Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study.

BACKGROUND: Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. PATIENTS AND METHODS: In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. RESULTS: Overall, 216 patients were randomized to gatipotuzumab (n  = 151) or placebo (n  = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P  = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. CONCLUSIONS: Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599.

SEOM Clinical Guideline of management of soft-tissue sarcoma (2020)

Soft-tissue sarcomas constitute an uncommon and heterogeneous group of tumors of mesenchymal origin. Diagnosis, treatment, and management should be performed by an expert multidisciplinary team. MRI/CT of the primary tumor and biopsy is mandatory before any treatment. Wide surgical resection with tumor-free tissue margin is the mainstay for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not suitable for re-excision. Perioperative chemotherapy should be discussed for high-risk sarcomas of the extremities and trunk-wall. In the case of oligometastatic disease, patients should be considered for local therapies. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. Other drugs have shown activity in second-line therapy and in specific histological subtypes but options are limited and thus, a clinical trial should always be discussed (AU)

SEOM Clinical Guideline of management of soft-tissue sarcoma (2020).

Soft-tissue sarcomas constitute an uncommon and heterogeneous group of tumors of mesenchymal origin. Diagnosis, treatment, and management should be performed by an expert multidisciplinary team. MRI/CT of the primary tumor and biopsy is mandatory before any treatment. Wide surgical resection with tumor-free tissue margin is the mainstay for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not suitable for re-excision. Perioperative chemotherapy should be discussed for high-risk sarcomas of the extremities and trunk-wall. In the case of oligometastatic disease, patients should be considered for local therapies. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. Other drugs have shown activity in second-line therapy and in specific histological subtypes but options are limited and thus, a clinical trial should always be discussed.

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.

Usefulness of omalizumab in rapid drug desensitization in patients with severe anaphylaxis induced by carboplatin: open questions

No disponible

Development of subcutaneous fat in Spanish and Latin American children and adolescents: Reference values for biceps, triceps, subscapular and suprailiac skinfolds.

Subcutaneous fat skinfolds represent a reliable assessment instrument of adiposity status. This study provides current percentile references for four subcutaneous skinfolds (biceps, triceps, subscapular, suprailiac) applicable to children and adolescents in Spain and in Latin American countries where data are scarce. The design consisted of a cross-sectional multicenter study performed with identical methods in 5 countries (Argentina, Cuba, Mexico, Spain and Venezuela). Total sample comprised 9163 children and youths (boys 4615 - girls 4548) aged 6-18 years, healthy and without apparent pathologies. Percentiles 3, 5, 10, 25, 50, 75, 90, 95 and 97 were calculated by the LMS method. Sexual dimorphism was assessed using the t-test and age differences with ANOVA. Normalized growth percentile references were obtained according to sex and age for each skinfold. The mean values of four skinfolds were significantly greater in girls than boys (p<0.001) and, in both sexes, all skinfolds show statistical differences through age (p<0.001) with different magnitudes. Except triceps in girls, peaks between 11 and 12 years of age are more noticeable in boys than in girls. Although the general model of growth is known, the skinfold measurements show variability among populations and differences of magnitude are presented according to the analyzed population. Therefore, these age and sex-specific reference percentile values for biceps, triceps, subscapular and suprailiac skinfolds, derived from a large sample of Spanish and Latin American children and adolescents, are a useful tool for adiposity diagnosis in this population for which no reference values were available.

Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions.

The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional 'window of opportunity' endpoints should be included.

Randomized study of sequential cisplatin-topotecan/carboplatin-paclitaxel versus carboplatin-paclitaxel: effects on quality of life.

