A new concept in the surgical treatment of gastroesophageal reflux.

Surgical treatment of gastroesophageal reflux has been thought to depend on the construction of a valve mechanism at the gastroesophageal junction (GEJ). Recently, a silicone prosthesis that does not construct a valve has been introduced, and in preliminary studies in the human, shown to be effective in the treatment of reflux. A precise mode of action has not been demonstrated for the prosthesis. This study was undertaken to investigate the mechanics of the prosthesis and determine its effectiveness in an animal model. Six canine gastroesophageal specimens were excised and the lower esophageal sphincter (LES) simulated by a rubber band placed around the GEJ at a tension calibrated to give 25 mmHg "sphincter" pressure. Circumferential silk ligatures of varying length were then placed on the stomach 3.0 cm distal to the GEJ. With no ligature, the LES opening pressure (LESOP) was 8.0 mmHg, varying to 17.0 mmHg with an 8.0 cm ligature. Further, 24 adult mongrel dogs were randomly divided into four equal groups: controls, circular myomectomy of the LES alone, myomectomy combined with fundoplication, and myomectomy combined with implantation of the silicone antireflux prosthesis. Evaluation included manometry, endoscopy, and histology. Although only the normal sphincter and fundoplication responded physiologically, the prosthesis was just as effective in preventing reflux, as evidenced by reducing acid exposure time of myomectomized dogs from 35.4% to 1.8%, and by preventing endoscopic esophagitis. It was concluded that the silicone antireflux prosthesis acts in the same fashion as the ligature in the model, by interrupting distraction of the LES by gastric wall tension. This concept is an effective method for raising LESOP, treating experimental gastroesophageal reflux, and eliminating the sequelae of reflux. Long-term evaluations of the prosthesis are required.     

Chronic Marijuana Smoke Exposure in the Rhesus Monkey I. Plasma Cannabinoid and Blood Carboxyhemoglobin Concentrations and Clinical Chemistry Parameters

Chronic Marijuana Smoke Exposure in the Rhesus Monkey I. PlasmaCannabinoid and Blood Carbxyhemoglobin Concentrations and ClinicalChemistry Parameters SLIKKER, W., JR., PAULE, M. G., ALI, S.F., SCALLET, A. C., AND BAILEY, J. R (1991). Fundam. Appl Toxicol17, 321–334. This report is the first in a series abouta large multidisciplinary study designed to determine whetherchronic marijuana (MJ) smoke exposure results in residual behavioraland/or neuropathological alterations in the rhesus monkey. Priorto the initiation of a year of chronic MJ smoke exposure, 64periadolescent male rhesus monkeys were trained for 1 year toperform five operant behavioral tasks and then divided, accordingto their performance in these tasks, into four exposure groups(n=15–16/group): (1) a high dose (HI) group, exposed 7days/week to the smoke of one standard MJ cigarette; (2) a lowd m (LO) group, exposed on weekend days only to the smoke ofa standard MJ cigarate; (3) an extracted MJ cigarette (EX) group,exposed 7 days/week to the smoke of one ethanol-extracted MJcigarette; and (4) a sham group (SH), exposed 7 days/week tosham exposure conditions. Daily exposures for 1 year were accomplishedusing a mask that covered the subjects' nose and mouth. Averagebody weights (initially 3.7?0.5 kg, mean?SD) and rates of weightgain (approximately 0.1 kg/month) were the same for all groupsthroughout the entire experiment. During the first week of expsure,plasma concentrations of -9-tetrahydrocannabinol and 11-nor-9-carboxy-THCin the HI group were 59?7 (mean?SE) and 5.5?1.5 ng/ml, respectively,45 min after MJ smoke administration and did not change significantlyat similar times after exposure throughout the remainder ofthe year. Whole blood carboxyhemoglobin levels increased toapproximately 13% 1 min after expsure to smoke in either theMJ or the EX groups. Comparison of blood chemistry and hematologyvalues before, during, and after exposure indicated no differencesfor most parameters. During exposure, lymphocytes, alkalinephosphatase and -glutamyl transferase were depressed in theHI group compared to in the SH group. During exposure, aspartateaminotransferase was elevatd for both the HI and EX groups,suggesting a general effect of smoke exposure. Because theseeffects were transient and remained within the range of reportednormal values, these data indicate that long-term, experimentalexperimental exposure to MJ smoke is feasible and does not compromisethe general health of the rhesus monkey.     

