The VACStent trial: combined treatment of esophageal leaks by covered stent and endoscopic vacuum therapy.

BACKGROUND: Endoscopic treatment of esophageal leaks, mostly by covered stents or endoscopic vacuum therapy (EVT), has largely improved the clinical outcome in the last decade. However, both techniques suffer from significant limitations. Covered stents are hampered by a high rate of migration and missing functional drainage, whereas endoluminal EVT devices are limited by obstruction of the GI tract. The new design of the VACStent makes it a fully covered stent within a polyurethane sponge cylinder, allowing EVT while stent passage is still open. Initial clinical applications have demonstrated the fundamental concept of the VACStent. METHOD: A prospective multicenter open-label study was performed with the primary endpoint safe practicality, complete leak coverage, and effective suction-treatment of esophageal leaks. Secondary endpoints were prevention of septic conditions, successful leak healing, and complications, in particular stent-migration, local erosions and bleeding. RESULTS: Fifteen patients with different, mostly postoperative anastomotic leaks were enrolled in three centers. A total of 41 VACStents were implanted. The mean number of VACStents per patient was 2.7, with a mean duration of VACStent treatment of 15 days. The primary endpoint was met in all VACStent applications (41/41 implants), resulting in a leak healing rate of 80% (12/15 patients). Septic episodes were prevented in 93% (14/15 patients) and there was no mortality. There were no severe device-related adverse events (SADE) nor significant local bleeding or erosion. Minor stent-dislocation and migration, respectively, was observed in 7%. Oral intake of liquids or food was documented in 87% (13/15 patients). One anastomotic stenosis was seen during follow-up. CONCLUSIONS: VACStent treatment is a safe and effective treatment in esophageal leaks which can be covered by the sponge cylinder. Its application was described as easy and resembling that of conventional GI stents, with an impressive clinical success rate comparable to EVT outcomes. The VACStent offers a new option for clinical treatment of critical situations in esophageal perforations and anastomotic sutureline failures.

Splenic artery switch for revascularization of the liver: a salvage procedure for inflammatory arterial hemorrhage.

BACKGROUND: Hemorrhage caused by inflammatory vessel erosion represents a life-threatening complication after upper abdominal surgery such as pancreatic head resection. The gold standard therapeutic choice is an endovascular minimally invasive technique such as embolization or stent placement. Hepatic arterial hemorrhage in presence of pancreatitis and peritonitis is a particular challenge is if a standard therapeutic option is not possible. METHODS: The management of five patients with massive bleeding from the common hepatic artery is described. All patients underwent a splenic artery switch. The splenic artery was dissected close to the splenic hilum and transposed end-to-end to the common hepatic artery after resection of the eroded part. Patients' medical records, radiology reports, and images were reviewed retrospectively. Technical success was defined as immediate cessation of hemorrhage and preserved liver vascularization. Clinical success was defined as hemodynamic stability and adequate long-term liver function. RESULTS: Total pancreatectomy and splenectomy were performed in four of the five cases. Hemodynamic stability and good liver perfusion was achieved in these patients. CONCLUSIONS: Splenic artery switch is an effective, safe procedure for revascularization of the liver in case of hepatic arterial hemorrhage following pancreatic surgery, pancreatitis, and/or peritonitis. The technique is a promising option if a standard procedure-e.g., stent implantation, embolization and surgical repair with alloplastic prosthesis or autologous venous interposition graft-is not possible.

[Stem cell-induced liver regeneration]. / Stammzell-induzierte Leberregeneration.

