Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.

BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.

IgA antiphospholipid antibodies are an independent risk factor for thromboses.

Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin and anti-beta(2)-glycoprotein I antibodies, mostly IgG isotype) are strong risk factors for thrombosis. Because a paucity of information on IgA isotype exists in the literature, we retrospectively evaluated the thrombotic significance of IgA antiphospholipid antibodies. We included 472 patients with clinical information on thrombotic events and complete laboratory work-up for antiphospholipid antibodies syndrome. Odds ratios (OR) of various antiphospholipid antibodies for thrombosis were calculated by univariate and multivariate analyses. Lupus anticoagulant alone was detected in 57 (12%) patients, ELISA-based antibodies (IgG, IgM, IgA) against cardiolipin, phosphatidylserine or beta(2)-glycoprotein-I alone were detected in 131 (28%) patients, whereas 80 (17%) patients had both. Antibody isotype distribution was IgG 32%, IgM 60% and IgA 56%. Univariate analysis showed a statistically significant risk of thrombosis in patients with elevated titres of IgA of any ELISA-based antiphospholipid antibodies (OR 1.77). Stepwise logistic regression (multivariate) analysis identified elevated titres of any ELISA-based IgA antiphospholipid antibodies as an independent risk factor for thrombosis (OR 1.6) in the entire cohort, and in the subgroup of patients without concurrent presence of lupus anticoagulant (OR 1.8). IgA antiphospholipid antibodies appear to be a significant independent risk factor for thrombosis, thereby meriting evaluation in patients with unexpected thrombosis.

DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers.

The transforming growth factor beta (TGFbeta)-signalling pathway is deregulated in many cancers. We examined the role of gene silencing via aberrant methylation of DRM/Gremlin and HPP1, which inhibit TGFbeta signalling, and RUNX3, which facilitates TGFbeta-signalling, of all genes that are thought to be tumour suppressors, are aberrantly expressed, and are thus thought to have important role in human cancers. We examined DRM/Gremlin mRNA expression in 44 cell lines and the promoter methylation status of DRM/Gremlin, HPP1, and RUNX3 in 44 cell lines and 511 primary tumours. The loss of DRM/Gremlin mRNA expression in human cancer cell lines is associated with DNA methylation, and treatment with the methylation inhibitor-reactivated mRNA expression (n=13). Methylation percentages of the three genes ranged from 0-83% in adult tumours and 0-50% in paediatric tumours. Methylation of DRM/Gremlin was more frequent in lung tumours in smokers, and methylation of all three genes was inversely correlated with prognosis in patients with bladder or prostate cancer. Our results provide strong evidence that these TGFbeta-related genes are frequently deregulated through aberrant methylation in many human malignancies.

[Correlation between severity of angina, its stability, and oxidative modification of lipids in patients with ischemic heart disease]. / Sviaz' mezhdu tiazhest'iu stenokardii, ee stabil'nost'iu i urovnem okislitel'noi modifikatsii lipidov u bol'nykh ishemicheskoi bolezn'iu serdtsa.

AIM: To elucidate the relations between angina severity, stability, concomitant arterial hypertension, diabetes mellitus, plasma oxidation. MATERIAL AND METHODS: The study included 152 patients with stable angina of effort (functional class II-III). Of them, 67 had concomitant arterial hypertension (AH), 20 AH and compensated diabetes mellitus type II, 14 patients with anginal functional class III were admitted to hospital for unstable angina, 11 patients with IHD with unstable angina and 28 healthy donors. The study was made of dynamic features of lipid oxidation using copper-induced plasma oxidation. Lipids were measured with enzyme assays. RESULTS: The degree of LP oxidation increases with aggravation of angina. IHD risk factors activate atherogenic modification of lipids in patients with stable angina. There was no differences between the groups in content of low density lipoproteins cholesterol. CONCLUSION: Plasma resistance to oxidation may serve an additional criterion for assessment of severity and stability of various IHD forms.

Assessment of HER-2/neu status in breast cancer. Automated Cellular Imaging System (ACIS)-assisted quantitation of immunohistochemical assay achieves high accuracy in comparison with fluorescence in situ hybridization assay as the standard.

