Direct effects of chemoradiotherapy following esophagectomy.

BACKGROUND: Esophageal cancer is a major cause of morbidity and mortality, but despite continuing research, few effective therapies have been identified. In recent years, surgical resection following chemoradiotherapy has been associated with improved survival in several clinical models. AIM: In a prospective, observational study, we evaluated the direct effects of chemoradiotherapy on postoperative mortality, morbidity, and inflammatory response in patients following esophagectomy. METHODS: The study cohort was divided into two groups: the first group received preoperative chemoradiotherapy, while the second group had surgical intervention without prior treatment. Nutritional status was evaluated for the members of both patient groups at various time points. RESULTS: Preoperative chemoradiotherapy did not influence morbidity or organ function, and the postoperative inflammatory response did not show immunosuppressive side effects directly after surgery. CONCLUSION: Preoperative chemoradiotherapy does not improve postoperative organ function, inflammatory response or nutritional status in the patients. These findings may help to improve outcome in patients with esophageal cancer in the future.

Correlation between tumor-associated proteins and response to neoadjuvant treatment in patients with advanced squamous-cell esophageal cancer.

BACKGROUND: Possible predictive markers of response to neoadjuvant radiochemotherapy (NRCT) of esophageal cancer have been identified. PATIENTS AND METHODS: Patient biopsies were obtained from both tumor and normal tissue before the NRCT of locally advanced esophageal squamous cell carcinoma. Protein solutions were separated and immunoblot analysis was performed with heat shock protein (Hsp)16.2, heme-binding protein 2 (SOUL), BCL2-associated X protein (Bax), B-cell-associated leukemia protein 2 (Bcl-2) and heat shock protein 90 (Hsp90) antibodies. Following NRCT, the patients were restaged according to the Response Evaluation Criteria In Solid Tumors (RECIST). Following resections the pathological down-staging was evaluated. RESULTS: Clinical restaging revealed a response rate of 65%. Pathological examination revealed down-staging in 30% and 25% of the cases for the T and N categories respectively. Compared to the normal esophageal mucosa, a decreased expression of Hsp16.2, Hsp90 and SOUL proteins and an increased Bax/Bcl-2 ratio was found in the responding tumors. CONCLUSION: Hsp16,2, Hsp90 and SOUL expression and Bax/ Bcl-2 ratio correlates to the efficacy of NRCT and predict outcome in patients with locally advanced squamous-cell esophageal cancer.

Effect of glutamine in patients with esophagus resection.

UNLABELLED: Glutamine is the most abundant amino-acid in the extra- and intracellular compartments of the human body, which accounts for over 50% of its free amino-acid content. Utilization of glutamine peptides is explicitly useful, resulting in a decrease in the number of postoperative infectious complications, period of hospitalization, and therapeutic costs. This article aims to study the effects of glutamine on systemic inflammatory response, morbidity, and mortality after esophagectomy. A prospective, randomized, double-blind, and controlled trial was used. Following sealed-envelope block randomization, the patients were divided into two groups. Members of the glutamine group (group G) received glutamine (Dipeptiven, Fresenius) as continuous infusion for 6 hours at 0.5 g/kg for 3 days prior to, and 7 days following surgery; while patients of the control group were given placebo. We examined 30 patients in group G, and 25 patients as controls. In both patient groups, the levels of total protein, albumin, pre-albumin, retinol binding protein, transferrin, transferring-saturation, C-reactive protein, procalcitonin, lymphocte, Interleukin-6, Interleukin-8, tumor necrosis factor alpha, and serum lactate were determined prior to surgery (t(0)), directly after surgery (t(u)), following surgery on day 1 (t(1)), day 2 (t(2)), and day 7 (t(7)). For statistical analysis Mann-Whitney U test and chi-square test were used. There was no significant difference between the two groups regarding age, male/female ratio, and SAPS II scores. Intensive care unit morbidity and mortality was similar in both groups (group G: 24 survivors/6 nonsurvivors; CONTROL: 17 survivors/8 nonsurvivors; P= 0.607). Daily Multiple Organ Dysfunction Score did not differ significantly between the two groups. The observed inflammatory markers followed the pattern we described without significant difference. Based on our study, the glutamine supplementation that we used had no influence on morbidity, mortality, or postoperative inflammatory response after esophagectomy.

