ESPEN Guidelines on Enteral Nutrition: Non-surgical oncology.

Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake in cases where normal food intake is inadequate. These guidelines are intended to give evidence-based recommendations for the use of ONS and TF in cancer patients. They were developed by an interdisciplinary expert group in accordance with officially accepted standards, are based on all relevant publications since 1985 and were discussed and accepted in a consensus conference. Undernutrition and cachexia occur frequently in cancer patients and are indicators of poor prognosis. EN should be started if undernutrition already exists or if food intake is markedly reduced for more than 7-10 days. Standard formulae are recommended for EN. Nutritional needs generally are comparable to non-cancer subjects. In cachectic patients metabolic modulators such as progestins, steroids and possibly eicosapentaenoic acid may help to improve nutritional status. EN is indicated preoperatively for 5-7 days in cancer patients undergoing major abdominal surgery. During radiotherapy of head/neck and gastrointestinal regions dietary counselling and ONS prevent weight loss and interruption of radiotherapy. Routine EN is not indicated during (high-dose) chemotherapy.

Isolation of the basal and lateral plasma membranes of rat kidney tubule cells.

A method was developed to isolate renal basolateral membranes from cortical kidney tubule cells of single rats. The isolated membrane fraction was characterized by the measurement of marker enzyme activities and by electron microscopy. 1. After centrifugation of crude plasma membranes on a discontinuous sucrose density gradient the basolateral membranes accumulated at a sucrose density of p= 1.14-1.15 g/ml. The yield was 147 mug membrane protein/g kidney wet weight. Protein recovery was 0.1%. 2. (Na+ + K+)-ATPase was enriched 22-fold from the homogenate. The recovery was 2.6%. The (Na+ + K+)/Mg2+-ATPase ratio was 4.1. 3. The contamination by brush borders was small. Alkaline phosphatase was 1.6-fold enriched and 0.2% was recovered. Aminopeptidase was 1-fold enriched with a recovery of 0.1%. The contamination by mitochondria, lysosomes and endoplasmic reticulum was negligible. 4. In electron micrographs the basolateral membranes showed a typical triple layered profile and were characterized by the presence of junctional complexes, gap junctions or tight junctions.

Investigations on the acute and chronic nephrotoxicity of the new platinum analogue carboplatin.

In order to detect even subclinical hints of nephrotoxicity after application of carboplatin, sensitive non-invasive methods, e.g. determination of urinary enzyme (lactate dehydrogenase, leucine aminopeptidase, gamma-glutamyltransferase, N-acetyl-beta-glucosaminidase), glomerular and tubular protein excretion (albumin, alpha-1-microglobulin) and determination of the creatinine clearance, were used. Eighteen patients with small-cell lung cancer entered the study. All patients were treated with the three-drug combination chemotherapy: vincristine (1.5 mg i.v. on days 1, 8, 15, 22), etopside (escalating doses: 100-160 mg/m2 on days 1-3) and carboplatin (300 mg/m2 day 1). Investigations were made during the first, third and fifth treatment cycles. Deterioration of renal function occurred in 4 out of 18 patients in all three observed treatment courses. Abnormal amounts in the excretion of at least one of four urinary enzymes were found in 6 out of 18 patients during the first cycle and in 4 out of 8 patients during the third and fifth cycles. All patients with pathological enzymuria during the first treatment course also developed an increased enzymuria during cycles 3 and 5. Four patients developed pathological proteinuria during the first and 2 patients during the third and fifth cycles. These findings demonstrate that the new platinum analogue, carboplatin, is capable of inducing renal damage. In comparison with cisplatinum, the nephrotoxicity of this new analogue is reduced but not completely eliminated.

Membrane plasma exchange in Goodpasture's syndrome.

We report two cases with Goodpasture's syndrome successfully treated by membrane plasma exchange. In both patients, pulmonary infiltrations and hemoptysis had already resolved after the first pulse methylprednisolone dose (1000 mg IV). Following plasma exchange, renal function did not further deteriorate in one patient and returned to normal in the other patient. From the clinical course of our patients and a review of the literature, we conclude that membrane plasma exchange is effective in preventing deterioration of renal function in Goodpasture's syndrome. Analysis of the literature shows that patients who respond to plasma exchange have significantly fewer crescents and lower plasma creatinine, while non-responders are more often oliguric or anuric and require dialysis at the time of plasma exchange.

