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Rationale: The inguinal hernia disease is associated with an imbalanced collagen metabolism including attenuated type V collagen synthesis. The aim of the present study was to normalise this distorted collagen equilibrium by supplying a combination of nutrients necessary for collagen synthesis to patients undergoing inguinal hernia repair. Methods: Twenty-one male patients scheduled for Lichtenstein inguinal hernia repair were randomized to an enriched nutritional supplementation (ENS-protein) group receiving 55 mg zinc, 1250 mg vitamin C, 14 g arginine and 14 g glutamine daily (n = 10) or to a control group (n = 11). Both groups received 1.5 g/kg of high-quality protein daily for 28 days. In addition, experimental epidermal wounds were created from raised suction blisters. Biomarkers of type I (CICP), type III (PRO-C3) and type V (PRO-C5) collagen synthesis were measured by enzyme-linked immunosorbent assays together with zinc and free amino acids in serum collected at baseline (day -14), day 0 before surgery and on postoperative day 1 (day 1). Wound fluids from surgical drain were analysed for CICP, PRO-C3 and PRO-C5 on postoperative days 1 and 2. Results: Fourteen days of ENS-protein raised the serum zinc level (p = 0.002) but reduced (p = 0.022) total amino acid levels preoperatively. Postoperatively, serum PRO-C5 decreased (p = 0.046) in the protein group but not in the patients receiving ENS-protein, who also had higher (p = 0.041) PRO-C5 levels than the protein group on day 1. CICP wound fluid levels increased from day 1 to day 2 in both groups and were higher on day 2 in the ENS-protein group compared with the protein group (P = 0.029). PRO-C3 increased (p = 0.028) from day 1–day 2 in the ENS-protein group, but not in the protein group. One patient in the ENS-protein group developed wound infection and subsequent hernia recurrence. In the protein group, two patients developed wound infections and hernia recurred in three other pa

Interleukin-6 (IL-6) has in vitro demonstrated growth regulatory effects on tumor cells from patients with chronic lymphocytic leukemia (CLL) and lymphoma. The proliferation rate of these cells is usually very low and this is thought to be one of the reasons for the lack of a curative potential of cytostatic chemotherapy in CLL and low grade NHL. Recombinant human (rh) IL-6 might increase the in vivo proliferation rate leading to a higher sensitivity for chemotherapy. We tested this hypothesis by administering rhIL-6 to 9 CLL patients and 3 NHL patients in doses of 2.5 micrograms/kg, 5 micrograms/kg and 10 micrograms/kg s.c. daily for 5 days followed by CHOP chemotherapy on the last day of rhIL-6 injection. Six patients had two treatment cycles. The proportion of cells in S-phase was determined by the bromodeoxyuridine labeling index (LI). Three patients achieved a partial remission, one patient had progressive disease and the remaining patients demonstrated no change. Two patients, who received 10 micrograms/kg/day rhIL-6, demonstrated a significant increase in LI, one of these was first observed in the second treatment cycle. A significant decrease was seen in two patients receiving 2.5 micrograms/kg and 5 micrograms/kg respectively. Immunophenotypic assessment demonstrated that rhIL-6 increased the expression of CD20 in all CLL patients with a reversal after cessation of rhIL-6. We conclude that rhIL-6, in the dosage and schedule used in this study, did not increase the proportion of the cells in S-phase and that the growth stimulatory effects of rhIL-6 in CLL in vivo probably are insignificant. However, the role of rhIL-6 in CLL as inducer of increased CD20 expression prior to anti-CD20 antibody treatment remains to be determined.

The plasma cell labeling index (PCLI) in patients with multiple myeloma (MM) is relatively low and this has been associated with the low rate of remission following chemotherapy. Interleukin-6 (IL-6) has been demonstrated to be a major growth factor of myeloma cells. In order to increase the S-phase proportion of myeloma cells, which might increase the sensitivity to chemotherapy, we gave rhIL-6 followed by chemotherapy to 15 myeloma patients with refractory disease. A total of 25 treatment cycles were administered since ten patients had two cycles. The rhIL-6 dose was 2.5 (n = 3), 5.0 (n = 6) and 10.0 microg/kg (n = 6) by subcutaneous injection once daily for 5 days and chemotherapy was administered on the last day of rhIL-6 injection. The effect of rhIL-6 treatment on labeling index (LI) was heterogeneous, but no statistically significant change was noted for this particular group as a whole. In two patients an increase (mean 7.7%) in LI of mononuclear bone marrow cells during the rhIL-6 treatment was demonstrated and in one patient a decrease of 2.8% was seen. Assessment of PCLI demonstrated an increase of 2.9% in one out of six patients and a decrease of 1.9% in one out of six patients. None of the 15 patients achieved remission according to standard criteria. During the rhIL-6 treatment, 14 of the 15 patients developed mild constitutional adverse events (AE) well known in patients treated with IL-6, and none of the AE in the subsequent chemotherapy phase were related to IL-6. In conclusion, our study demonstrated that rhIL-6 can be administered safely to patients with refractory MM, but the cell cycle recruitment approach was not sufficiently effective to be of clinical value.

