Influence of saliva on the results of global laboratory coagulation tests.

BACKGROUND: Oral wounds inevitably come into contact with saliva which can affect the time needed for bleeding to stop. The influence of saliva can be non-specific, related to dilution of blood, and/or mediated by salivary factors that affect haemostasis directly. The aim of this study was to assess if mixing blood with an individual's saliva would affect the rate of its coagulation measured by global coagulation tests, prothrombin time (PT) and activated partial thromboplastin time (APTT). METHODS: The study included 30 healthy non-smoking volunteers. Paired blood and unstimulated saliva samples were obtained from each participant and PT and APTT were determined in blood, blood + saliva and blood + water mixtures. Coagulation tests were performed using the mechanical clot detection method. RESULTS: PT was significantly longer in both blood + saliva and blood + water mixtures compared to blood alone. APTT was significantly longer only in blood + water mixture compared to blood. CONCLUSIONS: Similarly prolonged PT in both mixtures suggests that both saliva and water prolong coagulation evenly due to their non-specific effect of blood dilution. The finding that APTT was significantly prolonged only when blood was mixed with water could indicate presence of tissue factor in saliva, however, in a concentration too low to influence the results of PT.

An endogeous defensive concept, renewed cytoprotection/adaptive cytoprotection: intra(per)-oral/intragastric strong alcohol in rat. Involvement of pentadecapeptide BPC 157 and nitric oxide system.

With intra(per)-oral strong alcohol application at the tongue, swallowed, we renewed Robert's stomach cytoprotection/adaptive cytoprotection concept. We assessed strong (96%) alcohol-induced severe or minute lesions in stomach, tongue-esophagus-stomach-duodenum lesions, and sphincter pressure (lower esophageal and pyloric) upon administration intragastrically (at 1 h) or intra(per)-orally at the tongue, and swallowed (at 1, 5, 15, 30 min; and 1, 2, 24 h). The assessment also included combined administrations (intra(per)-oral at the tongue, swallowed and intragastric (at 1 h)). Immediate post-alcohol intraperitoneal medication (mg/kg) was the stable gastric pentadecapeptide BPC 157 (0.01, 0.00001; a Robert's cytoprotection mediator; with a therapeutic effect), NOS-blocker L-NAME (5), and NOS-substrate L-arginine (100 mg), (NO-system involvement). After intragastric strong alcohol administration, severe stomach ulcerations appeared along with widespread tongue, esophagus, duodenum redness, and minimal sphincter pressures. By contrast, a particular syndrome (immediate overlapping of cytoprotection/adaptive cytoprotection) (minute gastric lesion or largely attenuated hemorrhagic ulceration, tongue affected, minute esophageal and duodenal lesions, but with intact mucosa; sphincters pressures lowered) appeared after intra(per)-oral administration (1 min-24 h) as well as after combined administrations (intra(per)-oral + intragastric). BPC 157 apparently cured all alcohol-lesions, amplified the spontaneously initiated strong mucosal beneficial effect, rescued sphincter pressures; NO-agents (L-arginine (slight mucosal amelioration) and L-NAME (aggravation)) showed NO-system involvement, but no comparable effects on dropped sphincters pressures. In conclusion, minute gastric lesions (with oral application of strong alcohol at the tongue and swallowed, without, or with intragastric application of strong alcohol) renew and revise Robert's stomach cytoprotection/adaptive cytoprotection concept. The tongue becomes a new initial target, resulting in spontaneous reversal of strong alcohol-stomach lesions. BPC 157 therapy functions also within the redirected complexity of Robert's stomach cytoprotection/adaptive cytoprotection concept.

Visual presentation of a medical physiology seminar modifies dental students' perception of its clinical significance.

INTRODUCTION: The primary objective of this study was to assess whether exposing dental students to visual stimuli related to dental profession during the medical physiology seminar could affect their perception of the clinical relevance of the topic. SUBJECTS AND METHODS: A self-administered questionnaire on attitudes towards medical physiology was conducted amongst 105 students of the School of Dental Medicine in Zagreb, Croatia, aged 19-24 years (80% females) following a seminar on respiratory system physiology. Power-point presentation accompanying the seminar for a total of 52 students (study group) was enriched with pictures related to dental practice in order to assess whether these pictures could make the topic appear more clinically relevant for a future dentist. RESULTS: The results of the survey indicated that dental students in the study group perceived the topic of the seminar as more important for them as future dentists when compared to the perception of the control group (P = 0.025). DISCUSSION AND CONCLUSION: The results of this survey encourage physiology lecturers to present medical physiology as clinically relevant for dental students whenever possible as this could increase students' interest in the subject and their motivation for learning. Such an approach could be particularly beneficial if there is a significant time gap between basic courses and involvement of students into clinical training for it could promote meaningful learning.