BACKGROUND: The liver has an excellent regenerative capacity after resection. However, below a critical level of future liver remnant volume (FLRV), partial hepatectomy is accompanied by a significant increase of postoperative liver failure. There is accumulating evidence for the contribution of bone marrow stem cells (BMSC) to participate in liver regeneration. Here we report our experience with portal vein embolisation (PVE) and CD133+ BMSC administration to the liver, compared with PVE alone, to augment hepatic regeneration in patients with critically low FLRV or impaired liver function. PATIENTS AND METHODS: Eleven patients underwent PVE of liver segments I and IV-VIII to stimulate hepatic regeneration prior to extended right hepatectomy. In these 11 patients with a FLRV below 25% and/or limited quality of hepatic parenchyma, PVE alone did not promise adequate proliferation. These patients underwent additional BMSC administration to segments II and III. Two radiologists blinded to patients' identity and each other's results measured liver and tumour volumes with helical computed tomography. Absolute, relative and daily FLRV gains were compared with a group of patients that underwent PVE alone. RESULTS: The increase of the mean absolute FLRV after PVE with BMSC application from 239.3 mL±103.5 (standard deviation) to 417.1 mL±150.4 was significantly higher than that from 286.3 mL±77.1 to 395.9 mL±94.1 after PVE alone (p<0.05). Also the relative gain of FLRV in this group (77.3%±38.2%) was significantly higher than that after PVE alone (39.1%±20.4%) (P=0.039). In addition, the daily hepatic growth rate after PVE and BMSC application (9.5±4.3 mL/d) was significantly superior to that after PVE alone (4.1±1.9 mL/d) (p=0.03). Time to surgery was 27 days±11 in this group and 45 days±21 after PVE alone (p=0.02). Short- and long-term survival were not negatively influenced by the shorter waiting period. CONCLUSION: In patients with malignant liver lesions, the combination of PVE with CD133+ BMSC administration substantially increased hepatic regeneration compared with PVE alone. This procedure bears the potential to allow the safe resection of patients with a curative intention that would otherwise carry the risk post-operative liver failure.

Clinical implantation of 92 VACStents in the upper gastrointestinal tract of 50 patients-applicability and safety analysis of an innovative endoscopic concept.

Introduction: Endoscopic vacuum therapy (EVT) has emerged as a promising treatment option for upper gastrointestinal wall defects, offering benefits such as evacuation of secretions and removal of wound debris by suction, and reduction and healing of wound cavities to improve clinical outcomes. In contrast, covered stents have a high rate of migration and lack functional drainage, while endoluminal EVT devices obstruct the GI tract. The VACStent is a novel device that combines the benefits of EVT and stent placement. Its design features a fully covered Nitinol-stent within a polyurethane sponge cylinder, enabling EVT while maintaining stent patency. Methods: This study analyzes the pooled data from three different prospective study cohorts to assess the safe practicality of VACStent placement, complete leak coverage, and effective suction-treatment of esophageal leaks. By pooling the data, the study aims to provide a broader base for analysis. Results: In total, trans-nasal derivation of the catheter, suction and drainage of secretion via vacuum pump were performed without any adversity. In the pooled study cohort of 92 VACStent applications, the mean stent indwelling time was 5.2 days (range 2-8 days) without any dislocation of the device. Removal of the VACStent was done without complication, in one case the sponge was lost but subsequently fully preserved. Minor local erosions and bleeding and one subsequent hemostasis were recorded unfrequently during withdrawal of the device (5.4%, 5/92) but no perforation or pressure ulcer. Despite a high heterogeneity regarding primary disease and pretreatments a cure rate of 76% (38/50 patients) could be achieved. Discussion: In summary, insertion and release procedure was regarded as easy and simple with a low potential of dislocation. The VACStent was well tolerated by the patient while keeping the drainage function of the sponge achieving directly a wound closure by continuous suction and improving the healing process. The implantation of the VACStent provides a promising new procedure for improved clinical treatment in various indications of the upper gastrointestinal wall, which should be validated in larger clinical studies.Clinical Trial Registration: Identifier [DRKS00016048 and NCT04884334].

Ventilation with low tidal volumes during upper abdominal surgery does not improve postoperative lung function.

