[Prospective Evaluation of Risk Factors Concerning Intraoperative Conversion from Laparoscopic to Open Cholecystectomy]. / Prospektive Evaluation von Risikofaktoren bezüglich intraoperativer Konversion von laparoskopischer zu offener Cholezystektomie.

BACKGROUND: The surgical approach of choice in the treatment of symptomatic cholecystolithiasis is considered to be elective laparoscopic cholecystectomy (CCE) as the established gold standard. Today, approximately 80-90% of CCE are performed using a laparoscopic approach whereas the remaining portion undergoes primary conventional CCE, however, in 6% conversion is necessary. AIM: Since pathological aspects found intraoperatively and finally requiring conversion are correlated to an increased risk for complications, it appears reasonable to assess the risk factors prior to operation. PATIENTS AND METHODS: Through a well defined study period of 9 years, all consecutive patients who underwent CCE for cholecystolithiasis at the Municipal Hospital "HELIOS Klinikum Aue" were enrolled in a registry comparing laparoscopic and conversion CCE. Diverse parameters were tested as to whether they increase significantly the risk for conversion. The intensity of each factor-associated impact on a possible conversion was determined. RESULTS: From 2001 to 2009 1477 patients underwent CCE at the Municipal Hospital "Helios Klinikum Aue", out of them 131 (8.9%) cases were primarily treated by conventional CCE whereas in the vast majority (1346 subjects [91.1%]), laparoscopic CCE was the initial approach. However, conversion became necessary in 106 individuals resulting in a conversion rate of 7.9%. Comparing data obtained from laparoscopic CCE with those from open procedure after conversion, there were significant differences in operating time, complication rate and postoperative hospital stay (p = 0.01). Over the study period, there were 5 cases (0.37%) with iatrogenic injuries of the biliary system. Hospital mortality was 0.08% in the laparoscopic and 2.8% in the conversion group. The following parameters were found to have a significant impact on the risk for conversion (univariate analysis): elevation of CRP, preoperative ERCP, renal insufficiency, previous laparotomy, histological grade M3 (ulcerous, haemorrhagic necrotising cholecystitis, perforation of the gall bladder) and M4 (carcinoma of the gall bladder). While in the spectrum of preoperative factors former ERCP, elevation of CRP and terminal renal insufficiency were most relevant (2- to 3-fold each), histological grade M3 and M4, 7- and 14-fold, respectively, showed the greatest impact on conversion rate highlighting the profile of postoperative parameters. CONCLUSION: The main focus is directed to keep the conversion rate low. In case of diagnosing a severely inflamed gall bladder, a primarily open procedure or an early decision for conversion should be considered.

[Recurrent colorectal liver metastases: who benefits from a second hepatic resection?]. / Rezidivlebermetastasen kolorektaler Karzinome: Wer profitiert von einer zweiten Leberresektion?

BACKGROUND: Hepatic recurrence is seen in approximately 40 % of patients undergoing hepatectomy for colorectal metastases. The authors assessed the benefit and the main prognostic factors for a second liver resection of recurrent colorectal metastases. METHODS: This study reports the experience with second liver resections for recurrent liver metastases at a German University Hospital. A total of 39 parameters from 60 patients were identified from a prospective database and analysed as to their influence on recurrence-free survival and overall survival. RESULTS: At a median follow-up of 26 months (range: 2-173 months) after second hepatic resection, recurrence-free survival at 3 and 5 years were 50 % and 37 %, respectively. The overall survival at three and five years were 61 % and 52 %, respectively. Recurrence was identified in 58.3 % of the patients. Recurrences involved exclusively the liver in 19 patients (31.6 %). By multivariate analysis (Cox proportional hazard model), a time interval between diagnosis of the liver metastases of less than 24 months after operation for colorectal primary carcinoma (HR: 6.47, p = 0.002), a CEA level of 4.0 ng/mL or more (HR: 3.48, p = 0.004) at the time of first liver metastases and a size of second liver metastases of 80 mm or more (HR: 4.73, p = 0.007) were independent prognostic factors for a reduced recurrence-free survival. A repeat recurrence of liver metastases without the option of curative resection was the only risk factor for overall survival after second hepatic resection (p = 0.009). In these cases, mortality risk was 4.51-fold, however, when the second liver recurrence was resectable, the mortality risk increased only 1.4-fold. CONCLUSIONS: Technically resectable recurrent colorectal hepatic metastases should be resected the same as the first metastases. Characteristics of the primary metastasis as well as parameters of the hepatic recurrence are shown to influence the prognosis of patients after resection of recurrent liver metastases. Repeat resection of colorectal liver metastases allows for improved survival in patients even after two previous liver operations.

Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets.

AIMS/HYPOTHESIS: Immunosuppressive drugs used in human islet transplantation interfere with the balance between beta cell renewal and death, and thus may contribute to progressive graft dysfunction. We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. METHODS: C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. RESULTS: After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. CONCLUSIONS/INTERPRETATION: After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.

Presence of Borrelia burgdorferi sensu lato antibodies in the serum of patients with abdominal aortic aneurysms.

Infectious agents are likely to play a role in the pathogenesis of chronic inflammatory diseases, including abdominal aortic aneurysms (AAAs). The goal of this study was to determine if Borrelia burgdorferi sensu lato (sl), a microorganism responsible for Lyme disease, is involved in the etiology of AAAs. The presence of serum antibodies against B. burgdorferi sl was measured with enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blotting in 96 AAA and 108 peripheral artery disease (PAD) patients. Polymerase chain reaction (PCR) was used for the detection of Borrelia-specific DNA in the aneurysm wall. Among AAA patients 34% and among PAD patients 16% were seropositive for B. burgdorferi sl antibodies (Fisher's exact test, p = 0.003; odds ratio [OR] 2.79; 95% confidence interval [CI] 1.37-5.85). In the German general population, 3-17% are seropositive for Borrelia antibodies. No Borrelia DNA was detected in the aneurysm wall. Our findings suggest a relationship between AAAs and B. burgdorferi sl. We hypothesize that the underlying mechanism for B. burgdorferi sl in AAA formation is similar to that by the spirochete Treponema pallidum; alternatively, AAAs could develop due to induced autoimmunity via molecular mimicry due to similarities between some of the B. burgdorferi sl proteins and aortic proteins.

[Impact of morbidity and mortality conferences (M & M) on continuing surgical education]. / Welche Bedeutung hat die Morbiditäts- und Mortalitäts-(M & M)Konferenz für die Weiterbildung?

Morbidity and mortality conferences have been entitled the "golden hour" of surgical education. There is a long-standing tradition for these conferences in the USA and the United Kingdom. In Germany they are still not fully integrated in the daily clinical work although the positive influence on quality improvement, patient safety and surgical education has been repeatedly proven. Some factors are still hampering the establishment of M & M conferences: the lack of time, worrying about shame and blame and last not least some deficit for a culture of discussions. The commitment of surgeons in leading positions is required for the establishment and further support of -these conferences. In addition to patient safety, one of the main goals is the continuing education of young surgeons. Structuring M & M conferences as well as an intelligent moderation by an experienced surgeon and lively, open and interactive discussions - all these factors are obviously of great importance for improving success in surgery.

[Antithrombotic therapy after peripheral vascular treatment: what is evidence-based?]. / Antithrombotische Therapie nach peripheren Gefäßeingriffen. Was ist evidenzbasiert?

Peripheral arterial occlusive disease is one manifestation of the systemic disease atherosclerosis. The initial therapy for every arteriosclerotic disease is aimed at reducing cardiovascular risk factors by lifestyle modification and medication. Patients who require surgical revascularisation need long-term antiplatelet therapy or anticoagulation. This therapy has to be differentiated according to the vascular territory involved and the method used for revascularisation. After local thrombendarterectomy, alloplastic bypass graft surgery of the aortic, aorto-iliac, aorto-femoral or femoro-popliteal region above the knee, long-term ASA 100 mg/d or clopidogrel 75 mg/d should be initiated. After alloplastic bypass grafting below the knee the combination of ASA 100 mg/d and clopidogrel 75 mg/d should be used. In contrast, after venous grafts the patency rate is improved by anticoagulation with vitamin K antagonists (INR 2-3), if there is a low risk of bleeding. If there is a contraindication to vitamin K antagonists, ASA 100 mg/d should be used. After revascularisation, a structured surveillance programme should be implemented aiming at controlling cardiovascular risk factors and monitoring the vascular state, as well as the anticoagulation and the antiplatelet therapy.