Effect of L-arginine dietary supplementation on salivary urea concentration and pH in physically active individuals.

BACKGROUND: The aim of this study was to assess if the consumption of 3 g of a commercially available L-arginine dietary supplement causes a postabsorptive rise in urea concentration or pH of unstimulated saliva in a group of physically active individuals. METHODS: Salivary urea and pH were determined for 117 participants in a randomized double-blinded placebo-controlled study. Samples were collected by 'spitting' method in fasting conditions. One hour prior to their second visit, participants consumed three tablets of L-arginine or placebo. RESULTS: Urea concentration was significantly lower at second measurement for both the study and control group. The magnitude of the change was not significant between the groups. pH was higher for both groups at second measurement, but only significant for the study group. The magnitude of the change was significant between the groups. Participants who intermittently ingested protein dietary supplements and those with a Body Mass Index (BMI) higher than 25 had significantly higher basal urea concentration. CONCLUSIONS: The results of this study did not confirm the hypothesis. Further studies are needed to determine the effects of different doses of L-arginine supplements on the biochemical composition of saliva and the influence of their long-term consumption on the risk of developing dental diseases.

Cardioprotection with ICRF-187 (Cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen.

A study of cardioprotection with ICRF-187 (Cardioxane, Eurocetus) has been performed in 35 patients with metastatic breast cancer treated with the FDC regimen (5-fluorouracil 500 mg/m2 i.v., day 1; doxorubicin 50 mg/m2 i.v., day 1; cyclophosphamide 500 mg/m2 i.v., day 1). All patients had one or more cardiac risk factors for doxorubicin cardiotoxicity including 24 who had previously received left-chest-wall irradiation. Cardioxane was applied at a dosage of 1000 mg/m2 as a 15-min infusion in Ringer lactate solution 30 min before doxorubicin administration. Cardiological monitoring included left-ventricular ejection fraction (LVEF) determination by echocardiography before treatment and before each cycle following the cumulative doxorubicin dose of 200 mg/m2. Of the 35 patients, 34 were evaluable fore response, and the overall response rate was 19/34 (56%) with 3/34 complete responses and 16/34 partial responses. Statistical analysis of LVEF values in relation to increasing cumulative doxorubicin doses with Wilcoxon's test of equivalent pairs and Friedman's test has demonstrated that no cardiotoxicity was detected up to a cumulative doxorubicin dose of between 800 mg/m2 and 1000 mg/m2, except for 2 patients in whom a decrease of 20% in relation to the LVEF pretreatment level was demonstrated following a cumulative drug dose of 250 mg/m2. Thus Cardioxane provides an effective cardioprotection even in breast cancer patients with cardiac risk factors for doxorubicin cardiotoxicity treated with the FDC regimen.

[Pharmacotherapy of cancer pain]. / Farmakoterapija kancerskog bola.

Pain is the most frequent cause of suffering of cancer patients. Recent improvements in pharmacotherapy of cancer pain have made management successful in the majority of patients. Optimal pharmacotherapy program requires careful assessment of the origin and cause of pain. The choice of analgetics should be sequentional using WHO stepladder. Oral application by the clock in an individually titrated dosage is recommended. Morphine remains the most useful opioid. Some drugs without being classic analgetics contribute considerably to the treatment of cancer pain of specific origin. Membrane-stabilisers, antidepressants and steroids are effective in the treatment of neurogenic pain. Anxiolytics should be avoided bacause they cause sedation without improving the quality of analgesia. Finally, it is necessary to treat the side effects of analgetics.

[Chemotherapy with high dose of anthracyclines combined with cisplatin in the treatment of soft tissue sarcomas]. / Kombinovana hemioterapija visokim dozama antraciklina i cisplatine napredovalih sarkoma mekih tkiva.

