[Light, laser and PDT therapy for acne]. / Licht-/Laser-/PDT--Therapie bei Akne.

In recent years, a number of studies have evaluated the treatment of acne using electromagnetic waves, such as lasers, photodynamic therapy, visible light or radio waves. While the efficacy of laser treatment is still uncertain, photodynamic therapy shows promising results, but with marked side-effects, as destruction of sebaceous glands. Treatment with blue light (405-420 nm wavelength) also appears effective and can be regarded as an treatment option for inflammatory acne.

Pharmacokinetic studies of intramuscular midazolam in guinea pigs challenged with soman.

Studies have demonstrated that benzodiazepine compounds are effective at antagonizing seizure activity produced by the organophosphate (OP) cholinesterase inhibitor soman. In this present study we have investigated the pharmacokinetics of midazolam and its associated effects on electroencephalographic (EEG) activity following intramuscular (i.m.) injection to soman-exposed guinea pigs (Crl:(HA)BR). Prior to experiments, the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered the following pretreatment/OP/treatment regimen. Pyridostigmine bromide (0.026 mg/kg, i.m.) was given 30 min prior to soman (56 micrograms/kg, 2 x LD50; subcutaneously, s.c.), followed in one minute by atropine sulfate (2 mg/kg, i.m.) and pralidoxime chloride (25 mg/kg, i.m.). All animals receiving this regimen developed seizure activity. Midazolam 0.8 mg/kg, i.m., was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure-terminated or seizure not-terminated at 30 min following anticonvulsant administration. Serial blood samples were collected for the plasma midazolam analysis; the assay was accomplished with a gas chromatograph/mass spectrometer. The mean time to seizure termination was 8.8 +/- 1.6 min. The mean time-plasma concentration data were fit to standard pharmacokinetic models. The following parameter estimates were determined from the model-fit for seizure terminated and not-terminated animals respectively: apparent volumes of distribution (Vd) were 1.4 and 1.7 l/kg; area under the time-concentration curves (AUC), 15,990 and 15,120 ng.min/ml; times to maximal plasma concentration (Tmax), 1.66 and 2.91 min and maximal plasma concentrations (Cmax) 535.1 and 436.6 ng/ml. These data indicate that i.m. injection of midazolam is effective at terminating ongoing soman-induced seizure activity. Additionally, the relatively short Tmax and latency to seizure termination demonstrate the rapidity of drug absorption and action respectively.

Addition of etoposide to CHOP chemotherapy in untreated patients with high-grade non-Hodgkin's lymphoma.

BACKGROUND: Second- and third-generation chemotherapy protocols for the treatment of aggressive non-Hodgkin's lymphomas (NHL) have considerable, and age-related, toxic effects. In addition, they do not seem to prolong overall survival in comparison to standard CHOP chemotherapy. In this phase II study we investigated the feasibility and efficacy of the addition of etoposide to the conventional CHOP regimen. PATIENTS AND METHODS: Toxicity and clinical efficacy were determined in 132 patients with previously untreated high-grade NHL. There were 51 patients in clinical stage I and II and 81 patients in stage III and IV, with a median age of 54 years (range 17-85). Patients received standard-dose CHOP plus etoposide 100 mg/m2 i.v. on day 1 and 200 mg/m2 p.o. on days 2-3. RESULTS: The overall response rate was 84%, with 70% complete and 14% partial responses. The predicted three- and five-year survivals for the group as a whole were 60% and 53%, respectively, and the corresponding disease-free survivals for patients achieving complete remissions were 65% and 56%, respectively. Outcome was not different from that of CHOP-treated patients in a recently completed Nordic study performed during the same time period. Myelosuppression (WHO grade 3-4), observed in 87% of patients and infectious complications (WHO grade 3-4) in 33%, dominated the toxicity profile of this regimen. Fifty-seven of 92 complete responders (62%) received 6-8 CHOP-E cycles with no reductions in planned dose intensity. LDH level higher than normal, extranodal sites = 2, stage III-IV at diagnosis were all indicators of a poor survival. CONCLUSIONS: We conclude that CHOP-E treatment is effective in high-grade NHL. However, mainly due to severe myelosuppression frequent schedule modifications were required and the results are not obviously superior to those of conventional CHOP.

Fixed versus response-adapted MOPP/ABVD chemotherapy in Hodgkin's disease. A prospective randomized trial.

