Hyperbaric Oxygen Therapy and Tissue Regeneration: A Literature Survey.

By addressing the mechanisms involved in transcription, signaling, stress reaction, apoptosis and cell-death, cellular structure and cell-to-cell contacts, adhesion, migration as well as inflammation; HBO upregulates processes involved in repair while mechanisms perpetuating tissue damage are downregulated. Many experimental and clinical studies, respectively, cover wound healing, regeneration of neural tissue, of bone and cartilage, muscle, and cardiac tissue as well as intestinal barrier function. Following acute injury or in chronic healing problems HBO modulates proteins or molecules involved in inflammation, apoptosis, cell growth, neuro- and angiogenesis, scaffolding, perfusion, vascularization, and stem-cell mobilization, initiating repair by a variety of mechanisms, some of them based on the modulation of micro-RNAs. HBO affects the oxidative stress response via nuclear factor erythroid 2-related factor 2 (Nrf2) or c-Jun N-terminal peptide and downregulates inflammation by the modulation of high-mobility group protein B1 (HMGB-1), toll-like receptor 4 and 2 (TLR-4, TLR-2), nuclear factor kappa-B (NFκB), hypoxia-inducible factor (HIF-1α) and nitric oxide (NO•). HBO enhances stem-cell homeostasis via Wnt glycoproteins and mammalian target of rapamycin (mTOR) and improves cell repair, growth, and differentiation via the two latter but also by modulation of extracellular-signal regulated kinases (ERK) and the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway. The HBO-induced downregulation of matrix metalloproteinases-2 and 9 (MMP-2/-9), rho-associated protein kinase (ROCK) and integrins improve healing by tissue remodeling. Interestingly, the action of HBO on single effector proteins or molecules may involve both up- or downregulation, respectively, depending on their initial level. This probably mirrors a generally stabilizing potential of HBO that tends to restore the physiological balance rather than enhancing or counteracting single mechanisms.

Preoperative Glasgow Prognostic Score as additional independent prognostic parameter for patients with esophageal cancer after curative esophagectomy.

BACKGROUND: Inflammation accelerates tumor growth followed by reduced survival in patients with cancer. The aim of this study was to evaluate the prognostic relevance of preoperatively increased levels of C-reactive protein (CRP) and the corresponding Glasgow Prognostic Score (GPS) on patients with esophageal carcinoma undergoing curative esophagectomy. METHODS: The data of 174 operated esophageal cancer patients were evaluated retrospectively. Patient's demographic and clinico-pathological data, tumor specific data, preoperative plasma levels of CRP and albumin, the corresponding GPS, overall survival (OS) and progression free survival (PFS) were assessed. RESULTS: 103 (59.2%) had adenocarcinoma and 71 (40.8%) had squamous cell carcinoma. 71 patients (43%) had elevated CRP concentrations. 118 patients (71%) had GPS 0, 41 (25%) GPS 1 and 8 (4%) GPS 2. Mean GPS was 0.3 (0-2). 5-year OS was higher in patients with normal CRP than in those with increased CRP (68% vs. 39%; p = 0.007). 5-year OS in patients with GPS 0 and GPS 1 and 2 were 65% and 31% (p = 0.001). 5-year OS for the whole cohort was 56% (1 year: 83%, 3 years: 64%). Recurrence rate was 16.1% closely associated with GPS (p = 0.002). Median follow-up was 23 months (0-118 months). In multivariate analysis GPS, lymph node involvement, T stage and tumor histology were the independent prognostic parameters (p = 0.004, <0.001, 0.035, 0.010). CONCLUSIONS: Preoperatively increased GPS is significantly associated with reduced postoperative survival and tumor recurrence. The GPS as an independent prognosticator should be interpreted together with the TNM stage when the further postoperative treatment has to be scheduled.

PCK2 activation mediates an adaptive response to glucose depletion in lung cancer.

Cancer cells are reprogrammed to utilize glycolysis at high rates, which provides metabolic precursors for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis results in the generation of glucose from smaller carbon substrates such as lactate and amino acids. The key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been shown to provide metabolites for cell growth. Still, the role of gluconeogenesis in cancer is unknown. Here we show that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in three lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low-glucose conditions. PEPCK activity was elevated threefold in lung cancer samples over normal lungs. To track the conversion of metabolites along the gluconeogenesis pathway, lung cancer cell lines were incubated with (13)C3-lactate and label enrichment in the phosphoenolpyruvate (PEP) pool was measured. Under low glucose, all three carbons from (13)C3-lactate appeared in the PEP pool, further supporting a conversion of lactate to pyruvate, via pyruvate carboxylase to oxaloacetate, and via PCK2 to phosphoenolpyruvate. PCK2 small interfering RNA and the pharmacological PEPCK inhibitor 3-mercaptopicolinate significantly enhanced glucose depletion-induced apoptosis in A549 and H23 cells, but not in H1299 cells. The growth of H23 multicellular spheroids was significantly reduced by 3-mercaptopicolinate. The results of this study suggest that lung cancer cells may utilize at least some steps of gluconeogenesis to overcome the detrimental metabolic situation during glucose deprivation and that in human lung cancers this pathway is activated in vivo.