In the Institute of Oncology and Radiology in Belgrade 45 patients were treated with combined chemotherapy of Doxorubicin 75 mg/m2 and Cisplatin 120 mg/m2 per cycle, and 35 patients with Epirubicin substituting Doxorubicin; this second group received Epirubicin 180 mg/m2 and Cisplatin 120 mg/m2 per cycle. All patients were chemotherapy naive. The group receiving Doxorubicin recruited prognostically better patients with ECOG performance status 0 - 2 and median age of 41 years; the group receiving Epirubicin recruited patients with a larger ECOG performance score (0 - 3), and the median age was 48 years. All histological types of soft tissue sarcoma were equally represented in both groups. In the group receiving Doxorubicin 4/45 patients achieved complete response, the overall response rate was 18/45 and 18/45 patients had progressive disease. In the group receiving Epirubicin 10/35 patients achieved complete response, the overall response rate was 20/35 and only 6/35 patients had progressive disease. Although the response rate in the Doxorubicin group was unrealistically high due to recruitment of patients with relatively good prognostic parameters, the complete response rate in the Epirubicin group was found to be significantly higher in comparison to the Doxorubicin group. A significantly higher percentage in the Doxorubicin group was found to exhibit progressive disease despite treatment. The most significant toxicity in both groups was haematological, grade IV toxicity occurring slightly more frequently in the Epirubicin group (but in fact there was no statistically significant difference between the two groups).

[Influence of steroid receptors content in primary breast cancer on early relapse pattern]. / Uticaj sadrzaja steroidnih receptora u primarnom karcinomu dojke na prirodu ranog recidiva bolesti.

The early relapse pattern was followed in 165 operable breast cancer pts: 81 pts in stage I of the disease being without any adjuvant treatment, and 84 pts in stage II receiving systemic adjuvant chemo-, hormono-, or chemohormonal treatment, according to nodal status, histological grade of tumours and positivity of progesterone receptors (PR > 20 fmol/mg), as the functional parameter of primary tumour hormonodependency. The analyses of early relapses, occurring within the first 24 months, were based on quantitative oestrogen and progesterone receptor values, known as the prognostic and predictive factors for the early relapse pattern, and for the responce to adjuvant treatment. In stage I pts ER distribution showed lower values in pts with relapse, as compared to the group without relapse (0-115 vs. 0-464), and a tendency for relapse occurrence below the ER levels of 33 fmol/mg. Such a trend was not found for PR. In stage II pts a remarkable trend towards lower values of both receptors was observed in relapsed pts. A trend towards lower receptor values existed in both stages in pts with visceral metastases (ER = 0-50 fmol/mg, PR = 0-64 fmol/mg), while in those with bone metastases the receptor levels tended to be higher (ER = 0-1 15 fmol/mg, PR = 0-278 fmol/mg). Our results indicate the importance of steroid receptor status as a prognostic factor as well as its role in prediction of the localization of early relaps in operable breast cancer.

[Therapeutic possibilities of recombinant interferon alfa-2b (Intron A) in non-AIDS Kaposi sarcomas and angiosarcomas]. / Terapijske mogucnosti rekombinantnog alfa-2b interferona (Intron A) u non-AIDS Kaposi sarkomima i angiosarkomima.

Data concerning treatment of vascular neoplasia with biological response modifiers are still scanty, but encouraging results have been observed with alpha-2b interferon in AIDS related Kaposi sarcoma. In this study five treatment naive patients with Kaposi sarcoma and four heavily pretreated patients with angiosarcoma with still evolutive disease were treated with Etopozid 120 mg/m2/24h, days 1, 3 and 5, and recombinant alpha-2b interferon 6.000.000 U/24h, days 1-15, the intercycle interval being 21-28 days. All patients were negative for anti-HIV 1, anti-HIV 2 and anti-HTLV 1 antibodies; one patient had a high titer of IgG anti-chlamydia antibodies amounting to 1/4.194.304. This group differed from similar HIV 1 positive patients by having a normal CD4/CD8 ratio. In the Kaposi sarcoma group 1/5 achieved a complete response lasting 24+ months and 3/5 achieved a good partial response lasting 5+, 12+ and 35+ months. In the angiosarcoma group 1/4 patient achieved a complete response but relapsed after 18 months and one patient experienced stable disease lasting for 15+ months. These findings could be understood in two different ways. Since an infective etiology has been proposed for Kaposi sarcoma, the positive effect of alpha-2b interferon could be related to its "antiinfective" effects observed in viral disorders. However, similar activity in angiosarcoma points to the possibility that the positive effect of alpha-2b interferon in this group of disorders is related to interfering effects of the drug with factors implicated in neoplastic angiogenesis.

Therapeutic and endocrine effects of Decapeptyl, synthetic LH-RH agonistic analogue in premenopausal women with metastatic breast cancer. A pilot phase II study.

