Nomogram for predicting survival after first-line anti-PD-1-based immunotherapy in unresectable stage IV melanoma: a multicenter international study.

BACKGROUND: The introduction of anti-programmed cell death protein 1 (PD-1) immunotherapy has revolutionized the treatment landscape for melanoma, enhancing both response rates and survival outcomes in patients with advanced stages of the disease. Despite these remarkable advances, a noteworthy subset of patients (40%-60%) does not derive advantage from this therapeutic approach. This study aims to identify key predictive factors and create a user-friendly predictive nomogram for stage IV melanoma patients receiving first-line anti-PD-1-based immunotherapy, improving treatment decisions. MATERIALS AND METHODS: In this retrospective study, we included patients with unresectable stage IV melanoma who received first-line treatment with either anti-PD-1 monotherapy or anti-PD-1 plus anti-cytotoxic T-lymphocyte associated protein 4 between 2014 and 2018. We documented clinicopathological features and blood markers upon therapy initiation. By employing the random survival forest model and backward variable selection of the Cox model, we identified variables associated with progression-free survival (PFS) after the first-line anti-PD-1-based treatment. We developed and validated a predictive nomogram for PFS utilizing the identified variables. We assessed calibration and discrimination performance metrics as part of the evaluation process. RESULTS: The study involved 719 patients, divided into a training cohort of 405 (56%) patients and a validation cohort of 314 (44%) patients. We combined findings from the random survival forest and the Cox model to create a nomogram that incorporates the following factors: lactate dehydrogenase (LDH), S100, melanoma subtype, neutrophil-to-lymphocyte ratio (NLR), body mass index, type of immune checkpoint inhibitor, and presence of liver or brain metastasis. The resultant model had a C-index of 0.67 in the training cohort and 0.66 in the validation cohort. Performance remained in different patient subgroups. Calibration analysis revealed a favorable correlation between predicted and actual PFS rates. CONCLUSIONS: We developed and validated a predictive nomogram for long-term PFS in patients with unresectable stage IV melanoma undergoing first-line anti-PD-1-based immunotherapy.

[Optimal platelet inhibition therapy in unstable angina pectoris and after coronary interventions]. / Optimierte Plättcheninhibitortherapie bei instabiler Angina pectoris und nach Koronarinterventionen.

ASPIRIN AND HEPARIN: In several studies aspirin has been found to be very effective in unstable angina pectoris reducing fatal and non-fatal myocardial infarction by 50-70%. Unfortunately the optimal dose of aspirin is still an open question. Whereas heparin alone shows only a weak effectiveness the combination of aspirin and heparin is superior to aspirin alone and is still the basis of antithrombotic therapy in unstable angina. TICLOPIDINE AND CLOPIDOGREL: Experience with thienopyridine derivatives in unstable angina is limited. Ticlopidine has been found to be superior to aspirin alone. Data with the combination of clopidogrel and aspirin should be available soon. THERAPEUTIC RECOMMENDATION AFTER CORONARY INTERVENTION: Both, ticlopidine and clopidogrel have been found to be very effective in preventing coronary-stent thrombosis when combined with aspirin. Meanwhile ticlopidine has been widely substituted by clopidogrel due to the better safety profile of the latter one. 75 mg clopidogrel daily combined with aspirin is recommended for at least 4 weeks after coronary stenting.

[Low molecular weight heparins in acute coronary syndrome]. / Niedermolekulare Heparine bei akutem Koronarsyndrom.

BACKGROUND: Low molecular weight heparins (LMWH) have gained an increased role in the treatment of acute coronary syndrome within the last years. Compared to unfractionated heparins LMWH are user-friendly (high bioavailability after subcutaneous application, no needed routine control of plasma efficacy). RESULTS OF STUDIES: International trials have demonstrated a comparable (dalteparin, nadroparin) or even higher (enoxaparin) efficacy of LMWH compared to unfractionated heparin in the treatment of patients with unstable angina or non-Q-wave infarction. The use of LMWH has thereby been accompanied by a low rate of side effects. Enoxaparin appears to have the highest efficacy compared with other LMWH in the acute phase of disease, but confirming "head-to head" studies with different LMWH are lacking. A significant higher efficacy of a prolonged treatment with LMWH compared to placebo has been shown in one study (FRISC-2) in unstable patients who were not treated by coronary intervention in the early phase of disease. This lasted for about 60 days but was associated with a higher risk of bleeding. FUTURE ASPECTS: Currently, prospective clinical trials investigate the efficacy of combined use of LMWH with thrombolytics, GPIIb/IIIa blockers and the optimal dosage of LMWH during coronary interventions.