BACKGROUND: A recent phase III trial compared the efficacy of cisplatin-topotecan (a topoisomerase I inhibitor) followed by carboplatin-paclitaxel (Arm 1) versus paclitaxel-carboplatin (Arm 2) in women with newly diagnosed stage IIB or greater ovarian cancer. There was a significantly lower response rate in the experimental arm compared to standard treatment, and less likelihood of normalized CA125 within the first 3 months. At 43 months follow-up, there were no significant group differences in progression-free survival. There were also significantly more side effects in the experimental arm. METHODS: The current study examined quality of life (QoL) endpoints using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the ovarian cancer module, QLQ-OV28, administered prior to randomization, at day 1 of treatment cycles 3, 5, and 7, at completion of the last cycle, and at 3 and 6 months following completion of chemotherapy. RESULTS: Global QoL, physical symptoms, fatigue, and role, emotional, cognitive and social function (all from the EORTC QLQ-C30) significantly improved in both treatment arms, with no significant between-arm differences. Between-group differences in pain, insomnia, and peripheral neuropathy reported while on treatment did not differ at follow-up. Nausea and vomiting improved more with standard treatment both during and after treatment. Body image significantly differed between the groups only at cycle 5 (more deterioration in Arm 2) but group differences disappeared at follow-up. A stratified analysis of global QoL by debulking surgery status found no greater effect indicating that overall improvements in QoL were unrelated to surgical recovery. CONCLUSIONS: There was no significant QoL advantage of cisplatin-topotecan. This finding, combined with no progression-free survival conferred by this combination, reaffirms carboplatin-paclitaxel as the standard of care for women with newly diagnosed ovarian cancer.

Treatment guidelines in ovarian cancer.

National and international specialists have met with the aim of writing down the guidelines for the treatment of epithelial ovarian cancer (in the Spanish Castilian language). These guidelines are based on the International Consensus that was published in English in the Annals of Oncology in 2005. This condition is the leading cause of death from gynaecological cancer in western countries. Its low rate of survival, barely 30% at 5 years, is above all due to late diagnosis and inappropriate surgery, so emphasis is put on these aspects. After describing the methodology for early detection and a scheme of surgical diagnostic procedures in view of the staging of an ovarian mass, the following therapeutic strategies will be recommended: cytoreductive surgery together with platinum chemotherapy under normal conditions, and also in the case of relapse. Likewise, very recent models of treatment focused on molecular targets are presented, and a broad section on methodology of clinical assays. As for this, co-operation among groups is crucial in order to make the conclusions of these studies valid for the development of new therapies.

Treatment guidelines in ovarian cancer

National and international specialists have met with the aim of writing down the guidelines for the treatment of epithelial ovarian cancer (in the Spanish Castilian language). These guidelines are based on the International Consensus that was published in English in the Annals of Oncology in 2005. This condition is the leading cause of death from gynaecological cancer in western countries. Its low rate of survival, barely 30% at 5 years, is above all due to late diagnosis and inappropriate surgery, so emphasis is put on these aspects. After describing the methodology for early detection and a scheme of surgical diagnostic procedures in view of the staging of an ovarian mass, the following therapeutic strategies will be recommended: cytoreductive surgery together with platinum chemotherapy under normal conditions, and also in the case of relapse. Likewise, very recent models of treatment focused on molecular targets are presented, and a broad section on methodology of clinical assays. As for this, co-operation among groups is crucial in order to make the conclusions of these studies valid for the development of new therapies (AU)

Cardiac metastasis from uterine leiomyosarcoma.

Cardiac metastases are more frequent than primary heart neoplasias. Nearly any malignant tumour may metastasize to the heart, but the most common are carcinomas rather than sarcomas. We report the case of a patient who presented with heart metastasis 6 years after resection of an uterine leiomyosarcoma. The patient died thirty months after surgical resection without evidence of cardiac recurrence. Although cardiac metastases from uterine leiomyosarcoma are exceptional, they should be suspected in the presence of suggestive symptoms, since they can be associated with long survival after surgical treatment.

In vitro phagocytosis of carrier mouse red blood cells is increased by Band 3 cross-linking or diamide treatment.

