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Biomedical subjects

R Somers

Publications and source records attributed to R Somers.

At least 91 records · Page 5Linked to original sources
PubMed1987

Functional differences in the beta gamma complexes of transducin and the inhibitory guanine nucleotide regulatory protein.

We have examined the mechanism of inhibition of adenylate cyclase using the purified alpha and beta gamma subunits of bovine brain inhibitory guanine nucleotide regulatory protein (Ni) (i.e., alpha i and beta gamma N) and bovine retinal transducin (alpha T and beta gamma T) in reconstituted phospholipid vesicle systems. The addition of beta gamma N or beta gamma T to lipid vesicles containing the pure stimulatory guanine nucleotide regulatory protein (Ns) from human erythrocytes as well as a resolved preparation of the catalytic moiety (C) of bovine caudate adenylate cyclase results in significant inhibition of guanine nucleotide stimulated cyclase activity (80-90%). The inhibition by these beta gamma subunit complexes appears to fully account for the inhibitory effects observed with holo-Ni or holotransducin. A variety of structure-function comparisons of the beta gamma N and beta gamma T complexes were performed in order to further probe the molecular mechanisms involved in the inhibitory pathway. Whereas the beta subunits of beta gamma N and beta gamma T appear to be very similar, if not identical, on the basis of comparisons of their gel electrophoretic mobility and immunological cross-reactivity, clear differences exist in the apparent structures of gamma N and gamma T. Interestingly, functional differences are observed in the effectiveness of these two beta gamma complexes to inhibit adenylate cyclase activity. Specifically, while both beta gamma N and beta gamma T are capable of effecting significant levels of inhibition of the guanine nucleotide stimulated activities, the beta gamma N complex is consistently more potent than beta gamma T in inhibiting these activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1987

EORTC trial non-Hodgkin lymphomas.

Results of an EORTC trial (20751) in non-Hodgkin lymphomas are presented. Patients were treated in the same way independent of the histological type. There were 468 patients in the study of whom 124 patients were in stage I (85% 5 year survival), 57 in stage II (55%), 121 in stage III (55%) and 166 in stage IV (45%). Using the Kiel classification the low grade lymphomas were subdivided into two categories: those with a follicular (80% 5 year survival) and with a diffuse cell pattern (50% 5 year survival) with an intermediate prognosis compared with the high grade lymphomas (35% 5 year survival). Treatment was stratified according to stage. In stage I regional radiotherapy was given followed by randomization for maintenance chemotherapy with Vincristine, Cyclophosphamide and Prednisone. No influence in survival was seen (85% at 5 years), although disease free survival was better in the maintenance chemotherapy group (75% vs 55% at 5 years). In stage II regional radiotherapy was followed, after randomization, by transdiaphragmatic irradiation, all patients received maintenance chemotherapy. The group was too small to draw conclusions about the effect of this treatment. Primary radiotherapy in stage II disease with diffuse histology gave bad results. Patients in stage III and IV were treated with 8 courses of chemotherapy with Adriamycin, VM26, Cyclophosphamide and Prednisone, given in two different time schedules. Iceberg radiation was then given to areas with initially large or slowly responding disease. All patients had maintenance chemotherapy. No difference was found for the 2 chemotherapy schedules in remission rate, disease free interval and survival. In stage III and IV patients with a follicular lymphoma have a longer relapse free interval and total survival (39% and 68% at 5 years) compared with those with a lymphoma diffuse histology (19 and 30% at 5 years). Patients with stage IV disease due to bone marrow involvement only had a better prognosis compared with stage IV disease for other reasons.

Adolescent↗
PubMed1987

Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas.

