's reports of pancreaticoduodenectomy in octogenarians, evaluating early results and long-term survival in pancreatic cancer group. METHODS: Three hundred eighty-five patients who underwent pancreaticoduodenectomy for neoplasms from 1998 to 2011 were included in the study, and were divided in two groups: group 1, patients younger than 80 years of age, and group 2, patients 80 years of age and older. Operative morbidity, mortality, disease-free and long-term survival were analysed. English literature was systematically searched for pancreatic resection's outcome in octogenarians. RESULTS: There were 385 pancreaticoduodenectomies: 362 patients were in group 1 and 23 patients in group 2. There was no significant difference regarding gender, and pathologic findings between the two groups. Complications' rate (40 vs. 43%), mortality rate (4% vs. 0%), and overall median survival for pancreatic cancer patients were not statistically different in the two groups (median 21 vs. 19 months). Literature's review showed 14 reports of pancreatic resection in octogenarians. Most of the studies (particularly in centres with high-volume pancreatic surgery) showed that outcome after pancreatectomy was not different in octogenarians or in younger patients. CONCLUSION: Pancreaticoduodenectomy is an acceptable option for elderly patients. Age alone should not be considered a contraindication to major pancreatic resection, but a careful preoperative evaluation and an accurate postoperative management are mandatory.

Metastatic pancreatic tumors: what is the optimal treatment?

Although rare, metastases to the pancreas from other primary tumors are increasingly recognized in clinical practice, but the optimal treatment remains unclear. When a careful staging is performed and widespread disease is excluded, the indication of pancreatectomy may arise. This study was designated to review the published literature on the results of surgical treatment for the most common malignancies metastasizing to the pancreas. Analysis of the reports show that resection can be performed safely, but long term survival is substantially influenced by the tumor's biology. There are convincing evidences that pancreatic resection for metastasis from renal cell cancer may offer excellent results in term of prolonged survival, while for other type of cancer, pancreatic resection should be considered only a palliative procedure, with only anedoctical reported long-term survivors. So, comparison of the results of surgical and non-surgical management of metastatic tumors to the pancreas is very difficult to perform. There is a need of studies evaluating the role of chemotherapy in the neoadjuvant setting or the best sequential use of multimodality treatment (targeted therapy, radiotherapy, surgery, etc.). At the moment, pancreatic resection for metastasis should be reserved to patients in good health conditions, with isolated disease from renal cell cancer. For other types of tumor, surgery should be performed only in individual basis.

Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery. AIM: To demonstrate the superior efficacy of pancreatin 25 000 minimicrospheres (Creon 25000 MMS; 9-15 capsules/day) over placebo in treating PEI after pancreatic resection. METHODS: A 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study with a 1-year, open-label extension (OLE). Subjects ≥18 years old with PEI after pancreatic resection, defined as baseline coefficient of fat absorption (CFA) <80%, were randomised to oral pancreatin or placebo (9-15 capsules/day: 3 with main meals, 2 with snacks). In the OLE, all subjects received pancreatin. The primary efficacy measure was least squares mean CFA change from baseline to end of double-blind treatment (ancova). RESULTS: All 58 subjects randomised (32 pancreatin, 26 placebo) completed double-blind treatment and entered the OLE; 51 completed the OLE. The least squares mean CFA change in the double-blind phase was significantly greater with pancreatin vs. placebo: 21.4% (95% CI: 13.7, 29.2) vs. -4.2% (-12.8, 4.5); difference 25.6% (13.9, 37.3), P < 0.001. The mean ± s.d. CFA increased from 53.6 ± 20.6% at baseline to 78.4 ± 20.7% at OLE end (P < 0.001). Treatment-emergent adverse events occurred in 37.5% subjects on pancreatin and 26.9% on placebo during double-blind treatment, with flatulence being the most common (pancreatin 12.5%, placebo 7.7%). Only two subjects discontinued due to treatment-emergent adverse events, both during the OLE. CONCLUSIONS: This study demonstrates superior efficacy of pancreatin 25 000 over placebo in patients with PEI after pancreatic surgery, measured by change in CFA. Pancreatin was generally well tolerated at the high dose administered (EudraCT registration number: 2005-004854-29).

Extent of lymphadenectomy in the resection of pancreatic cancer. Analysis of the existing evidence.