BACKGROUND: Prolonged postoperative decrease in lung function is common after major upper abdominal surgery. Evidence suggests that ventilation with low tidal volumes may limit the damage during mechanical ventilation. We compared postoperative lung function of patients undergoing upper abdominal surgery, mechanically ventilated with high or low tidal volumes. METHODS: This was a double-blind, prospective, randomized controlled clinical trial. One hundred and one patients (age ≥ 50 yr, ASA ≥ II, duration of surgery ≥ 3 h) were ventilated with: (i) high [12 ml kg(-1) predicted body weight (PBW)] or (ii) low (6 ml kg(-1) PBW) tidal volumes intraoperatively. The positive end-expiratory pressure was 5 cm H(2)O in both groups and breathing frequency adjusted to normocapnia. Time-weighted averages (TWAs) of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) until 120 h after operation were compared (P<0.025 considered statistically significant). Secondary outcomes were oxygenation, respiratory and non-respiratory complications, length of stay and mortality. RESULTS: The mean (sd) values of TWAs of FVC and FEV(1) were similar in both groups: FVC: 6 ml group 1.8 (0.7) litre vs 12 ml group 1.6 (0.5) litre (P=0.12); FEV(1): 6 ml group 1.4 (0.5) litre vs 12 ml group 1.2 (0.4) litre (P=0.15). FVC and FEV(1) at any single time point and secondary outcomes did not differ significantly between groups. CONCLUSIONS: Prolonged impaired lung function after major abdominal surgery is not ameliorated by low tidal volume ventilation.

Loss of PTEN expression in neuroendocrine pancreatic tumors.

PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor.

Coincidence of mature cystic teratoma and serotonin-producing neuroendocrine tumor of the ileum.

Mature cystic teratomas are often found in gonadal sites, but are very rarely located extragonadally, for example, in retroperitoneum, mediastinum, central nervous system, lung, or liver. In the literature, only 10 cases of cystic teratoma originating from the diaphragm have been reported. Here, we report for the first time a metachronous occurrence of a benign mature cystic teratoma in the left diaphragm together with a serotonin-producing neuroendocrine tumor of the ileum. The 51-year-old, female patient received a partial resection of the ileum due to a neuroendocrine tumor (pT3N1M0) 4 years ago. Furthermore, she was operated for a benign cystadenoma of the right ovary 3 years ago. In her past medical history, she had an appendectomy in her childhood and a subtotal thyroidectomy 10 years ago. To our knowledge, this is the first report describing the metachronous occurrence of benign mature cystic teratoma in the diaphragm and a highly differentiated neuroendocrine tumor of the ileum. The possible coincidence of both diseases is discussed.

Global histone modification pattern predicts poor prognosis in organic hyperinsulinism.

Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p=0.004; H3K18Ac, p=0.001; H4K12Ac, p=0.006; H4R3diMe, p=0.002) except for H3K4diMe (p=0.183). Correlation of the histone modification with the WHO-classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" (≥8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p=0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively.

Randomized comparative long-term survival study of endoscopic and thoracoscopic esophageal wall repair after NOTES mediastinoscopy in healthy and compromised animals.

BACKGROUND AND STUDY AIMS: Natural orifice transluminal endoscopic surgery (NOTES) has not yet been widely adopted because of lack of suitable equipment and fear of possible serious complications, especially in the mediastinum. We compared endoscopic with thoracoscopic esophageal wall repair after full-thickness esophageal wall incision (FTEI) and NOTES mediastinoscopy in healthy versus compromised animals. METHODS: After FTEI for mediastinoscopy, 24 pigs (12 healthy, 12 compromised) were randomly allocated to endoscopic or thoracoscopic repair (each arm of each group, n = 6). They were kept alive for 3 months after endoscopic closure with prototype T-anchor suturing or thoracoscopic repair. RESULTS: FTEI and mediastinoscopy were uneventful in all as was the initial repair of the incision (mean repair times: thoracoscopic 65 +/- 3.2 minutes, endoscopic 52 +/- 5.1 minutes; P < 0.0005). Post procedure, all 12 healthy pigs thrived with no complications or deaths. Two compromised animals died during the preparation period, and had to be replaced. In the compromised group, during endoscopic repair, 2 / 6 pigs suffered from gastric reflux into esophagus and mediastinum; the repair was completed and the pigs kept alive; one subsequently died of mediastinitis, and in the other, autopsy showed a gastric abscess in the lower mediastinum. Regarding the compromised thoracoscopic subgroup, one animal died from mediastinitis and all had abscesses at or near the incision sites. CONCLUSION: Transesophageal mediastinoscopy could be performed equally well as the transthoracic procedure, both in healthy and compromised animals. However, on follow-up, the compromised animals had worse outcomes, with more complications and two deaths (17 %), one in each arm.

[Individualised and differentiated treatment of rectovaginal fistula]. / Individualisierte und differenzierte Therapie von rektovaginalen Fisteln.