Ifosfamide (IFOS) 5 g/m2 and its parent analog Cyclophosphamide (CYCLO) 1.5 g/m2 were studied in a randomized phase II study, accruing 171 patients with advanced soft tissue sarcoma. Both drugs were administered as 24 hr infusions, every 3 weeks, with comcomitant Mesna 400 mg/m2 i.v. bolus 4 hourly X 9 doses. Twenty-four patients were ineligible and 12 were not evaluable. The groups were well matched for age, previous chemotherapy (42% of the total) or radiotherapy, the presence of distant metastases and performance status, but there were more females (59% vs. 45%) in the IFOS arm. Among the 68 evaluable patients receiving IFOS, there were 2 CR, 10 PR (overall response 18%), 27 SD and 29 PD. For CYCLO, the corresponding results in 67 patients were 1 CR, 4 PR (overall response 8%), 23 SD and 39 PD. Using the chi-square test the P values for response rate and linear trend were 0.13 and 0.04 respectively. Response rates were higher for females (20% vs. 5%, P = 0.01) and patients who had not received previous chemotherapy (19% vs. 4%, P = 0.01). Fourteen of the 17 responses came from a group of 43 females, who had not received previous chemotherapy, for whom the overall response rate was 37.5%. Remissions were noted in only 4 histological subtypes (centrally reviewed material), i.e., 5 of 17 synovial sarcomas, 7 of 13 mixed mesodermal sarcomas and 2 of 7 fibrosarcomas. One of the 31 leiomyosarcomas responded to Cyclophosphamide. Durations of response did not differ significantly between the 2 arms--median 26, range 10-81+ weeks. Leucopenia was significantly more severe on CYCLO, particularly in patients who had received previous chemotherapy (P = 0.007). Serious infections occurred in approx. 7% of patients with no difference between the two drugs, although there was one toxic death on CYCLO. Nausea and vomiting were significantly worse on IFOS and alopecia, related in extent to dose, was seen in both arms. Other side-effects, such as hematuria or rises in serum creatinine and encephalopathy, were infrequent and mild. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination therapy.

Adolescent↗
PubMed1987

Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group.

The objective of this randomized phase II/phase III study was to investigate the efficacy and toxicity of equimolar doses of adriamycin (ADM) and 4-epiadriamycin (EPI) in patients with locally advanced and/or metastatic soft tissue sarcoma. Doses of ADM and EPI were 75 mg/m2 given as an i.v. bolus injection every 3 weeks. Two hundred and ten patients were entered into the study by 18 institutions. Twenty-eight patients were ineligible and 15 were non-evaluable, leaving 167 evaluable patients. The two treatment groups were well balanced for sex, performance status, age, prior radiotherapy, extent and site of disease. Rates of response were similar, 25% in the ADM group compared to 18% in the EPI group (P = 0.33), and there were no significant differences between the ADM and EPI groups with respect to median duration of response (45 weeks vs. 77 weeks, P = 0.08), time to progression (15 weeks vs. 12 weeks, P = 0.945), and median survival (41 weeks vs. 48 weeks, P = 0.363). Myelotoxicity as shown by leucopenia was significantly more pronounced in the ADM treated patients (P = 0.002). Other toxicities such as alopecia and nausea/vomiting were also more severe in the ADM group (P = 0.02 and 0.06, respectively). In conclusion, the use of equimolar doses of ADM and EPI in advanced soft tissue sarcoma produced response rates which did not differ significantly and were only slightly in favour of ADM. However, this was achieved at the expense of higher toxicity.

Adolescent↗
PubMed1986

Cyclophosphamide versus ifosfamide: preliminary report of a randomized phase II trial in adult soft tissue sarcomas.