Twelve premenopausal patients with advanced breast cancer were entered into pilot phase II study to assess efficacy, toxicity and influence of the synthetic LH-RH agonistic analogue D-Trp6-LH-RH (Decapeptyl) on the patients' hormonal status. The patients, aged 33-50, with newly diagnosed stage IV or recurrent breast cancer were not previously treated by any kind of endocrine therapy. Steroid receptor status was known in 9 patients. Decapeptyl was applied monthly at a dose of 3.75 mg i.m. until progression. The therapeutic response was evaluated in 11/12 patients. Partial remission was achieved in 5, stabilization in 3, and 3 consecutive patients failed to respond. The best therapeutic response was obtained in patients with pleuropulmonal and soft-tissue involvement, aged 41-45, including those with incomplete ovarian suppression, and regardless of steroid receptor status. The mean serum gonadotropins and estradiol levels were suppressed. The treatment was free of any side effects, except hot flushes in 7 patients.

CEA and CA 15-3 in pleural effusion of advanced breast cancer patients: clinical relevance and diagnostic value.

Serum and pleural effusion fluid were tested for CEA concentration in 83 advanced breast cancer patients, in 43 of whom CA 15-3 was also determined. All pleural effusions were clinically malignant. The sensitivity of the CEA test for the presence of pleural metastases was closer to that of the CA 15-3 test in effusion (0.59 and 0.79, respectively) than the sensitivity of CEA compared to CA 15-3 in serum (0.43 vs. 0.79). The use of two markers combined with cytology increased the diagnostic rate from 48% (cytologically positive) to 88% (cytologically positive and/or with one or both markers increased in effusion). A high diagnostic rate in cytologically negative effusions (65%), and in effusions presented as the sole metastatic involvement (100%), points to the clinical value of these two markers. Our results show that markers produced by pleural metastases may be secreted either into the effusion fluid or into serum, or both. This finding, as well as some other observations, are discussed in the present paper.

Combination of daily 4-h infusion of 5-fluorouracil and cisplatin in the treatment of advanced head and neck squamous-cell carcinoma: a South-East European Oncology Group study.

Between April 1986 and May 1989 a multicentre study was conducted to evaluate the efficacy of a 4-h intravenous infusion of 1000 mg/m2 5-fluorouracil (5-FU) followed by a 1-h infusion of 25 mg/m2 cisplatin (CDDP) given for 4 consecutive days every 4 weeks to patients with advanced squamous-cell carcinoma of the head and neck. A total of 189 consecutive patients entered the study, including 106 who had previously undergone chemotherapy and 83 who were chemotherapy-naive. Of the 165 evaluable patients, 96 (58%) responded to treatment, including 22 (13%) who achieved a complete remission (CR). In the group of previously untreated patients an objective response (CR+PR) was seen in 78% (CR, 14%) whereas in pretreated patients the response rate (CR+PR) was 40% (CR, 13%). The median survival period was 10 months. No significant difference in the duration of survival or of remission was found between the two groups in relation to previous therapy, tumour localisation, disease stage or performance status. Almost half of the patients (49%) experienced leucopenia but it was severe in only 11% of cases. Anemia (mainly WHO grades 1-2) occurred in 38% of the patients. Nausea and vomiting were common (84%). Nephrotoxicity (23%) was mild and of short duration. Moderate hair loss was seen in 42% of the patients, and phlebitis occurred in 8%. A few cases of cardiotoxicity and neurotoxicity were observed. This regimen is well tolerated and can be given even on an outpatient basis. The resultant response rate and side effects appear to be similar to those previously reported for combination chemotherapy with CDDP and continuous 5-FU infusion.

[Gonadotropin-releasing hormone analogues in the treatment of metastatic breast carcinoma]. / Lekovi analozi oslobadjajuceg hormona gonadotropina u lecenju metastatskog karcinoma dojke.

The recent data about the treatment of advanced breast cancer patients with synthetic LH-RH analogues are presented. Although synthetized 20 years ago, the agonistic analogues of LH-RH were introduced in clinical oncology recently. The inhibition of pituitary and gonadal function that occurs after chronic administration of agonists of LH-RH, with the creation of a sex steroid deprivation and elimination of stimulatory effects of oestrogen or testosterone, is the basis for their application in oncology. In advanced breast cancer patients they successfully replace surgical or radiological castration. The main advantage of medical castration is reversibility. However, the discovery of the specific LH-RH receptors effect on mammary tumor membranes as well as on some other tumor cells, suggested the possible direct antitumor effect of LH-RH agonists. This finding enlarge the oncological application of LH-RH agonistic analogues.

Estrogen dependence of primary breast cancer--correlation with histologic type and grade.

The purpose of this study was to investigate whether histologic type and grade of primary breast cancer are related to the estrogen and progesterone receptors. Our results showed that histologic type influenced the estrogen dependence through histologic grade. There was no difference in the estrogen and progesterone receptor content, when corresponding grades of different histologic types and estrogen dependence were confirmed by quantitative non-parametric analysis. It showed a direct relationship between estrogen and progesterone receptor content in all the three histologic grades and further that histologic grade defines three different groups in regard to progesterone receptor content.

