The clinical picture of cachexia: a mosaic of different parameters (experience of 503 patients).

BACKGROUND: Despite our growing knowledge about the pathomechanisms of cancer cachexia, a whole clinical picture of the cachectic patient is still missing. Our objective was to evaluate the clinical characteristics in cancer patients with and without cachexia to get the whole picture of a cachectic patient. METHODS: Cancer patients of the University Clinic "Klinikum rechts der Isar" with gastrointestinal, gynecological, hematopoietic, lung and some other tumors were offered the possibility to take part in the treatment concept including a nutrition intervention and an individual training program according to their capability. We now report on the first 503 patients at the time of inclusion in the program between March 2011 and October 2015. We described clinical characteristics such as physical activity, quality of life, clinical dates and food intake. RESULTS: Of 503 patients with cancer, 131 patients (26.0%) were identified as cachectic, 369 (73.4%) as non-cachectic. The change in cachexia were 23% reduced capacity performance (108 Watt for non-cachectic-patients and 83 Watt for cachectic patients) and 12% reduced relative performance (1.53 Watt/kg for non-cachectic and 1.34 Watt/kg for cachectic patients) in ergometry test. 75.6% of non-cachectic and 54.3% of cachectic patients still received curative treatment. CONCLUSION: Cancer cachectic patients have multiple symptoms such as anemia, impaired kidney function and impaired liver function with elements of mild cholestasis, lower performance and a poorer quality of life in the EORTC questionnaire. Our study reveals biochemical and clinical specific features of cancer cachectic patients.

Influence of an elevated nutrition risk score (NRS) on survival in patients following gastrectomy for gastric cancer.

In the last years, the impact of weight loss in patients with malignant tumors has come more and more into the focus of clinical research, as the occurrence of weight loss is often associated with a reduced survival. Weight loss can be a hint for metastases in patients suffering from malignant tumors; furthermore, these patients are usually not able to be treated with chemotherapy. The aim of the study was to show the influence of weight loss and an elevated nutrition risk score on survival following tumor resection in patients suffering from gastric cancer. In 99 patients in whom a gastrectomy due to gastric cancer was performed, the nutrition risk score was calculated and its influence on mortality, morbidity and survival was analyzed. Of the included patients, 45 % of the patients gave a history of weight loss; they had significantly more often a NRS ≥ 3. In UICC stage 1a/b, a NRS ≥ 3 was associated with a significantly reduced survival compared to patients with a NRS < 3. In early tumor stages (UICC 1a/b), a NRS ≥ 3 was associated with a significantly reduced survival, while in progressed tumor stage, the influence of a poor NRS was not significant. This seems to show that in progressed stages in patients with gastric cancer, the influence of a reduced NRS is negligible.

Transferring innovative freehand SPECT to the operating room: first experiences with sentinel lymph node biopsy in malignant melanoma.

PURPOSE: The purpose of this study was to report on the first experiences with freehand single-photon emission-computed tomography (freehand SPECT) in sentinel lymph node biopsy (SLNB) in patients with malignant melanoma. Freehand SPECT is a novel imaging modality combining gamma probes, surgical navigation systems, and emission tomography algorithms, designed to overcome some of the limitations of conventional gamma probes. METHODS: In this study 20 patients with malignant melanoma underwent conventional planar scintigraphy prior to surgery. In the operating room, the number and location of separable SLNs were detected first by a pre-incisional scan with freehand SPECT to render a 3D-image of the target site and afterwards by a scan with a conventional gamma probe. After SLNB another scan was performed to document the removal of all targeted SLNs. RESULTS: Planar scintigraphy identified 40 SLNs in 26 nodal basins. Pre-incisional freehand SPECT mapped 38 of these nodes as well as one additional node in one patient (95.0% node based sensitivity). The results of freehand SPECT were identical to those of planar scintigraphy in 25 basins, while it missed one basin (96.2% basin based sensitivity). In comparison, the gamma probe failed to detect 7 nodes in 4 basins (82.5% node based sensitivity and 84.6% basin based sensitivity). After resection freehand SPECT detected 9 remaining radioactive spots, two of whichwere resected as they matched the position of SLNs detected on preoperative planar scintigraphy. CONCLUSIONS: Freehand SPECT provides a real-time, intraoperative 3D-image of the radioactive labelled SLNs, facilitating their detection and resection.