One hundred and seventy-one patients with advanced soft tissue sarcoma entered a randomized crossover phase II study comparing cyclophosphamide (CYCLO) with a new analogue, ifosfamide (IFOS), both administered as 24 h i.v. infusions every 3 weeks. The doses used were CYCLO 1.5 g/m2 and IFOS 5 g/m2, with provision for dose escalation. All patients received mesna 400 mg/m2 as an i.v. bolus 4 hourly X 9 doses, commencing at the start of the oxazophosphorine infusion. Patients who had received previous chemotherapy were eligible provided this did not include a classical alkylating agent. There were 22 patients who were ineligible, and response could not be evaluated in 12 additional patients. IFOS produced two complete and ten partial remissions, for an overall response rate of 18%. CYCLO was significantly (P = 0.04) less active, producing one complete and five partial remissions, an overall response rate of 9%. Stabilization of disease was similar in both arms (27% and 24% respectively), but fewer patients showed progression on IFOS. The response rate was higher (20% vs 5%) for patients who had not received previous chemotherapy, and also for female compared with male patients (21% vs 5%). When only patients who had not received previous chemotherapy were considered, the respective response rates for IFOS and CYCLO were 24% and 15%. There were no responses in previously treated patients receiving CYCLO. There were four partial responses in 33 patients crossing from CYCLO to IFOS, but no responses in 18 patients receiving CYCLO after IFOS. Leucopenia was significantly more pronounced (P = 0.0004) with CYCLO, both after the first course and throughout treatment, although the incidence of severe infections, 6%, was the same in both arms. Nausea and vomiting were more severe with IFOS (P = 0.022), but other toxicities were mild. Grade 1 or 2 bladder (haematuria) or renal (rise in serum creatinine) toxicity was slightly more frequent with IFOS (7 vs 3 patients) and was a reason for stopping treatment for one patient in each arm. Three episodes of mild to moderate drowsiness after IFOS were reported, but no severe encephalopathy. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination with such active agents as adriamycin.

Adolescent↗
PubMed1986

Prognostic factors in non-Hodgkin's lymphoma.

The results obtained with the various types of treatment in non-Hodgkin's lymphoma are reviewed and the data from the recent EORTC trials are summarized. In patients with Stage I follicular histology, regional radiotherapy (RT) alone gives excellent results. The long-term relapse-free survival (RFS) is high and relapsing patients can be rescued by aggressive combination chemotherapy; initial chemotherapy with CVP improves RFS but not total survival (TS). In patients with Stage I diffuse histology, the long-term survival is less satisfactory. CVP chemotherapy does not improve either RFS or TS; therefore if adjuvant chemotherapy is justified, it should be more aggressive than CVP. In patients with Stage II follicular type, regional radiotherapy alone gives good results. The addition of abdominal bath irradiation to regional RT increases RFS but not TS. After relapse, patients can be rescued by combination chemotherapy. In patients with Stage II diffuse histology, extended RT followed by CVP gives poor results and RT should be combined with more aggressive combination CT; the preliminary results of an integrated alternating regimen being excellent. In patients with Stage III and IV follicular type, the 8 year TS of patients treated with combination CT regimen (CHVP) followed by localized irradiation is approximately 55%, however the indications for the various types of treatment are still unclear. In patients with diffuse Stage III and IV, the results obtained with a combination CT regimen (CHVP) are still unsatisfactory, but are better in patients treated by a more aggressive CT regimen (CHVP-Bleo-VCR). Therefore aggressive CT associated with localized irradiation appears to be the best treatment. Further research should aim to identify the optimal combination CT regimen. In patients with high grade lymphomas who have relapsed the use of bone marrow autografts will be investigated. The present data show that besides histological type and age, the main prognostic factor is total tumor body burden as assessed by clinical stage, number of involved lymph node areas, and bulk of the disease. The study of the biological characteristics of the disease may provide more powerful prognostic indicators.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

alpha-Transducin immunoreactivity in retinae and sensory pineal organs of adult vertebrates.

Antiserum against the alpha subunit of bovine rod-outer-segment transducin was used in an immunocytochemical study that identified the protein in retina (human, baboon, owl monkey, cow, rat, quail, newt, frog, salmon, eel, and lamprey), pineal organ (quail, newt, frog, salmon, eel, and lamprey), and parapineal organ (salmon and lamprey). No reaction was observed in the cow or rat pineal organ or the eel parapineal organ. The immunoreaction was very strong in outer segments but weak in perikarya. Immunoblots of crude tissue extracts of bovine rod-outer-segment membranes and frog and fish retina revealed a 39-kDa immunopositive band. The fish retina also contained two additional bands of mass 43 kDa and 25 kDa. Only the 43-kDa band was present in the fish pineal organ, which is photosensitive. This raises the possibility that the 43-kDa alpha transducin-immunopositive molecule present in the fish pineal organ and retina may be involved in phototransduction.