BACKGROUND: The optimal number of chemotherapy courses in responding patients with advanced-stage Hodgkin's disease (HD) is unknown. PATIENTS AND METHODS: With minimizing chemotherapy and thereby reducing late complications as the objective, patients with advanced HD were randomized to receive either 4 full MOPP/ABVD courses or treatment up to complete remission (CR). Forty-seven patients were given the fixed (FT) and 41 patients the individual treatment (IT). The two groups were balanced according to age, histopathology and sex, although stage IVB dominated in the IT group (20 vs. 8). RESULTS: Sixty-six of 88 patients (75%) achieved CR. No difference between the two treatment groups in the proportion of stage IVB patients was seen when those achieving CR, i.e., the efficacy population were compared. The mean number of single chemotherapy courses given was 3.7 of MOPP and 3.5 of ABVD in the FT group, compared to 2.6 of MOPP and 2.5 of ABVD in the IT group (p < 0.001). The predicted progression-free survival at 10 years was 81% in the FT and 68% on the IT arm, respectively (p < 0.05). No statistically significant difference in cause-specific 10 year survival was observed (82% and 83%, respectively; p = 0.18). Long-standing CRs were achieved following minimal chemotherapy. CONCLUSIONS: Since there are no available methods to identify long-term disease-free survivors among CR patients following a limited induction treatment, we suggest that the policy of giving 3-4 full MOPP/ABVD courses should continue. The price for such an approach is the overtreatment of a subset of already cured patients.

A combination of granulocyte colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes.

In an attempt to obtain a synergistic effect on the hemoglobin levels in anaemic patients with myelodysplastic syndromes (MDS), granulocyte colony-stimulating factor (G-CSF) and erythropoietin (epo) were combined in a clinical phase II trial. Twenty-two patients with MDS were included in the study. G-CSF was given alone for six weeks and then in combination with epo for the following twelve weeks. Eight (38%) of 21 evaluable patients showed a significant increase in hemoglobin. One patient with a previous response and subsequent failure to epo alone improved after the addition of G-CSF. Responses were more frequent in patients with less advanced pancytopenia, lower endogenous levels of serum-epo and in those with ring sideroblasts in the bone marrow. The response frequency of 38% is higher than in any study of epo as monotherapy. Moreover, patients with ring sideroblasts, who respond poorly to epo alone, showed a response rate of 60%. Our findings suggest a synergistic in vivo effect of granulocyte-CSF and erythropoietin in patients with myelodysplastic syndromes.

Low dose cyclophosphamide, alpha-interferon and continuous infusions of interleukin-2 in advanced renal cell carcinoma.

Pretreatment with a low dose of cyclophosphamide (CY) has been claimed to inhibit suppressor functions and augment various immune functions. A combination of a low dose of CY, alpha-interferon (IFN-alpha) and continuous infusion of interleukin-2 (IL-2) was used to treat patients with advanced renal cell cancer (RCC) (stage IV). Sixteen patients received four cycles consisting of CY (500 mg m-2) three days prior to daily i.m. injections of alpha-IFN (3 x 10(6) U), and continuous infusion of 18 x 10(6) IU rIL-2 for five days. The cycle interval was three weeks. Two patients had partial response (13%) (26+ and 12+ months), two had a minor response (9+ and 4 months), and three patients achieved stable disease (19+, 14+ and 8+ months). No patients required intensive care. Side effects were mainly fever, malaise, capillary leak syndrome and diarrhoea. Non-responders showed significantly higher eosinophil and platelet counts compared to responders. Serum concentration of IL-2 was significantly higher in responders. 5/11 patients had abnormally low values of serum thyroxine after therapy. Two patients needed thyroid hormone substitution. The difference between the initial and the lowest thyroxine values correlated significantly to survival (p < 0.03). The addition of CY to rIL-2 and IFN-alpha in the present protocol did not contribute to an increased major response rate.

Disease-related differences in antibody patterns against EBV-encoded nuclear antigens EBNA 1, EBNA 2 and EBNA 6.