The therapeutic results of programmed relaparotomy in diffuse peritonitis]

The therapeutical concept of programmed relaparotomy was performed in 184 patients with diffuse peritonitis from 4/1984 to 4/1991. Clinical results were prospectively documented and a total of 46 variables (e.g. risk factors, clinical parameters, laboratory tests, microbiological screenings, score systems) both univariate and multivariate were tested for prognostic significance. Total lethality rate was 26% (48/184 patients). If complete eradication of the source of infection was surgically achieved (150 patients/82%) lethality rate was only 9%. In contrast, lethality rate was 100% in patients with unsuccessful surgical focus eradication. Eradication of the source of infection during the first operation (104 patients/56%) resulted in a lethality rate of 6%, compared to 17% for patients who needed two or even more operations (46 patients/25%). Eradication of the source of infection during the first laparotomy ("focus eradication on time") was the most important prognostic parameters. Of further prognostic significance but with declining importance where serum-creatinine at the beginning of the treatment, patient's age (greater than less than 70 years) and preexistent hepatic disease.     

Fundoplication: How to do it? Peri-esophageal wrapping as a therapeutic principal in gastro-esophageal reflux prevention

The prerequisites for a successful outcome after fundoplication are careful patient selection, good technique, and an understanding of the principles of antireflux surgery. The most important aspect of any such operation is the construction of a peri-esophageal ring around the gastro-esophageal junction buttressing the sphincter and, thus, neutralizing the gastric opening pressure. Accordingly, the operation has to comprise: 1) generous dissection around the gastric fundus to allow the formation of a floppy fundoplication; 2) construction of the cuff as short as possible (2 cm to 3 cm); and 3) proper fixation of the cuff at the correct site in the region of the lower esophageal sphincter. Adherence to these principles will avoid postoperative dysphagia or functional gastro-intestinal disorders and produce long-lasting reflux control in approximately 90% of patients at 10 years. Problems of hypercontinence may occasionally occur since gastro-esophageal reflux suppression is usually complete and any physiological reflux abolished. With the advent of modern drug treatment, the excellent results achieved by fundoplication need to be maintained despite fewer operations. Careful postoperative quality control including pH monitoring is therefore mandatory. The principle of periesophageal wrapping is likely to remain the cornerstone of antireflux surgery. Current techniques are, however, likely to evolve. One direction being investigated is laparoscopic fundoplication, rendering the procedure much less invasive.

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Resumen Los prerrequisitos para obtener un resultado exitoso después de fundoplicación son: selección cuidadosa del paciente, depurada técnica operatoria y un buen conocimiento de los principios de la cirugía antirreflujo. El aspecto más importante de la operación es la construcción de un anillo (manguito) periesofágico alrededor de la unión gastroesofágica con lo cual se fija el esfínter y, por lo tanto, se neutraliza la presión de apertura gástrica. Por consiquiente, la operación debe incluir: 1) generosa disección alrededor del fundus gástrico que permita construir una fundoplicación floja (floppy); 2) construcción del manguito tan corto como sea posible (2–3 cm), y 3) fijación adecuada del manguito en el lugar correcto sobre la región del esfínter esofágico inferior. La cuidadosa observación de estos principios evita la disfagia postoperatoria o las alteraciones gastrointestinales funcionales y logra el control del reflujo a largo plazo. Los problemas de hipercontinencia pueden ocurrir ocasionalmente, puesto la supresión de reflujo gastroesofágico es usualmente total y queda abolido cualquier reflujo fisiológico. Con el advenimiento de la moderna terapia farmacológica es necesario mantener los excelentes resultados que se logran con la fundoplicación, a pesar de que actualmente se realizan menos operaciones; por lo tanto, aparece mandatario un meticuloso control de calidad postoperatorio, incluyendo la monitoría de pH. El principio de la envolutra periosofágica probablemente se mantendra como la piedra angular de la cirugía antirreflujo. Sin embargo, muy posiblemente las actuales técnicas quirúrgicas habrán de evolucionar. Una modalidad que es motivo de investigación es la fundoplicación laparoscópica, método que hace el procedimiento mucho menos invasivo.

