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.

Risk of preoperative understaging of duodenal neuroendocrine neoplasms: a plea for caution in the treatment strategy.

PURPOSE: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging. METHODS: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery. RESULTS: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent. CONCLUSIONS: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging.

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.

Patient Attitudes to Medical Photography: Study of a Spanish Population at the Pius Hospital de Valls in Tarragona, Spain. / Actitudes de pacientes hacia la fotografía médica. Estudio en población española: Pius Hospital de Valls (Tarragona, España).

INTRODUCTION: Medical photography is a noninvasive technique used for diagnostic, monitoring, and educational purposes. It is important to understand the patient's attitude to all or part of their body being photographed. The objective of this study was to analyze the attitudes of patients towards medical photography at a district hospital in Tarragona, Spain. METHODOLOGY: This exploratory study used a questionnaire to evaluate attitudes to medical photography among outpatients at Pius Hospital de Valls. The questionnaire explored the patients' beliefs about the usefulness of medical photography, the circumstances in which they would agree to be photographed and by whom, as well as their prior experience of medical photography. They were also asked whether they would authorize the use of photography and, if not, to explain their motives. RESULTS: The questionnaire was completed by 134 patients. The results showed that patients had a clearly positive attitude to being photographed for medical purposes (94.8%), treatment follow-up (88.1%), and consultation of their case with other physicians (86.6%). Acceptance was 88.8% if the lesion was malignant and 85.1% if it was extensive. For facial lesions, only 78.4% were willing to be photographed and in the case of genitals the percentage fell to 70.2%. Most patients (95.5%) would agree to being photographed by their doctor. The rate of acceptance was 66.4% in the case of a nurse, 64.9% for another doctor, and 21.6% for a professional photographer. CONCLUSIONS: Our study revealed that patients have a positive attitude to being photographed for medical purposes, particularly when they have a malignant lesion, when the photograph is taken by their specialist, and when they cannot be identified.

Ampullary neuroendocrine neoplasms: surgical experience of a rare and challenging entity.

PURPOSE: Ampullary neuroendocrine neoplasms (NENs) account for < 0.3% of gastrointestinal NENs. Surgical options include transduodenal ampullectomy/tumour excision or pancreaticoduodenectomy (PD). We report the experience of two high-volume pancreatic surgical centres of ampullary NENs. METHODS: Clinical records of patients who underwent surgery for ampullary NENs (January 2007-November 2017) in the study centres were retrieved retrospectively. We evaluated clinical-pathological features, post-operative outcome and follow-up (FU). RESULTS: Eighteen patients (9 M/9 F, averaging 62 years) were enrolled. All but one were non-functioning NENs; four (22%) patients presented with jaundice. Seven (39%) of the patients underwent ampullectomy/excision (median tumour size 1.5 cm), and 11 (61%) patients underwent PD (median tumour size 2.4 cm). The median operation time of ampullectomy/excision was 221 min with operative blood loss of 75 ml (vs. 506 min and 425 ml in PD). The median hospital stay was 10 days in both groups. Overall surgical morbidity was 33%, due to four biochemical leaks, one pancreatic fistula and one abdominal haemorrhage. No reoperations were needed. The median tumour size was 1.8 (range 0.5-6.7) cm. All G2-G3 NENs were N1 (vs. 1/7 in G1 NENs). Three (17%) cases were mixed exocrine/G3 NECs. After a median FU of 45 (up to 124) months, recurrence occurred in four G3 NEC (31%) patients (median disease-free survival 14 months) after an R0 PD. Disease-related survival was 93, 77 and 66% at 1, 3 and 5 years, respectively. CONCLUSION: Ampullary NENs are mostly G1-G2 neoplasms. Lymph node metastases rarely occur in G1 NENs < 2 cm in size, which may be treated with ampullectomy/excision. Survival is 66% 5 years after surgery.

OM-85 is an immunomodulator of interferon-ß production and inflammasome activity.