Pancreaticoduodenectomy is considered the standard procedure for the surgical treatment of the pancreatic head cancer. However, the extent of lymph node clearance associated to the procedure is still largely debated. Arguments in favour of an extended lymphadenectomy are the regular progression of lymph node invasion, without skip metastases, and the removal of the extrapancreatic neural plexus that is invaded in 52-72% of patients. Arguments against the extended lymphadenectomy are the failure of extended lymphadenectomy to improve survival in other cancers, and the severe diarrhoea that follows the skeletonisation of the superior mesenteric artery. After Ishikawa's paper, several retrospective studies supported a longer survival after an extended than after a standard lymphadenectomy, but as much retrospective studies failed to demonstrate any difference. Only three prospective randomised controlled trials have been performed so far. Unfortunately all are underpowered, and the substantial differences in the surgical procedures, in the adjuvant treatment, and in the length of follow-up make the comparison impossible. Only one study reports a significantly longer survival for lymph node positive patients who underwent an extended lymphadenectomy, but adjuvant treatment was not performed. Furthermore, the difference was of minimal clinical impact. At least two adequately powered prospective Randomised Controlled Trials including a true extended lymphadenectomy, and a standardised adjuvant treatment, would be required to answer the question. Unfortunately, we have not yet a standardised adjuvant (or neoadjuvant) treatment, and we do not know the impact of such treatment on the expected statistical difference in the survival after a standard or extended lymphadenectomy. The lot of work required to perform such trials probably doesn't worth the expected results.

[Enucleation-resection of pancreatic neuroendocrine tumors: 25 years of experience]. / Enucleoresezione di tumori neuroendocrini pancreatici venticinque anni di esperienza.

From 1980 to 2004, out of 109 patients who underwent surgery for neuroendocrine pancreatic tumor, 33 had a simple tumor excision. Seventy-two percent of cases were insulinomas. Age, sex, site and size of the tumor, associated diseases, hospital stay and complications were retrospectively reviewed by the clinical records. Patients (12 males and 21 females) averaged 56.8 years, range 20-86. Mean size of the tumor was 1.7 cm and 54.5% were in the pancreatic head; 78.8% of cases had medical associated diseases. Hospital stay was 12 days (median; range, 6-81 days) and mean period of gastric suction was 4 days. Forty-eight percent had a uneventful postoperative course. Complications were divided in early (related to pancreatic surgery, related to general open surgery and medical) and late events. Complication related to pancreatic surgery were 6/33 (18%); 5 pancreatic fistulas (4 low output) and 1 acute pancreatitis, while 5/33 had a general surgery complication (2 leacking due to gastric and duodenal associated operations). Medical complications were recorded in 13 cases. Late complications occurred in 4 cases (2 incisional hernias, 1 pseudocyst and 1 keloid). No patient was re-operated for pancreatic complications; 1 was reoperated for evisceration and 1 for hyper-parathyroidism in the early post-operative period. No mortality occurred. Re-evaluation of the clinical records in order to be submitted to laparoscopic surgery excluded 17/33 cases (51%) as candidate to laparoscopic approach.

[Positron emission tomography with fluorodeoxyglucose in gastro-entero-pancreatic tumors: diagnostic role and prognostic implications]. / La tomografia ad emissione di positroni con fluorodesossiglucosio nei tumori neuroendocrini gastro-entero-pancreatici: ruolo diagnostico e implicazioni prognostiche.

From November 1994 to November 2004, seventy-seven patients with neuroendocrine gastro-entero-pancreatic tumor (71% pancreatic) were investigated with 18-fluorine-deoxi-glucose positron emission tomography (FDG-PET). PET results were compared with CT-scan, MRI and octreoscan scintigraphy and clinico-pathologic features of patients and survival. Overall PET sensitivity was 57%; 78% of malignant tumors, 67% of borderline and 17% of benign tumors were detected by FDG-PET. No duodenal tumor was detected by PET scan. Only 16% of primary less than 2 cm in size was localized. In 16% of cases PET scan provided new information able to change therapeutic management. In PET positive patients the addictive information obtained by PET scan when compared with octreoscan, MRI and CT scan were respectively 50% more, 26% more and 30% more. In malignant neuroendocrine tumors PET positivity was related to short survival. No patient with malignant tumor died for disease progression in the follow-up when PET was negative, while 13/35 PET positive patients died (p <0.003). FDG-PET proved to be a second line technique in neuroendocrine digestive tumors. PET results improve clinical staging of disease and is related to survival in malignant cases; in 16% of cases may change the therapeutic option.

Epidemiology of pancreatic cancer in Northeastern Italy: incidence, resectability rate, hospital stay, costs and survival (1990-1992).