Animals↗
PubMed1986

Phase II study of low-dose methotrexate in advanced osteosarcoma followed by escalation after disease progression: a study of the Soft Tissue and Bone Sarcoma Group of the European Organization for Research on Treatment of Cancer.

Twenty-seven patients with osteosarcoma and measurable metastases were treated with low-dose methotrexate (LDMTX) (80 mg/m2), followed by high-dose methotrexate (HDMTX) (7.5 g/m2) after disease progression in 14 patients. LDMTX was administered on Days 1, 8, and 15; if response or stable disease occurred, it was repeated on Days 29 and 43. If response occurred by Day 57, LDMTX was continued every 2 weeks until disease progression. If stable disease occurred by Day 57, the patient crossed over (optional) to HDMTX. HDMTX was given weekly during the first 3 weeks and continued once every 14 days until disease progression. Twenty-five of the patients were evaluable for response. Three patients (12%) achieved complete remission, with durations of 5, 14, and 34 weeks, respectively. The time to disease progression from the start of treatment was 19, 28, and 42 weeks. Twelve patients (48%) had stable disease, with a median duration of 7.5 weeks (range, 6-20). Ten patients (40%) had disease progression. In general, toxicity with LDMTX was mild. The most frequent toxic effect was stomatitis. Twelve of 14 patients who crossed over to HDMTX were evaluated for response. Six patients had stable disease and six had disease progression. We conclude that the results achieved with LDMTX seem inferior to the results achieved with HDMTX described in the literature.

Adolescent↗
PubMed1985

Specificity of the functional interactions of the beta-adrenergic receptor and rhodopsin with guanine nucleotide regulatory proteins reconstituted in phospholipid vesicles.

We have assessed the functional interactions of two pure receptor proteins with three different pure guanine nucleotide regulatory proteins in phosphatidylcholine vesicles. The receptor proteins are the guinea pig lung beta-adrenergic receptor (beta AR) and the retinal photon receptor rhodopsin. The guanine nucleotide regulatory proteins were the stimulatory (Ns) and inhibitory (Ni) proteins of the adenylate cyclase system and transducin (T), the regulatory protein from the light-activated cyclic GMP phosphodiesterase system in retinal rod outer segments. The insertion of Ns with beta AR in lipid vesicles increases the extent of binding of [35S] GTP gamma S to Ns and in parallel, the total GTPase activity. However, there is little change in the actual rate of catalytic turnover of GTPase activity (defined as mol of Pi released/min/mol of Ns-guanine nucleotide complexes). Enhancement of this turnover rate requires the beta-agonist isoproterenol and is accounted for by an isoproterenol-promoted increase in the rate and extent of [35S]GTP gamma S binding to Ns. The co-insertion of the beta AR with Ni or transducin results in markedly lower stimulation by isoproterenol of both the GTPase activity and [35S]GTP gamma S binding to these nucleotide regulatory proteins indicating that their preferred order of interaction with beta AR is Ns much greater than Ni greater than T. This contrasts with the preferred order of interaction of these different nucleotide regulatory proteins with light-activated rhodopsin which we find to be T approximately equal to Ni much greater than Ns. Nonetheless the fold stimulation of GTPase activity and [35S]GTP gamma S binding in T, induced by light-activated rhodopsin, is significantly greater than the "fold" stimulation of these activities in Ni. This reflects the greater intrinsic ability of Ni to hydrolyze GTP and bind guanine nucleotides (at 10 mM MgCl2, 100-200 nM GTP or [35S] GTP gamma S) compared to T. The maximum turnover numbers for the rhodopsin-stimulated GTPase in both Ni and T are similar to those obtained for isoproterenol-stimulated activity in Ns. This suggests that the different nucleotide regulatory proteins are capable of a common upper limit of catalytic efficiency which can best be attained when coupled to the appropriate receptor.