Udgivelsesdato: 1991-Apr, Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to inhibit the chemotaxis and enhance the oxidative burst response of human neutrophils in vitro. The present study describes the effect of recombinant GM-CSF on the neutrophil and monocyte function in patients with lymphoma undergoing GM-CSF treatment. Patients with either Hodgkin's or non-Hodgkin's lymphoma were treated with various dosages (2-16 micrograms kg-1 body weight per day for 5 days) of rhGM-CSF by intravenous or subcutaneous route. Prior to and on day 5 of rhGM-CSF treatment, neutrophil and monocyte chemotaxis and chemiluminescence responses to f-Met-Leu-Phe, zymosan activated serum (ZAS) and opsonized zymosan (OZ) were determined. It was observed that chemotactic response of neutrophils to f-Met-Leu-Phe and ZAS was reduced, whereas the chemiluminescence response of both cell types to f-Met-Leu-Phe and zymosan was enhanced by up to 43-fold. rhGM-CSF treatment did not affect degranulation of the neutrophils as measured by release of vitamin B12 binding protein. Degree of modulation of neutrophil and monocyte function by rhGM-CSF was independent of rhGM-CSF dosages administered. These data suggest that phagocytic defence system may be enhanced by GM-CSF treatment and that this cytokine may be a useful therapeutic adjunct in compromised patients.

Since the Rye classification of Hodgkin's disease, many lesions which resemble Hodgkin's disease microscopically have been described. The histological features of Hodgkin's disease, including the BNLI subclassification of nodular sclerosis, and the lesions which resemble Hodgkin's disease microscopically such as reactive lymph node hyperplasias, some non-Hodgkin's B- and T-cell lymphomas are reviewed. Recent reclassifications of lymphomas originally diagnosed as Hodgkin's disease have indicated that the disease was overdiagnosed, before the description of these lesions and before the development of monoclonal antibodies.

171 episodes of bacteremia and candidemia in 142 patients were recorded during the period 1981-1985 in patients with hematological malignancies. Overall mortality, within 1 week of onset of bacteremia, was 20%. Increased mortality was found in patients with poor disease-prognosis (39%), with granulocytopenia for more than 6 days (30%), and in those developing hypotension (49%). Compared to a similar previous study from 1970-1974, the incidence of bacteremia remained unchanged, but the mortality had decreased by 50%. This result could not be explained by changes in microbial spectrum, in patient groups, or in the initial antibiotic regimen used. An improved general condition of these patients due to better supportive treatment may be the single most important factor in improving the outcome of septicemia.

Two hundred ninety patients with Hodgkin's disease pathologic stage (PS) I or II were treated in the prospective randomized trial of the Danish National Hodgkin Study (see Appendix) with radiotherapy +/- adjuvant combination chemotherapy. The initial tumor burden of each patient was assessed, combining tumor size of each involved region and number of regions involved. Multivariate analyses of prognostic factors including treatment, tumor burden, histologic subtype, pathologic stage, number of involved regions, mediastinal size, systemic symptoms, erythrocyte sedimentation rate (ESR), sex, and age were carried out. With regard to disease-free survival tumor burden was by far the most important prognostic factor for patients treated with adjuvant chemotherapy as well as for patients treated with radiotherapy alone. With regard to survival from Hodgkin's disease only tumor burden and age were independently significant. A combination of tumor burden, histologic subtype, and sex singled out patients with a high relapse rate both after radiotherapy only, and after radiotherapy plus chemotherapy. This combination also singled out patients destined to die from Hodgkin's disease more accurately than other prognostic factors.