[Anemia in malignant tumor diseases. I. Tumor-induced loss of transferrin and its relation to tumor size and degree of malignancy in the rat model]. / Die Anämie bei malignen Tumorerkrankungen. I. Tumorbedingte Verluste von Transferrin und ihre Abhängigkeit von Tumorgrösse und Malignitätsgrad am Modell der Ratte.

Cellular uptake of 67Ga-labelled transferrin by the tumor tissue was studied in rats with tumors of different malignancy and different tumor mass using the slowly growing Morris hepatoma 5123C, the moderately growing Novikoff hepatoma and the very fast and aggressive Yoshida hepatoma AH130. The cellular accumulation of 67Ga-transferrin was found to correlate with the proliferation activity of the tumor. The 67Ga-transferrin concentration in the very fast growing Yoshida hepatoma was 4.8 times higher than the concentration in the slowly growing Morris hepatoma. The uptake of 67Ga-transferrin by the tumors resulted in a faster disappearance of circulating 67Ga-transferrin from the blood. The rate of disappearance correlated with the proliferation activity and the spread of the tumors. Using tumors of identical size the elimination of 67Ga-transferrin from the blood was much faster in the rats with Yoshida hepatoma than in those with the slowly growing Morris hepatoma. On the other hand, using tumors of different tumor size it could be demonstrated that the rate of disappearance of 67Ga-transferrin from the blood correlated directly with tumor mass. It is concluded that cellular incorporation of transferrin within the tumor cells results in a loss of circulating transferrin, which correlates with tumor mass and proliferation of tumor. This mechanism is supposed to be the cause for the hypotransferrinemia seen in patients with malignant tumors.

[Anemia in malignant tumor diseases. II. Tumor-induced loss of transferrin as a cause of the development of anemia based on a rat model]. / Die Anämie bei malignen Tumorerkrankungen. II. Tumorbedingte Verluste von Transferrin als Ursache für die Entwicklung einer Anämie am Modell der Ratte.

The cellular uptake and lysosomal accumulation of 67Ga-labelled transferrin within tumors of different malignancy were examined using tissue fractionation and immunological techniques. As tumor models the slowly growing Morris hepatoma 5123 C, the moderately growing Novikoff hepatoma and the fast and aggressive Yoshida hepatoma AH130 were investigated. Isolation of subcellular fractions of tumor homogenates was performed by differential centrifugation and density-gradient centrifugation. The intracellular 67Ga-transferrin was found to be highly concentrated within the purified lysosomes. The transferrin within the lysosomal fraction was identified by radial immunodiffusion technique using monospecific antiserum. The accumulation of 67Ga-transferrin by the tumors resulted in a faster disappearance of 67Ga-transferrin from the blood. This loss of circulating 67Ga-transferrin correlated with the proliferation activity and the spread of the tumors. Since transferrin is indispensible for the utilization of iron by the heme-synthesizing red cell precursors, transferrin concentration in the blood is the limiting factor for the utilization of iron in hemoglobin synthesis. Thus, in a further series of experiments we investigated the development of anemia in tumor-bearing rats. With increasing tumor mass a progressive fall of hemoglobin concentration was found. The anemia was more severe in the faster growing Novikoff hepatoma than in the slowly growing Morris hepatoma. The most significant reduction of hemoglobin concentration was found in the very fast growing Yoshida hepatoma. After total tumor resection hemoglobin concentration and red blood cell count normalized completely within 6-8 weeks. We conclude from these data that the uptake of transferrin by the tumor cells results in a faster disappearance of transferrin from the blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of 67Ga accumulation in normal rat liver lysosomes.