[Which are the conditions for practicing interdisciplinary operative intensive care?]. / Unter welchen Voraussetzungen ist das Konzept einer interdisziplinären operativen Intensivmedizin praktikabel?

BACKGROUND: The creation of a center for interdisciplinary operative intensive care through the fusion of several smaller intensive care units from various specialties is mainly driven by economic reasons. To specify some conditions for making such a fusion less expensive and to identify the impact of larger intensive care units on the quality of patients' treatment and on surgical training are the subjects of this study. MATERIALS AND METHODS: Based on a review of the literature and on our own experience in this field, the influence of the size of the unit should be analysed not just regarding the economic aspects but also concerning the medical and surgical training issues. RESULTS: The economic advantages of scale of a larger unit are limited because of management problems when reaching a number of more than ten to twelve patients. This number probably leads to an optimal quality in medical care - especially if the patients are treated by specialists. The claim for a specific surgical training is thereby conceeded. The economical and medical advantages by connecting subunits to a larger operative intensive care unit will be achieved by economies of scale. For coordinating and running such a large unit an experienced intensive care doctor should be appointed. CONCLUSION: The concept of an interdisciplinary surgical ICU is obviously most practicable and reasonable if subunits with approximately twelve beds are concentrated in one centre for operative intensive care. This offers an advantage concerning the organisation and for the philosophy of treating special diseases by specialised medical teams. The size maintains the advantage of economies of scale as well the economies of scope and also promises effective logistics. For the management, an experienced intensive care specialist, either an anaesthesiologist or a surgeon should be assigned. All subject-specific advanced skills in intensive care have to be covered by an interdisciplinary continuing education.

[Arterial injuries combined with open fractures--management and therapy]. / Arterielle Gefässverletzungen im Rahmen offener Frakturen--Management und Versorgung.

Vascular injuries are an uncommon finding. In times of peace vascular injuries occur in approximately 1-4 % during traffic accidents. Especially challenging is the treatment of open fractures combined with arterial lesions. These fractures are usually accompanied with severe soft tissue damage and injuries to neurological structures. The overall prognosis of these trauma patients is dependent on fast and sufficient diagnostics and therapy. In particular, for unstable patients time-consuming diagnostics can be dispensed and a primarily operative therapy should be targeted. Vascular reconstruction by direct suture is sometimes only possible with interposition and should be the primary goal. Interposition should be performed with autologous vein material because of the high risk of infection. Here we demonstrate on the basis of our patients the interdisciplinary -management of such trauma patients in our hospital.

Co-expression of KLK6 and KLK10 as prognostic factors for survival in pancreatic ductal adenocarcinoma.

Kallikreins play an important role in tumour microenvironment and as cancer biomarkers in different cancer entities. Previous studies suggested an upregulation of KLK10 and KLK6 in pancreatic ductal adenocarcinoma (PDAC). Therefore, we evaluated the clinicopathological role of these kallikreins and their value as biomarkers in PDAC.Differential expression was validated by DNA-microarrays and immunohistochemistry in normal and malignant pancreatic tissues. Sera concentrations of both kallikreins were evaluated using ELISA. In silico analysis of possible protein interactions and gene silencing of KLK10 in vitro using siRNAs gave further insights in the pathomechanisms.Gene expression analysis and immunohistochemistry demonstrated a strong expression for KLK10 and KLK6 in PDAC. Statistical analysis showed that co-expression of these kallikreins correlated with an R1-resection status (P=0.017) and worse outcome for overall survival (P=0.031). Multivariate analysis proofed that co-expression is an independent prognostic factor for survival (P=0.043). Importantly, KLK10 knockdown in AsPC-1 cells significantly reduced cell migration, whereas computational analysis suggested interaction of KLK6 with angiogenetic factors as an important mechanism.Co-expression of KLK10 and KLK6 plays an unfavourable role in PDAC. Our results suggest that this effect is likely mediated by an interaction with the factors of the extracellular matrix and enhancement of cancer cell motility.