This retrospective study of formalin-fixed infiltrating breast cancer specimens compared manual immunohistochemical assay with a new image analyzer-assisted immunohistochemical quantitation method, using fluorescence in situ hybridization assay (FISH) as the standard. Following the manual immunohistochemical assay, 189 cases, including most manual immunohistochemically positive and some random negative cases, were analyzed by FISH assay for Her-2/neu gene amplification and by the Automated Cellular Imaging System (ACIS) for immunohistochemical staining. Using the FISH standard, the ACIS immunohistochemical assay attained a higher concordance rate and sensitivity than the manual immunohistochemical assay (91.0% and 88% vs 85.7% and 71%, respectively), with only a slight decrease in specificity (93% vs 96%, respectively). In particular, the ACIS immunohistochemical assay resulted in a higher correlation with the FISH assay in the manual immunohistochemical assay 2+ cases. The ACIS immunohistochemical assay achieved higher accuracy than the manual method according to receiver operating characteristic curve analysis. The ACIS method represents a substantial improvement over the manual method for objective evaluation of the HER-2/neu status.

[Specific features of lipid atherogenic modification in patients with ischemic heart disease and diabetes mellitus]. / Osobennosti aterogennoi modofikatsii lipidov u bol'nykh ishemicheskoi bolezn'iu serdtsa s soputstvuiushchim sakharnym diabetom.

A comparative study of the effect of concomitant compensated diabetes mellitus (DM) on plasma oxidation in patients with ischemic heart disease (IHD) with stable angina of effort (functional class II-III) in 28 anginal patients with IHD, arterial hypertension and DM, 67 anginal patients with IHD and hypertension, 57 anginal patients with IHD and 28 donors. Lipoproteins oxidation was studied by enzymic methods. A significant effect of the type of DM on dynamics of plasma oxidation in IHD patients was found. This may be an additional prognostic criterion of IHD progression in DM patients.

Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice.

This study describes a novel approach to the treatment of brain tumors with the combination of recombinant L-methionine-alpha-deamino-gamma-lyase and chemotherapeutic regimens that are currently used against such tumors. The growth of Daoy, SWB77, and D-54 xenografts in athymic mice was arrested after the depletion of mouse plasma methionine (MET) with a combination of a MET- and choline-free diet and recombinant L-methionine-alpha-deamino-gamma-lyase. The treated tumor-bearing mice were rescued from the toxic effects of MET withdrawal with daily i.p. homocystine. This regimen suppressed plasma MET to levels below 5 microM for several days, with no treatment-related deaths. MET depletion for 10-12 days induced mitotic and cell cycle arrest, apoptotic death, and widespread necrosis in tumors but did not prevent tumor regrowth after cessation of the regimen. However, when a single dose of 35 mg/m(2) of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), which was otherwise ineffective as a single therapy in any of the tumors tested, was given at the end of the MET depletion regimen, a more than 80-day growth delay was observed for Daoy and D-54, whereas the growth of SWB77 was delayed by 20 days. MET-depleting regimens also trebled the efficacy of temozolomide (TMZ) against SWB77 when TMZ was given to animals as a single dose of 180 mg/m(2) at the end of a 10-day period of MET depletion. The enhanced responses of both Daoy and SWB77 to DNA alkylating agents such as BCNU and TMZ could be attributed to the down-regulation of O(6)-methylguanine-DNA methyltransferase activity. However, the synergy of MET depletion and BCNU observed with D-54 tumors, which do not express measurable O(6)-methylguanine-DNA methyltransferase protein, is probably mediated by a different mechanism. MET depletion specifically sensitizes tumors to alkylating agents and does not significantly lower the toxicity of either BCNU or TMZ for the host. In this regard, the combination approach of MET depletion and genotoxic chemotherapy demonstrates significant promise for clinical evaluation.

Topoisomerase I inhibition with topotecan: pharmacologic and clinical issues.

Topoisomerase I (topo-I) inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most, if not all, topo-I inhibitors are derivatives of the plant extract camptothecin. Topotecan is a derivative of camptothecin which has been structurally modified to increase water solubility. The pharmacokinetic profile of topotecan is usually characterised by a two-compartment model and is linear in the dose range of 0.5 - 3.5 mg/m(2). Current clinical trials suggest antitumour activity against a variety of human tumour types, including ovarian cancer, non-small cell lung cancer (NSCLC) and non-lymphocytic haematologic malignancies. The main dose-limiting toxicity (DLT) is non-cumulative myelosuppression. Non-haematologic toxicities are usually mild. Based on several Phase I studies, the recommended Phase II dose was 1.5 mg/m(2)/day iv. for 5 days. Current Phase I and Phase II trials are evaluating the combination of topotecan with other chemotherapeutic agents to increase the therapeutic benefits of topotecan. The DLT in these trials is mainly myelosuppression.