First Experiences with Navigated Radio-Guided Surgery Using Freehand SPECT.

BACKGROUND: Sentinel lymph node biopsy (SLNB) in melanoma using one-dimensional gamma probes is a standard of care worldwide. Reports on the performance are claimed by most groups to successfully detect the SLNs during the surgical procedure in almost 100% of the patients. In clinical practice, however, several issues remain which are usually not addressed: the difficulty of intraoperative detection of deeply located nodes, SLN detection in obese patients or in the groin and the impossibility to make a scan of the entire wound after SLN resection to avoid false negative testing for eventually remaining SLNs. MATERIALS AND METHODS: The concept behind freehand SPECT is to combine a gamma probe as used for conventional radio-guided surgery with a tracking system as used in neurosurgical navigation. From this combination and a proper algorithm framework the 3D reconstruction of radioactivity distributions and displaying these intraoperatively is possible. CONCLUSION: In summary, the feasibility of freehand SPECT could be shown and provides an image-guided SLNB and a truly minimally invasive and optimized surgical procedure.

[Molecular mechanisms and its clinical impact in cancer cachexia]. / Molekulare Mechanismen und klinische Auswirkungen der Tumorkachexie.

Cachexia is a term used to describe the poor status of a patient suffering from a benign disease (Crohn's disease, chronic heart and kidney failure) as well as from a malignant disease. Cachexia has an important impact on the survival and morbidity in patients with cancer. The aim of this study is to elucidate the pathophysiology in cancer cachexia with a special emphasis on pancreatic cancer. The dramatic weight loss in malignant diseases is due to anorexia resulting in malnutrition and is characterised by a progressive loss of muscle and fat tissue. Different cytokines like TNF-alpha, IFN-gamma, IL-1, IL-6 are involved in this process. Via the ubiquitin-proteasome pathway, in which also the proteolysis inducing factor (PIF) is involved, the majority of protein is degraded. In patients with cancer cachexia we find an elevated level of lipases, which indicates that rather fat catabolism and not reduced fat synthesis is the main factor in fat metabolism. The development of an effective (pharmacological) treatment is still the main challenge. As yet, none of the used therapies show a long-lasting effect on weight stabilisation and survial. Cachexia is an important issue, especially in pancreatic cancer; it influences the qualitiy of life and has an important impact on survival. Today, there are only a few different pharmacological therapies used in the treatment of cancer cachexia, but each and every single treatment has failed to show a persistent effect on survival. The aim of research and treatment is to interrupt the natural clinical course of cachexia.

Comparing the TiOblast and Osseospeed surfaces. Histomorphometric and histological analysis in humans.

The aim of the present study was to compare two implant surfaces, the TiOblast (Astra Tech) surface, manufactured by blasting the surface and already present in literature and the Osseospeed (Astra Tech) surface, manufactured by blasting and treating the surface with fluoride ions and recently launched onto the market with the modified surfaces of the latest generation. This study is part of a more extensive research project whose protocol required the insertion of 10 couples of implants; thus in the present discussion partial data are being taken into consideration, with an eye at collecting more data in the future, regarding both microscopy and histomorphometric histological analysis on 5 couples of implants. The purpose of the study is to investigate how the modified surfaces of the latest generation can guarantee a greater osseointegration both from a qualitative and quantitative level compared to the surfaces presently used and that they may represent the first example of "bioactivity", that is, an active interaction with the processes of new bone formation and tissue healing.

Randomized clinical trial of the influence of local water-filtered infrared A irradiation on wound healing after abdominal surgery.

