VO2 kinetics in supra-anaerobic threshold constant tests allow the visualization and quantification of the O2 saving after cytochrome c oxidase inhibition by aerobic training or nitrate administration.

We tested whether the known cytochrome c oxidase (COX) inhibition by nitric oxide (NO) could be quantified by VO(2) kinetics during constant load supra-Anaerobic Threshold (AT) exercises in healthy trained or untrained subjects following aerobic training or nitrate administration. In cycle ergometer constant load exercises supra-AT, identified in previous incremental tests, VO(2) kinetics describe a double exponential curve, one rapid and one appreciably slower, allowing the area between them to be calculate in O(2) l. After training, with increased NO availability, this area decreases in inverse ratio to treatment efficacy. In fact, in 11 healthy subjects after aerobic training for 6-7 weeks, area was decreased on average by 51 %. In 11 untrained subjects, following the assumption of an NO donor, 20 mg isosorbide 5 mononitrate, area was decreased on average by 53 %. In conclusion, supra-AT VO(2) kinetics in constant load exercises permit the quantification of the inhibitory effect NO-dependent on COX after either physical training or nitrate assumption.

Predictors of the short-term effect of isoleucine-proline-proline/valine-proline-proline lactotripeptides from casein on office and ambulatory blood pressure in subjects with pharmacologically untreated high-normal blood pressure or first-degree hypertension.

Our aim was to evaluate the predictors of Isoleucine-Proline-Proline/Valine-Proline-Proline (IPP-VPP) lactotripeptides (LTPs) antihypertensive effect in the context of a short-term large double-blind randomized clinical trial involving 164 pharmacologically untreated subjects in primary prevention for cardiovascular disease. When compared with the baseline, office systolic blood pressure (SBP) (-3.42 mm Hg, P < .001) and diastolic blood pressure (DBP) (-2.35 mm Hg, P < .001) significantly decreased, in the LTP-treated patients only. No significant change in predictors during the study of ambulatory blood pressure measurement (ABPM) parameters was observed. A short-term supplementation with LTPs significantly improves the office SBP and DBP, especially in male subjects. The main predictor of LTP antihypertensive effect was the baseline BP.

Effectiveness of a continuous quality improvement program on colonoscopy practice.

BACKGROUND AND STUDY AIM: Continuous quality improvement (CQI) is recommended by professional societies as part of every colonoscopy program, but little is known with regard to its effectiveness for colonoscopy outcomes. We prospectively assessed whether the implementation of a CQI program in routine clinical practice influences the quality performance of colonoscopy. METHODS: In an open-access endoscopy unit at a secondary care center in Northern Italy, 6-monthly audit cycles were carried out over a 4-year period, to identify reasons for poor colonoscopy outcomes and institute appropriate changes to improve performance. The colonoscopy completion rate and the polyp detection rate as detected by endoscopists were considered to be key measures for improvement. RESULTS: The initial crude colonoscopy completion rate was 84.6%, with a range for individual endoscopists 80.4%-94%. Four endoscopists had a completion rate lower than 90%. The overall polyp detection rate was 34%, with a wide variation among endoscopists (range 14%-42%). Poor patient tolerance and differences in colonoscopist expertise were the main determinants of lack of completion and variation in polyp detection rate. Changes to sedation practice, greater access to endoscopy sessions for the endoscopists with the lowest performance rates, and other organizational arrangements, were implemented to improve quality performance. The crude completion rates improved consistently, up to 93.1%, over the study period. This trend was confirmed even when adjusted completion rates were calculated. All endoscopists reached a crude completion rate of 90% or more and a polyp detection rate of over 20%. The introduction of CQI did not significantly change the overall incidence of procedure-related complications. CONCLUSIONS: The effectiveness of colonoscopy can be improved by implementing a CQI program in routine colonoscopy practice.

The determination of gemcitabine and 2'-deoxycytidine in human plasma and tissue by APCI tandem mass spectrometry.