Rectovaginal fistuale (RVF) are a serious and disabling problem for the patients and a surgical challenge for the treating physicians. The most common causes of RVF are postoperative complications, inflammatory bowel disease, complications of radiotherapy, obstetric complications, and neoplasia. Therapeutic options are diverse and results often unsatisfactory. This article presents the treatment of patients with rectovaginal fistulae in the general surgery department of University Hospital in Duesseldorf, Germany. The therapeutic strategy for treatment of RVF is divided according to aetiology, localisation, and comorbidity. A diverting ileostomy is particularly useful if acute inflammation exists. Secondary repair may then be a better option. An initial approach with a local repair by preanal repair is justified in low RVF. For failures muscle flaps are promising.

Standard-radical vs. function-preserving surgery of benign nodular goiter: a sonographic and biochemical 10-year follow-up study.

BACKGROUND: The necessary extent of thyroid resection in benign nodular goiter is under debate. The aim of our study was to compare the long-term outcome of different thyroid resection modes with special interest in the incidence of recurrent nodules and the use of oral thyroid hormone medication. MATERIALS AND METHODS: We performed a follow-up examination of 109 patients (23 men and 86 women) having been operated for benign nodular goiter at our department 10 years ago. Unilateral resections and function-preserving resections of at least one thyroid lobe were classified as function-preserving (FP). Total thyroidectomy, Dunhill's operation and bilateral subtotal thyroidectomy were rated as standard-radical (STR). On follow-up, we recorded current oral thyroid hormone medication, thyroid function tests and ultrasound of the neck. RESULTS: Seventy-three patients had FP resection (67%), while 36 were STR-operated (33%). The subsequent medical treatment was performed by dedicated endocrinologists (n = 19), internists (n = 11) or primary-care physicians (n = 59). Twenty patients had no medical attendance. Recurrent nodules were found in 13 cases in the FP group (18.6%) vs. 3 cases in the STR group (2.5%; p < 0.001). In both groups, about 80% of patients used thyroid hormone medication 10 years after operation. CONCLUSION: There was no advantage in thyroid function tests nor lesser medication in the FP group. The risk for recurrent nodules was significantly higher in the FP than in the STR-operated patients.

Interdisciplinary treatment of primary hepatic angiosarcoma: emergency tumor embolization followed by elective surgery.

Among primary hepatic malignancies, sarcomas represent a minority of 2 %. Of those, primary hepatic angiosarcoma is the most common one. In the past its incidence has been related to the exposure of certain chemicals like thorotrast, vinyl-chloride or arsenic. - Patients suffering from this aggressive, highly vascular tumor have a poor prognosis in general. Without treatment most of them die after rapid tumor progression with multifocal dissemination. In case of tumor perforation, fatal abdominal hemorrhage has been observed. - We herein report the successful interdisciplinary treatment of an 81 year-old woman with a perforated primary hepatic angiosarcoma of the left hepatic lobe. Initially, tumor bleeding was stopped by emergency interventional coil embolization. After stabilization of the patient, we performed an elective tumor resection. The patient could eventually be discharged in a good clinical condition. - So far, no standard therapy has established for patients with primary hepatic angiosarcoma. Surgery seems to be the treatment of choice. In addition, preoperative interventional embolization of the tumor supplying vessels reduces the risk of pre- and intraoperative bleeding. The value of adjuvant chemotherapy is not yet clarified. - The outcome of most patients with primary hepatic angiosarcoma remains poor and there is a need for clinical studies.

The detection of oesophageal adenocarcinoma by serum microsatellite analysis.