High-dose epirubicin-cisplatin chemotherapy for advanced soft tissue sarcoma.

A chemotherapy regimen with epirubicin (60 mg/m2, days 1, 2 and 3) and cisplatin (30 mg/m2, days 2, 3, 4 and 5) was started for 35 patients with advanced soft tissue sarcoma (28 males and 7 females; median age, 50 years). All patients were chemotherapy-naive and with an expected survival of more than 2 months. All patients were evaluable for activity and toxicity. The intercycle interval was 4 weeks. Median number of cycles applied was 4 (range, 2-8). The overall response rate was 20/35 (57.1%). A complete response (CR) was achieved in 7/35 patients (20%), lasting for 26+, 26+, 13+, 13+, 9+, 9+ and 5 months; 13/35 patients (37.1%) entered a partial remission (PR), 9/35 patients (25.7%) had stable disease (SD), and 6/35 (17.1%) had progressive disease (PD). In non-responders (SD + PD), the median survival was 4 months; the median survival of responders (CR + PR) was 9+ months (the median has not yet been reached). Hematologic toxicity of grade 4 was present at least in one cycle for hemoglobin in 6/35 patients, for leukocytes in 22/35, and for platelets in 13/35. No hemorrhagic syndrome was observed. The leukopenia was usually of short duration (nadir on days 10-12). Febrile episodes were present in 18 patients during the nadir of leukopenia. No other significant toxicity was noted (apart from grade III alopecia in all patients), and specifically, there was neither acute nor cumulative cardiotoxicity.

Phase II study of 4'-epi-doxorubicin in patients with untreated, extensive small cell lung cancer. South-East European Oncology Group (SEEOG).

The purpose of the study was to investigate the antitumour activity and toxicity of high dose (120 mg m-2) single agent epirubicin therapy in untreated extensive small cell lung cancer patients. Out of 80 patients entered, 71 were evaluable for both antitumour activity and toxicity, 4 only for toxicity and 5 were lost for follow-up. The drug possessed a high antitumour activity, the overall response rate was 47.9% (34/71) with 4 complete remissions (CR) and 30 partial remissions (PR). The median remission duration was 3.5 months. Particular drug activity was observed in the primary tumours, lymph nodes and pleural metastases. Toxicity (leukopenia, anaemia, vomiting, reversible rhythmic cardiac disorder, stomatitis) was mild, alopecia was registered less than in adriamycin medication. One fatal congestive heart failure occurred. The actual mean survival time calculated on the basis of the data gained from 64 patients was 7.0 months (range 2-22). The high antitumour activity and no increase in toxicity justify the incorporation of high dose epirubicin into combination therapy.

EDTA clearance in monitoring cisplatin dose escalation in patients with bulky metastatic germ cell tumors of the testis.

A fast cisplatin clearance may reduce exposure time of tumor cells to the drug, and thus impair the expected effects of dose escalation. This hypothesis was tested in 23 patients with bulky metastatic germ cell tumors of the testis, treated with etoposide, bleomycin and high-dose cisplatin (60 mg/m2/24 h x 4). The daily dose was retrospectively calculated in mg/l EDTA clearance/24 h. A daily dose of 60 mg/m2 of cisplatin in a person with a body surface of 1.7 m2 and EDTA clearance of 100 ml/min was equivalent to 0.69 mg cisplatin/l EDTA clearance/24 h. In the whole group, 10 patients had complete remission (CR), 10 partial response (PR) and 3 progressive disease (PD). The mean daily cisplatin dose (mean) in the whole group was 0.86 mg/l EDTA clearance/24 h (range 0.35-2.00). For patients with CR, mean +/- SD was 1.00 +/- 0.46, for those with PR 0.80 +/- 0.44, and for those with PD only 0.61 +/- 0.07. A cisplatin dose over 0.86 mg/l EDTA clearance/24 h x 4 was obtained in 6/10 patients with CR versus 2/13 patients with PR + PD. Patients with PD received a significantly lower cisplatin dose than the whole group (0.61 versus 0.86 mg cisplatin/l EDTA clearance/24 h x 4.) The difference between the average toxicity grade after cisplatin dose over and below 0.69 mg/l EDTA clearance/24 h x 4 was significant only for leukocytes (WHO grade 2.17 versus 1.36). Thus, the effective escalated dose of cisplatin should preferably be calculated not per m2 body surface but per 1 liter EDTA clearance. The 'ideal' escalated dose might be about 0.86-1.0 mg cisplatin/l EDTA clearance 24 h x 4.