Phase I study of paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute-sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks). RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed > or = 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m(2)/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m(2)/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels > or = 6.5 mg/m(2)/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%). CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m(2)/d with RT for SCCHN.

Balloon cervical ripening with extra-amniotic infusion of saline or prostaglandin E2: a double-blind, randomized controlled study.

OBJECTIVE: To compare extra-amniotic infusion of diluted prostaglandin (PG) E2 solution with saline infusion in balloon cervical ripening and labor induction. METHODS: Women with pregnancy complications and Bishop scores of 3 or lower (n = 116) were assigned randomly to receive extra-amniotic infusion (1 mL/minute) of normal saline or PGE2 in saline (0.5 microg/mL) through a Foley catheter with a 30-mL inflated balloon. We induced labor using intravenous oxytocin only when labor had not developed by 6 hours after balloon expulsion. Analysis was by intent-to-treat. We assessed ripening efficiency and course of labor in women who had spontaneous balloon expulsion (n = 110) and trial of labor (n = 107), respectively. RESULTS: Ripening with PGE2 was associated with significantly shorter mean (+/- standard error of the mean [SEM]) time for balloon expulsion (4.7 +/- 0.4 versus 6.5 +/- 0.6 hours) and with significantly higher Bishop scores (P <.002), compared with ripening with saline. In the PGE2 group, rates of labor induction (15%) and oxytocin use (37%) were significantly lower than in the saline group (51% and 72%, respectively). The groups did not differ significantly in other labor abnormalities, labor duration, mode of delivery, birth weight, Apgar scores, and puerperal morbidity. CONCLUSION: Cervical ripening by extra-amniotic balloon and PGE2 infusion is faster and more effective than by balloon and saline infusion, resulting in a higher rate of spontaneous labor and a lower rate of oxytocin use.

L-asparaginase-provoked seizures as singular expression of central nervous toxicity.

Patients treated with L-asparaginase may present with hemorrhagic and thrombotic cerebrovascular events. This syndrome generally occurs after a few weeks of therapy and may occur after L-asparaginase therapy is completed. Complications appear to result from depletion of plasma proteins involved in coagulation and fibrinolysis. Seizures are uncommon symptoms, and are always caused by cerebrovascular events. We report a case of seizure associated with L-asparaginase therapy but no evidence of hemorrhagic or thrombotic cerebrovascular events.

Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin B12 (cobalamin) in pregnancy and gynecology.

Classically, deficiency of folic acid (folate) or vitamin B12 (cobalamin) was recognized by the presence of a macrocytic anemia resulting from megaloblastic changes in the bone marrow. A markedly changing paradigm has identified both new mechanisms for altered folate and cobalamin status and new sequelae and clinical interrelationships that include altered mechanisms of absorption, a changing pattern of neurologic deficits, an increased risk of vascular occlusive lesions, and an important relationship with the mechanisms of neoplastic transformation. Several of these newer characterizations relate to issues of neoplasia in the nonpregnant woman and to issues in pregnancy, such as the potential for developmental abnormalities of the fetal nervous system.

Laboratory assessment of the status of Her-2/neu protein and oncogene in breast cancer specimens: comparison of immunohistochemistry assay with fluorescence in situ hybridisation assays.