A fast, sensitive and accurate method for the determination of gemcitabine (difluorodeoxycytidine; dFdC) and deoxycytidine (CdR) in human plasma/tissue was developed using LC-MS/MS techniques. Effectiveness of the method is illustrated with the analysis of plasma from a phase I trial of dFdC administered as a 24h infusion. The method was developed using (15)N(3) CdR as an internal standard across the concentration range of 1-500ng/ml, using a cold alcohol-protein precipitation followed by desorption with freeze drying. Sample clean-up for LC-MS/MS analysis was performed by an innovative liquid/liquid back extraction with ethyl acetate and water. Chromatography was performed using a Chrompak-spherisorb-phenyl-column (3.1mmx200mm, 5microm) with a 50mM formic acid: acetonitrile (9:1) mobile phase eluted at 1ml/min. Extracted samples were observed to be stable for a minimum of 48h after extraction when kept at 4 degrees C. Detection was performed using an atmospheric pressure chemical ionization (APCI) source and mass spectrometric positive multi-reaction-monitoring-mode (+MRM) for dFdC (264 m/z; 112 m/z), CdR (228 m/z; 112 m/z), and (15)N(3) CdR (231 m/z; 115 m/z) at an ion voltage of +3500V. The accuracy, precision and limit-of-quantitation (LOQ) were as follows: dFdC: 99.8%, +/-7.9%, 19nM; CdR: 100.0%, +/-5.3%, 22nM, linear range LOQ to 2microM. During 24h infusion dFdC levels were detected with no interference from either CdR or difluorodeoxyuridine (dFdU). CdR co-eluted with dFdC but selectivity demonstrated no "crosstalk" between the compounds. In conclusion the analytical assay was very sensitive, reliable and robust for the determination of plasma and tissue concentrations of dFdC and CdR.

Analysis of deoxycytidine accumulation in gemcitabine treated patients.

Deoxycytidine (CdR) analogs are increasingly popular as chemotherapeutic agents and their effectiveness can be linked to the direct competition with active forms of endogenous CdR. A tandem mass spectrometric assay was developed to determine the plasma concentrations of CdR. Plasma extracts were prepared by protein precipitation and an ethyl acetate/water back extraction, and then separated chromatographically. Detection parameters were optimized for multi-reaction monitoring (MRM) tandem mass spectrometry and assay efficiency was improved using 15N3 CdR as an isotopic internal standard. Preliminary results from a gemcitabine trial are shown which indicate that CdR concentrations increase systemically during infusion, from about 5 nM to 78 nM after hepatic artery infusion and to 102 nM after systemic infusion for 24 hours. The developed assay demonstrated good sensitivity and selectivity for CdR.

Stop-flow technique for loco-regional delivery of high dose chemotherapy in the treatment of advanced pelvic cancers.

AIM: To verify the rationale of a pelvic stop-flow technique for the perfusion of high-doses of mitomycin C and anthacyclines in patients with inoperable, recurrent pelvic cancer. METHODS: The stop-flow technique was realized by using percutaneous double-balloon arterial-venous catheters that selectively isolate the pelvic vascular section and a perfusion provided by an extracorporeal pump for 20 min. Ten patients (pts) with unresectable pelvic recurrence from colon-rectal cancer were treated with a combination of Mitomycin C (MMC, 20 mg/sqm) plus doxorubicin (DOXO, 75 mg/sqm; 8pts) or epirubicin (EPI, 75 mg/sqm; 2pts) infused into the isolated pelvic compartment. Blood samples were collected from the extracorporeal vascular flow and from peripheral plasma, and analysed for drug quantitation. RESULTS: During the procedure, there were no technical or hemodynamic complications, and no deaths occurred during surgery or in the postoperative period. MMC and DOXO peak levels measured in the extracorporeal system which irrotates the tumor area, were on average 21.6 (range: 4.3-44.3, MMC) and 17.2 (range: 1.8-48.4, DOXO) times higher than those observed in the peripheral blood. Similarly; the area under concentration (AUC) versus time curves measured in the pelvic compartment during stop-flow perfusion were 19.9 (range: 3.8-45.0, MMC) and 13.4 (range: 1.2-26.6, DOXO) times higher than the corresponding value in peripheral circulation. The drug percentage eliminated in the ultra filtrate was only 7.7% (MMC) and 0.9% (DOXO), and the plasmatic AUC(0-24) were similar to those observed with iv bolus of equivalent drug doses. Minimal systemic and local toxicities were observed. One complete pathological and 2 partial responses were observed; pain remission in 8/10 patients. median survival was 12 months (8-31). CONCLUSION: The endo-arterial administration into the local vasculature produces high pelvic-systemic concentration gradients during the stop-flow perfusion with limited local and systemic toxicity. The encouraging clinical results suggest further evaluation.