Resection in stage I/II non-small cell lung cancer.

In spite of the developments in chemo- and radiotherapy, surgery remains the mainstay of curative treatment of early stage non-small cell lung cancer (NSCLC). In stage Ia/Ib (T1, T2, N0), NSCLC lobectomy offers the best chance for cure, yielding survival rates of between 58 and 76%. Since the extent of mediastinal lymph node dissection does not seem to play a major prognostic role in stage Ia, video-thoracoscopic lobectomy yields equally good results as the open approach. Due to the necessity for a small thoracotomy when harvesting the specimen and the time-consuming lymph-node dissection minimally invasive lobar resections have failed to become routinely used. Minor resections, though sometimes necessary from the functional point of view, have a lower curative potential. They yield the best results if applied in tumors measuring less than 2 cm. Stage II, characterized by involvement of the N1-position and/or a more central tumor growth, has a 5-year survival of 45-52% and requires treatment by lobectomy or pneumonectomy. Sleeve resection may obviate the need for pneumonectomy in central upper-lobe tumors. In interlobar N1, however, pneumonectomy is indicated from the oncological point of view, since even meticulous lymph-node dissection is unable to achieve tumor control in this situation.

Influence of route of gastric transposition on oxygen supply at cervical oesophagogastric anastomoses.

BACKGROUND: The microcirculation and oxygen supply at the oesophagogastric anastomosis are crucial factors that influence anastomotic healing after oesophagectomy. METHODS: Twenty-nine patients (mean age 61.7 years) underwent gastric transposition via an orthotopic (14) or retrosternal (15) route. Interstitial partial pressure of oxygen (PO2) of the stomach in the anastomotic region was measured during oesophagectomy and in the intensive care unit. Interstitial PO2 values were determined after ligation of the short gastric vessels, after ligation of the left gastric artery, after forming the conduit and after gastric transposition. Postoperative measurements were recorded during endotracheal intubation, while breathing oxygen by mask or through the nose, and while breathing air. RESULTS: Interstitial PO2 levels were significantly higher before ligation of the left gastric artery than after ligation (mean 76.1 (95 per cent confidence interval 54.9 to 103.1) versus 44.9 (24.6 to 77.1) mmHg; P = 0.001). Levels were also higher following orthotopic transposition compared with the retrosternal route (68.2 (44.0 to 118.8) versus 24.6 (10.7 to 39.4) mmHg; P = 0.001) and during each postoperative measurement period. No differences were found between the various oxygen supply systems. CONCLUSION: Oxygen supply at the anastomosis of the gastric conduit reaches higher levels after orthotopic than retrosternal gastric transposition.

How to chase a red herring and come up with a smallmouth bass.

The collaboration between Alick Isaacs and myself started in the summer of 1956. Our initial project was to show, by electron microscopy, that interference between inactivated influenza virus and live virus involved the transfer of material from the interfering virus to the host cell. This approach failed for technical reasons. However, in the course of this work it appeared that more interfering activity remained in the system than we were entitled to expect. One possible explanation was that a substance, not identical with the initial interfering virus, was being generated. Subsequent experiments, aimed at checking this hypothesis, led to the description of interferon.

Hyperbaric oxygenation in the treatment of life-threatening isobutyl nitrite-induced methemoglobinemia--a case report.

Methemoglobinemia usually results from exposure to oxidizing substances such as nitrates or nitrites. Iron within hemoglobin is oxidized from the ferrous (Fe2+) state to the ferric (Fe3+) state, resulting in the inability to transport oxygen and carbon dioxide. Clinically, this condition causes functional cyanosis. As methemoglobin levels increase, patients show evidence of cellular hypoxia in all tissues. Death usually occurs when methemoglobin fractions approach 70% of total hemoglobin. We describe the case of a 35-year-old female patient with severe life-threatening isobutyl nitrite-induced methemoglobinemia of 75% of total hemoglobin. Toluidine-blue was administered as first-line antidotal therapy immediately, followed by hyperbaric oxygenation. The patient recovered uneventfully and could be discharged 3 days later.

Early enteral feeding compared with parenteral nutrition after oesophageal or oesophagogastric resection and reconstruction.