BACKGROUND: Postoperative local water-filtered infrared A (wIRA) irradiation improves tissue oxygen partial pressure, tissue perfusion and tissue temperature, which are important in wound healing. METHODS: The effect of wIRA irradiation on abdominal wound healing following elective gastrointestinal surgery was evaluated. Some 111 patients undergoing moderate to major abdominal surgery were randomized into one of two groups: wIRA and visible light irradiation (wIRA group) or visible light irradiation alone (control group). Uncovered wounds were irradiated twice a day for 20 min from days 2-10 after operation. RESULTS: Irradiation with wIRA improved postoperative wound healing in comparison to visible light irradiation alone. Main variables of interest were: wound healing assessed on a visual analogue scale (VAS) by the surgeon (median 88.6 versus 78.5 respectively; P < 0.001) or patient (median 85.8 versus 81.0; P = 0.040), postoperative pain (median decrease in VAS score during irradiation 13.4 versus 0; P < 0.001), subcutaneous oxygen tension after irradiation (median 41.6 versus 30.2 mmHg; P < 0.001) and subcutaneous temperature after irradiation (median 38.9 versus 36.4 degrees C; P < 0.001). The overall result, in terms of wound healing, pain and cosmesis, measured on a VAS by the surgeon (median 79.0 versus 46.8; P < 0.001) or patient (79.0 versus 50.2; P < 0.001) was better after wIRA irradiation. CONCLUSION: Postoperative irradiation with wIRA can improve normal postoperative wound healing and may reduce costs in gastrointestinal surgery.

Clinical impact of cachexia on survival and outcome of cancer patients.

Approximately one half of all cancer patients experience a complex metabolic status involving progressive exhaustion of adipose and skeletal muscle tissue. This condition, known as cachexia, is responsible for more than 20% of the overall deaths in cancer patients. Although its main mechanisms remain unknown, several hypotheses have been proposed. One of the pathogenic mechanisms involves leptin and hypothalamic neuropeptide-containing pathways. Orexigenic and anorexigenic neuropeptides are down-regulated respectively upregulated as a result of cancer. Other pathogenic theories consider tumour derived factors, such as LMF (Lipid Mobilising Factor) and PIF (Proteolysis-inducing Factor), to be responsible for the weight losing pattern of cancer patients via activation of various catabolic pathways (e.g. ubiquitin-proteasome proteolytic-pathway, etc.). Despite the controversial discussion of cachexia-inducing mechanisms it is clear that proinflammatory cytokines, such as TNFalpha, IFNgamma, IL-1, IL-6 and IL-8, are linked to all pathways that induce cachexia. Although only limited treatment exists for patients with cancer cachexia, recent studies with eicosapaentanoic acid showed promising effects in reversing weight losing pattern of cachectic patients. Cytokine targeted monoclonal antibodies, cytokine traps and genetic therapies are also evaluated for future therapeutic strategies.

Endothelin receptor antagonists are not beneficial in the therapy of acute experimental pancreatitis.

BACKGROUND AND AIM: Due to increased capillary permeability and the early appearance of vasoactive and toxic agents, patients suffering from necrotizing pancreatitis frequently develop a systemic inflammatory response syndrome (SIRS). Endothelin, a potent vasoconstrictor, is thought to play a major role in these changes via the regulation of microcirculation. An improved outcome of acute experimental necrotizing pancreatitis by blocking the endothelin receptors ETA and ETB, either selectively (only ETA) or unselectively (ETA and ETB), has been suggested. The aim of this study was to investigate further the beneficial effects of new, highly potent endothelin-receptor (ET-R) antagonists in acute experimental pancreatitis. METHODS: The influence of the selective ET-RA antagonist BSF208075 (1 mg/kg) on mortality was studied in three severity groups of acute necrotizing pancreatitis (retrograde injection of 4%, 5% and 6% of sodium taurocholate into the main pancreatic duct). The effects of the selective ET-RA antagonists LU135252 (LU13) and BSF208075 (BSF20) and of the unselective endothelin receptor (ET-R(A/B)) antagonist BSF420627 (BSF42) were additionally analyzed in 4% taurocholate-induced necrotizing pancreatitis. Furthermore, the significance of variable doses of the endothelin receptor antagonist LU13 (1 mg/kg, 3 mg/kg and 100 mg/kg) was determined in a 4% sodium taurocholate model and in a cerulein pancreatitis model. RESULTS: Prophylactic ET-R antagonism increased the mortality rate in the 4% sodium taurocholate-induced pancreatitis. No reduction in pancreatic damage after induction of taurocholate pancreatitis was found by ET-R blockage. Application of ET-R antagonists had no beneficial influence in ascites development. However, administration of LU13 (100 mg/kg) resulted in a non-significant increase in pancreatic oedema, whereas peritoneal necrosis was not affected. CONCLUSION: The selective and unselective ET-R antagonists BSF20, BSF42 and LU13 failed to improve survival and pancreatic damage during acute experimental pancreatitis. Therefore, previously reported beneficial effects of ET-R antagonists in experimental acute pancreatitis have to be critically evaluated before conclusions for further clinical development are made.