New challenges and old problems: end of life care and the dilemma of prognostic accuracy.

Dignity of the natural end of life for everybody is one of the new great challenges of medicine and social care for the beginning 21st century. However, many end of life care providing doctors are confused about how to categorize the help they give. One of the central problems is predicting the life expectancy of an individual patient. Difficulties in this field can become ethical dilemmas when physicians are obliged to predict accurately a patient's prognosis as the basis for a certain care strategy. Clinical estimation of the duration of life for patients with end of life cancer needs experience and training. Education programmes in the field should include this topic much more until now. Prognosis should be based more on proven indices and less on intuition. However, there is no doubt that daily clinical practice limits the use of highly sophisticated computer-based score models. Even maximal accuracy of prognosis will not exclude the risk of errors in a great part of patients. This limits their classification in care categories too strictly defined. Health care systems should avoid models for care with standards and budgets based on prognostic estimates and the medical community should avoid claim by disciplines of certain categories of patients defined by their prognoses. What we need is a network of assistance for incurable patients with single parts defined by patients needs and not by predicted life expectancy. Separating palliative and terminal care is artificial and often in contrast to the needs of the patients.

Acute self-limiting jejunitis as the first manifestation of microscopic polyangiitis associated with Sjogren's disease: report of one case and review of the literature.

We report a case of acute self-limiting ulcerative jejunitis of unknown aetiology in a 72-year-old female patient in which a subsequent diagnosis of microscopic polyangiitis and Sjogren's syndrome was made. All known causes of jejunal ulceration and inflammation were excluded. Previously reported cases of acute self-limiting jejunitis are reviewed and the possibility that acute jejunitis in this patient had been the first manifestation of systemic vasculitis is discussed.

Advanced ovarian cancer patients with no evidence of disease after platinum-based chemotherapy: retrospective analysis of the role of second-look.

From 1981 to 1992, 230 previously chemotherapy-untreated epithelial ovarian cancer patients (Stages IIb-III or IV) received platinum-based polychemotherapy at our Division. In this presentation, time to progression and overall survival rates were retrospectively analyzed in 89 epithelial ovarian cancer patients (stage IIb, c - III or IV) with no clinical evidence of disease (clinical complete remission--CCR--in 26 patients with postsurgical residual tumor > or = 2 cm, and no clinical evidence of disease--NED--in 63 patients with post-surgical residual tumor < 2 cm) after first-line platinum-containing chemotherapy. After at least 6 courses of chemotherapy, 62 patients (group A) were submitted to second-look (SL) laparotomy (n=47) or laparoscopy (n=15); 27 patients (group B) did not undergo second-look surgery because of patient refusal, the surgeon's decision or clinical contro-indications to surgery. Groups A and B were comparable in terms of post-surgical residual tumor (< 2 cm: 71% vs 70%), median Performance Status (WHO: 1) and median age (56 vs 57 yrs). FIGO stage IIb, c was more frequent in group B (26% vs 18%--p=0.004). In 9/18 (50%) patients with clinical CR and in 31/44 (70%) NED patients no residual tumor was confirmed at SL (pathological CR--pCR). After a median follow-up of 10 years (range 5-16 years), 72% (64/89) of patients relapsed and 65% (58/89) died. Survival was significantly longer in patients with pCR (median survival 76 months vs 32, 29 and 16 months for patients with pPR, pNC or pPD, respectively, p=0.0001). Multivariate analysis identifies pCR as the only significant prognostic factor exerting an influence on survival after second-look laparotomy (p=0.0000). This study confirms that the second-look can provide an important prognostic evaluation in patients without evidence of disease after chemotherapy for ovarian cancer stages III-IV.