Pancreatic disorders and diabetes mellitus.

Diabetes mellitus is a common disease among patients with pancreatic cancer and chronic pancreatitis, disorders of the exocrine pancreas. Different clinical features of diabetes are associated with these two conditions: hyperinsulinemia and peripheral insulin resistance are the prevailing diabetic traits in pancreatic cancer, whereas reduced islet cell mass and impaired insulin secretion are typically observed in chronic pancreatitis. Whether or not a causal relationship exists between diabetes and pancreatic carcinoma is an intriguing but unanswered question. Diabetes often precedes pancreatic cancer and is thus regarded as a potential risk factor for malignancy. Conversely, pancreatic cancer may secrete diabetogenic factors. Given these findings, there is increasing interest in whether close monitoring of the glycemic profile may aid early detection of pancreatic tumor lesions.

Role of NFkappaB in the mortality of sepsis.

Binding activity for nuclear factor kappa B (NFkappaB) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (10 surviving and 5 not surviving). Nonsurvivors could be distinguished from survivors by an increase in NFkappaB binding activity during the observation period (P < 0.001). The increase in NFkappaB binding activity was comparable to the APACHE-II score as a predictor of outcome. Intravenous somatic gene transfer with an expression plasmid coding for IkappaBalpha was used to investigate the role of members of the NFkappaB family in a mouse model of endotoxemia. In this model, increased NFkappaB binding activity was present after injection of LPS. Intravenous somatic gene transfer with IkappaBalpha given before LPS attenuated renal NFkappaB binding activity and increased survival. Endothelial cells and monocytes/macrophages were the major target cells for somatic gene transfer, transfected with an average transfection efficiency of 20-35%. Tissue factor, a gene under regulatory control of NFkappaB, was induced by LPS. Somatic gene transfer with a reporter plasmid containing the functional tissue factor promoter demonstrated NFkappaB-dependent stimulation by LPS. Intravenous somatic gene transfer with IkappaBalpha reduced LPS-induced renal tissue factor expression, activation of the plasmatic coagulation system (decrease of thrombin-antithrombin III complexes) and renal fibrin/fibrinogen deposition. Somatic gene transfer with an expression plasmid with tissue factor cDNA in the antisense direction (in contrast to sense or vector alone) also increased survival. Furthermore, antisense tissue factor decreased renal tissue factor expression and the activation of the plasmatic coagulation system.

[Inherited tumors of the gastrointestinal tract. Diagnosis and therapeutic aspects]. / Erbliche Tumoren im Gastrointestinaltrakt. Diagnostik und therapeutische Konsequenzen.

Familial tumors of the gastrointestinal tract, which often appear as autosomal-dominantly inherited tumor syndromes, account for only a small proportion of all gastrointestinal tumors. With the opportunities of modern molecular diagnostics, identifying the pathogenic mutation in families is often possible, with the option of predictive molecular testing and differentiation between mutation carriers and noncarriers. Thus a good chance exists for detection of early tumor stages by individually tailored surveillance programs and for improving prognosis by early intervention and prophylactic resection. Clinical manifestation, molecular basis at the root, individual surveillance programs, and their consequences for the treatment of familial gastric cancer, familial adenomatous polyposis coli, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis, hyperplastic polyposis, and familial pancreatic cancer are presented.

Lack of correlation between carcinoembryonic antigen content of tumor extracts and leukocyte migration reactivity of tumor patients.

Tumor extracts varying in carcinoembryonic antigen (CEA) content (0.4--2,280 ng/mg protein) did not affect the reactivity of cancer patients' leukocytes in the leukocyte migration inhibition test (LMIT). In addition, variations in the plasma CEA levels of tumor-bearing leukocyte donors did not influence the frequency of significant LMIT reactivity.

Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome.

