Potential impact of cycle of care on Diabetes services in secondary care.

Diabetes Cycle of Care is a new initiative recently introduced by the Health Service Executive (HSE). In this review we found that a quarter of patients attending a secondary care diabetes outpatient clinic in a large teaching hospital could potentially be managed in primary care upon implementation of Diabetes Cycle of Care.

Significance of serum CA125 and TPS antigen levels for determination of overall survival after three chemotherapy courses in ovarian cancer patients during long-term follow-up.

PURPOSE OF INVESTIGATION: To evaluate the prognostic significance for overall survival rate for the marker combination TPS and CA125 in ovarian cancer patients after three chemotherapy courses during long-term clinical follow-up. METHODS: The overall survival of 212 (out of 213) ovarian cancer patients (FIGO Stages I-IV) was analyzed in a prospective multicenter study during a 10-year clinical follow-up by univariate and multivariate analysis. RESULTS: In patients with ovarian cancer FIGO Stage I (34 patients) or FIGO Stage II (30 patients) disease, the univariate and multivariate analysis of the 10-year overall survival data showed that CA125 and TPS serum levels were not independent prognostic factors. In the FIGO Stage III group (112 patients), the 10-year overall survival was 15.2%; while in the FIGO Stage IV group (36 patients) a 10-year overall survival of 5.6% was seen. Here, the tumor markers CA125 and TPS levels were significant prognostic factors in both univariate and multivariate analysis (p < 0.0001). In a combined FIGO Stage III + FIGO Stage IV group (60 patients with optimal debulking surgery), multivariate analysis demonstrated that CA125 and TPS levels were independent prognostic factors. For patients in this combined FIGO Stage III + IV group having both markers below respective discrimination level, 35.3% survived for more than ten years, as opposed to patients having one marker above the discrimination level where the 10-year survival was reduced to 10% of the patients. For patients showing both markers above the respective discrimination level, none of the patients survived for the 10-year follow-up time. CONCLUSION: In FIGO III and IV ovarian cancer patients, only patients with CA 125 and TPS markers below the discrimination level after three chemotherapy courses indicated a favorable prognosis. Patients with an elevated level of CA 125 or TPS or both markers after three chemotherapy courses showed unfavorable prognosis.

Evidence that the decreased liver folate status following vitamin B-12 inactivation in the mouse is due to increased loss rather than impaired uptake.

Using N2O to inactivated B-12, mouse liver polyglutamate distribution has been examined at short time intervals after injection of [3H]pteroyglutamate. An increased monoglutamate pool is found initially which is lost by 24 h. This finding strongly supports the suggestion that the reduction in total liver folate in vitamin B12 deficiency is due to increased loss rather than decreased uptake.

Carboplatin/cyclophosphamide combination chemotherapy for advanced ovarian cancer.

The efficacy and toxicity of combination intravenous carboplatin (300 mg/m2) and cyclophosphamide (600 mg/m2) were evaluated in 70 newly diagnosed patients with advanced-stage epithelial ovarian cancer. Cycles were administered at 4-week intervals for a total of six cycles, and treatment was provided on an outpatient basis without prehydration or forced diuresis. During treatment, patients were assessed by physical, gynecologic, and radiologic examinations. Seventy patients with a median age of 58 years (range, 35 to 77 years) were entered into the study. Most patients had serious cystadenocarcinoma; 78% had stage III or IV disease and 91% had grade II or III histologic subtype. Optimal debulking surgery was performed in only 46% of patients. The overall response rate to carboplatin/cyclophosphamide combination chemotherapy was 81%, with 66% achieving a clinical complete response. The median survival for all patients was 19+ months. For patients who had undergone optimal debulking surgery, median survival was 26 months, compared with a median survival of 13+ months for those who had undergone suboptimal surgery. Treatment was well tolerated by most patients. Significant nausea and vomiting (World Health Organization grades 2 to 3) occurred in only 6% of 377 cycles of therapy. Myelosuppression was mild, with leukopenia (WBC count less than or equal to 2 x 10(9)/L) observed in only 11 of 295 cycles (4%) and thrombocytopenia (less than or equal to 100 x 10(9)/L) in 17 of 279 cycles (6%). Nadir levels generally occurred on day 21 of each cycle. Symptomatic anemia requiring transfusion occurred in 18 of 290 cycles (6%). Moderate alopecia, necessitating use of a hairpiece, occurred in six patients; no signs or symptoms of neurotoxicity, ototoxicity, or nephrotoxicity were observed in any patient. Renal function was normal on follow-up investigation, which was performed a median of 5 months after completion of treatment. This study demonstrates that carboplatin/cyclophosphamide combination chemotherapy is well tolerated in women with advanced-stage epithelial ovarian cancer, and produces overall response rates and median survival times similar to those obtained with cisplatin-containing regimens.