BACKGROUND AND AIMS: Organ-confined oesophageal cancer in an early stage can be cured in many patients, whereas more extensive lesions have a poor prognosis. We sought to develop a non-invasive test for cancer detection and evaluation of the prognosis of the patients by using a novel molecular approach. MATERIAL AND METHODS: Matched normal-, tumour- and serum-samples were obtained from 32 patients with adenocarcinoma of the oesophagus. DNA was extracted and the samples were subjected to microsatellite analysis using 12 markers. Serum and normal samples from 10 healthy individuals served as controls. RESULTS: Twenty-seven of the 32 patients (84.4%) with malignant tumours were found to have one or more microsatellite DNA alterations in their primary tumour. Twenty-six of the 32 patients (81.3%) had alterations in the serum by microsatellite analysis. Interestingly, all patients without lymphatic metastasis and three early carcinomas (pT1pN0) already displayed LOH alteration in the serum, while all serum DNA of samples from normal control subjects were negative. Survival was not significantly correlated with either LOH in the tumour or LOH in the serum. CONCLUSION: These data suggest that microsatellite DNA analysis in serum specimens might provide a potentially valuable tool for early detection of oesophageal cancer. The evidence of circulating tumour DNA reflects the propensity of these tumours to spread to distant sites. Up to now the follow-up is still too short to draw further conclusions on the prognostic impact of this finding.

Hyperinsulinemic hypoglycemia due to adult nesidioblastosis in insulin-dependent diabetes.

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-dependent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody (2/3) genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus II has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be considered.

Diagnosis of renal cancer by molecular urinalysis.

BACKGROUND: Organ-confined renal malignancies can be cured in the majority of patients, whereas more extensive lesions have a poor prognosis. We sought to develop a noninvasive test for renal cancer detection based on a novel molecular approach. METHODS: Matched urine and serum DNA samples were obtained before surgery from 30 patients with clinically organ-confined solid renal masses (25 with malignant tumors and five with tumors of low malignant potential) and were subjected to microsatellite analysis. Serum samples and urine samples obtained from 16 individuals without clinical evidence of genitourinary malignancy served as controls. RESULTS: Nineteen (76%) of the 25 patients with malignant tumors were found to have one or more microsatellite DNA alterations in their urine specimen, and 15 (60%) were found to have alterations in their serum DNA by microsatellite analysis. In every case, the microsatellite changes in urine or serum were identical to those found in the primary tumor. Three of five patients with tumors of low malignant potential were found to have DNA alterations in their urine, but none displayed alterations in their serum. Moreover, microsatellite alterations were not identified in either the urine or the serum samples from normal control subjects and patients with hematuria due to nephrolithiasis (renal stones). CONCLUSION: These data suggest that microsatellite DNA analysis of urine specimens provides a potentially valuable tool for the early detection of resectable kidney cancer. Furthermore, microsatellite analysis of serum samples reveals evidence of circulating tumor-specific DNA in approximately half of these patients and may reflect the propensity of these tumors to spread to distant sites at an early stage.

Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer.

BACKGROUND: Conventional cytologic analysis of sputum is an insensitive test for the diagnosis of non-small-cell lung cancer (NSCLC). We have recently demonstrated that polymerase chain reaction (PCR)-based molecular methods are more sensitive than cytologic analysis in diagnosing bladder cancer. In this study, we examined whether molecular assays could identify cancer cells in bronchoalveolar lavage (BAL) fluid. METHODS: Tumor-specific oncogene mutations, CpG-island methylation status, and microsatellite alterations in the DNA of cells in BAL fluid from 50 consecutive patients with resectable (stages I through IIIa) NSCLC were assessed by use of four PCR-based techniques. RESULTS: Of 50 tumors, 28 contained a p53 mutation, and the identical mutation was detected with a plaque hybridization assay in the BAL fluid of 39% (11 of 28) of the corresponding patients. Eight of 19 adenocarcinomas contained a K-ras mutation, and the identical mutation was detected with a mutation ligation assay in the BAL fluid of 50% (four of eight) of the corresponding patients. The p16 gene was methylated in 19 of 50 tumors, and methylated p16 alleles were detected in the BAL fluid of 63% (12 of 19) of the corresponding patients. Microsatellite instability in at least one marker was detected with a panel of 15 markers frequently altered in NSCLC in 23 of 50 tumors; the identical alteration was detected in the BAL fluid of 14% (three of 22) of the corresponding patients. When all four techniques were used, mutations or microsatellite instability was detected in the paired BAL fluid of 23 (53%) of the 43 patients with tumors carrying a genetic alteration. CONCLUSION: Although still limited by sensitivity, molecular diagnostic strategies can detect the presence of neoplastic cells in the proximal airway of patients with surgically resectable NSCLC.

Second esophageal tumors in patients with head and neck squamous cell carcinoma: an assessment of clonal relationships.