Antibodies to Epstein-Barr virus (EBV) nuclear antigen family (EBNA) and three of its individual members, EBNA 1, EBNA 2 (A and B) and EBNA 6, were measured by anticomplement immunofluorescence (ACIF) in sera of 75 healthy controls, 13 patients with chronic EBV infection, 38 with non-Hodgkin lymphoma (NHL), 23 with Hodgkin's disease (HD), 105 with nasopharyngeal carcinoma (NPC) and 7 patients with infectious mononucleosis (IM). Their anti-EBV lytic antigens were also measured. We observed that: (1) anti-EBNA 2A and E6 rose in parallel 4-6 weeks after IM, followed by anti-EBNA 1 at 3-6 months, (2) all seropositive individuals had anti-EBNA 1; 74% also had anti-EBNA 2A and E6, (3) anti-EBNA 1 accounted for most of the anti-EBNA reactivity in non-IM sera. Striking disease-associated differences were noted on the humoral responses to the lytic and transformation-associated antigens. Compared to the controls, anti-EBNA 1, -EBNA 2A and -EBNA 6 were simultaneously four to 10 times higher in chronic reactivations, whereas only anti-EBNA 1 was elevated (10 times) in NPC. Individual EBNA titres were normal in NHL or HD patients.

Lymphocyte abnormalities predicting a poor prognosis in Hodgkin's disease. A long-term follow-up.

Two hundred sixty-two adult patients with Hodgkin's disease (HD) were studied. Incorporation of carbon-14-thymidine was measured in unstimulated monocyte-depleted lymphocyte cultures, and in cultures activated by concanavalin A (Con-A) before institution of therapy in all patients. Total blood lymphocytes and T-cell subsets were enumerated in the last 108 patients. Patients had significantly decreased total (CD3+, CD4+, CD8+) and relative (CD3+, CD4+) T-cell counts compared with healthy controls. Stage IV patients tended to have lower total lymphocyte and subset counts than remaining patients. However, significantly reduced total lymphocyte and CD8+ counts were only observed in comparison to patients in clinical stage II. Thirty-three percent of patients had an increased spontaneous and a decreased Con-A-induced blood lymphocyte DNA synthesis. Functional lymphocyte abnormalities were related to advanced clinical stage, high age, mixed cellularity, and lymphocyte depletion histopathology and presence of B symptoms. The 10-year survival of patients in this group was 36%, compared with 62% for the remainder. In a multivariate analysis of the whole series lymphocyte DNA synthesis was besides age the strongest predictor of prognosis. In univariate analyses of the second patient series total lymphocyte, T-cell and subset counts were related to prognosis. These relatively simple lymphocyte functional tests may help to identify young HD patients for whom intensive cytoreductive therapy with or without autologous stem cell support may be the best therapeutic option.

Mitoxantrone, etoposide, cytarabine and prednisone as salvage therapy for refractory non-Hodgkin lymphoma (NHL) and alternated with CHOP in previously untreated patients with NHL.

The treatment of relapsing or refractory high-grade malignant non-Hodgkin lymphoma (NHL) following CHOP chemotherapy remains a challenge for the clinician. In this study, 29 patients with relapsing or refractory high- or refractory low-grade malignant NHL received a combination of mitoxantrone 12 mg/m2 i.v. on days 1-2, cytarabine 100 mg/m2 i.v., b.d. d 1-2, etoposide 100 mg/m2 i.v. d 1-3 and prednisone 100 mg/m2 orally d 1-3 (ENAP). An overall response rate of 55% encouraged us to use ENAP alternated with conventional CHOP chemotherapy in 45 previously untreated NHL patients (35 with high-grade and 10 with "aggressive" low-grade malignant NHL). All patients responded with a complete remission rate (CR) of (27%) and a partial remission rate (PR) of 73% after only one course of ENAP. After a median number of 3.5 ENAP/CHOP courses, the CR and PR rate was 69 and 22%, respectively. Myelosuppression was pronounced and fever of unidentified origin and documented infections followed 59% of all cases given ENAP courses. In the last 19 previously untreated patients mitoxantrone was given at a dose of 10 mg/m2 on d 1 and cytarabine 100 mg i.v., b.d. during d 1-2. Nonhematologic toxicity was mild. We conclude that this novel chemotherapy program is effective both as first-line and salvage treatment in patients with high-grade malignant NHL. Furthermore, ENAP appears clinically to be partly non-cross resistant with CHOP chemotherapy. The dose-limiting toxicity is myelosuppression. The combination should be explored as primary therapy in combination with other chemotherapy or radiotherapy programs.

A Randomized Comparison of Doxorubicin and Doxorubicin-DNA in the Treatment of Acute NonLymphoblastic Leukemia.