Non-M CK--a practical measure of creatine kinase isoenzymes in cancer patients.

The individual creatinine kinase (CK) isoenzymes CK-BB and CK-Macro II have previously been investigated as potential tumour markers. We believe there is a need for a system to measure those CK forms not usually present in serum. We have studied a CK-MB immunoinhibition kit which measures all residual CK activity following inactivation of M-subunit activity. In 162 patients with cancer we found no difference in grading (+ or -) between detailed isoenzyme studies and the simple non-M assay. In 33 samples with elevated non-M CK, detailed analysis showed BB alone (45%), Macro II alone (9%), or both (36%). Raised activities were mainly found in patients with small cell lung cancer (SCLC) (17/40; 43%) and GI Tumours (6/11; 55%). In patients with SCLC, elevated activities were associated with disseminated disease. Preliminary evidence indicates that Non-M CK may also be a simple means of monitoring initial treatment response.

Prognostic significance of CA 125 and TPS levels after chemotherapy in ovarian cancer patients.

The analysis of survival data of patients with epithelial ovarian cancer proved that both CA 125 and TPS were good markers for clinical outcome prediction. Patients receiving chemotherapy were analyzed for 2-year overall survival (OS). Kaplan-Meier survival analysis showed highly significant differences in OS between patients with stage I+II (survival for 2 years 68%) and stage III+IV (survival for 2 years 33%; p = 0.0008). CA 125 levels above or below 35 kU/I and TPS levels above or below 80 U/l after 3 chemotherapy courses were not significantly correlated with OS in stage I+II patients (p = 0.06 respectively 0.07). However, in the subgroup of patients with stage III+IV the cut-off levels of CA 125 and TPS were excellent discriminators of OS: With CA 125 levels below the cut-off 52% of the patients survived, while with CA 125 levels above the cut-off only 13% survived (p < 0.0001). With TPS levels below the cut-off 49% of the patients survived, while with levels above the cut-off only 19% of the patients survived (p < 0.0001). In the subset of patients with CA 125 levels less than 35 kU/I after 3 chemotherapy courses (n = 50) analysis of their TPS levels allowed further discrimination of the prognostic significance. With TPS levels below the cut-off 63% of the patients survived, while 35% of the patients survived with TPS levels above the cut-off. The sum value of CA 125 and TPS cut-off values (115) as discriminator correlated even better with survival rate: With levels below this sum value 63% of the patients survived, while this was only 17% with sum values above the summed cut-off level (p = 0.0004). The extent to which the tumor was removed at operation also correlated with the 2 years survival rate. None of the patients with a staging laparotomy (n = 10) showed a 2-years survival. The difference in OS between patients with complete debulking and partial debulking was significant: OS 51% versus 23% (p = 0.027). Prognosis was not significantly correlated with histological type.

Serum levels of CA 125 and TPS during treatment of ovarian cancer.

Two hundred and sixty ovarian cancer patients (including all FIGO stages) were enrolled in a prospective multicentre study. In this interim study we analyzed 206 patients receiving combined chemotherapy for at least 3 courses for two-year overall survival (OS). CA 125 and TPS were applied for monitoring treatment and the relationship between marker levels, marker changes and clinical assessments was established. Preoperative CA 125 or TPS levels were not correlated with OS in FIGO stage I and II patients. After 3 chemotherapy courses the marker levels were not correlated with OS in stage I and II. Partial debulking in stage II patients was a bad prognostic factor. CA 125 or TPS levels (using a CA 125 discrimination level of 25 kU/l and a TPS discrimination level of 100 U/l) after 3 courses of chemotherapy were highly significantly correlated with OS in FIGO stages III and IV patients: CA 125 two-year OS 67% versus 26% (p < 0.0001) and TPS two-year OS 55% versus 22% (p < 0.0001). The prognostic value of CA 125 levels after 3 chemotherapy courses could be further increased by combining CA 125 and TPS levels. When both CA 125 and TPS levels were below their respective discrimination levels, the two-year overall survival was 75%. When both levels were above the discrimination level, the two-year overall survival was only 17%.