Laparoscopic repair of large hiatal hernia with teres ligament: midterm follow-up: a new surgical procedure.

BACKGROUND: Although laparoscopic repair of large, mostly paraesophageal hiatal hernias is widely applied, there is a great concern regarding the higher recurrence rate associated with this procedure. In order to reduce this high recurrence rate, several techniques have been developed, mostly applying a mesh prosthesis for hiatal reinforcement. METHODS: We have recently introduced a new laparoscopic technique in which the hiatal closure is reinforced with the teres ligament. To date 26 patients have been entered into this ongoing prospective study. After the operation patients were called back on a regular basis for symptom evaluation and barium swallow. All 26 patients agreed to undergo barium swallow, with a mean follow-up of 35 months. RESULTS: The mean operative time was 115 min. Perioperative morbidity was 11.5%, and conversion to an open procedure was performed in six cases. No mortality was registered. Anatomic recurrence, investigated by barium swallows was observed in four patients (15.3%). Of those four, only one (3.85%) had a symptomatic recurrent paraesophageal hernia; the other three had asymptomtic sliding hernias. In three of the four patients with anatomic recurrence, the diameter of the hiatal hernia was greater than 9 cm at the original operation, and the fourth patient underwent reoperation for recurrent hiatal hernia. No symptomatic recurrence was found in patients with diameter of hiatal hernia between 6 and 9 cm. CONCLUSIONS: Laparoscopic reinforcement of the hiatal closure with the ligamentum teres is safe and effective treatment for large hiatal hernias. However, it appears that patients with extremely large hiatal hernias are at greater risk of recurrence, and therefore large hernias are not suitable for this new technique.

P2 purinoceptor antagonists inhibit the non-adrenergic, non-cholinergic relaxation of the human colon in vitro.

Neurotransmitters released by myenteric neurons regulate movements of intestinal smooth muscles. There has been little pharmacological evidence for a role of purinergic mechanisms in the non-adrenergic, non-cholinergic (NANC) relaxation of the human large intestine. We used P(2) purinoceptor antagonists to assess whether such receptors are involved in the NANC relaxation of the circular muscle of the human sigmoid colon. It was also investigated whether the guanylate cyclase enzyme mediates the NANC response. Human colonic circular strips were tested in organ bath experiments with isotonic recording. NANC, non-nitrergic relaxations induced by electrical field stimulation (1 and 10 Hz, in the presence of atropine, guanethidine, and 100 microM N(G)-nitro-L-arginine [L-NOARG]) were strongly inhibited by a combination of the P(2) purinoceptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-sulfonic acid (PPADS) (50 microM) and suramin (100 microM). PPADS plus suramin was ineffective in the absence of L-NOARG. L-NOARG alone significantly reduced the NANC relaxation to electrical stimulation. PPADS plus suramin strongly inhibited the relaxation in response to exogenous alpha,beta-methylene ATP. The guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (3 microM) inhibited the NANC relaxation, but did not add to its reduction by L-NOARG. L-NOARG was still slightly effective in the presence of ODQ. Vasoactive intestinal polypeptide tachyphylaxis failed to influence the non-nitrergic NANC relaxation. It is concluded that nitric oxide (NO) and ATP co-mediate, in a non-additive manner, the NANC relaxation. NO probably acts through the guanylate cyclase, though a small fraction of its effect might be mediated by other mechanisms. Activators of the guanylate cyclase other than NO do not seem to participate in the NANC relaxation.

Does transthoracic compared to transhiatal resection alter the early postoperative course of oesophagectomy?