A double-blind evaluation of the analgesic efficacy and toxicity of oral ketorolac and diclofenac in cancer pain. The TD/10 recordati Protocol Study Group.

AIM: To compare the analgesic efficacy and toxicity of the nonsteroidal anti-inflammatory analgesic drug, ketorolac (Toradol, Recordati spa, Milan) 10 mg p.o. (t.i.d.) with diclofenac (Voltaren, Novartis Farma, Origglo, VA) 50 mg p.o. (t.i.d.) in cancer patients with moderate to severe chronic pain. METHODS AND STUDY DESIGN: The study was a multicenter randomized double-blind cross-over trial. Each treatment lasted 7 days, after which the patients crossed over to the other drug. Pain intensity was evaluated by the visual analogue scale (VAS) after the first dose and by the 5-point verbal rating scale (VRS) by the patient and by the physician following the 7-day treatment. RESULTS AND CONCLUSIONS: A total of 138 advanced cancer patients were enrolled in the study. Overall 251 single-dose administrations (117 cross-over observations) and 257 multiple treatments (127 cross-over experiments) were assessable. After a single administration of ketorolac and diclofenac, no significant difference could be observed in analgesic activity, as indicated by the area under the pain-intensity time curve (AUC0-8), in the maximum efficacy, or the duration of efficacy of the two drugs. The Westlake confidence intervals of the AUC0-8 ratio (ketorolac: diclofenac) (1.07; 90% CI, 0.94-1.19), of the maximum efficacy ratio (1.03; 90% CI, 0.92-1.14), and the duration of efficacy ratio (1.05; 90% CI, 0.97-1.11) showed the bioequivalence of the two drugs. Satisfactory pain relief was reported for multiple 7-day treatments, with no significant differences between the two therapies: according to the physician's evaluation, in 93/128 (73%; 95% CI, 65-80%) ketorolac treatments and 91/129 (71%; 95% CI, 63-78%) diclofenac treatments; according to the patient's evaluation, in 83/128 cases (65%; 95% CI, 57-73%) after ketorolac and in 74/129 cases (57%; 95% CI, 49-66%) after diclofenac. Adverse symptoms were acceptable with both drugs. Interestingly, a pronounced sequence effect was found: gastric disturbances after ketorolac were observed mainly (10 out of 15 observed events) when the drug was given to patients pretreated with diclofenac.

Multicenter randomized clinical trial on high-dose epirubicin plus cis-platinum versus vinorelbine plus cis-platinum in advanced non small cell lung cancer.

BACKGROUND: High dose Epirubicin (HD-EPI) (>90 mg/m2) and Vinorelbine (VNR) demonstrated antitumor activity as single agent (about 20%) in the treatment of advanced NSCLC. This trial compares these two agents combined with cisplatin (CP). PATIENTS AND METHODS: From August 1992 to February 1996, 228 patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 as i.v. bolus plus Cisplatin (CP) 60 mg/m2 on day 1 (regimen A) or VNR 25 mg/m2 as i.v. bolus on day 1 and 8 plus CP 60 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days up to a maximum cumulative dose of EPI of 840 mg/m2 or 12 cycles. Eligible patients were 212 and 198 patients were evaluable for objective response (95 in arm A and 103 in arm B). The main characteristics of eligible patients were: male/female 179/33; median age 61 (42-72); median Karnofsky PS 80 (70-100); stage IIIA 12%, stage IIIB 40%, stage IV 41%, recurrence 7%; histotype: epidermoid 48%, adenoca 36%, others 16%. RESULTS: The following response rates were observed in regimens A and B, respectively; CR, 1 and 2%, PR, 32 and 25% (P = 0.4567). Median CR + PR duration was 9 and 8 months, respectively. Median survival was 10.5 and 9.6 months, respectively. Grade III-IV leucopenia occurred in 38 and 21% in arm A and arm B, respectively(P = 0.01), thrombocytopenia in 6 and 0% (P = 0.02), anemia in 8 and 7% (n.s.). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88 vs. 33% in arm A and B, respectively). Supraventricular arrhythmia occurred in three patients on regimen A; a >15% LVEF absolute decrease was observed in 9 (22.5%) and three (14%) patients on arm A and arm B, respectively (n.s.). No congestive heart failure was observed. CONCLUSION: HD-EPI+CP and VNR+CP are both active combinations in advanced NSCLC with a similar response rate, response duration and survival but regimen A was significantly more toxic (myelosuppression and alopecia).