BACKGROUND: The incidence of pancreatic cancer and relative hospital stay and costs are not well known. AIMS: To define the incidence, hospital stay and cost of pancreatic cancer in a well-defined area of Italy. PATIENTS AND METHODS: Each new case of pancreatic cancer diagnosed between 1990 and 1992 among 669,703 inhabitants in the Veneto Region of Northern Italy was recorded and followed until death or for 5 years after diagnosis. Four types of hospital stay were defined. Type 1: undiagnosed pancreatic cancer; type 2: first diagnosis of pancreatic cancer, treatment excluded; type 3: main treatment; and type 4: follow-up and disease-related complications. Data were analysed for hospital stay-related procedures, costs and survival. RESULTS: Pancreatic cancer was diagnosed in 253 patients (12.6/100,000 per year), 43 patients (17.7%) underwent surgical resection, and 93 (36.8%) palliative surgery. The mean duration of type 3 hospital stay was similar for resection, palliative and exploratory surgery. The estimated hospital cost was significantly higher for surgical resection, almost the same for palliative and exploratory surgery, and only slightly lower for medical treatment. Each patient spent a mean of 57.7 days in the hospital. The hospital mortality rate was 4.6% for surgical resection, 22.1% for palliative surgery, and 18.7% for exploratory laparotomy. Overall, the 1-, 2-, 3- and 5-year survival rates were 20.9%, 5.1%, 2.9% and 1.2%, respectively. CONCLUSIONS: Pancreatic cancer is an expensive, almost incurable disease. Integrated treatments in specialized Centres should reduce the mortality rate and costs.

Pancreatic head resection for noninflammatory benign lesions of the head of the pancreas.

INTRODUCTION: Duodenum-preserving pancreatic head resection (DPPHR) has been safely performed in patients with chronic pancreatitis. The procedure has rarely been used to remove benign or borderline lesions of the head of the pancreas. AIMS: To review our experience with 13 patients who underwent DPPHR and to review reports in the literature on the same subject. METHODOLOGY: From October 1991 to September 2000, 13 patients underwent DPPHR to resect endocrine pancreatic tumors (n = 4), beta cell hyperplasia (n = 1), pancreatic pseudocysts (n = 2), serous cystadenomas (n = 3), congenital (n = 1) and choledochal (n = 1) cysts, and intraductal papillary mucinous tumor (n = 1). The Kocher maneuver was performed in seven patients (group 1) and avoided in six (group 2). Type 1, 2, and 3 DPPHR were defined depending on the amount of pancreatic tissue left at the inner surface of the duodenum. Ten patients underwent evaluation that included an oral glucose tolerance test and exocrine pancreatic function test. RESULTS: The mortality rate was zero; the complication rate was 69%. Patients in whom the Kocher maneuver was not performed (group 2) experienced fewer complications, shorter stay on nasogastric tube and abdominal drain(s), and earlier water intake and discharge. Type of DPPHR did not influence the postoperative course. One patient died 3 months after surgery of unrelated disease. Twelve patients were alive and well 2 months to 8 years after surgery. CONCLUSION: DPPHR is a low-risk procedure in patients with benign or borderline noninflammatory lesions of the head of the pancreas in whom pylorus-preserving pancreaticoduodenectomy is otherwise indicated. Whenever possible, the Kocher maneuver should be avoided.

Value of 18-fluorodeoxyglucose positron emission tomography in the management of patients with cystic tumors of the pancreas.

OBJECTIVE: To assess the reliability of 18-fluorodeoxyglucose positron emission tomography (18-FDG PET) in distinguishing benign from malignant cystic lesions of the pancreas. SUMMARY BACKGROUND DATA: The preoperative differential diagnosis of cystic lesions of the pancreas remains difficult: the most important point is to identify malignant or premalignant cysts that require resection. 18-FDG PET is a new imaging procedure based on the increased glucose metabolism by tumor cells and has been proposed for the diagnosis and staging of pancreatic cancer. METHODS: During a 4-year period, 56 patients with a suspected cystic tumor of the pancreas underwent 18-FDG PET in addition to computed tomography scanning, serum CA 19-9 assay, and in some instances magnetic resonance imaging or endoscopic retrograde cholangiopancreatography. The 18-FDG PET was analyzed visually and semiquantitatively using the standard uptake value. The accuracy of 18-FDG PET and computed tomography was determined for preoperative diagnosis of a malignant cyst. RESULTS: Seventeen patients had malignant tumors. Sixteen patients (94%) showed 18-FDG uptake with a standard uptake value of 2.6 to 12.0. Twelve patients (70%) were correctly identified as having malignancy by computed tomography, CA 19-9 assay, or both. Thirty-nine patients had benign tumors: only one mucinous cystadenoma showed increased 18-FDG uptake (standard uptake value 2.6). Five patients with benign cysts showed computed tomography findings of malignancy. Sensitivity, specificity, and positive and negative predictive values for 18-FDG PET and computed tomography scanning in detecting malignant tumors were 94%, 97%, 94%, and 97% and 65%, 87%, 69%, and 85%, respectively. CONCLUSIONS: 18-FDG PET is more accurate than computed tomography in identifying malignant pancreatic cystic lesions and should be used, in combination with computed tomography and tumor markers assay, in the preoperative evaluation of patients with pancreatic cystic lesions. A positive result on 18-FDG PET strongly suggests malignancy and, therefore, a need for resection; a negative result shows a benign tumor that may be treated with limited resection or, in selected high-risk patients, with biopsy, follow-up, or both.