SUMMARY: Several techniques for esophageal resections have been reported. However, clear clinical evidence is still lacking whether any of the procedures is superior to the others regarding morbidity and mortality in the early postoperative period. Two operative approaches for esophageal carcinoma, transhiatal and transthoracic, were compared with respect to operative morbidity, mortality and systemic inflammatory response. In our prospective study between 2000 and 2002 83 patients were investigated. In a retrospective post hoc analysis patients were divided into two groups due to the performed operational procedure, transhiatal (TH) or transthoracic (TT). Multiple Organ Dysfunction Score (MODS) was monitored daily (t1,t2,t3). Serum procalcitonin (PCT) levels were determined on admission to the ICU (t0), then 24 hourly (t24,t48,t72). Microalbuminuria (M:Cr) was measured before (tp), and after surgery (t0,t6,t24,t48,t72). For statistical analysis Wilcoxon rank sum test, Mann-Whitney U-test and chi-square test were used as appropriate. We examined 52 patients in the TH group, and 31 patients in the TT group. There was no significant difference between the two groups regarding age, male/female ratio, and SAPS II scores. Operations lasted significantly longer in the TT group: 375 (300-480) min compared to the TH group 240 375 (180-319) min, P < 0.001. ICU mortality was similar in both groups (TH: 46 survivors/6 non-survivors; TT: 27 survivors/4 non-survivors; P = 0.607, respectively). Daily MODS did not differ significantly between the two groups. The observed inflammatory markers (PCT and M:Cr) followed the pattern we described earlier, without significant difference. In this study there was no difference in the clinical and biochemical variables of the patients between the transthoracic and transhiatal groups. The observed early postoperative morbidity and mortality may indicate, that both procedures can be considered as procedures with similar postoperative risk.

Prevention of recurrence by reinforcement of hiatal closure using ligamentum teres in laparoscopic repair of large hiatal hernias.

UNLABELLED: BACKGROUND. Several attempts were made to develop an effective technique to reduce the high recurrence rate associated with the repair of large hiatal hernias. METHODS: A new laparoscopic technique was introduced to reinforce hiatal closure with the ligamentum teres. Its feasibility, safety, and efficacy were evaluated. Four patients with gastroesophageal reflux disease and large hiatal hernia (>6 cm) entered the study. After closure of the diaphragmatic crura the teres ligament was dissected, brought behind the esophagus, and sutured to the crura. A fundoplication was also added. Patients were followed with barium swallow at 3 months postoperatively. RESULTS: The mean operation time was 109.5 min. No intraoperative complications, perioperative morbidity, or mortality were registered. At the follow-up, barium swallows revealed no recurrence. CONCLUSION: On the basis of these preliminary results laparoscopic reinforcement of the hiatal closure with the ligamentum teres seems feasible and safe; therefore this promising technique should be considered as an option for the treatment of large hiatal hernias.

Comparison of quality of life and nutritional parameters after total gastrectomy and a new type of pouch construction with simple Roux-en-Y reconstruction: preliminary results of a prospective, randomized, controlled study.

The aim of the study was to introduce a new type of gastric substitute, the aboral pouch, after total gastrectomy and to compare nutritional, motility, and quality of life parameters of patients with an aboral pouch to those undergoing simple Roux-en-Y reconstruction in a prospective, randomized, and controlled trial. To date 40 patients have entered the study. In 22 of them the aboral pouch was created; the remaining 18 patients with simple Roux-en-Y reconstruction served as the control group. Laboratory measurements, passage studies, lipid and carbohydrate absorption tests, and quality of life interviews were carried out as follow-up examinations. Preliminary results suggest that the aboral pouch has some advantages over simple Roux-en-Y reconstruction. Serum immunoglobulin M level and the quality of life estimated by the gastrointestinal quality of life index, yielded significantly better results in the pouch group.

Nutritional and life-quality consequences of aboral pouch construction after total gastrectomy: a randomized, controlled study.

AIMS: The aboral pouch, a new type of gastric substitute, has been introduced after total gastrectomy and compared to simple Roux-en-Y reconstruction in a prospective, randomized study. Anthropometric data, serum nutritional parameters, small intestinal passage, lipid and carbohydrate absorption and quality of life were measured 6 and 12 months after total gastrectomy. PATIENTS AND METHODS: Between September 1997 and April 2000 46 patients entered the study, 24 to the aboral pouch group and 22 to the control, simple Roux-en-Y group. RESULTS: Interim analysis of the data revealed significantly higher serum cholesterol levels, better lipid absorption and quality of life in patients who underwent aboral pouch construction. CONCLUSION: Aboral pouch construction is a feasible reconstruction method after total gastrectomy providing better lipid absorption and quality of life for patients after total gastrectomy.