In the light of previous findings that treatment of leukemia patients with DNA-linked doxorubicin gave higher doxorubicin concentrations in leukemic cells than treatment with doxorubicin alone, the Leukemia Group of Middle Sweden performed a randomized clinical trial to compare the effects of doxorubicin and doxorubicin-DNA in patients with acute non-lymphoblastic leukemia. One hundred and twenty consecutive patients within the age range 15 to 60 years were randomized to one of three treatment groups. In two of these, remission induction treatment was performed with prednisolone, vincristine, ara-C and thioguanine combined with either doxorubicin or doxorubicin-DNA. Patients entering a complete remission received intensive consolidation during 16 months with 4 courses each of doxorubicin (+/ - DNA)/ara-C, doxorubicin (+/ - DNA)/azacytidine, ara-C and amsacrine. The third treatment group followed a protocol from a previous study with daunorubicin and ara-C for induction therapy and a less intensive maintenance therapy. No further patients were assigned to this "control" group after 3 years or to the two other groups after 6 years. This report is based on a follow-up 31 months thereafter. The overall rate of complete remission was 67% and the mean time to complete remission was 71 days, with no differences between the treatment groups. Patients treated with the doxorubicin-DNA conjugate had a significantly longer survival [median for all patients 27.2 months (p < 0.01) and for patients in CR 47.0 months (p < 0.025)] and longer duration of first remission (median 23.6 months, p < 0.025) than the other groups. There were significantly fewer reports of cardiotoxicity (p < 0.05) and severe intestinal toxicity (p < 0.02) in patients treated with the doxorubicin-DNA conjugate and there was a tendency towards less hepatic (p < 0.08) and renal toxicity (p < 0.08). The frequency of myelosuppression, fever and infectious complications was similar in all three groups. Complex binding to DNA appears to increase the therapeutic effects and reduce some toxic effects of doxorubicin in patients with ANLL.

Immune deficiency in family members of patients with Hodgkin's disease.

Indirect data supporting a preexisting immunologic impairment in patients with Hodgkin's disease (HD) have been presented in recent years. These immunologic defects are supposed to be related to genetic and/or environmental factors. In this study, 65 first-degree relatives and 12 spouses of 21 consecutive patients with HD were studied immunologically. Furthermore, seven twin pairs in which one partner had HD and four additional nonmatched healthy co-twins were also included in the study. A decreased lymphocyte DNA synthesis induced by Concanavalin A, a high spontaneous DNA synthesis, or a low CD4+/8+ ratio was found in 21 (32%) consanguineous, two (17%) nonconsanguineous relatives, and five (50%) healthy co-twins. The corresponding figures for the untreated patients with HD and the control series were 14 of 21 (65%) and 21 of 127 (16%), respectively. Total lymphocyte counts or lymphocyte subpopulations did not differ between HD relatives and controls. The increased frequency of blood lymphocyte defects among consanguineous first-degree relatives favors the existence of a genetically determined immune deficiency in at least a proportion of apparently healthy relatives of patients with HD. However, nongenetic factors such as age and environment may add to the defect.

The incidence of cancer among blood donors.

This study presents data on cancer incidence among 37,795 blood donors in an attempt to test the hypothesis that blood donation might be associated with cancer development. At a median follow-up time of nine years (range 5-13 years) a total of 1152 cancer cases have been diagnosed. The expected number of cancer cases derived from an age-matched population was 1459 giving a relative risk ratio (RR) of 0.79 (p less than 0.001). Calculations were made with and without latency periods between first blood donation and the diagnosis of cancer (0, 5, 10, 15 years). Overall, significantly decreased cancer incidence was observed (p less than 0.001) though the number of observed cases of haematological malignancies was not significantly different from that expected. For polycythaemia vera, however, the O/E ratio was 1.81 possibly indicating an association with blood donation. A more likely explanation is that this reflects increased diagnosis of polycythaemia vera in the blood donor population.

Epidemiological study of Hodgkin's disease in Cuba and Sweden.

In this register study the epidemiologic features of Hodgkin's disease (HD) in Cuba and Sweden during 1964-1981 are compared. HD in the adult (greater than or equal to 15 years of age) is more common in Sweden than in Cuba (age-standardized incidence rate 3.6 X 10(5) vs. 3.1 X 10(5) but for childhood HD the opposite is true (2.1 X 10(5) vs. 3.0 X 10(5). In both countries a male predominance is found. A decrease in the incidence of HD is noted only in the Swedish population after 1973. The study reveals a stable bimodal age incidence pattern in Sweden but a shift from a linear increasing to a bimodal incidence pattern in Cuba, which parallels the Cuban development from an agricultural to an industrialized country.