The occurrence of distant metastases is the most feared manifestation of breast cancer, often occurring years after the primary surgery and associated with poor survival. The dominant metastatic clone is characterized by an accumulation of genetic alterations, but it is not actually known at what stage of the metastatic cascade these alterations have occurred. We investigated allelic losses during breast cancer progression in a series of 17 primary breast carcinomas and 22 corresponding brain, liver, lung, and bone metastases (mean metastasis-free interval, 31 months) by analyzing 19 microsatellite markers on seven breast cancer- or metastasis-related chromosomal regions and correlated the incidence of combined loss of heterozygosity (LOH) with metastasis-free and postmetastatic survival. We found that, in comparison with the corresponding primary tumor, additional LOH events are frequently found in metastases and that the incidence of combined LOH in the primary tumor, plus the occurrence of additional LOH events in the distant metastases, correlated significantly with decreased postmetastatic survival. Combined LOH of the three breast cancer-related chromosomal regions alone or in combination with allelic loss at the p53 gene region seems to have a specific influence on the aggressive behavior of metastases. We hypothesize that the occurrence of additional LOH events is either involved in termination of dormancy of micrometastatic tumor cells at distant organ sites or acquired during further progression of metastases.

Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma.

An active specific immunization (ASI) procedure with two types of autologous tumor cell vaccines (ATVs) is tested for adjuvant immunotherapy of resected colorectal carcinoma to provide preliminary information on local immunological skin responses, side effects, and 2-year survival rates. For vaccine preparation, the tumor-derived freshly isolated and cryopreserved cells were thawed, purified by Percoll density centrifugation, and depleted of tumor-infiltrating lymphocytes by immunomagnetic beads. After inactivation by 200 Gy, the cells of this ATV were either infected by Newcastle disease virus (NDV) or they were admixed with Bacillus Calmette Guérin (BCG) organisms. Vaccination was performed in the arm beginning 6-8 weeks after operation, three times at 2-week intervals. Of 57 patients that received ASI, 48 were treated by virus-infected ATV (ATV-NDV) and 9 were treated with the BCG-admixed vaccine (ATV/BCG). The mean value of delayed hypersensitivity skin reactions from ATV-NDV-treated patients was 18 mm for the first vaccination and 26 and 29 mm for the succeeding ones. Although the application of ATV-NDV was associated with only mild side effects, the ATV/BCG vaccine led to long-lasting ulcers and to more serious side effects. The 2-year survival rate obtained with ATV-NDV was 97.9%, whereas the survival rate with ATV/BCG was 66.7%. The mean survival of 661 patients from a historical control was 73.8%. These data suggest that the type and quality of the tumor vaccine for ASI treatment is important. The findings with ATV-NDV necessitate corroboration in a prospective, randomized controlled study.

Lower frequency of allele loss on chromosome 18q in human breast cancer than in colorectal tumors.

Inactivation of tumor suppressor genes is thought to be a critical step in tumorigenesis. The DCC (deleted in colorectal carcinoma) gene, located on the long arm of chromosome 18, has been shown to be frequently deleted in colorectal tumors. To investigate the involvement of allelic deletions on chromosome 18q in breast cancer tumorigenesis we analyzed 28 primary breast tumors and 28 colorectal tumors (24 carcinomas, 4 adenomas) with four different polymorphic DNA markers detecting RFLPs on chromosome 18q. In breast cancer we found loss of heterozygosity (LOH) in 4 of 27 (15%) informative cases whereas 15 of 25 (60%) colorectal tumors showed allelic deletions. In all cases of allelic loss the DCC locus or its proximal vicinity (locus SSAV1) were involved. LOH on chromosome 18q occurs both in breast and colorectal cancer, yet the frequency of these deletions in breast tumors is lower than in colorectal tumors. Moreover, in breast cancer these mutations were only detected in large and undifferentiated tumors.

[Emergent cholecystectomy after acute cholecystitis with no improvement from i.v. antibiotics]. / Notfallcholezystektomien bei akuter Cholezystitis ohne Besserung unter i.v.-Antibiose.