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Résumé Les conditions nécessaires pour obtenir un bon résultat de la fundoplicature sont une sélection judicieuse des candidats à ce type de chirurgie, une technique irréprochable et une bonne compréhension des principes de la chirurgie du reflux. L'aspect principal est la construction d'un anneau périoesophagien autour de la jonction oesogastrique renforçant le sphincter et le rendant capable de vaincre la pression d'ouverture gastrique. Cela veut dir que l'intervention doit comporter une dissection poussée du fundus gastrique pour permettre la construction d'une valve adèquate et souple, courte (2 á 3 cm) et sa fixation correcte juste à l'endroit anatomique qui correspond au sphincter inférieur de l'oseophage. Si l'on observe ces principes, on évite la dysphagie postopératoire ou des désordres fonctionnels et on obtient en même temps un contrôle du reflux de longue durée chez approximativement 90% des patients à 10 ans. Les problèmes dus à un surserrage sont rares. Les résultats de ce type de chirurgie sont généralement excellents et doivent être confirmés par un contrôle par pHmétrie qui est presque obligatoire. Le principe de la fundoplicature reste la base de ce type de chirurgie. Les progrès actuels viennent de la chirurgie par coelioscopie qui permet une correction du reflux de manière moins invasive.

     

Preoperative Evaluation of Pancreatic Masses with Positron Emission Tomography Using 18F-fluorodeoxyglucose: Diagnostic Limitations

Identification of pancreatic cancer in patients presenting with an enlarged pancreatic mass is a major diagnostic problem. Positron emission tomography (PET) using the radiolabeled glucose analogue ¹⁸F-fluorodeoxyglucose (FDG) has been suggested to provide excellent accuracy for noninvasive determination of suspicious pancreatic masses. We conducted a prospective study to verify these results. Forty-two patients admitted for pancreatic surgery underwent PET scanning. Image analysis was based on visual film evaluation and quantification of regional tracer uptake. PET imaging was visually analyzed by three observers blinded for the results of other diagnostic tests; they qualitatively graded the scans using a five-point scale (I = low to V = high) for the presence and intensity of focal FDG uptake. Diagnosis was proven by histology (n= 38) or follow-up (n= 4). Furthermore, the results of PET were compared with helical computed tomography (CT) and conventional ultrasonography (US), done during the routine diagnostic workup before pancreatic cancer surgery. Regarding only the results with scores of IV and V as positive for representing definite malignancy yielded a sensitivity of 71% and a specificity of 64% for film reading. Quantification of regional tracer uptake contributed no significant diagnostic advantage for differentiation between benign and malignant tumors. Helical CT revealed a sensitivity of 74% and a specificity of 45.5% and abdominal US 56% and 50%, respectively. We concluded that PET imaging provides only fair diagnostic accuracy (69%) for characterizing enlarged pancreatic masses. PET does not allow exclusion of malignant tumors. In doubtful cases, the method must be combined with other imaging modalities, such as helical CT. The results indicate that the number of invasive procedures is not significantly reduced by PET imaging.     

Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment.

PURPOSE: To evaluate the time course of therapy-induced changes in tumor glucose use during chemoradiotherapy of esophageal squamous cell carcinoma (ESCC) and to correlate the reduction of metabolic activity with histopathologic tumor response and patient survival. PATIENTS AND METHODS: Thirty-eight patients with histologically proven intrathoracic ESCC (cT3, cN0/+, cM0) scheduled to undergo a 4-week course of preoperative simultaneous chemoradiotherapy followed by esophagectomy were included. Patients underwent positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) before therapy (n = 38), after 2 weeks of initiation of therapy (n = 27), and preoperatively (3 to 4 weeks after chemoradiotherapy; n = 38). Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUVs). Results Mean tumor FDG uptake before therapy was 9.3 +/- 2.8 SUV and decreased to 5.7 +/- 1.9 SUV 14 days after initiation of chemoradiotherapy (-38% +/- 18%; P <.0001). The preoperative scan showed an additional decrease of metabolic activity to 3.3 +/- 1.1 SUV (P <.0001). In histopathologic responders (< 10% viable cells in the resected specimen), the decrease in SUV from baseline to day 14 was 44% +/- 15%, whereas it was only 21% +/- 14% in nonresponders (P =.0055). Metabolic changes at this time point were also correlated with patient survival (P =.011). In the preoperative scan, tumor metabolic activity had decreased by 70% +/- 11% in histopathologic responders and 51% +/- 21% in histopathologic nonresponders. CONCLUSION: Changes in tumor metabolic activity after 14 days of preoperative chemoradiotherapy are significantly correlated with tumor response and patient survival. This suggests that FDG-PET might be used to identify nonresponders early during neoadjuvant chemoradiotherapy, allowing for early modifications of the treatment protocol.     

Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma.