Increased incidence of Kaposi sarcoma in Sweden before the AIDS epidemic.

Clinical factors of possible importance for the greater than two-fold rise in the incidence of Kaposi sarcoma of the elderly in Sweden before the AIDS epidemic were reviewed in 63 regional patients. 5 patients had lymphoproliferative disease before or at the time of Kaposi sarcoma, and 4 patients had been receiving steroids (including 1 with lymphoma) at diagnosis. 2 of these 9 patients plus 2 additional patients had received blood transfusions 1-9 years before diagnosis. None of 17 patients tested was positive for HIV-1, and none had signs of an unexplained progressive immune defect. Of the evaluable cases, 27% had diabetes mellitus and 7% had had previous myocardial infarction. However, only the frequency of congestive heart failure (47%) was significantly greater than that of an ambulatory control group (P = 0.001) in the age group 75-84 years. Exposure to cytomegalovirus (CMV) was not more common in 15 Kaposi sarcoma patients than in an age and sex matched control group. No single factor could account for increased Kaposi sarcoma among the elderly. If the classical form has an infectious aetiology, the tumour could arise after effective transmission of the agent (as by a transfusion), especially combined with some degree of immune deficiency or perhaps congestive failure late in life.

Clinical features of Hodgkin's disease in Cuba and Sweden.

A clinical study of 182 Swedish and 164 Cuban consecutive adult patients with Hodgkin's disease was performed comparing age, sex, histopathology, clinical stage, symptoms, and various laboratory tests. A bimodal age distribution was observed which was more pronounced in the Swedish series. A male/female ratio 1.8/1.0 in both samples was observed. Nodular sclerosis and Stage IA and IIA were more common in Swedish patients while in the Cuban, mixed cellularity and Stage IIIB and IVB dominated in patients below fifty years of age. The Swedish patients exhibited an age distribution similar to that found in other industrialized Western countries, while the Cuban patients had an age distribution pattern typical for countries with an intermediate epidemiological pattern.

Delayed skin hypersensitivity in man. The effect of repeated tests with low-dose antigen.

The effects of repeated applications of low doses of antigen on subsequent delayed cutaneous hypersensitivity (DCH) responses induced by the same antigen were evaluated. Fourteen healthy individuals were tested with seven different antigens given intracutaneously with the Multitest system device (Institute Mérieux). The procedure was repeated on four occasions at 2-week intervals. At the first test, 11 and 13 participants displayed DCH to tetanus and tuberculin, respectively. Neither the proportion of responding individuals nor the mean diameter of the reactions was changed in subsequent tests. However, the DCH pattern varied significantly between subjects (p less than 0.001; variance analysis). There was also a significant variation between the test occasion and skin reactivity. It is concluded that repeated applications of low-dose antigen by Multitest do not boost the DCH response. However, because of the low frequency of response to certain antigens and the low reproducibility of the test, the usefulness of this test system to evaluate DCH reactivity is limited.

Cyclic autoimmune hemolytic anemia as a presenting manifestation of splenic Hodgkin's disease.

The case report of a 52-year-old woman with an eight-year history of cyclic autoimmune hemolytic anemia and progressive splenic enlargement is presented. At laparotomy the enlarged spleen and splenic hilar lymph nodes showed lymphocyte-predominant Hodgkin's disease. No specific antitumor treatment was given and three years following splenectomy the patient is in excellent health and has not experienced any new hemolytic episodes. The patient illustrates the association between Hodgkin's disease and autoimmune hemolytic anemia as well as the extreme variation in the clinical picture of the disease.

Pancreatic secretion of benzylpyrimidines. Experimental studies in dogs.

The high mortality of septicaemic complications in pancreatic diseases requires the prophylactic use of suitable antimicrobial agents. Thus, the pancreatic distribution of benzylpyrimidines has been studied in dogs. After injection of 5 mg/kg followed by constant infusion of 0.5 mg/kg/h, maximum concentrations of 3.88 +/- 1.46 micrograms/ml (metioprim, MTP), 6.07 +/- 4.95 micrograms/ml (trimethoprim, TMP) and 7.78 +/- 1.84 micrograms/ml (tetroxoprim, TXP) were reached in canine pancreatic secretion. With respect to plasma, the drugs show 2.72- (MTP), 3.57- (TMP) and 4.18fold (TXP) concentrations in pancreatic secretion as can be shown by calculation of the AUC-ratios.