After resective and reconstructive surgery in the gastrointestinal tract, oral feeding is traditionally avoided in order to minimize strain to the anastomoses and to reduce the inherent risks of the postoperatively impaired gastrointestinal motility. However, studies have given evidence that the small bowel recovers its ability to absorb nutrients almost immediately following surgery, even in the absence of peristalsis, and that early enteral feeding would preserve both the integrity of gut mucosa and its immunological function. The aim of this study was to investigate the impact of early enteral feeding on the postoperative course following oesophagectomy or oesophagogastrectomy, and reconstruction. Between May 1999 and November 2002, forty-four consecutive patients (thirty-eight males and six females; mean age 62, range 30-82) with oesophageal carcinoma (stages I-III), who had undergone radical resection and reconstruction, entered this study (early enteral feeding group; EEF). A historical group of forty-four patients (thirty-seven males and seven females; mean age 64, range 41-79; stages I-III) resected between January 1997 and March 1999 served as control (parenteral feeding group; PF). The duration of both postoperative stay in the Intensive Care Unit (ICU) and the total hospital stay, perioperative complications and the overall mortality were compared. Early enteral feeding was administered over the jejunal line of a Dobhoff tube. It started 6 h postoperatively at a rate of 10 ml/h for 6 h with stepwise increase until total enteral nutrition was achieved on day 6. In the controls oral enteral feeding was begun on day 7. If compared to the PF group, EEF patients recovered faster considering the duration of both stay in the ICU and in the hospital. There was a significant difference in the interval until the first bowel movements. No difference in overall 30 d mortality was identified. A poor nutritional status was a significant prognostic factor for an increased mortality. Early enteral feeding significantly reduces the duration of ICU treatment and total hospital stay in patients who undergo oesophagectomy or oesophagogastrectomy for oesophageal carcinoma. The mortality rate is not affected.

Invasion of blood vessels as significant prognostic factor in radically resected T1-3N0M0 non-small-cell lung cancer.

OBJECTIVES: Radical resection is the therapy of choice in non-small-cell lung cancer (NSCLC). However, even in early stages (T1N0, T2N0) up to 35% of patients will experience recurrence. The aim of this retrospective study was to evaluate the prognostic influence of lymph vessel or blood vessel invasion in N0 patients. METHODS: A total of 72 patients (male, 49; female, 23; median age 59; range 40-72) with NSCLC entered the study. The stages were T1-3N0 (T1, 25; T2, 41; T3, 6). Thirteen pneumonectomies and 59 lobectomies or bilobectomies with systematic lymphadenectomy and R0 resection were performed. Histologically, 24 adenocarcinomas, 31 squamous cell carcinomas and 14 subtypes of large cell carcinoma were found. In 22 cases microscopic invasion of the lymphatic vessels and in 11 invasions of blood vessels were found. Six patients showed invasion of either structure. RESULTS: The patients were followed up for at least 5 years or until death. During the follow-up period 27 patients died (21 because of recurrence and 6 because of diagnosis not related to NSCLC). The 5 years overall survival amounted to 62.5%. In cases with invasion of the blood vessels the survival rate was 23.5%, in cases without invasion 74.5% (P< or = 0.01), whereas lymph vessel invasion had no significant impact on survival. Multivariate analysis covering T stages, histological subtypes, location of the tumor, grading, age, sex, and invasion of the lymphatic or the blood vessels showed invasion of the blood vessels as the only factor with significant prognostic impact in the study population. CONCLUSIONS: In resectable N0 patients with NSCLC the microscopic invasion of blood vessels should be considered as an additional prognostic parameter.

[Transgressing the limits of naturopathy]. / Grenzüberschreitungen der Naturheilkunde.

Three examples of the tendency of nonconventional medicine to transgress its self-imposed limits are presented: (1) the efforts of Benveniste to confer scientific respectability on homeopathy; (2) the attempt, by press conference, to popularize home delivery; (3) the creation of a new demand by the offer of subaquatic delivery.

[Jejunum perforation following blunt abdominal trauma--a case report]. / Jejunumperforation nach stumpfem Bauchtrauma--ein Fallbericht.

We describe an intestinal perforation in a football player who had been hit with the knee in the abdomen. Perforation of the small bowel, following blunt abdominal trauma, is relatively rare. Its most frequent cause is a deceleration trauma, usually from a traffic accident. Clinical signs are frequently discrete and nonspecific. The most frequent symptom is abdominal pain. Lack of bowel sounds is reported in 64% oft the cases. Enteric lesions should be suspected in the presence of a corresponding history (deceleration trauma) and of other pathologies (fractures of vertebrae and/or pelvis). Sonography and computed tomography are rarely helpful. Delayed perforations have been described, necessitating prolonged observation for 48 to 72 h. after painful abdominal trauma. Repeated examinations are essential to rule out enteric perforation. Initially, less than 50% of the cases show free air, thus limiting the usefulness of thoracic and abdominal radiography. Mortality reaches 30%. This rate is adversely affected by concomitant lesions in other organs and by delay (more than 10 h.) in diagnosis. When laparotomy has been delayed and peritonitis is present, antibiotic treatment should be started immediately during surgical intervention (cephalosporin, aminoglycoside, metronidazole). Postoperative complications include septicaemia, wound infection and, rarely, enterocutaneous fistulae.