AIM: To evaluate the clinical usefulness of three commercially available assays for Her-2/neu oncogene and protein measurements. The Her-2/neu protein is overexpressed, mostly as a result of gene amplification, in 20-30% of human breast cancers, and has been shown to have prognostic and predictive value for treatment with chemotherapy or the new monoclonal antibody, Herceptin. METHODS: An immunohistochemistry (IHC) assay using the Dako polyclonal antibody A0485, which measures the Her-2/neu protein, was compared with two new Food and Drug Administration (FDA) approved fluorescence in situ hybridisation (FISH) assays--INFORM and PathVysion, in a cohort of 52 formalin fixed, paraffin wax embedded breast tissues. These tissues were selected randomly from 84 consecutive infiltrating breast cancer specimens, which were first stratified according to the Her-2/neu protein levels as measured by IHC. RESULTS: The two FISH assays achieved a 98% concordance rate: 14 specimens (27%) showed Her-2/neu gene amplification and 37 specimens (71%) showed no Her-2/neu gene amplification. The PathVysion assay had certain advantages over the INFORM assay. In contrast, the IHC assay detected Her-2/neu overexpression in a high percentage of cases, including 13 high positive specimens (25%) and 13 medium positive specimens (25%). Although 10 of these 13 IHC high positive specimens showed gene amplification by FISH, nine of 13 IHC medium positive specimens showed no gene amplification. Statistical analyses showed that the differences between IHC and FISH assays were primarily in the specimens with medium positive IHC, but negative FISH results. CONCLUSIONS: Because of the increasing importance of the Her-2/neu oncogene and oncoprotein in the clinical management of patients with breast cancer, the accurate and consistent evaluation of Her-2/neu status is crucial. This study suggests that the best approach is to combine both IHC and FISH assays; that is, to use the IHC assay as a triage step, followed by the PathVysion FISH assay to analyse the IHC medium and high positive cases.

Reversible renal toxicity resulting from high single doses of the new radiosensitizer gadolinium texaphyrin.

Gadolinium (III) texaphyrin (Gd-Tex) (NSC 695238) is a potential radiation sensitizer that selectively localizes in tumors and is detectable by magnetic resonance imaging (MRI). In this single-dose phase I trial, reversible renal injury was the dose-limiting toxicity. This report details that renal injury. A single intravenous dose of Gd-Tex was followed 2 hours later by radiation therapy. The Gd-Tex dose was escalated in 13 patient cohorts. Doses ranged from 0.6 to 29.6 mg/kg. The maximum tolerated dosage (MTD) was 22.3 mg/kg. Three patients had grade II and one had grade III acute nonoliguric renal failure at the 22.3 and 29.6 mg/kg dose levels. The injury was always transient, and responded to fluid restriction and renal diet. In all patients, transient green discoloration including urine developed at doses > or =7.1 mg/kg. MRI studies demonstrated image enhancement in the liver, kidneys, and in primary and metastatic tumors in all patients receiving >5.4 mg/kg. It is important that the liver and kidneys be excluded from the radiation volume. Gd-Tex was well tolerated at doses below the MTD. It is important that the liver and kidneys be excluded from the radiation volume. We recommend that 16.7 mg/kg be used as the maximum single dose to obviate even low grade renal toxicity.

Prothrombin G20210A gene mutation, heparin cofactor II defects, primary (essential) thrombocythemia, and thrombohemorrhagic manifestations.

This article addresses the issue of thromboembolic disorders associated with the prothrombin G20210A gene mutation, with heparin cofactor II (HC-II) defects and with primary (essential) thrombocythemia. The prothrombin gene mutation is of recent discovery, is inherited as an autosomal dominant disorder, and seems to be highly prevalent in the general white population. The incidence is almost as high as that known for factor V Leiden. Both venous and arterial thromboses are noted, especially deep venous thrombosis, including cerebral venous events and myocardial infarction. As with other congenital thrombophilic states, additional risk factors or multiple defects seem to precipitate the events. Although initially elevated plasma prothrombin levels were described in these patients, this is no longer valid for all patients. At this time there is no easy screening test to detect this defect, but, because of the high prevalence, prothrombin G20210A gene mutation should routinely be assayed for in thrombophilic patients. The association between HC-II defects and thromboembolism is more controversial, and reports both confirming and denying this association have been described. The congenital form of HC-II defect is autosomal dominant. HC-II can be determined by its activity and immunologically. HC-II defects very likely play a role in conjunction with other congenital or acquired defects. Acquired HC-II defects are found in association with systemic disseminated intravascular coagulation (DIC) but not with local activation of the hemostasis system. HC-II levels are also decreased in preeclamptic women, and newborns have physiologically low levels. HC-II defects in thrombophilic patients should be considered after the more common disorders have been ruled out. Primary (essential) thrombocythemia can be associated with both thromboembolic events and bleeding. Typical thrombotic manifestations are erythromelalgia and microvascular thrombosis. Also, pregnant females suffer high rates of complications, such as spontaneous abortion. A number of treatment modalities are at present available to not only decrease platelet counts but also manage thromboembolic events.