The inflammasome-IL-1 axis and type I interferons (IFNs) have been shown to exert protective effects upon respiratory tract infections. Conversely, IL-1 has also been implicated in inflammatory airway pathologies such as asthma and chronic obstructive pulmonary disease (COPD). OM-85 is a bacterial extract with proved efficacy against COPD and recurrent respiratory tract infections, a cause of co-morbidity in asthmatic patients. We therefore asked whether OM-85 affects the above-mentioned innate immune pathways. Here we show that OM-85 induced interferon-ß through the Toll-like receptor adaptors Trif and MyD88 in bone marrow-derived dendritic cells. Moreover, it exerted a dual role on IL-1 production; on the one hand, it upregulated proIL-1ß and proIL-1α levels in a MyD88-dependent manner without activating the inflammasome. On the other hand, it repressed IL-1ß secretion induced by alum, a well-known NLRP3 activator. In vivo, OM-85 diminished the recruitment of inflammatory cells in response to peritoneal alum challenge. Our findings therefore suggest that OM-85 favors a protective primed state, while dampening inflammasome activation in specific conditions. Taken together, these data bring new insights into the mechanisms of OM-85 action on innate immune pathways and suggest potential explanations for its efficacy in the treatment of virus-induced airway diseases.

Prosthetic mesh "slim-cigarette like" for laparoscopic repair of ventral hernias: a new technique without transabdominal fixation sutures.

Prosthetic mesh rolled up and fixed with stitches like a slim cigarette ("slim-mesh") for laparoscopic ventral hernia (VH) repair is an new technique which allows an easy intraperitoneally introduction, distension and circumferential fixation of a prosthetic mesh without transabdominal fixation sutures even for meshes larger than 16 cm up to 30 cm for the "slim-mesh" repair of wide ventral hernias. We report the technique of laparoscopic repair of VH with "slim-mesh". This technique enables an easy intra-peritoneally introduction of the mesh through the trocar because it reduces consistently its size, it allows a rapid intra-abdominal handling of the mesh and a fast and easy fixation for VH repair. The average time of surgery with "slim-mesh" for treatment of all 28 VH was 97 min ranging from 57 to 160 min. The average time for the repair of the 24 VH smaller than 10 cm was 91 and 135 min for the four VH larger than 10-22 cm. This new surgical technique leads to a reduction of surgical risks avoiding the use of transfascial sutures with the associated complications. This new surgical procedure in our experience is fast, safe, simple and also easily reproducible by surgeons in laparoscopic training. This technique may be used in wide VH (larger than 10-22 cm) that generally require open surgery.

P.R.L. platelet rich lipotransfert: our experience and current state of art in the combined use of fat and PRP.

The authors report their experience about the use of P.R.L. PLATELET RICH LIPOTRANSFERT method (platelet rich plasma mixed fat grafting) in 223 patients affected by soft tissue defects (ulcers, Romberg syndrome, Hemifacial atrophy, loss of substance, and signs of aging). This paper introduces the reader to PRP therapy and reviews the current literature on this emerging treatment modality, showing at the current clinical use of PRP in plastic and reconstructive surgery, with description of innovative methods and future prospects. This technique provides a promising alternative to surgery by promoting safe and natural healing. Here recent studies concerning the use of PRP in the treatment of chronic ulcers and soft tissue defect are reviewed.

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.

RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours.

The Ras-association domain family 1A (RASSF1A) tumour suppressor gene is inactivated in a variety of solid tumours, usually by epigenetic silencing of the promoter and/or allelic loss of its locus at 3p21.3. RASSF1A induces cell cycle arrest through inhibition of cyclin D1 accumulation. In this work, 62 endocrine tumours from different sites in the gut were investigated for methylation of the RASSF1A promoter using the polymerase chain reaction, the presence of 3p21.3 deletions by loss of heterozygosity analysis, and cyclin D1 expression by immunohistochemistry. Methylation was found in 20/62 (32%) cases and was restricted to foregut tumours; deletion at 3p21.3 was found in 15/58 (26%) informative cases and restricted to malignant foregut tumours; cyclin D1 hyper-expression was found in 31/58 (53%) cases and correlated with RASSF1A methylation. Our data suggest that RASSF1A is involved in the development of endocrine tumours derived from the foregut only, and that the presence of both RASSF1A methylation and 3p21.3 deletion is associated with malignancy. These results may provide a rationale for foregut-targeted therapy for aggressive endocrine carcinomas entailing the use of demethylating agents.

[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.

p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior.