Median pancreatectomy for tumors of the neck and body of the pancreas.

BACKGROUND: When enucleation is too risky because of possible damage of the main pancreatic duct, benign tumors located in the neck or body of the pancreas are usually removed by a left (spleno)-pancreatectomy or by a pancreatoduodenectomy. But standard pancreatic resection results in an important loss of normal pancreatic parenchyma and may cause impairment of exocrine and endocrine function. The aim of this study was to evaluate early and longterm results of median pancreatectomy, a limited resection of the midportion of the pancreas, in selected patients with benign or borderline tumors of the pancreas. STUDY DESIGN: Records of patients at Ospedale Busonera between November 1985 and September 1998 were reviewed. Ten patients with tumors of the neck or body of the pancreas underwent median pancreatectomy; the cephalic stump was sutured and the distal stump was anastomosed with a Roux-en-Y jejunal loop. Followup included clinical evaluation and routine laboratory tests: abdominal ultrasonography, exocrine and endocrine pancreatic function with fecal chymotrypsin, and an oral glucose tolerance test. RESULTS: Pathologic examination showed: insulinoma (n = 3), mucinous cystadenoma (n = 3), nonfunctioning endocrine tumor (n = 1), papillary-cystic neoplasm (n= 1), serous cystadenoma (n = 1), and intraductal mucinous tumor (n = 1). Operative mortality and morbidity were 0% and 40%, respectively; pancreatic fistula occurred in three patients. At mean followup of 62.7 months, no recurrence was found and no patient had exocrine insufficiency or glucose metabolism impairment. CONCLUSIONS: Median pancreatectomy is a safe and effective alternative to major pancreatic resection in selected patients with benign or low-malignant lesions of the pancreas. This procedure carries a surgical risk similar to that of the standard operation, but avoids extensive pancreatic resection and pancreatic function impairment.

Macrocystic serous cystadenoma of the pancreas: clinicopathologic features in seven cases.

BACKGROUND: Serous cystic neoplasms of the pancreas are uncommon tumors classified as microcystic adenomas. In this article, the authors report clinico-pathologic features of seven cases of macrocystic variant of the serous cystadenoma. METHODS: Seven patients (5 females and 2 males) with a diagnosis of cystic lesion of the pancreas were observed after 1995. Clinical, radiological, and pathologic features, including immunohistochemistry, were reported. Enzymes and tumor markers CEA, CA 19-9, CA 125, CA 15-3, CA 72-4, and mucin-like carcinoma-associated antigen (MCA) were investigated in the serum and cyst fluid of the patients. Cytology was also performed. RESULTS: Six patients were symptomatic complaining abdominal pain. All cases had radiologic evidence of unilocular cyst of the pancreas. The suspected diagnosis was consistent with mucinous cystic neoplasm. Serum tumor markers were all in the normal range. After surgery, pathology showed in all cases a cyst lined with cuboidal, periodic acid-Schiff (PAS)-positive epithelium, without mucin content or atypia. Minute microcysts were found surrounding the main cavity. Immunohistochemical stains were positive for cytokeratin, CA19-9, CA15-3, CA 72-4, and MCA. CEA was unexpressed. CA 125 in the cyst fluid were found elevated in three cases and CA 19-9 in three cases. Cytology was negative in all cases. CONCLUSION: When a unilocular pancreatic cyst is found, without history of pancreatitis and gallstones, having low serum tumor markers levels and negativity of CA 72-4 and MCA in the cyst fluid, the diagnosis of the macrocystic variant of the serous cystadenoma may be suggested. At present, the diagnosis is still based on pathological examination after cyst removal.