The complete rotation of the gall bladder followed by acute inflammation is a very rare and dangerous event. Volvulus of the gall bladder almost seems to be caused by an abnormal motility of this organ. Because of the rarity of this disease, the preoperative diagnosis frequently is correct. With this report of three cases who had laparoscopic or conventional surgery within a period of 7 years at our department, the peculiarity of this disease is demonstrated.

Immunotherapy of metastatic melanoma with interferon-alpha and interleukin-2: pattern of progression in responders and patients with stable disease with or without resection of residual lesions.

This evaluation was performed in melanoma patients after successful immunotherapy to describe the pattern of relapse. 63 patients received interferon (IFN)-alpha and high-dose interleukin (IL)-2, resulting in three complete responses (CR), 13 partial responses (PR), three mixed responses (MR) and 17 stable diseases (SD). Median duration of response was 7 months (range 3-28) without surgery. Most relapses occurred at pre-existing sites. Duration of CR was 14-37+ months. In 11 patients, residual tumour lesions were resected. Interestingly, histology revealed almost complete tumour regression in 6 patients, including 2 of 4 with SD. 5 of these 11 patients have relapsed so far, 6 patients are still free of disease with a median of 17 months (range 8-34). Following relapse, 4 of 6 patients responded to retreatment with the identical IFN alpha/IL-2 protocol. The authors conclude that initial disease progression is mostly at previous sites of disease. Resection of residual lesions may offer a chance for extended disease-free survival similar to patients with CR to immunotherapy. Retreatment of relapsing patients is favourable.

An intronic germline transition in the HNPCC gene hMSH2 is associated with sporadic colorectal cancer.

The aim of this study was to determine whether an intronic germline substitution in the hereditary non-polyposis colorectal cancer (HNPCC) gene hMSH2 represents a genetic risk factor for sporadic CRC. Possible effects of this substitution were investigated by assessment of microsatellite instability and hMSH2 cDNA sequencing. Constitutional DNA from patients with sporadic CRC and healthy controls from the same region in Germany was analysed for the intronic germline T-->C transition six bases upstream of exon 13 of hMSH2. 29 of 106 patients (27%) were found to harbour the germline T-->C transition as opposed to only 13 of 125 controls (10%; P < 0.001; OR 3.2, CI 1.58-6.63). CRCs from patients with the substitution displayed neither clinical HNPCC-like features nor an increased rate of microsatellite instability. No abnormal cDNA sequence was found at the exon 12-13 border. These data suggest a 3.2-fold increased risk of sporadic CRC for individuals with the intronic hMSH2 transition. However, this substitution might not be pathogenic itself, but may be linked to a locus nearby that is.

Multiple endocrine neoplasia type 2-associated RET proto-oncogene mutations do not contribute to the pathogenesis of sporadic parathyroid tumors.

BACKGROUND: Parathyroid disease occurs sporadically or as part of hereditary multiple endocrine neoplasia (MEN) syndrome. The aim of this study was to evaluate the possible role of the RET proto-oncogene not only in hereditary MEN 2-associated hyperparathyroidism but also in different forms of sporadic hyperparathyroidism. METHODS: We investigated 22 patients with parathyroid disease whose family history and results of laboratory and clinical examinations excluded MEN 2 syndrome. DNA extractions of histologically confirmed tumor tissue of patients with primary hyperparathyroidism (n = 18), renal hyperparathyroidism (n = 2), and parathyroid carcinoma (n = 2) were performed. Using solid phase DNA sequencing, mutation analysis of polymerase chain reaction amplified products focused on exons 10, 11, and 16 of the RET proto-oncogene. Parathyroid tissue from four patients with known MEN 2A served as positive controls. RESULTS: No mutations of the codons 609, 611, 618, 620, 634, and 918 were found in the sporadic parathyroid tumors analyzed. DNA sequencing revealed heterozygous mutations in codon 634 of the RET proto-oncogene in four parathyroid glands from four patients with MEN 2A. CONCLUSIONS: Mutations of the RET proto-oncogene contributing to MEN 2 syndromes are absent in sporadic parathyroid tumors. Our data in conjunction with the literature suggest at least three different modes of tumorigenesis in parathyroid disease.