A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging.

Gadolinium Texaphyrin (Gd-Tex) is a radiation sensitizer with a novel mechanism of action that sensitizes both oxic and hypoxic cells, localizes selectively in tumors, and is detectable by magnetic resonance imaging (MRI). This Phase I single-dose trial of Gd-Tex administered concurrently with radiation therapy was carried out to determine the maximally tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and biolocalization of Gd-Tex as determined by MRI. Adults with incurable cancers of any histology requiring radiation therapy were eligible. A single i.v. dose of Gd-Tex was followed at least 2 h later by radiation therapy. The Gd-Tex dose was escalated in cohorts of 3 to 5 patients. Thirty-eight patients (median age, 58 years; range, 35-77 years) with incurable cancers of the lung (26), cervix (3), or other solid tumors (9) received a total of 41 single administrations of Gd-Tex. The Gd-Tex dose was escalated from 0.6 to 29.6 mg/kg. Irradiated sites included the thorax, brain, pelvis, bone, soft tissue, and sites of nodal metastases. The MTD was 22.3 mg/kg, determined by reversible acute tubular necrosis as the dose-limiting toxicities. Gd-Tex selectively accumulated in primary and metastatic tumors as demonstrated by MRI. No increase in radiation toxicity to normal tissues was seen. The median half-life of Gd-Tex after single-dose administration is 7.4 h. This study demonstrates that Gd-Tex is well tolerated in doses below the MTD, and that there is selective biolocalization in tumors. The maximum recommended dose for single administrations is 16.7 mg/kg.

Antiphospholipid-thrombosis syndromes.

Antiphospholipid antibodies are strongly associated with thrombosis and appear to be the most common of the acquired blood protein defects causing thrombosis. Based upon our experience, approximately 25% of patients with unexplained venous thrombosis, approximately 60% of patients with cerebrovascular thrombosis, approximately 37% of patients with transient ischemic attacks, approximately 18% with premature coronary artery thrombosis and approximately 60% of patients with recurrent fetal loss (recurrent miscarriage syndrome) harbor antiphospholipid antibodies. Although the precise mechanism(s) whereby antiphospholipid antibodies alter hemostasis to induce a hypercoagulable state remain unclear, several theories have been advanced. Since the aPTT is unreliable in patients with lupus anticoagulant and is not usually prolonged in patients with anticardiolipin antibodies, definitive tests, ELISA for IgG, IgA and IgM anticardiolipin antibodies and the dilute Russel's viper venom time (followed by cephalin correction for confirmation) for lupus anticoagulant should be immediately ordered when suspecting the antiphospholipid syndrome in individuals with otherwise unexplained thrombotic or thromboembolic events or recurrent fetal loss. However, if one strongly suspects antiphospholipid thrombosis syndrome clinically and assays for lupus anticoagulants and anticardiolipin antibodies are negative, specific assays for all three idiotypes of phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol are available and should be considered. These may clearly be indicated for difficult diagnostic cases of fetal wastage syndrome, and cerebrovascular events, but their significance in other types of thrombosis, particularly venous, remains unclear at present. Since about 65% of patients with antiphospholipid antibodies will fail warfarin therapy (rethrombose), it is important to define this common defect and institute appropriate antithrombotic therapy for appropriate time periods.

Disseminated intravascular coagulation. clinical and pathophysiological mechanisms and manifestations.