Comparative crossover trial of two intravenous doses of granisetron (1 mg vs 3 mg) + dexamethasone in the prevention of acute cis-platinum-induced emesis.

BACKGROUND: The 5HT3 receptor antagonist Granisetron (GRA) is available on the market as a 1 mg vial in USA and as a 3 mg vial in Europe. This study aimed to compare the two i.v. doses of GRA (3 mg vs 1 mg), both of which combined with Dexamethasone (DEX) (20 mg) in the prevention of acute Cisplatinum (CP)-induced emesis. PATIENTS AND METHODS: One hundred and ninety-eight consecutive chemotherapy-naive cancer patients, mainly suffering from lung and bladder cancer, were randomized at their first cycle to receive either GRA 1 mg + DEX or GRA 3 mg + DEX as i.v. bolus prior to chemotherapy and crossed-over to another GRA dose at the second cycle. The cytotoxic treatment included different multi-drug regimens containing CP (median dose 60 mg/m2, range 50-70) administered on day 1 and repeated every 21-28 days. RESULTS: Of the 192 evaluable patients complete protection from acute emesis with GRA 1 and GRA 3, was observed after the 1st + 2nd cycles as follows: nausea 70% and 74%, vomiting 90% and 94%, nausea and vomiting 67% and 74% respectively (no statistically significant difference). No carry-over effect was observed on the complete protection from emesis. The crossover analysis comprising 156 patients confirmed there were no differences between the two antiemetic treatments. Twenty-seven per cent of patients preferred GRA 1, 31% preferred GRA 3, while 42% expressed no preference (P = 0.75). Nor was any difference observed for tolerability, the only reported side-effects being mild headache (16% vs 17%) and constipation (18% vs 25%). CONCLUSION: This study shows that, under the above conditions, the 1 mg and 3 mg i.v. GRA doses are comparably effective when combined with DEX 20 mg in the prevention of acute CP-induced emesis.

Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor.

BACKGROUND: The increased prostaglandin synthesis that might follow stimulation of the arachidonic acid cascade by angiotensin-converting-enzyme inhibition (ACE-I) has been suggested to underlie the appearance of cough on ACE-I treatment. We investigated whether the prostanoid thromboxane was involved. METHODS: Nine patients with essential hypertension who had cough after enalapril 20 mg once a day (coughers) were treated, while continuing the enalapril, in a double-blind crossover study with placebo or picotamide, 600 mg twice daily. Picotamide is a platelet antiaggregant that acts through both inhibition of thromboxane synthase and thromboxane-receptor antagonism. Thirteen hypertensive patients with no history of ACE-I-induced cough were also treated with enalapril and served as controls. Cough frequency was measured by a visual analogue scale and by a daily cough diary. 24 h urinary recovery of 11-dehydro-thromboxane-B2 and 6-keto-PGF1 alpha were measured to assess any changes in endoperoxide metabolism during the study periods. FINDINGS: 11-dehydro-thromboxane-B2 (TXB2) recovery was significantly reduced by picotamide, which led to the disappearance of cough in eight patients within 72 h. Picotamide urinary recovery data suggested incomplete absorption in the non-responder. At baseline and after rechallenge with enalapril, 11-dehydro-TXB2 excretion was in the same range in the controls and in the coughers, but the latter showed significantly lower excretion of 6-keto-PGF1 alpha, and their ratio of 11-dehydroTXB2 to 6-keto-PGF1 alpha was twice that of the controls (1.40 [95% CI 0.86-1.95] vs 0.61 [0.37-0.84]). INTERPRETATION: A thromboxane antagonist is effective in ACE-I-induced cough. An imbalance between thromboxane and prostacyclin may represent a marker of patients susceptible to ACE-I-induced cough.