Comparison of histological features and inflammatory cell reaction in alcoholic, idiopathic and tropical chronic pancreatitis.

BACKGROUND: There is increasing evidence that immune mechanisms may be crucial in the development of alcoholic chronic pancreatitis. However, it is not known whether differences in underlying aetiology influence the inflammatory reaction in patients with chronic pancreatitis. The histological features and the pattern of inflammatory cell infiltration were studied in three aetiological forms of chronic pancreatitis: alcoholic, idiopathic and tropical pancreatitis. METHODS: Forty-three patients, ten with alcoholic, 12 with idiopathic and 21 with tropical chronic pancreatitis, were evaluated for the pattern of pancreatic inflammatory cell infiltration and histological features. Ten organ donors served as controls. Haematoxylin and eosin-stained tissue sections were used for histological evaluation. For immunohistochemical characterization of the inflammatory reaction, four antibodies-CD4, CD8, CD45 and CD68-were used. Quantitative evaluation of the various cell infiltrates was performed with computer-assisted image analysis. The inflammatory cell infiltration pattern was also evaluated. RESULTS: The degree of endophlebitis and the overall density of plasma cells were greater in tropical than in alcoholic chronic pancreatitis. The grade of intralobular fibrosis was significantly higher in tropical chronic pancreatitis compared with the idiopathic form. No significant quantitative differences in the specific cellular infiltrates (CD4, CD8, CD45, CD68) were observed in the three different groups. However, the perivascular inflammation number score was significantly higher in alcoholic compared with idiopathic pancreatitis (P = 0.037), and the perivascular inflammation area score was significantly lower in idiopathic than in alcoholic (P = 0.024) or tropical (P = 0.020) pancreatitis. CONCLUSION: Different aetiological forms of chronic pancreatitis result in similar histological features and a comparable inflammatory cell reaction, indicating that the disease, independent of the underlying aetiology, reaches a common immunological stage beyond which it appears to progress as a single distinctive entity.

Neural alterations in surgical stage chronic pancreatitis are independent of the underlying aetiology.

BACKGROUND AND AIMS: Among various causes, nerve alterations and neuroimmune interactions have been suggested to participate in the generation of pain in chronic pancreatitis (CP). In this study, we compared neural changes and the pattern of perineural inflammatory cell infiltrates in three different aetiological forms of CP (alcoholic, idiopathic, and tropical) and evaluated whether differences exist between these groups. PATIENTS AND METHODS: A total of 35 patients with CP (12 tropical, 12 idiopathic, and 11 alcoholic) were included. Ten normal pancreatic tissues obtained from healthy organ donors served as controls. In all samples, the number of nerves, area of neural tissue, nerve size, and percentage of neural tissue and perineural inflammatory cell infiltrates were analysed histologically. RESULTS: The median number of nerves per 10 mm2 tissue area was 2.3, 4.3, 4.4, and 2.6 in the normal pancreas, alcoholic CP, idiopathic CP, and tropical CP, respectively. Median area of neural tissue per 10 mm2 was 2550, 21 803, 18 595, and 24 666 microm2 in the normal pancreas, alcoholic CP, idiopathic CP, and tropical CP, respectively. Median nerve diameter was 36.85 microm in the normal pancreas, 80.6 microm in alcoholic CP, 68.95 microm in idiopathic CP, and 93.05 microm in tropical CP. In comparison with normal controls, all of these parameters were significantly increased except the number of nerves in tropical CP. For all parameters there were no significant differences between alcoholic, idiopathic, and tropical CP. When the degree of perineural inflammation was evaluated, no differences were observed among the three CP groups. CONCLUSIONS: Independent of the underlying aetiology, CP is associated with an increase in neural tissue, and neural alterations occur in a similar fashion irrespective of the type of initiating event.