67Ga accumulates in various malignant tumors and parenchymatous tissues. It was found to be associated with the soluble fraction of lysosomes (11). The present work investigates the mechanism of 67Ga accumulation in normal liver cells. Lysosomes were isolated from rat liver after intravenous injection of carrier free 67Ga. The soluble lysosomal fraction was obtained by sonication followed by centrifugation at 105,000 xg for 2 hrs. Gel filtration on Sephadex G 25 superfine was carried out on the soluble lysosomal fraction in order to investigate the stability of the 67Ga-protein complex within the lysosomes under EDTA treatment. After treatment with 1 mM/l EDTA a considerable amount of the protein bound radioactivity was found to be liberated. In further experiments the 67Ga binding lysosomal proteins were fractionated by electrophoresis on 7% polyacrylamide gels (0.5 cm x 5.5 cm). After staining with Coomassie blue 18 separated protein bands were apparent. 67Ga distribution within the gels was assessed by direct counting of radioactivity in gel slices. A considerable amount of the intralysosomal protein bound radioactivity migrated with a relative mobility of 0.36 corresponding to a protein band of molecular weight 85,000--90,000. This peak corresponded to the peak of 67Ga-labelled purified transferrin in control gels. These data were confirmed by immunoelectrophoresis combined with autoradiography: within the soluble lysosomal fraction a slight transferrin line could be identified. We conclude that 67Ga which is transported in the blood by transferrin (23) and taken up by the hepatic cell through endocytosis (32) is accumulated in the lysosomes associated with transferrin and its degraded fragments.

[Ferritin in myeloproliferative diseases]. / Ferritin bei myeloproliferativen Erkrankungen.

Serum ferritin concentration was studied in 79 patients with chronic granulocytic leukemia (CGL), 14 patients with polycythemia vera (PV), eleven patients with osteomyelosclerosis (OMS) and four patients with megakaryocytic myelosis (MM). Pretreatment serum ferritin concentrations were found to be normal or slightly decreased in patients with PV, OMS, MM and in the chronic phase of CGL. Patients entering the blastic crisis of CGL had highly increased serum ferritin concentrations. The severity of hyperferritinemia in these patients depended on the cytomorphological type of the blastic crisis. Highest levels of serum ferritin concentration were found in the immature myeloblastic type according to the M1- and M2-type of the FAB-classification of acute leukemias (i.e. 30-fold and 18-fold increased). In contrast, the rise of the serum ferritin concentration in the more mature types of blastic crisis was less pronounced (i.e. nine-fold in the M3-type and six-fold in the M4- and M5-type of blastic crisis). Patients with complete remission after bone marrow transplantation had normal serum ferritin concentrations. Investigation of the intracellular ferritin concentration showed, that the serum ferritin levels paralleled the intracellular ferritin concentration within the leukemic blasts: During the myeloic blastic crisis the intracellular ferritin concentration was found to be 17-fold increased compared to the intracellular ferritin concentrations in the chronic phase of CGL. Thus, our data support the concept that an increased synthesis of ferritin by the leukemic blasts is responsible for the increased serum ferritin concentration during the blastic crisis of CGL.(ABSTRACT TRUNCATED AT 250 WORDS)

[Beta 2 microglobulin in serum--a "tumor marker" in malignant lymphomas?]. / Beta 2-Mikroglobulin im Serum--ein "Tumormarker" bei malignen Lymphomen?

Serum beta 2-microglobulin concentration was investigated in 221 patients with malignant lymphoma (Hodgkin type and non-Hodgkin type). In 55% of the unselected group of patients increased serum concentrations of beta 2-microglobulin were found. There was a close correlation between tumor extension and beta 2-microglobulin levels. In the tumor stage I the beta 2-microglobulin concentration was 1.65 +/- 0.45 mg/l, in the stage II 2.41 +/- 0.65 mg/l. The levels in the stage III (3.48 +/- 1.15 mg/l) and in the stage IV (5.49 +/- 1.99 mg/l) were significant higher than normal. Using longitudinal studies, measurement of beta 2-microglobulin was followed up during the course of the disease. During tumor regression by an effective antineoplastic therapy initially elevated beta 2-microglobulin concentrations decreased. In patients who achieved a complete remission a normalization of beta 2-microglobulin concentration was seen. We conclude from our findings that beta 2-microglobulin has the characteristics of a tumor associated marker in patients with malignant lymphomas. The low specificity and sensitivity limits the clinical use of this parameter.