General aspects of surgical treatment of pancreatic cancer.

BACKGROUND: Different results and opinions exist concerning the use of a standard or an extended lymphadenectomy, and about the indications for portal vein resection in the surgical treatment of pancreatic cancer. The site of recurrence of pancreatic cancer may help to define the usefulness of different treatments in avoiding local and/or distant recurrences. METHODS: From personal experience and a literature review, 841 patients who underwent portal vein resection were collected, and 29 papers reporting the results of extended lymphadenectomy in the surgical treatment of pancreatic cancer were analyzed. A review of the site of relapse according to the surgical treatment, with or without various adjuvant treatments, was performed. Personal experience on survival rate according to the site of relapse (local, distant, local and distant) is also reported. RESULTS: Portal vein resection has been performed without a significant increase in morbidity and mortality rate in a large number of patients. However, its usefulness for increasing the resectability rate and the long-term survival has yet to be established. Extended lymphadenectomy does not increase the morbidity and mortality rate, but conflicting results on long-term survival have been reported. Distant metastases, undetectable by the radiologist and the surgeon, usually kill more than 40% of the resected patients within 12 months. Only lymph node-positive patients with limited undetectable distant metastases seem to benefit from an extended lymphadenectomy. Although many data are lacking, the incidence of the different sites of relapse is the same whatever the surgical and/or adjuvant treatment performed. Overall survival and disease-free survival rate are not affected by the site of relapse. A significantly worse survival rate was observed after the radiological detection of local and distant metastasis than after an only local or only distant metastasis. CONCLUSION: Portal vein resection and extended lymphadenectomy can be performed without increasing the surgical morbidity and mortality rate. We still have insufficient data to decide which patient can benefit from a more extended procedure. Standardization of operations, terminology, pathological reporting, and follow-up, together with well-designed prospective studies, will help to decide the operation of choice for pancreatic cancer.

Neuroendocrine tumor imaging: can 18F-fluorodeoxyglucose positron emission tomography detect tumors with poor prognosis and aggressive behavior?

We evaluated the clinical value of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) for neuroendocrine tumor (NET) detection. Sixteen patients with cytologically or histologically proved NETs were investigated. Patients were divided in two groups of eight patients each according to the clinicopathologic features related to prognosis: slow-growing NETs and aggressive NETs. Results of FDG tumor uptake as detected by PET were compared with computed tomography (CT) scans and with scans obtained with 111In-octreotide scintigraphy (n = 13). Tumor FDG uptake was increased in the primary lesion of all eight aggressive NETs; the tracer was shown also in lymph nodes, liver metastases, or both in five of six of them (83%). In four cases, additional unknown tumor sites undetected by CT scan were identified. A slight positivity was found in only one of eight cases with a slow-growing NET. The overall octreotide scintiscan sensitivity was 85%, but in the aggressive NETs it failed to detect the primary lesion in two of seven cases. Uptake of the tracer in some but not all tumor lesions in the same patient was seen by both FDG-PET and octreotide scintiscans. From our limited experience 18F-FDG PET seems to be useful for identifying NETs characterized by rapid growth or aggressive behavior. Uptake of the FDG tracer by the tumor may be related to a worse prognosis. Despite the heterogeneity of tracer uptake in the various lesions of NETs with multiple tumor sites, FDG-PET was able to detect unsuspected distant metastases, contributing to better staging of advanced disease.

Transforming growth factor beta, fibrogenesis and hyperglycemia in patients with chronic pancreatitis.

UNLABELLED: It has been suggested that transforming growth factor beta (TGFb) mediates liver fibrosis, which can be monitored by the serum determination of the N-terminal peptide of type III procollagen (PIIIP) and laminin. Fibrosis is also an important phenomenon in patients with chronic pancreatitis (CP). In 23 patients with CP, 38 with liver cirrhosis (LC) and 20 healthy controls we compared the serum patterns of PIIIP, laminin and TGFb and assessed whether in CP these markers are correlated with exocrine and endocrine function. In patients with LC, PIIIP and laminin levels were significantly higher, whereas TGFb levels were significantly lower than those of controls. In CP patients, no significant variations were found for PIIIP and laminin, although levels were high in 7/23 and in 5/23 patients, respectively. TGFb levels in CP patients were higher than those in LC patients, levels being raised in 6/23 patients. In LC patients an inverse correlation was found between PIIIP and TGFb, whereas in CP patients, a direct correlation was found between TGFb and PIIIP. Moreover, in CP patients, there was also a positive correlation between TGFb and fasting serum glucose levels, while laminin was correlated with PABA test results. IN CONCLUSION: serum biochemical markers of liver fibrosis can be considered of limited value in assessing pancreatic fibrosis; in liver cirrhosis there may be a negative feed-back regulation between TGFb production and the fibrogenetic process; and in chronic pancreatitis TGFb appears to favor fibrosis on the one hand and the development of hyperglycemia on the other.