The role of methionine in the intracellular accumulation and function of folates.

It is suggested that mammalian cells have evolved to respond to methionine deficiency since in such circumstances vital methylation reactions are put at risk, due to decreased levels of S-adenosyl-methionine. Enzymatic changes occurring as a result of decreased methionine, S-adenosylmethionine and S-adenosylhomocysteine, optimize the remethylation of homocysteine to methionine by decreasing homocysteine catabolism and channelling cellular folates into 5-methyltetrahydropteroylglutamate (5-CH3-H4 PteGlu). The latter, in addition to optimising the remethylation cycle, directs the folate cofactors away from purine and pyrimidine biosynthesis and decreases the rate of proliferation of rapidly dividing cells thus reducing competition for methionine incorporation into proteins. Decreased cellular homocysteine, as a result of decreased methionine, would also restrict cell division by decreased conversion of plasma 5-CH3-H4PteGlu into intracellular polyglutamates. Cobalamin deficiency, either nutritional or due to exposure to the Co (I) cobalamin inactivating agent nitrous oxide, prevents the demethylation of 5-CH3-H4PteGlu, which even in the presence of adequate amounts of homocysteine and methionine prevents rapidly proliferating cells from converting enough of the plasma 5-CH3-H4 PteGlu into folylpolyglutamate forms to permit normal DNA biosynthesis and cell replication. This, together with the trapping of the cellular folate cofactors in the 5-CH3-H4PteGlu form, results in megaloblastic changes occurring in tissues such as the marrow. The vital role of the methylation reactions was demonstrated by exposing monkeys to nitrous oxide which inactivated their methionine synthetase. The resultant ataxia and severe demyelination was prevented and diminished by methionine supplementation. When methionine synthetase was similarly inactivated in mice it was shown that while 5-CH3-H4PteGlu enters mammalian cells, it is not converted into a polyglutamyl form and subsequently leaves the cell unmetabolised. In similar experiments in rats methionine was found to have only a small effect in restoring folylpolyglutamate biosynthesis, contrary to previous reports using nutritionally cobalamin deficient animals. It was found that a decrease in the deoxythymidine salvage pathway by methionine, under the experimental conditions used, has led others to the mistaken conclusion that methionine has an 'anti-folate' effect in bone marrow, i.e. that it decreases folate availability for thymidylate synthetase.

The prognostic value of post chemotherapy serum CA 125 in epithelial ovarian cancer.

In a study of 33 newly diagnosed patients with ovarian cancer, we have correlated serum levels of the tumour marker CA 125 with disease stage, response to cytotoxic therapy and survival. Elevated levels were found in 22/28 patients (79%) with Stage III/IV disease, compared with 0/5 patients with Stage I disease and 7/38 patients (19%) with non-ovarian malignancies. Of 15 patients with measurable disease, serum CA 125 levels correlated with clinical response to treatment in 11; the remaining 4 patients had persistently elevated CA 125 levels in spite of clinical response and subsequently developed early relapse. Among the 13 patients with no measurable disease, 11 remained in clinical and radiological remission with treatment, with a fall to normal CA 125 levels; 2 patients who had persistently elevated CA 125 levels developed disease recurrence after completion of chemotherapy. Sequential measurements of CA 125 for up to 2 years in 8 patients showed that rising CA 125 levels preceded clinical relapse by a median of 3 months. The most important prognostic value of CA 125 was the level following 3 cycles of chemotherapy, independent of clinical status--median survival for 15 patients with normal CA 125 at 3 months was 15+ months compared with a median survival of 6 months in 13 patients who had elevated CA 125 at 3 months. These data confirm that 1) serum CA 125 levels are more sensitive than clinical or radiological assessment in monitoring response/relapse in ovarian cancer and 2) the CA 125 level after 3 cycles of chemotherapy is of major prognostic value in predicting survival.

Cholesterol levels in normal Irish adults: the Mater Hospital Cholesterol Screening Survey.