[Ferritin in acute leukemia. Serum ferritin concentration as a nonspecific tumor marker for M1 and M2 myeloid leukemia]. / Ferritin bei akuten Leukämien. Die Serumferritinkonzentration als unspezifischer "Tumormarker" für die myeloische Leukämie M1 und M2.

Serum ferritin concentration was studied in 136 patients with different types of acute leukemia. Pretreatment serum ferritin concentrations in the immature myeloblastic leukemia (M1 and M2 of the FAB-classification of acute leukemias) was found to be highly increased compared to the more mature types of acute myeloblastic leukemias (M3 to M5) and the acute lymphoblastic leukemias (L1 to L3). Investigation of the intracellular ferritin concentration showed, that the serum ferritin levels paralleled the intracellular ferritin concentration within the leukemic blasts. Within the immature myeloic blasts (M1) the intracellular ferritin concentration was 14-fold increased compared to normal granulocytes. This correlated with the 17-fold increased serum ferritin levels in these patients. Intracellular ferritin concentrations within the leukemic blasts of more mature types of acute leukemia (M3 to M5) were found to be only slightly increased. These data support the concept, that an increased synthesis and release of ferritin by the leukemic blasts is responsible for the increased serum ferritin concentration. This concept is also supported by the observation, that a further increase of serum ferritin concentration was seen during a cytotoxic chemotherapy. It is noteworthy, that this increase was more pronounced in the immature leukemias obviously caused by a loss of intracellular ferritin from the damaged leukemic blasts. The serum ferritin levels followed closely the activity of the disease. Increased pretreatment serum ferritin concentrations normalized completely when patients achieved complete remission. In contrast, in patients with tumor relapse or tumor progression serum ferritin concentrations increased again. These data suggest that the serum ferritin in immature myeloblastic leukemia has the characteristics of a tumor associated marker.(ABSTRACT TRUNCATED AT 250 WORDS)

[Anemia in malignant tumor diseases. VI. Secondary siderosis caused by the shift of iron, unused for hemoglobin synthesis, into iron stores]. / Die Anämie bei malignen Tumorerkrankungen. VI. Sekundäre Siderose durch die Umverteilung des für die Hämoglobinsynthese nicht verwertbaren Eisens in die Eisenspeicher.

Impaired utilization of iron by the heme synthesizing red cell precursors was investigated in 258 patients with malignant tumors of different histological types and different tumor spread. There was evidence, that impaired iron uptake by the erythropoietic cells results in an increased flow of iron to the reticuloendothelial iron stores. Investigations on bone marrow smears showed that sideroblast counts were significant lower than in healthy controls reflecting a deficient iron supply to the erythropoietic cells. In contrast, reticuloendothelial storage iron was increased paralleled by an increased serum ferritin concentration. Both abnormalities correlated with the malignancy and the stage of the tumor. It could be demonstrated that the degree of the hyperferritinemia paralleled very closely the severity of the anemia becoming more pronounced with increasing tumor mass. This parallelism indicates that the siderosis is pathophysiologically related to the defect of erythropoiesis observed in malignant disease. Since the iron uptake by the erythropoietic cells is mediated by transferrin in a further series of experiments the serum transferrin concentration was investigated in malignant diseases. There was found a close inverse correlation between serum transferrin concentration and serum ferritin concentration. This correlation supports the concept of a defect in erythropoiesis due to an impaired transferrin mediated iron supply caused by tumor induced hypotransferrinemia. This defect is responsible for a shift of iron to the iron stores and a secondary siderosis.

[Principles of symptom control in palliative medicine]. / Prinzipien der Symptomkontrolle in der Palliativmedizin.