Adenylyl Cyclases↗
PubMed1985

Reproducibility and prognostic value of different non-Hodgkin's lymphoma classifications: study based on the clinicopathologic relations found in the EORTC trial (20751).

In the EORTC trial 20751, six pathologists belonging to five different centers classified tumoral lymph nodes from 406 untreated patients with non-Hodgkin's lymphoma (NHL) into three different NHL classifications. NHL were most easily and reliably subdivided according to the growth pattern (the rate of consensus being 93%). Classification according to growth pattern proved to be of prognostic significance. The rate of consensus of classifying cases in the different NHL classifications ranged from 74% for the Rappaport, through 70% for the Kiel to 67% for the international working formulation. It is concluded that NHL are reliably classified according to their growth pattern, and that this subdivision is of primary prognostic significance.

Humans↗
PubMed1985

Phase II study of elliptinium in metastatic soft tissue sarcoma.

A phase II study was carried out with 9-hydroxy-methyl-elliptinium (9-HME) in metastatic soft tissue sarcoma. The dose was 100 mg/m2 weekly in 1 1/2 hr intravenous infusion protected from light. Nineteen cases were evaluable for response, all previously treated with other chemotherapy regimens. No remissions were seen. Major toxicities were nausea and vomiting, dryness of the mouth and anorexia. It is concluded that 9-HME is not an effective drug in metastatic soft tissue sarcoma.

Adult↗
PubMed1985

A multivariate analysis of prognostic factors in early stage Hodgkin's disease.

A multivariate analysis of the prognostic factors was carried out with a Cox model on 1,139 patients with clinical Stage I + II Hodgkin's disease included in three controlled clinical trials. The following indicators had been prospectively registered: age, sex, systemic symptoms, erythrocyte sedimentation rate (ESR), number and sites of involved lymph node areas, histologic type, clinical stage, pattern of presentation, results of staging laparotomy when performed, as well as the date and type of treatment. A linear logistic analysis showed that most of the indicators are interrelated. This emphasizes the necessity of a multivariate analysis in order to assess the independent influence of each of them. The two main prognostic indicators for relapse-free survival are systemic symptoms and/or ESR and number of involved areas. The only significant factor for survival after relapse is age. Sex has a small but significant influence on relapse-free survival. The relative influence of each indicator varies with the type of treatment and these variations may help in understanding the biologic significance of the indicators.

Adult↗
PubMed1985

Phase II study of cisplatin in advanced osteogenic sarcoma. European Organization for Research on Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

The activity of cisplatin (CDDP) against advanced osteogenic sarcoma was evaluated in 37 of 50 patients registered by the members of the European Organization for Research on Treatment of Cancer Soft Tissue and Bone Sarcoma Group between 1979 and 1982. All patients had measurable lung metastases. Thirty-one patients (84%) had received previous chemotherapy consisting mainly of high-dose methotrexate, doxorubicin, and vincristine. CDDP (100 mg/m2) was given as a 24-hour continuous infusion every 3 weeks for a minimum of two cycles, with appropriate fluids and diuretics. In the absence of impairment of the renal function and/or myelosuppression, the dose could be escalated by 20%. The overall response rate was 19% (seven responses among 37 patients), with one complete remission for 51 weeks and six partial remissions from 12 to 26 weeks. The median number of courses of CDDP administered was three, ranging from two to 11. Of 143 courses administered, only 18 (12%) had to be modified because of toxicity. In 16% of the patients some transient impairment of the renal function was observed. CDDP adds to the limited number of chemotherapeutic agents with useful properties in osteogenic sarcoma, and CDDP-containing combination chemotherapy regimens should be actively investigated.

Adolescent↗