The immunohistochemical expression of the inhibitors of cyclin-dependent kinases p21 and p27 was investigated in 109 endocrine tumors of the pancreas and gastrointestinal tract and compared with that of Ki67 and p53. p21 was found to be scarcely expressed without significant differences between benign and malignant or between differentiated and undifferentiated tumors. This suggests no relationship between changes in p21 levels and clinical behavior in these endocrine tumors. p27 was found to be highly expressed in differentiated neoplasms and proved to be inversely related to Ki67 labeling (P =.02), which was usually low. These data indicate that p27 may have an important inhibiting role on the low proliferation rate of the tumors. Moreover, the protein may have a role in the resistance of differentiated endocrine tumors to chemotherapeutic agents. p27 high-expressor neoplasms were frequent in either benign (70.6%) or malignant (81.4%) differentiated tumors, thus not allowing the use of this protein for the differential diagnosis of malignant neoplasms as suggested for endocrine tumors of parathyroid and pituitary. Poorly differentiated endocrine carcinomas, which differred from the differentiated tumors for their very high Ki67 levels and frequent p53 expression, showed low or absent p21 and p27 in most cases. Classical midgut carcinoids were characterized by a sharp discrepancy between malignant behavior and very bland proliferative pattern, with Ki67 and p27 expressions similar to that of benign tumors.

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.

Multiple endocrine neoplasia type 1 and adrenal lesions.

PURPOSE: We investigated the relationship of long-term pancreatic hormone hypersecretion with adrenal lesions in patients with multiple endocrine neoplasia type 1 and in those with sporadic pancreatic endocrine tumors. MATERIALS AND METHODS: We assessed the prevalence of adrenal lesions in 20 patients with multiple endocrine neoplasia type 1 and in a control group of 12 with sporadic pancreatic endocrine tumors. We also performed genetic testing for germline mutations of MEN1, the multiple endocrine neoplasia type 1 gene. RESULTS: Adrenal lesions were common in multiple endocrine neoplasia type 1, accounting for 35% of cases. All adrenal lesions were nonfunctioning and benign. The relative risk of adrenal tumors was higher in patients with multiple endocrine neoplasia type 1 than in controls (p <0.05). No apparent relationship was observed of hormonal pattern or genotype with adrenal disease. CONCLUSIONS: Hormone hypersecretion by pancreatic endocrine tumors is not the primary cause of the development of adrenal lesions and the role of the MEN1 gene in adrenal tumorigenesis remains unclear. Adrenal lesions follow a benign course in most multiple endocrine neoplasia type 1 cases but careful morphological and functional followup is advisable.

ME-PCR for the identification of mutated K-ras in serum and bile of pancreatic cancer patients: an unsatisfactory technique for clinical applications.

Our aim was to assess the clinical reliability of mutated K-ras detection in serum or bile for the diagnosis of pancreatic cancer using ME-PCR. DNA was extracted from 1 ml serum obtained from 29 patients with pancreatic cancer and 12 control subjects. ME-PCR was optimized using a mixture of normal DNA added with different amounts of mutated DNA. The analysis of sera obtained from the 29 patients and of bile obtained from 11 pancreatic cancer patients demonstrated the presence of mutated K-ras in two (6.9%) and four cases (36%). By contrast K-ras was not amplifiable in any of the 12 serum samples obtained from healthy controls. In conclusion the DNA obtained from pancreatic cancer patients' sera is suitable for K-ras amplification and for the identification of codon 12 point mutations. However ME-PCR alone has an unsatisfactory sensitivity for the detection of pancreatic cancer using serum DNA as starting template.

Mapping and identification of protein-protein interactions by two-dimensional far-Western immunoblotting.

Studies of protein-protein interactions have proved to be a useful approach to link proteins of unknown function to known cellular processes. In this study we have combined several existing methods to attempt the comprehensive identification of substrates for poorly characterized human protein tyrosine phosphatases (PTPs). We took advantage of so-called "substrate trapping" mutants, a procedure originally described by Flint et al. (Proc. Natl. Acad. Sci. USA 1997, 94, 1680-1685) to identify binding partners of cloned PTPs. This procedure was adapted to a proteome-wide approach to probe for candidate substrates in cellular extracts that were separated by two-dimensional (2-D) gel electrophoresis and blotted onto membranes. Protein-protein interactions were revealed by far-Western immunoblotting and positive binding proteins were subsequently identified from silver-stained gels using tandem mass spectrometry. With this method we were able to identify possible substrates for PTPs without using any radio-labeled cDNA or protein probes and showed that they corresponded to tyrosine phosphorylated proteins. We believe that this method could be generally applied to identify possible protein-protein interactions.

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.