Palliative care is the active total care of patients whose disease is not or no more responsive to curative treatment. Its action strategies should be applied at the time when the goals change from cure to care. Palliative care is total care of body, mind and spirit. Control of pain, of other symptoms and of psychosocial, social and spiritual problems, is paramount. The goal of palliative care is the achievement of the best quality of life for patients and their families. Psychosocial support plays a vital role in the assessment and treatment of anxiety and depression in patients with advanced illness. Appropriate intervention of psychosocial distress in patients and families can ease the family bereavement period. It can also decrease occupational stress and burnout in the professional caregivers. One of the principal functions of palliative care is the prevention and control of distressing symptoms. Freeing sick people, emancipating them from pain and unendurable symptoms is one of the conditions that sick and dying people need most. This allows them to live their remaining time as fully as possible. The general principles of treating dyspnoea and pain are the same as for any other aspect of treatment in palliative care: 1. to define and treat the underlying cause of dyspnoea wherever possible and reasonable for the patient. This includes oncological interventions such as chemotherapy and radiotherapy as far as the patient's status allows it. 2. to relieve dyspnoea without adding new problems by way of sideeffects, interactive effects, social or financial burdens. The rule of proportionality to treatment affirms that symptom control and life-prolonging treatment are contraindicated when they cause more suffering than benefit. 3. to consider whether a treatment will be worthwhile for the patient and his family bearing in mind his prognosis and adverse effects of invasive procedures. 4. to discuss all reasonable treatment options (including the decision of "no intervention") with the patient and his family, allowing them to make the final decision as far as possible by themselves.

[The psychological aspect of cancer pain.]. / Die psychische Dimension des Krebsschmerzes.

The perception and expression of pain are primarily psychological phenomena and are not directly correlated with the intensity of the nociceptive stimulus. They are often influenced by earlier experiences of pain, and also by current expectations and fears. The cancer patient interprets pain as a sign of the continued existence and of the progression of the malignant disease: if the pain can be controlled the patient will take this as an indication that the underlying disease can be cured. Inappropriately treated pain, on the other hand, can initiate a vicious circle leading to really excruciating pain and functional destabilization of the patient. Conversely, the personality and the psychological condition of the patient can have a profound effect on how pain is experienced. Fear, for example, is known to exacerbate pain, and fear is often due to a less than ideal doctor-patient relationship, e.g. one in which the patient does not receive adequate information about the disease. Pain can be interpreted as a message that has to be understood before an adequate therapeutic response is possible. For desperate patients who are socially isolated after a long period of illness, pain may be the only way of communicating their unhappiness to other people and of feeling alive at all. Patients with intractable pain are sometimes given placebo therapy, particularly if the pain is interpreted as "only" psychogenic in character or if traditional methods of treatment have failed. Confrontation with terminally ill patients is an especially difficult and frustrating experience for health professionals. The fact that the disease cannot be cured and that a patient is in constant pain reminds the physician of the limitations of curative medicine. This can trigger defense mechanisms in the physician, which may in turn cause insecurity and fear in the patient. In the course of treatment for pain, cancer patients derive most psychological support from the emotional empathy of the therapist, whose availability for the patient is the most important means of preventing the patient's with-drawal into depression. If cancer pain is accompanied by an emotional, psychic and vegetative imbalance, psychotropic drugs are beneficial. In particular, antidepressants and neuroleptics have become an important component of the treatment of chronic pain in cancer patients. Due consideration of the emotional and motivational status of the patient will make it possible to choose between the different effect profiles of these drugs. However, the use of psychotropic drugs should complement, and cannot replace, empathic care from the physician.

[Serum ferritin--a tumor marker in malignant lymphomas?]. / Ferritin im Serum--Ein "Tumormarker" bei malignen Lymphomen?

Serum ferritin concentration as a tumor associated marker was investigated in 535 patients with malignant lymphomas. The study included 207 patients with Hodgkin lymphomas, 196 patients with low grade malignant Non Hodgkin lymphomas and 132 patients with high grade malignant Non Hodgkin lymphomas of different tumor stages. Increased serum ferritin concentrations were found in 54% of the unselected patients. In particular, serum ferritin concentration was elevated in 12.3% of patients with stage I, in 33.8% of patients with stage II, in 72.2% of patients with stage III and in 94% of patients with stage IV. The serum ferritin levels correlated with the tumor mass. There was no difference between Hodgkin lymphomas and Non Hodgkin lymphomas. In patients with concomittant hepatocellular disease or during chemotherapy inadequate high serum ferritin concentrations were found, which did not correlate with tumor mass. In patients with primary bone marrow infiltration by some low grade malignant Non Hodgkin lymphomas serum ferritin levels correlated better with the tumor stages according to Rai than with the Ann-Arbor-classification. The serum ferritin concentration followed closely the activity of the disease: Increased pretreatment serum ferritin levels normalized completely, when patients achieved complete remission. In contrast, in patients with tumor relapse or tumor progression serum ferritin levels increased again. The data suggest that the serum ferritin concentration can be used for follow-up of patients with malignant lymphomas. Because of its limited specifity and low sensitivity it cannot be used as a screening test. Nevertheless, it is a helpful additional parameter for the control of the activity of the disease.