[Gastric pouch with preserved duodenal passage: attempt to optimize reconstruction after total gastrectomy]. / Aborális pótgyomor a duodenális passzázs megtartásával: az optimális rekonstrukciós típus keresése totális gastrectomia után.

A new method--aboral pouch with preserved duodenal passage--has been introduced for reconstruction after total gastrectomy. After excising the stomach, preparation of the Roux loop and construction of an end-to-side esophago-jejunostomy, the Roux loop is anastomosed to the duodenal stump side-to-end approximately 40-50 cm distal from the esophago-jejunostomy. Right beneath this second anastomosis the Roux limb is closed with a stapler to provide unidirectional passage through the duodenum. An aboral pouch is constructed by a 15 cm long side-to-side anastomosis between the Roux limb under the stapled segment and the aboral end of the Y limb. The advantages of both the reservoir constructing and the interposition methods (duodenal passage preserved) are combined with this new form of reconstruction. The additional benefit is that the reservoir is constructed in aboral position, as previously suggested by the authors.

Larynx-preserving pharyngo-esophagectomy after chemoradiation in the treatment of cancer of the pharyngo-esophageal junction.

Pharyngo-laryngo-esophagectomy in the treatment of advanced tumors of the pharyngo-esophageal junction is associated with a high morbidity and poor quality of life due to loss of the larynx. Neoadjuvant chemoradiotherapy resulted in a considerable tumor reduction in 6 patients allowing radical tumor resection by larynx-preserving pharyngo-esophagectomy. The operation consisted of total esophagectomy and resection of the posterior pharyngeal wall and reconstruction by a pharyngogastrostomy in 5 patients, and ileocolon interposition in 1 patient.

[Comparing aboral pouch construction with Roux-en-Y reconstruction after total gastrectomy]. / Totális gastrectomia után végzett aboralis pouch-képzés összehasonlítása Roux-Y rekonstrukcióval.

The aim of this study was the introduction of a new type of gastric substitute, the aboral pouch after total gastrectomy and comparing the motility, nutritional and quality of life parameters of the patients with aboral pouch to the simple Roux-en-Y group in a prospective, randomized, controlled trial. Between September of 1997 and February of 1999 25 patients entered the study. In the pouch group after Roux-en-Y reconstruction aboral pouch was created as a side to side anastomosis approximately 50 cms distal to the esophagojejunostomy, 15 cms in length. In the control group simple Roux-en-Y reconstruction was performed. During the follow up examinations nutritional measurements, scintigraphic evaluation of the gastrointestinal passage, absorption tests and quality of life interviews were carried out. In the first year of the study 15 patients underwent pouch construction, while 10 patients served as controls. Preliminary results suggest that there is no marked difference in the postoperative adaptation between the two groups. However serum immunoglobulin and serum iron measurements, lipid absorption test and quality of life questionnaires predict a slight superiority of the patients with aboral pouch over the simple Roux-en Y group.

Complications following esophageal surgery.

Chronologically, complications can be classified as intraoperative, early, and late. The authors analyze complications according to this classification on the basis of more than 400 esophageal operations and related literary data. As regards intraoperative complications, they deal only with those occurring at transhiatal esophagectomy (e.g., tracheal tear, bleeding, pneumothorax, laryngeal nerve injury). Among the early complications, they survey the incidence of transplant necrosis and related mortality, further sequelae ensuing from subacute ischemia of the replaced organ and analyze in detail the questions which arise regarding anastomotic leakage. Firstly, they deal with those causative factors that influence the frequency of anastomotic insufficiency, such as the technical "know-how" of anastomosis making (e.g., one layer vs two layers; stapling or manual suture; interrupted or running suture), the way of replacement using whole stomach or tube-stomach and the consequences originating from the route of replacement (e.g., anterior or posterior mediastinal route). Incidence and management of chylothorax are also dealt with. While dealing with late complications, the authors give a detailed comment on anastomotic strictures and also other factors facilitating the development of late dysphagia, such as peptic stricture and tumor of the organ remnant. Finally, some cases successfully treated by surgery are presented (skin-tube formation in cases following transplant necrosis; abolition of a pharyngogastric anastomosis stricture using a free jejunal transplant and surgical solution of an anastomotic stricture from median sternotomy approach).