Serum samples from 954 Irish adults (604 males, 350 females) aged 18 to 65 years were analyzed within 24 hours of receipt for non-fasting total serum cholesterol levels. The subjects were volunteer blood donors (Blood Transfusion Service Board, Pelican House, Dublin) presenting from June 1990 to February 1991. Serum cholesterol increased significantly with age in both males and females. Mean serum cholesterol in males increased from 4.5 (+/- 0.9) mmol/l in those < 25 years, to 5.7 (+/- 1.0) mmol/l at age 55-64 years. In females, mean serum cholesterol increased from 4.3 (+/- 0.9) mmol/l less than 25 years to 6.2 (+/- 0.8) mmol/l at age 55-64 years. Options for reporting cholesterol ranges are discussed. The overall mean cholesterol concentration of 5.1 mmol/l seen in this study is lower than that reported for comparable studies of U.K. and American subjects, but higher than observed in Japanese individuals. Almost 48% of the studied population had a serum cholesterol value less than 5 mmol/l and over 56% had levels less than 5.2 mmol/l.

A study of PSA requests from general practitioners received by one Dublin hospital.

Patterns of PSA requesting by General Practitioners were studied in one Dublin hospital for 11/1994-8/1995 and 11/1996-8/1997. 58% of requests (421/723) had PSA < 2ug/L and 82% had PSA < 4ug/L. Patients under 60 years accounted for 32% of the total requests but only 7% of these showed PSA levels over 4ug/L. PSA requests on these younger patients constitute a significant proportion of the PSA workload and yet appear to have low diagnostic yield. The mean age for all patients studied dropped from 68 years in 1994/1995 to 63 years in 1996/1997. This may reflect an increasing tendency to test all men over 50 years of age. This review of PSA requesting within our hospital's catchment area supports the view that PSA testing is not focused on higher risk individuals and shows tendencies towards a screening approach.

The role of methionine and vitamin B12 in folate incorporation by rat liver.

The decreased folate uptake induced by exposure of rats to nitrous oxide can be partly reversed by methionine supplementation. This is consistent with the theory that N2O inhibits methylcobalamin-dependent methionine synthetase (EC 2.1.1.13) in rat liver and previous observations showing decreased folate incorporation in rats made nutritionally vitamin B12 deficient.

Ketosis, a complication of theophylline toxicity.

A case of prolonged theophylline toxicity in a young non-diabetic female is reported. Blood gas analysis revealed a mixed respiratory alkalosis and metabolic acidosis. The metabolic acidosis was due to ketoacids, which were detected in the patient's breath and urine. The ketones cleared rapidly when theophylline elimination was increased with activated charcoal, i.v. metoprolol reduced excessive b-adrenergic stimulation and a 10% dextrose infusion repleted hepatic glycogen. Theophylline is known to increase free fatty acid levels. It is postulated that prolonged fasting led to depletion of hepatic glycogen and that ketones were generated by metabolism of elevated serum fatty acids. In previous reviews of the metabolic abnormalities associated with theophylline toxicity ketosis has not been described.

Prognostic significance of CA 125 and TPS levels after 3 chemotherapy courses in ovarian cancer patients.

OBJECTIVE: To evaluate the prognostic significance of and predictive value for survival of CA 125 and TPS levels after three chemotherapy courses in ovarian cancer patients. METHODS: We analyzed in a prospective multicenter study the 1- and 2-year overall survival (OS) in ovarian carcinoma patients. The prognostic significance of CA 125 and TPS levels above the discrimination value (25 kU/L and 100 U/L, respectively) was examined by univariate and multivariate analyses. RESULTS: Of the 213 cases included, 64 patients were staged as FIGO I + II and 149 patients were staged as FIGO III + IV. Tumor marker levels in stage I + II were not correlated with survival. However, stage III and IV patients with elevated levels of CA 125 or TPS after three chemotherapy courses had a worse 2-year OS (69% vs 26%, P < 0.0001 and 57% vs 20%, P < 0.0001, respectively) than patients with normal levels of the markers. In univariate analysis the result of operation (staging laparatomy and partial debulking) and advanced FIGO stage (IV) were also adverse prognostic factors. Independent factors predictive of low 2-year OS by multivariate analysis were staging laparotomy, TPS elevated, and CA 125 elevated. The only factors predictive of low 1-year OS were TPS elevated and staging laparotomy. CONCLUSIONS: Ovarian cancer patients with elevated CA 125 levels after three chemotherapy courses have a poor prognosis. However, the prognostic accuracy can be significantly increased by the parallel determination of serum TPS.