Chemical alteration of red blood cells (RBCs) can induce increased phagocytosis of modified cells by macrophages. In this study we have used different chemical treatments for the modification of the mouse red-blood-cell membrane surface, namely oxidant compounds, such as ascorbate/Fe(+2) and diamide [azodicarboxylic acid bis(dimethylamide)], or Band 3-cross-linking reagents. We monitored the phagocytosis of oxidized or Band 3-cross-linked mouse red blood cells by peritoneal macrophages. The extent of phagocytosis of RBCs is not affected by oxidation with ascorbate/Fe(3+), but it is increased (up to 10%) by oxidation with 2 mM diamide. Furthermore, phagocytosis is greatly increased (up to 40%) as a result of cross-linking with either of two Band 3 bifunctional reagents [bis(sulphosuccinimidyl) suberate (BS(3)) and 3,3'-dithiobis(sulphosuccinimidyl propionate) (DTSSP)]. To evaluate targeting towards macrophages of such modified RBCs for therapeutical purposes, we have determined the phagocytosis of Band 3 carrier RBCs loaded with carbonic anhydrase. In this case phagocytosis is high enough (25%) to deliver the enzyme into macrophages. We have also assayed the influence of serum components and IgG on the efficiency of phagocytosis and discuss the possible phagocytosis mechanisms. In the case of BS(3)-cross-linked carrier RBCs, phagocytosis is markedly enhanced (from 12% up to 25%) by serum components. This opens a way for therapeutic application of these carrier RBCs, with special relevance in short-term delivery to cells of the mononuclear phagocytic system.

Influence of aerobic oxidation of mouse erythrocytes on their recognition by macrophages.

Membrane protein modification can change cell surface properties which can be correlated with altered macrophage-erythrocyte interactions. Mouse erythrocytes were incubated in phosphate buffer for different times to induce protein modification. Mouse erythrocyte membrane changes were analyzed by infrared analyses and gel electrophoresis. Proteolytic digestion of membrane proteins was observed. After 22 hours preliminary incubation, the number of erythrocytes adhering to a monolayer of macrophages reached a maximum, the majority of which had not been phagocytosed. Most of the erythrocytes incubated for 40 hours underwent phagocytosis after adhesion to the macrophages.

Hypotonically loaded rat erythrocytes deliver encapsulated substances into peritoneal macrophages.

Previous work has shown increased uptake of hypotonically loaded rat RBCs by the spleen and liver "in vivo," suggesting that the cells of MPS are involved in their elimination from the circulation. In order to elucidate the mechanism of such elimination, we have undertaken studies on the interaction of such loaded RBCs, in comparison with native RBCs, with peritoneal macrophages. Erythrophagocytosis assays were performed in well plates to which thioglycollate-induced peritoneal macrophages had adhered. Native or loaded 51Cr-RBCs were added under different opsonization conditions to monolayer adherent macrophages, and then the amount of RBCs that were recognized was determined, with separation into adhesion and phagocytosis fractions. Native RBCs are slightly recognized by peritoneal macrophages, about one RBC per macrophage (Mphi). Osmotic treatment of rat RBCs used for encapsulation (independently of the encapsulated substance, 125I-CA or FITC-dextran) produces some modification in the erythrocyte membrane that induces higher recognition of these cells, about three loaded RBCs per macrophage. Consequently, both fluorescent (FITC-Dx) and radioactive (125I-CA) substances previously encapsulated in RBCs were transferred to M(phi)s. The fluorescence microscopic observations confirmed these results. Moreover, in the case of carrier 51Cr-cells loaded with 125I-CA, the amount of 125I-radioactivity delivered into M(phi)s was relatively higher than that of 51Cr. The highest ratio, 125I-CA (encapsulated substance)/51Cr-RBCs (carrier cells), present in M(phi)s means there was a stronger interaction with macrophages of RBCs that carry a higher amount of encapsulated CA, as a function of the heterogeneity of the loaded rat RBCs population previously reported. Finally, the adhesion and phagocytosis of loaded RBCs seem not to involve complement receptors or Fc receptors on the macrophages.

In vitro properties and organ uptake of rat band 3 cross-linked erythrocytes.