Serine proteinase activation in esophageal cancer.

BACKGROUND: Activation of the plasminogen/plasmin system seems to contribute to tumor aggressiveness and shorter post-operative survival. In the present study we examined the relation of uPA (urokinase plasminogen activator), uPAR (uPA receptor) and PAI-1 (plasminogen activator inhibitor type 1) to the biological growth behavior of esophageal cancer, as well as their influence on survival in esophageal cancer. MATERIALS AND METHODS: The expression and distribution of uPA, uPAR and PAI-1 were analyzed by Northern blot analysis and immunostaining in 41 resected esophageal cancers and in normal esophagi. RESULTS: Northern blot analysis revealed a 5.0-, 3.6- and 5.4-fold increase in uPA, uPAR, and PAI-1 mRNA levels in esophageal cancer, respectively, in comparison to normal controls (p<0.01). These mRNA moieties were concomitantly increased in 86% of the tumors. uPA activity was 2.3-fold increased in esophageal cancer compared with normal controls (p<0.01). Statistical analysis revealed no differences in uPA, uPAR and PAI-1 immunoreactivity between well-differentiated, moderately-differentiated and poorly-differentiated tumors. Furthermore, survival analysis showed no difference in patients whose tumors exhibited positive uPA and uPAR immunostaining (median 11 months, range 4-36 months) versus patients whose tumors exhibited negative uPA and uPAR immunostaining (median 11 months, range 3-51 months). CONCLUSION: Our data revealed that overexpression of uPA, uPAR and PAI-1 is often present in human esophageal carcinomas. However, up-regulation of these factors is not correlated with tumor differentiation or survival. These findings indicate that, unlike other tumors, uPA, uPAR and PAI-1 seem not to be prognostic markers for esophageal carcinomas.

Late mortality in patients with severe acute pancreatitis.

BACKGROUND: Mortality due to severe or necrotizing acute pancreatitis most often results from multiorgan dysfunction syndrome (MODS) occurring either early (within the first 14 days) or 2 weeks or more after the onset of symptoms due to septic complications. The aim of this study was to analyse the course of the disease in patients who died from severe acute pancreatitis. METHODS: Between January 1994 and August 2000 details of 263 consecutive patients with acute pancreatitis were entered prospectively into a database. All patients were treated in an intermediate or intensive care unit. RESULTS: The overall mortality rate was 4 per cent (ten of 263 patients). The mortality rate was 9 per cent (ten of 106) in patients with necrotizing disease. No patient died within the first 2 weeks of disease onset. The median day of death was 91 (range 15-209). Six patients died from septic MODS. Ranson score, Acute Physiology and Chronic Health Evaluation (APACHE) II score during the first week of disease, pre-existing co-morbidity, body mass index, infection and extent of necrosis were significantly associated with death (P < 0.01 for all parameters). However, only infection of the necrotic pancreas was an independent risk factor in the multivariate analysis. CONCLUSION: Early deaths in patients with severe acute pancreatitis are rare, mainly as a result of modern intensive care treatment. Nine of the ten deaths occurred more than 3 weeks after disease onset. Infection of pancreatic necrosis was the main risk factor for death.

Differential expression of metastasis-associated genes in papilla of vater and pancreatic cancer correlates with disease stage.

PURPOSE: Papilla of Vater cancer has a much better prognosis than pancreatic cancer. It is not known whether this is the result of differences in the tumor biology of the two malignancies. Because metastasis formation is a critical step in tumor progression and a negative prognostic factor, we compared the expression of nm23-H1 and KAI1, two metastasis-suppressing genes, in papilla of Vater cancer and pancreatic cancer. PATIENTS AND METHODS: Analysis was performed in nine normal human papilla of Vater samples, 27 papilla of Vater cancers, 16 normal pancreatic samples, and 29 pancreatic cancers. Expression of nm23-H1 and KAI1 was analyzed by Northern blot analysis and in situ hybridization. In addition, immunohistochemistry was performed to localize the respective proteins. RESULTS: There was no difference in nm23-H1 and KAI1 mRNA expression levels in normal versus cancerous papilla of Vater samples. In contrast, nm23-H1 and KAI1 RNA expression was upregulated in early tumor stages of pancreatic cancer and reduced in advanced tumor stages. When expression of nm23-H1 and KAI1 RNA was analyzed by use of in situ hybridization, normal epithelial cells of the papilla of Vater exhibited mRNA staining intensity similar to that of papilla of Vater cancer cells. Similar levels of nm23-H1 and KAI1 immunoreactivity also were observed in these samples. In contrast, early stage pancreatic cancer samples exhibited stronger nm23-H1 and KAI1 immunoreactivity than normal controls. Furthermore, early pancreatic cancer stages exhibited higher KAI1 and nm23-H1 immunostaining than advanced tumor stages. CONCLUSION: Differences in the expression patterns of the two tumor suppressor genes nm23-H1 and KAI1 may contribute to the different prognoses of papilla of Vater cancer and pancreatic cancer. Our findings support the hypothesis that biologic differences rather than earlier diagnosis influence the different outcomes of these two tumor entities.

Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy.

BACKGROUND: The role of preoperative biliary drainage in patients with biliary obstruction undergoing pancreatoduodenectomy remains controversial. Several authors failed to show any effect of preoperative biliary drainage, whereas others even reported an increased morbidity following pancreatoduodenectomy. METHODS: Retrospective analysis was performed in a consecutive series of 257 patients undergoing pancreatoduodenectomy between November 1993 and November 1999. RESULTS: Ninety-nine patients (38%) underwent preoperative biliary drainage for a median time period of 10 days (range 1 to 41) prior to resection. Cumulative postoperative morbidity was 47% (120 patients), the reoperation rate was 4.3% (11 patients), and mortality was 2.3% (6 patients). There was no difference in total morbidity, infectious complications, reoperation rate, mortality, or long-term survival between patients with or without preoperative biliary drainage. CONCLUSIONS: Preoperative biliary instrumentation and biliary drainage do not affect early or late outcome in patients undergoing pancreatoduodenectomy.

Pancreatic cancer--new aspects of molecular biology research.

Pancreatic ductal adenocarcinoma (PDAC) presently has an incidence of approximately 8 to 10 cases per 100,000 citizens in European countries, and the incidence has been increasing throughout the last decades. Approximately 30,000 patients die every year from PDAC in Western Europe and most of the newly diagnosed patients present with an already unresectable tumor stage. Self-sufficiency in growth signals, insensitivity to antigrowth signals, and evasion of apoptosis are hallmarks of malignant growth. In PDAC a variety of growth factors are expressed at increased levels. For example, the concomitant presence of the EGF-receptor and its ligands EGF, TGF-alpha, and/or amphiregulin is associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection. In addition, PDACs often exhibit alterations in growth inhibitory pathways such as Smad4 mutations and Smad6 and Smad7 overexpression, and evade apoptosis through p53 mutations and aberrant expression of apoptosis regulating genes such as members of the Bcl family. Taken together, the abundance of growth promoting factors and the disturbance of growth inhibitory and apoptotic pathways give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival prognosis.

Enteral nutrition prolongs delayed gastric emptying in patients after Whipple resection.

BACKGROUND: Delayed gastric emptying is one of the most frequent postoperative complications after Whipple resection. In the present study we evaluated the role of enteral nutrition in the development of delayed gastric emptying after Whipple resection. PATIENTS AND METHODS: Between January 1996 and June 1998, 64 patients (30 female, 34 male) underwent a classic (n = 27) or pylorus-preserving (n = 37) Whipple resection. Two patients were excluded; 30 patients received enteral and 32 patients received no-enteral nutrition. RESULTS: Delayed gastric emptying occurred significantly more in patients with enteral (17 of 30, 57%) than in patients with no-enteral nutrition (5 of 32, 16%) (P <0.01). Consequently, patients in the enteral nutrition group had a nasogastric tube for a significantly (P<0.01) longer period and had a significantly (P<0.01) longer hospital stay than patients in the no-enteral nutrition group. There were no differences in the frequency of occurrence of other postoperative complications between patients with enteral and no-enteral nutrition. CONCLUSION: In patients undergoing a Whipple resection, enteral nutrition is associated with a higher frequency of delayed gastric emptying with no advantages regarding other postoperative complications and should therefore be restricted to specific indications.