Ferritin--a tumor marker in myeloid leukemia.

High serum ferritin levels without any correspondence to the amount of total body storage iron have been found in patients with leukemia. Investigating 96 adults with different types of leukemia, we found that serum ferritin can be used as a tumor marker in myeloid leukemias. Extremely high serum ferritin levels were seen in acute myeloblastic leukemia before treatment and in blastic crisis of chronic myeloid leukemia (ie, 21-fold increased serum ferritin concentrations). Patients with acute myeloblastic leukemia in complete remission had their ferritin concentrations decreased to normal. A relapse of the disease was paralleled by a repeated increase of serum ferritin level. In patients with chronic myeloid leukemia during the chronic phase we found normal serum ferritin concentrations, whereas blast crisis was associated with highly raised serum ferritin levels. We conclude that serum ferritin concentration must be valued as a clinically useful tumor marker in these types of leukemia, exhibiting a helpful and simple parameter in monitoring the activity of the disease.

[Anaphylactic reaction in cyclophosphamide infusion]. / Anaphylaktische Reaktion unter Cyclophosphamid-Infusion.

A number of drugs used in cancer chemotherapy have produced hypersensitivity reactions. Generalized urticaria to cyclophosphamide has been reported previously in 5 cases. We have recently observed a 25-year-old patient with M. Hodgkin who developed an anaphylactic shock immediately following an intravenous infusion of cyclophosphamide. Total serum IgE was significantly elevated (1280 U/ml). Using the epicutan skin testing highly positive papulo-vesicular reaction to cyclophosphamide was observed.

Inhibition of (Na+K+)-ATPase and cation transport by an antibody against renal plasma membranes.

An antibody was raised in rabbits against NaI extracted plasma membranes of rat kidney. The antibody inhibited (Na+K+)-ATPase of basolateral membranes and of rat erythrocyte ghosts. Also K+-stimulated pNPase was inhibited. No effect on Mg-ATPase and basal pNPase activity was registered. Kinetic experiments with Na+,K+ and Mg-ATP showed a noncompetitive inhibition of (Na+K+)-ATPase by the antibody. Hill constants were unchanged. In renal epithelial cell cultures as well as in intact rat erythrocytes ouabain sensitive 22Na-efflux and 42K influx was inhibited by the antibody. It is concluded that outward facing Na+K+-ATPase is immunogenic. The antibody can be raised when the antigen is adequately disintegrated to open otherwise hidden antigenic sites.

[Anemia in malignant tumor diseases. V. The relation of tumor-induced hypotransferrinemia and the degree of anemia]. / Die Anämie bei malignen Tumorerkrankungen. V. Die Beziehung zwischen der tumorbedingten Hypotransferrinämie und dem Grad der Anämie.

Transferrin is a growth factor in malignancy. In this function, transferrin is taken up into the proliferating malignant cell. The tumor-induced loss of circulating transferrin results in a hypotransferrinemia which correlates with tumor mass and proliferation rate. The cellular uptake of iron into the erythropoietic precursors depends on the presence of iron-saturated transferrin. Thus, iron utilization for the hemoglobin synthesis correlates with the transferrin concentration in blood. In 256 patients with malignancies of different histological types and different tumor extension a strong correlation was found between the degree of tumor-induced hypotransferrinemia and anemia. This correlation between transferrin concentration and hemoglobin concentration could be demonstrated in the different histological tumor entities. Tumor progression was accompanied by a progressive fall in transferrin concentration and hemoglobin concentration. By contrast, tumor remission achieved by an effective antineoplastic therapy resulted in an improvement of hypotransferrinemia and anemia. These variations in the two parameters were found to be strongly correlated. We conclude from our data that tumor-induced loss of transferrin is one of the most important factors responsible for the development of anemia in malignancy.