Horst D. Becker

Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing

For many years, lactate has been known to accelerate collagen deposition in cultured fibroblasts and, without detailed explanation, has been presumed to stimulate angiogenesis. Similarly, hypoxia has been linked to angiogenic effects and collagen deposition from cultured cells. Paradoxically, however, wound angiogenesis and collagen deposition are increased by breathing oxygen and decreased by hypoxia. Lactate accumulates to 4–12 mM in wounds for several reasons, only one of which is the result of hypoxia. Oxygen in wounds is usually low but can be increased by breathing oxygen (without change in lactate). We have reported that lactate elicits vascular endothelial growth factor (VECF) from macrophages, as well as collagen, some heat shock proteins, and VECF from endothelial cells, and collagen from fibroblasts, even in the presence of normal amounts of oxygen. Hypoxia exerts many of these same effects in cultured cells. In this study, we elevated extracellular lactate in wounds by implanting purified solid‐state, hydrolysable polyglycolide. A steady‐state 2–3 mM additional elevation of lactate resulted. With it, there was a significant short‐term elevation of interleukin‐1β, a long‐term elevation of VECF (2×) and transforming growth factor‐β1 (2–3×), a 50% elevation in collagen deposition, and a large reduction of insulin‐like growth factor‐1 (− 90%). We propose that lactate induces a biochemical “perception” of hypoxia and instigates several signals that activate growth factor/cytokine signals while the continued presence of molecular oxygen allows endothelial cells and fibroblasts to reproduce and deposit collagen. The data are consistent with ADP‐ribosylation effects and oxidant signaling. (WOUND REP REG 2003;11:504–509)

Identification of tumor-associated MHC class I ligands by a novel T cell-independent approach.

Specific immunotherapy of cancer utilizes tumor‐directed cytotoxic T lymphocytes (CTL) that lyse tumor cells presenting MHC class I‐associated peptides derived from tumor‐associated proteins. Many tumor‐associated gene products are known, but corresponding T cell epitopes are only known for relatively few of these. The most commonly used approaches to identify such antigens require pre‐existing CTL lines or clones. By using a CTL‐independent high performance liquid chromatography mass spectrometry (HPLC MS)–based approach we identified HLA‐A2‐presented peptides from carcinoembryonic antigen and wild‐type p53 with a copy number as low as eight molecules per cell. Potential epitopes were predicted from the sequences of known tumor antigens and the corresponding synthetic peptides were analyzed by nanocapillary HPLC MS. In parallel, peptides were extracted from fresh, solid tumor tissue or tumor cell lines and analyzed in the same way. Upon co‐elution of a natural peptide with a predicted peptide of the same mass, the peptide sequence was confirmed by on‐line tandem MS. This approach allows rapid screening of large numbers of tumor‐associated gene products for naturally processed peptides presented by different MHC class I molecules as a prerequisite for efficient epitope identification and rapid transfer to therapeutic vaccine trials.

High prevalence of bone disorders after gastrectomy

BACKGROUND Studies indicate that gastrectomy might alter calcium and bone metabolism, resulting in bone disorders. No data are currently available on the prevalence of bone disorders after gastrectomy. METHODS Sixty gastrectomy patients were investigated for serum parameters of calcium and bone metabolism 5 to 20 years postoperatively and compared to an age- and sex-matched healthy control population. Forty patients agreed to a radiological investigation of the spine by anterior-posterior and lateral radiographs of the thoracic and lumbar spine and by computed tomography (CT) osteodensitometry. RESULTS Serum calcium and 25-(OH)-vitamin D were decreased in gastrectomized patients, while parathyroid hormone and 1,25-(OH)2-vitamin D were increased. Serum parameters of calcium metabolism were altered in as many as 68% of patients. We found 31 vertebral fractures in 13 patients, 30 grade 2 vertebral deformities in 18 patients, and osteopenia in 15 patients, corresponding to a prevalence of 33%, 45%, and 37% in gastrectomized patients, respectively. The overall rate of gastrectomy patients having vertebral fractures and/or osteopenia was 55%. The risk of having a vertebral deformity was increased by more than sixfold after gastrectomy. Our study is the first report evaluating vertebral deformities in gastrectomized patients, and the largest series of gastrectomized patients investigated by CT osteodensitometry. CONCLUSION We found a high prevalence of bone disorders in gastrectomized patients, possibly resulting from disorders in calcium metabolism. Postgastrectomy bone disease might derive from a calcium deficit, which increases calcium release from bone and impairs calcification of newly build bone matrix.