Pseudoxanthoma elasticum: a rare cause of gastrointestinal bleeding.

Pseudoxanthoma elasticum (PXE) is a rare connective tissue disorder. The main clinical features of this condition are characteristic skin lesions, angioid streaks of the fundus oculi, and occlusive vascular disease. Gastric hemorrhage is a rare complication. A gastroscopic examination was performed on two patients with PXE who presented with upper gastrointestinal tract bleeding. The two patients had submucosal yellowish nodular lesions similar to the xanthoma-like skin lesions seen in the disease. We suggest that a diagnosis of PXE be considered for any patient with gastrointestinal hemorrhage, especially if routine clinical and endoscopic examination fail to reveal the cause, and if raised yellow plaque-like lesions are seen in the stomach by endoscopy.

An open randomised cross-over study on granisetron versus ondansetron in the prevention of acute emesis induced by moderate dose cisplatin-containing regimens.

The aim of the study was to compare granisetron (GRA) with ondansetron (OND) in the prevention of acute emesis in consecutive chemotherapy-naive patients admitted to our department to receive a cytotoxic treatment containing cisplatinum (CP) at a dose > or = 50 mg/m2. Eligible patients were randomised at their first cycle to receive either OND or GRA with cross-over of the anti-emetic treatment on the second cycle. The cytotoxic treatments included five different multidrug regimens containing CP (median dose 60 mg/m2, range 50-70 mg/m2) administered on day 1 and repeated every 21-28 days. OND was administered at the dose of 8 mg x 3 i.v. on day 1 and 8 mg x 2 orally on day 2. GRA was always administered at the dose of 3 mg i.v. on day 1. 124 patients entered the study. 58 patients received OND at their first cycle and 66 received GRA. Complete protection of acute emesis with OND and GRA was observed, with the first and second cycles combined as follows: nausea 53 and 60%, vomiting 68 and 71%, respectively (no statistically significant difference). The cross-over analysis comprising 101 patients confirmed no difference between the two anti-emetic treatments. 21 patients (19%) on OND and 14 patients (12%) on GRA suffered headaches (P = 0.15). 25 (25%) patients preferred OND, 45 (45%) preferred GRA, while 31 (30%) expressed no preference (P = 0.003). However, these differences also depended on the sequence of anti-emetics in the cross-over. In conclusion, in this study, a single dose of GRA is demonstrated to be as effective as multiple doses of OND in the prevention of acute emesis.

CEA, MCA, CA 15.3 and CA 549 and their combinations in expressing and monitoring metastatic breast cancer: a prospective comparative study.

Serum levels of carcinoembryonic antigen (CEA), mucin-like carcinoma-associated antigen (MCA), CA 15.3 and CA 549 were concurrently assayed in patients with metastatic breast cancer. Overall sensitivity in detecting metastatic breast cancer (201 pts) was CEA 45%, MCA 59%, CA 15.3 71% and CA 549 72% (P < 0.01). Sensitivity increased by only 6% to 8% when two or more antigens were simultaneously considered. An overall sensitivity of correlation with objective response (n = 71) was observed in the range of 53-67% (P = n.s.) in patients with abnormal baseline marker values, and in the range of 42-87% (P < 0.05) in patients with normal baseline values. The combination of two or more markers did not improve sensitivity, but decreased specificity of correlation with objective response. In conclusion, CA 15.3 and CA 549 have individually higher sensitivity in detecting metastatic breast cancer. No clinical advantage was observed for using two or more markers concurrently over CA 15.3 or CA 549 alone in the monitoring of metastatic breast cancer.