Mucinous cystadenoma of the pancreas as a cause of acute pancreatitis.

Acute pancreatitis is only rarely the first presentation of a cystic neoplasm of the pancreas. Mucinous cystadenomas have not been reported to be a cause of acute pancreatitis; however, we present two cases of mucinous cystadenoma of the pancreas which have caused acute pancreatitis. Both patients (female) presented acute abdominal pain, with serum amylase elevation and ultrasound scan (US) and computed tomography (CT) evidence of moderate pancreatitis, which resolved with medical treatment; fluid collection in the distal pancreas had been misinterpreted as a pseudocyst. There was no history of alcohol abuse or gallstone disease. After distal pancreatectomy the diagnosis of mucinous cystadenoma was confirmed; in one case a large pseudocyst was associated with this diagnosis. Pre-operative differential diagnosis between inflammatory and neoplastic cysts is difficult, especially when the patient's first presentation is due to an episode of acute pancreatitis. A neoplastic cyst should be considered when acute pancreatitis attacks occur in non-alcoholic women, who do not have gallstone disease.

Ductal adenocarcinoma of the body and tail of the pancreas.

BACKGROUND: Carcinoma arising from the body and tail of the pancreas is less frequent than pancreatic head cancer, and its prognosis is known to be worse. This aggressive behavior is reported by few large clinical studies. STUDY DESIGN: We retrospectively reviewed our 24 years experience on adenocarcinoma of the body and tail of the pancreas and analyzed survival and longterm results after resection. Recent large series on cancer of the distal pancreas were also reviewed. RESULTS: Among 148 patients observed, 109 were surgically treated. Resectability rate was 16%; ductal adenocarcinoma in 22% of patients who underwent surgery was resectable. Macroscopic radical resection was achieved in only 16 cases. Overall 5-year survival rate was 2%. In resected cancers the actual 5-year survival rate was 12.5%. Patients with unresectable cancers did not survive more than 17 months. All three patients who survived more than 5 years had a small tumor (T1 according to TNM staging). In the literature, among 360 evaluable resected patients, only 7 survived at 5 years (2%). CONCLUSIONS: The prognosis for patients with adenocarcinoma of the distal pancreas is poor, even after resection of the tumor; however, the results are not substantially different for those reported after resection for pancreatic head carcinoma. Surgical resection can offer longterm survival for patients with localized cancer.

Expression of mucin-like carcinoma-associated antigen in the cyst fluid differentiates mucinous from nonmucinous pancreatic cysts.

OBJECTIVES: Differential diagnosis of pancreatic cystic lesions may be difficult: the main problem is to distinguish mucinous neoplasms from nonmucinous cysts. We evaluated the usefulness of the mucin-like carcinoma-associated antigen (MCA) in the fluid of pancreatic cysts for detecting mucinous neoplasms. Results were compared with those of CA 15-3, carcinoembryonic antigen (CEA), and CA 72-4 fluid content, and cytology. METHODS: Twenty-four pancreatic cyst fluids were collected from 10 pseudocysts, eight mucinous cystic tumors, and six serous cystadenomas. RESULTS: MCA was elevated in seven of eight mucinous tumors (sensitivity 87.5%, specificity 100%). A significant difference was found between MCA levels in mucinous neoplasms versus pseudocysts (p = 0.0003) and serous cystadenomas (p = 0.001). Mean MCA levels were higher (133.7 U/ml) in mucinous cystadenocarcinomas than in cystadenomas (37.5 U/ml). The sensitivity of CA 15-3, CEA, and CA 72-4 in detecting mucinous neoplasms was 50, 87.5, and 87.5%, respectively, with a specificity of 94%, 44%, and 94%, respectively. Cytology showed mucinous epithelial cells in only four of eight mucinous neoplasms, with a specificity of 100%. CONCLUSIONS: These data suggest that MCA determination in the cyst fluid is a promising new tumor marker for the preoperative diagnosis of mucinous cystic neoplasms of the pancreas.