PURPOSE: The objective of the study was to evaluate microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] and mutation in the p53 gene in relation to response and patient survival to a cisplatin-based neoadjuvant chemotherapy in gastric cancer. EXPERIMENTAL DESIGN: Fifty-three pretherapeutic gastric carcinoma biopsies were analyzed with 11 microsatellite markers. The entire coding region of the p53 gene (exons 2-11) was analyzed for mutations by denaturing high-pressure liquid chromatography and sequencing. p53 protein expression was evaluated by immunohistochemistry. Patients were treated with a cisplatin-based, neoadjuvant chemotherapy regimen. Therapy response was evaluated by computed tomography scan, endoscopy, and endoluminal ultrasound. The median follow-up of the patients was 45.6 months. RESULTS: p53 mutations were identified in 19 of the 53 (36%) analyzed tumors. No significant association with response or survival was found for p53 mutation or for p53 protein expression. MSI (either high-grade MSI or low-grade MSI) did not show a correlation with response. With respect to LOH, LOH at chromosome 17p13 showed a significant association with therapy response (P = 0.022) but did not reach statistical significance in terms of patient survival. The global LOH rate, expressed as fractional allelic loss (FAL), was assessed, and tumors were classified into tumors with a high (>0.5), medium (>0.25-0.5), and low (0-0.25) FAL value. A statistically significant association of FAL with therapy response was found (P = 0.003), with a high FAL being related to therapy response. The sensitivity, specificity, positive predictive value, and negative predictive value for FAL > 0.5 were 45%, 93%, 82%, and 72%, respectively. CONCLUSIONS: A high level of chromosomal instability (high FAL value) defines a subset of patients who are more likely to benefit from cisplatin-based neoadjuvant chemotherapy. p53 mutation status is not significantly associated with therapy response and is not a useful marker for response prediction.     

Non-invasive detection of fecal protein kinase C betaII and zeta messenger RNA: putative biomarkers for colon cancer

We have developed a non-invasive method utilizing feces, containing sloughed colonocytes, as a sensitive technique for detecting diagnostic colonic biomarkers. In this study, we used the rat colon carcinogenesis model to determine if changes in fecal protein kinase C (PKC) expression have predictive value in monitoring the neoplastic process. Weanling rats were injected with saline or azoxymethane (AOM) and 36 weeks later fecal samples and mucosa were collected, poly A+ RNA isolated, and quantitative RT-PCR performed using primers to PKC betaII and zeta. Fecal PKC betaII and zeta mRNA levels were altered by the presence of a tumor, with tumor-bearing animals having a 3-fold higher (P < 0.05) PKC betaII expression as compared with animals without tumors. In addition, AOM-injection increased mucosal PKC betaII mRNA expression compared with saline controls. No effect of tumor incidence on mucosal PKC betaII expression was observed. In contrast, fecal PKC zeta expression was 2.5-fold lower (P < 0.05) in animals injected with azoxymethane versus saline. Since tumor incidence exerts a reciprocal effect on fecal PKC betaII and zeta mRNA expression, data were also expressed as the ratio between PKC betaII and zeta. The isozyme ratio was strongly related to tumor incidence, i.e. ratio for animals with tumors was 2.18 +/- 1.25, animals without tumors was 0.50 +/- 0.16, P = 0.025. We demonstrate that the expression of fecal PKC betaII and zeta may serve as a noninvasive marker for development of colon tumors. A sensitive technique for the detection of colon cancer is of importance since early diagnosis can substantially reduce mortality.      

Advances in computer-assisted single-photon emission computed tomography (SPECT) for epilepsy surgery in children

Epilepsy surgery has emerged as an important option in the treatment of children with epilepsy that is refractory to antiepileptic drug management. The cornerstone of successful surgery is accurate localization of the brain region of seizure onset. Traditional techniques of seizure onset localization, e.g. surface electroencephalography (EEG) recording and magnetic resonance imaging (MRI), allow accurate localization in a significant number of patients. When the focus of seizure onset is not apparent from these non-invasive techniques, other methods of localization, e.g. intracranial EEG recording, may be needed before resection of the focus. Single-photon emission computed tomography (SPECT) is a nuclear medicine blood-flow technique that has been used to identify a region of epileptogenic brain associated with low blood flow in the resting state (interictal SPECT) or increased blood flow at the time of seizure activity (ictal SPECT). This report describes the validation and utility of a computer-assisted method of subtracting the interictal from the ictal SPECT scans and co-registering the difference image on the MRI. This method, called subtraction ictal SPECT co-registered on MRI (SISCOM), is used in guiding the location and the extent of intracranial electrode implantation, or in obviating the need for the implantation in some cases.