Patients with squamous cell carcinoma of the head and neck (HNSCC) often develop second carcinomas elsewhere in the upper aerodigestive tract. Some of these paired tumors share a common origin, reflecting the ability of a single progenitor cell to replicate, expand, and populate contiguous regions of the upper aerodigestive tract-a process referred to as clonal expansion. The geographical limitations of clonal expansion, however, have not been adequately addressed. For example, it is not known whether a neoplastic clone from the oral cavity, pharynx, or larynx can migrate to the esophagus. We compared paired tumors from 16 patients with HNSCC and a second squamous cell carcinoma of the esophagus (ESCC) for patterns of allelic loss on chromosomal arms 3p, 9p, and 17p. Losses at these loci occur early during neoplastic transformation of the respiratory tract. In 14 cases (87%), the paired tumors had discordant patterns of allelic loss, suggesting that these tumors were not clonally related. Conversely, two (13%) of the 16 paired tumors had identical genetic alterations, which suggests clonal expansion as the mechanism underlying tumor multifocality. One clone spread from the hypopharynx into the cervical esophagus, and the other spread from the tonsil to the distal esophagus. Although most second ESCCs appear to arise as independent neoplasms, a clonal population of neoplastic cells is capable of traveling across substantial distances to give rise to second tumors at different anatomical sites.

Detection of head and neck squamous cell carcinoma among exfoliated oral mucosal cells by microsatellite analysis.

Prompt detection of head and neck squamous cell carcinoma (HNSCC) is vital to successful patient management. In this feasibility study, we used microsatellite analysis to detect tumor-specific genetic alterations in exfoliated oral mucosal cell samples from patients with known cancer. Exfoliated mucosal cells in pretreatment oral rinse and swab samples were collected from 44 HNSCC patients and from 43 healthy control subjects (20 nonsmokers and 23 smokers). We tested a panel of 23 informative microsatellite markers to assay DNA from the matched lymphocyte, tumor (from cancer cases), and oral test samples. Loss of heterozygosity or microsatellite instability of at least one marker was detected in 38 (86%) of 44 primary tumors. Identical alterations were found in the saliva samples in 35 of these 38 cases (92% of those with markers; 79% overall) including 12 of 13 cases with small primaries [stage Tt or Tx (occult primary)] and 4 of 4 cases of patients that had undergone prior radiation. Microsatellite instability was detectable in the saliva in 24 (96%) of 25 cases in which it was present in the tumor, and loss of heterozygosity was identified in the test sample in 19 (61%) of 31 cases. No microsatellite alterations were detected in any of the samples from the healthy control subjects. This approach must now be refined and validated for the detection of clinically occult disease. Microsatellite analysis of oral samples may then become a valuable method for detecting and monitoring HNSCC.

Comparative microsatellite analysis in discerning origin of disseminated tumor: the case of a patient with malignant ascites and a history of multiple tumors.

The origin of metastatic carcinoma is now always easily resolved on the basis of conventional dinical and pathological parameters, particularly in patients with more than 1 primary tumor. When 1 of the tumors is a renal cell carcinoma, the clinical picture is further confounded by the tendency of these tumors to be locally silent, to metastasize to unusual sites, and to disseminate long after removal of the primary tumor. We compared tumors for loss (ie, deletion) of loci on chromosomal arms 3p, 5q, 11q, and 18q in a patient with a malignant ascites fluid, a remote history of renal and colonic neoplasms, and a strong clinical suspicion of disseminated gastrointestinal adenocarcinoma. DNA from microdissected tumors and normal tissues was subjected to polymerase chain reaction-based microsatellite analysis. Even though the clinical picture suggested a gastrointestinal origin, comparison of genetic alterations clearly showed that the malignant ascites represented recurrence of the renal cell carcinoma. The malignant ascites and the primary renal cell carcinoma showed identical patterns of allelic loss at all loci tested. In contrast, the malignant ascites and colonic adenoma showed discordant patterns of allelic loss. Comparative microsatellite analysis provides a rapid genetic approach for discerning the origin of metastatic tumor spread. This may be a useful diagnostic adjunct when tumor origin is not clear on clinical or morphological grounds. In some instances, it may even provide a reasonable alternative to an extensive and costly conventional work-up.