Chemical conditions for cross-linking rat erythrocytes with bis(sulfosuccinimidyl)suberate (BS3) and 3,3' dithiobis(sulfosuccinimidyl propionate) (DTSSP) have been studied. These two cross-linking reagents seem to react with band 3 proteins in rat erythrocyte membrane. Two different conditions have been assayed using different cell/cross-linker concentration ratios. Similar cell volumes were observed in cross-linked rat erythrocytes compared to rat control erythrocytes. Cell yields after cross-linking account for about 65% when a high ratio of cell-to-cross-linker was used. Slightly lower cell yields (about 62%) were obtained when this ratio was reduced. Estimation of band 3 cross-linking by gel electrophoresis revealed a level of cross-linking of around 45% and 50% at the different conditions used. In vivo behavior of these modified rat erythrocytes revealed that they do not circulate, showing a predominant localization in the liver. This effect is evident from the concentration (5 mM BS3 or DTSSP) used. Based on these results, BS3 and DTSSP can be considered as useful tools to cross-link rat erythrocyte band 3 and to target rat erythrocytes to the liver.

Regulation of the complement-mediated elimination of red blood cells modified with biotin and streptavidin.

Red blood cells (RBC) modified with biotin and streptavidin (SA) present an interesting potential drug delivery system. Biotinylation and SA attachment, however, alter the biocompatibility of RBC. We have reported that polyvalent SA attachment induces lysis of biotinylated RBC (b-RBC) by homologous complement via the alternative pathway. Lysis occurs due to inactivation of the membrane regulators of complement, DAF and CD59, cross-linked by SA. However, monovalent SA attachment does not induce lysis. On the basis of these findings we hypothesized that reduction of the biotin surface density on b-RBC would allow for monovalent SA attachment to b-RBC and that such SA/b-RBC should then be stable in the circulation. In the present work we injected into rats several different radiolabeled RBC probes: rat RBC biotinylated to varying degrees (bn-RBC, where bn represents the input micromolar concentration of biotinylating agent), as well as SA/bn-RBC. Extensively biotinylated rat RBC (b700-RBC, stable in serum in vitro) were rapidly cleared from the bloodstream. We further found that extensively biotinylated human b1000-RBC bound C3b from serum in vitro without detectable lysis, and that rat b700-RBC bound to isolated macrophages in a complement-dependent fashion. Therefore, nonlytic C3b flxation and uptake of C3b-carrying b700-RBC by macrophages appears to be the mechanism leading to clearance of b700-RBC in vivo. Moderately biotinylated RBC (b70-RBC and b240-RBC) were stable in serum in vitro. SA attachment to b240-RBC led to their rapid lysis in serum in vitro, lysis in the bloodstream, and clearance by the liver and spleen. SA attachment to b70-RBC led to fast elimination of SA/b70-RBC from the bloodstream, while in vitro SA/ b70-RBC were stable in serum. Modestly biotinylated RBC (b22-RBC) demonstrated only marginally decreased 60-min survival in the bloodstream regardless of SA attachment. Our in vitro studies indicate that b23-RBC bound approximately 10(5) SA molecules per cell, and the resulting SA/b23-RBC bound 5 x 10(4) molecules of biotinylated IgG (b-IgG) per cell. About 60% of the injected dose of b-IgG/SA/b23-RBC labeled with 51Cr was detected in the rat blood cells 1 day after iv injection. To assess whether b-IgG/SA/b23-RBC circulate in the bloodstream as a stable complex, we have injected 125I-labeled b-IgG/ SA/51Cr-labeled b23-RBC in rats. Up to 60 min after injection, both radiolabels display similar level in bloodstream. Up to 3 h after injection, about 70% of 125I was detected in the blood cells. In contrast, 100% of 125I was detected in plasma after injection of nonconjugated 125I-labeled b-IgG. Thus, major portion of SA/b23-RBC-attached b-IgG circulates as a complex with RBC. About 30% of RBC-bound b-IgG undergoes detachment from the carrier b-RBC, probably in the pulmonary capillaries, because lung level of 125I was twice as high as that of 51Cr. Therefore, the surface density of biotin on the b-RBC membrane appears to play a key role in regulating complement-mediated clearance of bn-RBC and SA/bn-RBC from the bloodstream. Modest biotinylation generates b-IgG/SA/b23-RBC circulating for several hours as stable immunoerythrocytes without detectable lysis or marked elimination, and it may be possible to use these RBC in a drug delivery system.