Surgical management of peptic ulcer disease today-indication, technique and outcome

Abstract  Aims: The current surgical management of peptic ulcer disease and its outcome have been reviewed. Results: Today, surgery for peptic ulcer disease is largely restricted to the treatment of complications. In peptic ulcer perforation, a conservative treatment trial can be given in selected cases. If laparotomy is necessary, simple closure is sufficient in the large majority of cases, and definitive ulcer surgery to reduce gastric acid secretion is no longer justified in these patients. Laparoscopic surgery for perforated peptic ulcer has failed to prove to be a significant advantage over open surgery. In bleeding peptic ulcers, definitive hemostasis can be achieved by endoscopic treatment in more than 90% of cases. In 1–2% of cases, immediate emergency surgery is necessary. Some ulcers have a high risk of re-bleeding, and early elective surgery might be advisable. Surgical bleeding control can be achieved by direct suture and extraluminal ligation of the gastroduodenal artery or by gastric resection. Benign gastric outlet obstruction can be controlled by endoscopic balloon dilatation in 70% of cases, but gastrojejunostomy or gastric resection are necessary in about 30% of cases. Conclusions: Elective surgery for peptic ulcer disease has been largely abandoned, and bleeding or obstructing ulcers can be managed safely by endoscopic treatment in most cases. However, surgeons will continue to encounter patients with peptic ulcer disease for emergency surgery. Currently, laparoscopic surgery has no proven advantage in peptic ulcer surgery.

Perianal abscess in Crohn's disease.

PURPOSE: Perianal disease is frequent in patients with Crohns disease, and many of these patients will eventually have abscess formation. In a prospective follow-up study, we evaluated factors influencing the occurrence and recurrence of perianal abscesses. METHODS: Of 126 consecutive patients with perianal Crohns disease seen regularly in an outpatient clinic, 61 (48.4 percent) had at least one perianal abscess (mean follow-up, 32±17 months). In all, 110 episodes of an abscess with 145 anatomically distinct abscesses were documented. RESULTS: The occurrence of first abscesses was dependent on the type of anal fistula (ischiorectal, 73 percent; transsphincteric, 50 percent; superficial, 25 percent;P< 0.02). Surgical therapy consisted of seton drainage (34 percent), mushroom catheter drainage (49 percent), or incision and drainage (29 percent) and led to inactivation in all patients. Cumulative two-year recurrence rates after the first and second abscess were 54 and 62 percent, respectively. Abscess recurrence was less frequent in patients with a stoma (13vs.60 percent in patients without stoma after two years) and in patients with superficial anal fistulas (0vs.55 percent/56 percent in patients with transsphincteric/ischiorectal fistulas). Only two abscesses recurred within one year after removal of seton drainage, whereas 13 abscesses recurred with the seton still in place. Neither intestinal nor rectal activity of Crohns disease significantly influenced the occurrence of an abscess. During the study period, only two patients developed partial stool incontinence. CONCLUSION: Development of perianal abscesses in Crohns disease depends on the fecal stream and the anatomic type of anal fistula. Seton and catheter drainage are safe and highly effective in treatment. Long-term use of setons to prevent recurrent abscesses is not supported by our data.

C-fos protein expression in the nucleus of the solitary tract correlates with cholecystokinin dose injected and food intake in rats

C-fos protein expression was investigated in the nucleus of the solitary tract (NTS) in response to increasing cholecystokinin (CCK) doses and food intake in rats by counting the number of c-fos protein positive cells in the NTS. C-fos protein expression in the NTS dose-dependently increased in response to CCK, the lowest effective dose being 0.1 microg/kg. The ED(50) for c-fos protein expression in the NTS in response to CCK was calculated to be 0.5 to 1.8 microg/kg, depending on the anatomical level of the NTS investigated. Food intake increased c-fos protein expression in the NTS, the maximum number of c-fos protein positive cells being reached at 90 min after the start of food intake. Regression analysis identified a positive correlation between c-fos protein expression and the amount of food intake. Our data indicate that subpopulations of the NTS that are activated by CCK or food intake are involved into the short-term regulation of food intake and the neural control of feeding by the caudal brainstem.