Skin tube esophagus: present indications and late malignization.

If there is no other possibility for the replacement of the whole esophagus, skin tube esophageal reconstruction gives a good result. Three successful cases treated with the antethoracal neoesophagus formed from musculocutaneous flaps are discussed. All patients recovered successfully. However, there exists the possibility of late malignization in the skin tube esophagus. Two such cases are also presented.

[Larynx-preserving pharyngoesophagectomy in the treatment of cancer of the pharyngoesophageal junction]. / A gégemegtartó pharyngo-oesophagectomia helye a pharyngo-oesophagealis átmenet daganatainak sebészi kezelésében.

UNLABELLED: Pharyngo-laryngo-esophagectomy has been the sole surgical option in the management of advanced tumors arising from the pharyngoesophageal junction. This operation is associated with high morbidity, mortality and poor quality of life due to loss of larynx. The aim of the author was to achieve a reduction in tumor size by means of neoadjuvant chemoradiotherapy and so to make the tumor amenable to a larynx preserving operation avoiding pharyngo-laryngo-esophagectomy. Between 1. January 1998 and 31. December 1999, 11 consecutive patients with advanced cancer of pharyngo-esophageal junction were treated with neoadjuvant chemoradiotherapy (carboplatin, 5-fluorouracil, 30-35 Gy telecobalt irradiation). The tumor regressed in all cases and moreover, in 6 patients a larynx preserving pharyngo-esophagectomy could be carried out. This operation consists of total esophagectomy, resection of posterior pharynx wall and Akiyama-type gastric pull up with side-to-side pharyngo-gastrostomy. All 6 patients recovered. In 2 cases after neoadjuvant therapy the tumor disappeared from the cervical esophagus and so that a pharyngo-laryngectomy and free jejunum transfer could be performed. 3 other patients remained irresectable due to lymph node metastases. CONCLUSION: Larynx preserving pharyngo-esophagectomy is a safe operation by means of which the larynx can be preserved even in those patients whose tumor is located at the level of pharyngo-esophageal junction, on the posterior wall of the pharynx.

[Repeated resection of hepatocellular carcinoma and its recurrences and removal of pulmonary metastases]. / Hepatocellularis carcinoma és recidíváinak ismételt resectiója tüdömetastasisok eltávolításával.

A case of a 67 year old male successfully treated local recurrence of previously radically resected hepatocellular carcinoma with distant metastases of the lung is reported. Two years after a complete removal of the primary liver malignoma a local recurrence was resected which was followed by selective intraarterial cytostatic treatment and chemoembolisation. A three-year disease-free interval was achieved, then recurrence in the liver and lung metastases were detected at the regular check-up. All of the malignant focuses were eliminated by parenchyma sparing surgical resections, then a postoperative adjuvant chemotherapy (FAM scheme) has been followed. After eight months the patient remained symptom-free. The long-term survival seems to justify the aggressive approach of this kind of malignancies.

Structure and evolution of linalool synthase.

Plant terpene synthases constitute a group of evolutionarily related enzymes. Within this group, however, enzymes that employ two different catalytic mechanisms, and their associated unique domains, are known. We investigated the structure of the gene encoding linalool synthase (LIS), an enzyme that uses geranyl pyrophosphate as a substrate and catalyzes the formation of linalool, an acyclic monoterpene found in the floral scents of many plants. Although LIS employs one catalytic mechanism (exemplified by limonene synthase [LMS]), it has sequence motifs indicative of both LMS-type synthases and the terpene synthases employing a different mechanism (exemplified by copalyl diphosphate synthase [CPS]). Here, we report that LIS genes analyzed from several species encode proteins that have overall 40%-96% identity to each other and have 11 introns in identical positions. Only the region encoding roughly the last half of the LIS gene (exons 9-12) has a gene structure similar to that of the LMS-type genes. On the other hand, in the first part of the LIS gene (exons 1-8), LIS gene structure is essentially identical to that found in the first half of the gene encoding CPS. In addition, the level of similarity in the coding information of this region between the LIS and CPS genes is also significant, whereas the second half of the LIS protein is most similar to LMS-type synthases. Thus, LIS appears to be a composite gene which might have evolved from a recombination event between two different types of terpene synthases. The combined evolutionary mechanisms of duplication followed by divergence and/or "domain swapping" may explain the extraordinarily large diversity of proteins found in the plant terpene synthase family.