In vivo survival and organ uptake of loaded carrier rat erythrocytes.

Rat RBCs loaded with 125I-CA by hypotonic dialysis and isotonic resealing were evaluated as a carrier system. Loaded RBCs stored at 4 degrees C remained unlysed (90% survival) allowing release of encapsulated 125I-CA for up to 4 days. Thereafter, cellular lysis increased significantly. IP-injected loaded RBCs reached the maximum level (50%) in circulation at 24 h post-injection. Circulating loaded RBCs showed a half-life of 8-10 days, which was advantageous for carrier function. In contrast to IP-injected free CA, which remained in circulation for only a short time, encapsulated CA showed significant levels in circulation up to 10 days post-injection. The profile of organ uptake with time is essentially not altered for loaded with respect to native cells, being higher the removal of loaded cells and mainly localized in spleen. Nevertheless, liver is the organ with highest elimination capacity for both native and loaded cells, showing its maximum at 24 h post-injection. Concomitantly, the concentration of 125I-CA in all organs studied was highest at this time. These data demonstrate that rat loaded RBCs can potentially be used as a carrier system for long-term dissemination of drug into the organism, with specially increased delivery to the spleen. They also support the use of the rat as an experimental model for biochemical and pharmacological studies in these therapeutic systems.

Fluorescence analysis of carrier rat and human erythrocytes loaded with FITC-dextran.

Rat and human erythrocytes are inherently different with respect to slow dialysis encapsulation used in preparing carrier erythrocytes. The incorporation process, commonly measured with radioactive tracers, is always larger in human erythrocytes, mainly because the rat carrier cells are more fragile. When FITC-Dextran (Dx) is used in the encapsulation process, and loaded rat and human RBCs are studied by fluorescence intensity, some additional events are evident. Not all cells of each population appear with a fluorescence signal, and not all show similar fluorescence intensity. Human RBCs show a higher percentage of marked cells and a higher fluorescence intensity than rat RBCs. Two populations, of high and low fluorescence, appear in FITC-Dx loaded rat erythrocytes. The human loaded RBCs show a similar peak distribution together with another peak in the middle scale of fluorescence. Therefore, a heterogeneity in the cell population as a result of the encapsulation process is manifested for both species. The fractionation of RBCs, loaded with either FITC-Dx or 125I-CA, by centrifugation on Ficoll-Paque reveals that the low density cells have much more substance incorporation than the counterpart cell subpopulation in the pellet. Therefore, the cell modifications produced by the encapsulation process are independent of the substance being incorporated. On the other hand, FITC-Dx, but not 125I-CA, shows a certain degree of association to RBCs membranes, especially in humans.

Behaviour of isolated rat and human red blood cells upon hypotonic-dialysis encapsulation of carbonic anhydrase and dextran.

Rat and human carrier red blood cells (RBCs) were prepared by hypotonic-dialysis encapsulation. The standard conditions used for encapsulation were 80 mOsm/kg for 60 min. The encapsulation behaviour of rat and human RBCs was studied using radiolabelled carbonic anhydrase and fluorescently labelled dextran. Both markers are incorporated to slightly greater extents by human than by rat RBCs by hypotonic treatment. Cell recovery of rat and human RBCs loaded with either carbonic anhydrase or fluorescent dextran accounted for 49% and 80% respectively. The cellular integrity of the loaded cells was revealed by the presence of fluorescence labelling in rat and human RBCs. Fluorescence studies showed an increase of size dispersion in loaded rat and human RBCs, giving cellular volume variations in both types of cells resulting from the encapsulation procedure. Two loaded cell populations were evident in both species, one with high fluorescence content and another with background staining. Apparently the proportion of high fluorescently labelled loaded cells was higher in the case of the human RBCs. A reduced level of fluorescence labelling was observed in rat and human RBC membranes, which indicates a process of adsorption of dextran to the membranes.