47 patients with advanced Hodgkin's disease (stage IIIB or IV) and mediastinal involvement, treated during the period 1969-78 and followed till death or from 36 to 126 months after initiation of therapy, were analysed. All 47 patients had received combination chemotherapy (MOPP or equivalent regimens). 20 had also received additional radiotherapy to mediastinum (and in some cases to other involved areas as well). The 2 treatment groups did not differ significantly with regard to the more important prognostic factors. Both in the case of stages IV and IIIB patients in the group treated with combination chemotherapy alone, remissions were significantly more often only partial, the frequency of relapse and of treatment failure was significantly higher, and relapse-free survival was significantly poorer than in the group treated with additional radiotherapy. Furthermore, survival from Hodgkin's disease and crude survival including all causes of death were significantly better for patients treated with combination chemotherapy plus mediastinal irradiation. Consequently, for patients with advanced Hodgkin's disease and mediastinal involvement a combined approach including radiotherapy as well as combination chemotherapy would seem advisable.

Udgivelsesdato: 1982-null, A spontaneous change in DNA content of a human colonic carcinoma grown in nude mice was observed fortuitously. The tumor initially had a G1 cell DNA content of 1.3 times that of normal cells. Flow cytometric DNA analysis showed in transplant generation 56 the appearance of a new subpopulation which in three passages completely overgrew the original population. The DNA content of the new subpopulation was twice that of the original population. The observation supports the hypothesis of clonal evolution of tumor cell populations. The growth rates of the tumor before and after the change showed no significant difference (p greater than 0.05). Cell kinetic factors, therefore, offer no obvious explanation of how the overgrowth took place. It is not known whether the original population disappeared completely or survived as a small population below the detection limit. The heterogeneity created by clonal evolution of a tumor would be less pronounced if old subpopulations often become extinct as new ones emerge. Heterogeneity of human tumors is of clinical importance because the individual subpopulations may have different sensitivity patterns to antineoplastic drugs.

Udgivelsesdato: 1980-Nov, Flow-cytometric DNA analysis yields information on ploidy and proliferative characteristics of a cell population. The analysis was implemented on small-cell anaplastic carcinoma of the lung using a rapid detergent technique for the preparation of fine-needle aspirates for DNA determination and a newly developed procedure for storing aspirates at -80 degrees. Thirty-eight different metastases in 30 consecutive patients with small-cell anaplastic carcinoma of the lung were examined with a total of 273 fine-needle aspirations. The results on ploidy are reported in this paper. The degree of contamination of the aspirates with normal cells was determined by differential counts. The ratio of the peak channel numbers for the G1 phase of the tumor cells to that of the diploid standard (DNA index) was calculated and used for ploidy identification. Twenty-nine patients were evaluable with respect to DNA index determination. The coefficient of variation of the DNA index determinations was estimated as 0.039. In 23 (79%) patients, only one cell line could be detected. Evidence of the presence of 2 tumor cell clones with different ploidy was obtained in the remaining 6 (21%) patients. Of the 35 malignant clones thus demonstrated, 26 (74%) were significantly different from diploid (p less than or equal to 0.01). Four (11%) were hypodiploid, 3 (9%) were hypotriploid, and 19 (54%) were hypo- or near-tetraploid. Clonal heterogeneity in the tumors of 21% of the patients is a conservative estimate. Assessment of the detection limit set by the methodology used and the restricted number of samples studied in each patient indicate that the true occurrence of clonal heterogeneity in small-cell carcinoma of the lung may be much higher.

Udgivelsesdato: 1983-Mar, A simple procedure for long-term storage of cells for flow cytometric DNA analysis was developed and tested. The cells were stored as single cells or fine-needle aspirates suspended in a citrate buffer with dimethylsulfoxide (DMSO), or as small blocks of tissue from solid tumors. The cells were stored for up to one year by freezing at -80 degrees C. Statistical analysis of the results showed no change in the fractions of cells in the cell cycle phases as determined by deconvolution of the DNA-histograms. It was found that in addition to the intrinsic sample variation from the parameter estimation by deconvolution, there was significant intraday and interday variation. Hence the most accurate results are obtained if different aliquots of a sample are measured on different days rather than on the same day. Use of the storage method thus has the potential of increasing the accuracy of the analysis. The storage method makes sample collection independent of immediate subsequent analysis. This has enabled us to perform large internally controlled experiments, involving more samples than can be analyzed in one day, to examine tumor samples from different hospitals and to utilize fully the capacity of our flow cytometer. The method was a prerequisite for developing an accurate standardization procedure for DNA content determination.