Disseminated intravascular coagulation (DIC) is a complex disorder, with pathophysiology being variable and highly dependent upon the triggering event(s), host response(s) and comorbid conditions. As a result of these complicated interactions, the clinical expression and laboratory findings are varied, thereby affecting the specifics of diagnosis and therapeutic approaches. The highly complex and variable pathophysiology of DIC often results in a lack of uniformity in clinical manifestations, a lack of consensus in the specific appropriate laboratory criteria of diagnosis, and a lack of specific therapeutic modalities. Indeed, recommendations for therapy are often difficult because the morbidity and survival is more dependent on the specific cause of DIC and because the generally used specific therapeutic approaches, which include for example heparin, low-molecular-weight-heparin antithrombin concentrate and protein C concentrate, have never been subjected to objective prospective randomized trials, except antithrombin concentrates. An analysis of the complex and varied pathophysiological events in DIC provide objective guidelines and criteria for the clinical diagnosis, the laboratory diagnosis, and the definition of severity. These data compounded by an understanding of complex and varied pathophysiology can be used for objective evaluation of therapeutic responses and results. DIC is an intermediary mechanism of disease usually seen in association with well-defined clinical disorders. The pathophysiology of DIC serves as an intermediary mechanism in many disease processes, which sometimes remain organ specific. This catastrophic syndrome spans all areas of medicine and presents a broad clinical spectrum that is confusing to many. Most physicians consider DIC to be a systemic hemorrhagic syndrome; however, this is only because hemorrhage is evident and often impressive. Less commonly appreciated is the profound microvascular thrombosis and sometimes, large vessel thrombosis. The hemorrhage is often simple to contend with in patients with fulminant DIC, but it is the small- and large-vessel thrombosis, with impairment in blood flow, ischemia, and associated end-organ damage that usually leads to irreversible morbidity and mortality. In conclusion, the pathophysiological mechanisms, clinical, and laboratory manifestations of DIC are complex in part due to interrelationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiological interrelationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and lack validation. Nevertheless, newer antithrombotic agents, and agents which can block, blunt or modify cytokine activity and the activity of vasoactive substances appear to be of value. The complexity and variable degree of clinical expression suggests that therapy should be individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis and hemodynamics and other appropriate clinical parameters.

Clinical aspects of heparin-induced thrombocytopenia and thrombosis and other side effects of heparin therapy.

Heparin, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, heparin remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of heparin are meritorious, but side effects do exist. Bleeding is the primary untoward effect of heparin. Major bleeding is of primary concern in patients receiving heparin therapy. However, additional important untoward effects of heparin therapy include heparin-induced thrombocytopenia, heparin-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of heparin, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated heparin, at present the incidences of these side effects with newer low molecular weight heparins appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations.

Characteristics of normal lochia.

The objective of this paper is to determine the characteristics of each phase of lochia and how these may be influenced by a number of obstetric variables. Thirty-nine healthy women who had spontaneous vaginal delivery following uncomplicated pregnancy volunteered to complete a diary sheet immediately postpartum. The women were instructed to assess the color of their lochia by a color slide with differential gradation from dark red to white. The color was labeled as rubra (red, red-brown), serosa (brown-pink, brown), or alba (yellow, white). The overall duration of lochia was 36.0 +/- 7.5 days (range 17 to 51 days, median 37 days). Three types of lochia color patterns were identified: type 1--rubra-->serosa-->alba sequence (n = 20); type 2-rubra-->serosa-->alba sequence with prolonged rubra phase and short serosa and alba phases (n = 11); and type 3-with two rubra phases (rubra-->serosa/alba-->rubra-->serosa/alba sequence with near-equal duration of each phase) (n = 8). The rubra phase lasts 12.1 +/- 6.7 days in type 1, 24.8 +/- 5.0 days in type 2, and 5.5 +/- 2.5 days (the first rubra) in type 3 pattern (p < 0.05). There was a higher proportion of lactating women among women with type 1 pattern as compared with type 2 (11/20 and 2/11, p < 0.05, respectively). Women with type 2 pattern were of higher parity (2.8 +/- 1.3) as compared with those with type 1 (1.8 +/- 0.8) (p < 0.05). There were no significant differences in infants' birth weight between the various color types (3,276.0 +/- 379.8 g, 3,564.4 +/- 737.9 g, and 3,080.0 +/- 180.0 g for type 1, type 2, and type 3, respectively. There were no significant differences in overall duration of lochia or gestational age at delivery between the various color types. The results confirm the clinical impression that lochia persists longer than classically reported and is of diverse patterns. Three unique types of color patterns were identified. Type 1 is the most prevalent and is associated with prolonged breast feeding and thus can be considered as the classic type. Type 2 is associated with short or no breast feeding and higher parity. Type 3 may be a variant of type 2. We suggest that traditional teaching on lochia characteristics needs reappraisal.