Indications, new surgical technique and results of colon interposition or bypass in esophageal surgery.

Over a 5-year period, 29 patients with esophageal disease underwent colon interposition or bypass. The indication was cure of cancer in 11 patients, who underwent earlier a gastric resection. Other indications was benign stricture in 7 patients, bypass for unrespectable cancer in 6, having a caustic injury in 3 and after an esophageal perforation in 2. In 14 patients the left colon, in 15 the right colon was used. The colon was transected without dividing the mesentery other than just along its mesenteric border. This preserves additional blood supply from the marginal artery, also improves the function of the graft in transporting food. Anastomosis leakage occurred in 4 cases (13.7%). Graft necrosis occurred in 2 of 29 patients, one of whom alter underwent a successful second reconstruction. The 30 day operative mortality rate was 13.7%. A colon interposition provides good quality of deglution, and is the organ of choice for patients who require an esophageal substitute and are potential candidates for long survival, or when the stomach is unsuited for replacement or bypass.

Identification, characterization, and molecular cloning of a homologue of the bacterial FtsH protease in chloroplasts of higher plants.

In an attempt to identify and characterize chloroplast proteases, we performed an immunological analysis of chloroplasts using an antibody against Escherichia coli FtsH protease, which is an ATP-dependent metalloprotease bound to the cytoplasmic membrane. A cross-reacting protein of 78 kDa was found in the thylakoid membrane of spinach, but not in the soluble stromal fraction. Alkali and high salt washes, as well as trypsin treatment of thylakoid membranes, suggest that the chloroplastic FtsH protein is integral to the membrane, with its hydrophilic portion exposed to the stroma. The protein is not bound to any photosynthetic complex and is exclusively located in the stromally exposed regions of the thylakoid membrane. Its expression is dependent on light, as it is present in green pea seedlings, but absent from etiolated ones. An Arabidopsis cDNA was isolated, and the deduced amino acid sequence demonstrated high similarity to the E. coli FtsH protein, especially in the central region of the protein, containing the ATP- and zinc-binding sites. The product of this clone was capable of import into isolated pea chloroplasts, where it was processed to its mature form and targeted to the thylakoid membrane. The trans-bilayer orientation and lateral location of the FtsH protein in the thylakoid membrane suggest its involvement in the degradation of both soluble stromal proteins and newly inserted or turning-over thylakoid proteins.

Evolution of floral scent in Clarkia: novel patterns of S-linalool synthase gene expression in the C. breweri flower.

Flowers of Clarkia breweri, an annual plant from the coastal range of California, emit a strong sweet scent of which S-linalool, an acyclic monoterpene, is a major component. Chromosomal, chemical, and morphological data, and the species' geographic distribution, suggest that C. breweri evolved from an extant nonscented species, C. concinna. A cDNA of Lis, the gene encoding S-linalool synthase, was isolated from C. breweri. We show that in C. breweri, Lis is highly expressed in cells of the transmitting tract of the stigma and style and in the epidermal cells of petals, as well as in stamens, whereas in the nonscented C. concinna, Lis is expressed only in the stigma and at a relatively low level. In both species, changes in protein levels parallel changes in mRNA levels, and changes in enzyme activity levels parallel changes in protein levels. The results indicate that in C. breweri, the expression of Lis has been upregulated and its range enlarged to include cells not expressing this gene in C. concinna. These results show how scent can evolve in a relatively simple way without the evolution of highly specialized "scent glands" and other specialized structures. Lis encodes a protein that is structurally related to the family of proteins termed terpene synthases. The protein encoded by Lis is the first member of this family found to catalyze the formation of an acyclic monoterpene.