Level of the anastomosis does not influence functional outcome after anterior rectal resection for rectal cancer

Anorectal function was studied in 55 patients undergoing low anterior resection for rectal adenocarcinoma. Patients were examined preoperatively and 3 months postoperatively by anorectal manometry and standardized interview. Postoperatively, the patients showed, in general, an impairment of anorectal functions. After 3 months, continence for flatus was defective, the ability to discriminate flatus from feces, and the ability to defer defecation were compromised. Stool frequency was elevated, and anal resting pressure, squeeze pressure, and rectal compliance were decreased. The rectoanal inhibitory reflex was abolished in all patients. However, the two groups with the level of the anastomosis less than or equal to 6 cm (n = 27, range 3 to 6) and more than 6 cm (n = 28, range 7 to 10) above the anal verge showed no differences in manometric values, stool frequency, or fecal continence assessed by the interview. No correlation was found between the level of the anastomosis and manometric values and between the level of the anastomosis and stool frequency (regression analysis = not significant). We concluded that anorectal function after anterior resection and low colorectal anastomosis are not influenced by the remaining length of the rectum but by the surgical trauma to the sphincter and its innervation.

Functional results after transanal endoscopic microsurgery

PURPOSE: Compared with traditional operations, superior results after transanal endoscopic microsurgery (TEM) for rectal tumors have been demonstrated in terms of morbidity and mortality. However, no data were available on functional outcome after TEM. We, therefore, studied 42 patients who were undergoing TEM. METHODS: Patients were examined by anorectal manometry and participated in a standardized interview preoperatively and three months and one year after surgery. RESULTS: Anorectal function as assessed by manometry was impaired three months after surgery but improved again during the first postoperative year. In parallel, some patients complained of impaired continence or defecation disorders in the interview three months postoperatively. These functions improved during the first year after surgery, too. CONCLUSIONS: Correct comparison of our results with functional outcome after anterior rectal resection is impossible. We feel, however, that functional results after TEM are likely to be superior to those after anterior resection for rectal tumors.

Long-term outcome of conservative treatment in patients with diverticulitis of the sigmoid colon.

Introduction The indication for surgery after conservative treatment of acute diverticulitis is still under debate. This is partly as a result of limited data on the outcome of conservative management in the long run. We therefore aimed to determine the long-term results of conservative treatment for acute diverticulitis. Methods The records of all patients treated at our institution for diverticulitis between 1985 and 1991 were reviewed (n=363, median age 64 years, range 29–93). Patients who received conservative treatment were interviewed in 1996 and 2002 [follow-up time 7 years 2 months (range 58–127 months) and 13 years 4 months (range 130–196 months). Results A total of 252 patients (69%) were treated conservatively, whereas 111 (31%) were operated on. At the first follow-up, 85 patients treated conservatively had died, one of them from bleeding diverticula. A recurrence of symptoms was reported by 78 of the remaining 167 patients, and 13 underwent sugery. At the second follow-up, one patient had died from sepsis after perforation during another episode of diverticulitis. Thirty-one of the 85 patients interviewed reported symptoms and 12 had been operated on. In summary, at the second follow-up interview, 34% of patients treated initially had had a recurrence and 10% had undergone surgery. No predictive factors for the recurrence of symptoms or later surgery could be determined. Conclusion Despite a high rate of recurrences after conservative treatment of acute diverticulitis, lethal complications are rare. Surgery should thus mainly be undertaken to achieve relief of symptoms rather than to prevent death from complications.

Local therapy of rectal tumors

PURPOSE: The aim of the study is to outline the rising importance of local treatment of rectal tumors and a changing strategy in therapy of early rectal cancer. METHODS: As the surgical procedure, transanal endoscopic microsurgery was used. Indications for the local procedure were pT1 low-risk tumors and tumors of higher stages in patients with severe risk factors and of those who refused the operation according to oncologic guidelines. RESULTS: A total of 236 rectal adenomas and 98 carcinomas were locally excised using the transanal endoscopic microsurgery technique. Mortality rate was 0.3 percent, and rate of complications requiring surgical reintervention was 5.5 percent in adenomas and 8 percent in carcinomas. Final histology of removed carcinomas revealed 56 pT1, 27 pT2, and 15 pT3 stages. After an average follow-up time of 24 months, two recurrences were observed in the group of patients with pT1 low-risk carcinomas who only underwent local therapy. In both cases, a second intervention for cure was undertaken but for tumors in a late stage. CONCLUSIONS: In selected cases, local therapy of rectal carcinoma avoids high morbidity and mortality of the classical operation. Quality of life will be improved, especially if an artificial anus can be avoided. In case of recurrence, the chance of a secondary procedure for cure is not to be underestimated.