Interferon-alpha for the treatment of elderly patients with chronic myeloid leukaemia.

The present retrospective analysis is based on data of 213 patients with chronic myeloid leukaemia (CML). They were treated with interferon (IFN)alpha-2C (Berofor) at daily doses of 3.5 MU subcutaneously (s.c.), alone or in combination with low-dose ara-C or hydroxyurea, according to four consecutive studies of the Austrian CML Study Group. Comparisons were made between 41 patients aged > or = 60 years and 172 younger patients. The elderly patients (median: 64 years; range: 60-73) showed similar pretreatment characteristics compared with the younger group, but included a higher percentage of Sokal Stage three (51 vs 20%). Median observation periods were similar (38 vs 39 months), whereas the duration of IFNalpha treatment was shorter in the elderly group (median 57 vs 42 weeks). The rate of overall haematological responses (73 vs 78%) and complete haematological response (44 vs 54%), was similar in both cohorts. Differences seen in partial (5 vs 12%) and complete cytogenetic response (10 vs 13%), were not statistically significant, but a tendency in favour of the younger cohort had to be noted. Summing up, in elderly patients acceptable rates of haematological and cytogentic response can be expected after treatment with IFNalpha alone or in combination with LD ara-C or HU.

Interferon-alpha-2C and LD ara-C for the treatment of patients with CML: results of the Austrian multi-center phase II study.

Small pilot studies of patients with CML have reported on encouraging response rates after treatment with interferon-alpha (IFNalpha) in combination with low-dose cytosine arabinoside (LD ara-C). We therefore initiated a multi-center phase II trial in order to investigate the efficacy and tolerability of this combination in newly diagnosed patients with Ph-positive chronic myelogenous leukemia (CML). Eighty-four patients were treated with IFN-alpha-2c at daily subcutaneous doses of 3.5 MU and LD ara-C added subcutaneously for 10 days every month at a dose of 10 mg/m2, following an initial reduction of WBC to less than 20 x 10(9)/l with hydroxyurea (HU). Within a median observation period of 28 (5-59) months the patients received a median of 7 (1-35) IFNalpha and LD ara-C cycles. Treatment was stopped due to side effects in 16 cases (19%) and to primary or secondary treatment failure in 38 cases (45%). In 45 patients (54%) complete hematological response (CHR) was achieved; in 39 patients (46%) cytogenetic responses including 15 (18%) complete cytogenetic responses (CHR) were observed. Median duration of cytogenetic responses was 15 months. Relapses were seen in 8/15 patients (53%) with complete cytogenetic remission (CCR), in 3/6 patients (50%) with partial cytogenetic response and in 9/18 patients (50%) with minor cytogenetic response. In conclusion, the combination of IFNalpha and LD ara-C resulted in encouraging rates of hematological and cytogenetic responses in patients with CML with low to moderate toxicity.

Relation of fibrinogen to presence and severity of coronary artery disease is independent of other coexisting heart disease. The ECAT Angina Pectoris Study Group.

Six hundred fifty seven patients with angina pectoris underwent coronary angiography after measurement of plasma fibrinogen levels. Coronary artery disease (CAD) was angiographically confirmed in 75% of the patients. Other cardiac disease, either alone or in combination with CAD, was diagnosed in 8% and 11% of cases, respectively; 17% of the patients had no evidence of overt heart disease. Fibrinogen concentrations showed a graded increase according to the severity of coronary stenosis (p = 0.02) but were not significantly associated with any other cardiac heart disease. However, patients with valvular heart diseases had on average a 5.9% elevation of fibrinogen levels as compared to patients without proven cardiac disease (p = 0.08), similar to the observed 6.9% increase for CAD (p = 0.005). On average, patients with cardiomyopathies or pulmonary hypertension had only a 1.6% or 1.2% increase, respectively. The increase in fibrinogen levels associated with CAD was similar in patients with and without coexisting heart diseases. The results demonstrate a significant positive relation of fibrinogen to the presence and severity of CAD irrespective of a possible confounding influence from other cardiac diseases. The results therefore lend support to the hypothesis of a pathogenetic role for fibrinogen as a cardiovascular risk factor.

Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening.

Data in the literature on the prevalence of hereditary deficiency of the natural coagulation inhibitors are conflicting. We conducted a prospective study on 680 consecutive patients with a history of venous thrombosis to determine the prevalence of hereditary deficiency of antithrombin III (AT III), protein C(PC) and protein S(PS) and to establish selection criteria for rational patient screening. The mean age of the patients at investigation was 44.3 +/- 15.4 years, while that at the first thrombotic event was 38.5 +/- 14.8 years. The total prevalence of inhibitor deficiency states was 48/680 (7.1%). 19/680 patients (2.8%) had AT III-deficiency, 17 (2.5%) PC-deficiency, nine (1.3%) PS-deficiency and three (0.4%) a combined deficiency. In 37/48 deficient patients family studies were performed and the hereditary nature was established in 19 cases (2.8% of total patient population, six with AT III-deficiency, eight with PC-deficiency, four with PS-deficiency and one with a combined deficiency). Family studies in these 19 patients revealed 46 additional individual patients with a hereditary deficiency state. A positive family history was found in 15/19 (79%) with a proven hereditary deficiency state, in 153/619 (25%) of non-deficient patients and in 11/29 (38%) of deficient patients without established hereditary nature. The mean age at the first thrombotic event was significantly lower in patients with a hereditary deficiency state (26.8 years) compared with the other two groups (39.0 and 39.7 years, respectively). In all patients with a hereditary deficiency the first thrombotic event occurred before the age of 45 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Coincidence of acquired factor-X deficiency and disseminated intravascular coagulation in patients with acute nonlymphoblastic leukemia.

Systematic clotting studies were performed in 157 patients with de novo acute nonlymphoblastic leukemia (ANLL) prior to treatment. Sixteen patients had disseminated intravascular coagulation (DIC). Three of the patients with DIC (two with M3, one with M5 leukemia) had a marked isolated factor-X deficiency (factor X:C 21%, 33%, and 41%, respectively). Another four patients had a mild isolated factor-X deficiency (factor X:C 55%-68%). In these seven patients the remaining liver-synthesized clotting factors (factors II, VII, IX, V) as well as serum albumin and cholinesterase were within the normal range. Liver disease or vitamin-K deficiency could therefore be excluded. In none of the 141 patients without DIC was a marked isolated factor X deficiency observed; two patients had moderately reduced factor X:C levels but normal liver-synthesized proteins. Induction treatment led to the control of DIC with an almost parallel increase of fibrinogen and factor X up to normal in all patients with factor-X deficiency who achieved complete remission. In one patient, recurrence of leukemia was associated with reoccurrence of DIC and marked factor-X deficiency. We conclude that there is a coincidence of isolated factor-X deficiency and DIC in some patients with ANLL. In some patients, this factor-X deficiency may be severe enough to contribute to the bleeding tendency.

Activation of coagulation and fibrinolysis in patients with arteriosclerosis: relation to localization of vessel disease and risk factors.

Activation markers of blood coagulation and fibrinolysis and several fibrinolytic parameters were determined in arteriosclerotic patients to investigate the relation between extension and main localization of vessel disease, risk factors and disturbances within the blood coagulation and the fibrinolytic system. Indications of an increased intravascular fibrin formation and subsequent fibrinolysis were found in peripheral artery disease (PAD) patients but not in coronary artery disease (CAD) patients. Compared with healthy controls PAD patients had elevated TAT (median: 3.2 ng/ml, 1.5-70 vs. 2.1, 1.2-4.7, p less than 0.005) and D-Dimer (median: 365 ng/ml, range 85-2000 vs. 185, 79-360; p less than 0.0001) plasma levels, whereas TAT (2.4, 1.2-13) and D-Dimer (190, 58-1000) levels of CAD patients were in the normal range. No associations were detected between risk factors of arteriosclerosis (hyperlipidemia, diabetes mellitus, cigarette smoking, hypertension) and the plasma levels of the activation markers TAT and D-Dimer. Independent from risk factors PAD and CAD patients had elevated plasma plasminogen activator inhibitor capacity (PAI cap). Our results provide evidence that 1) increased plasma levels of blood coagulation and fibrinolysis activation markers are not related to risk factors of arteriosclerosis but seem to be unspecifically caused by activation processes on arteriosclerotic vessel wall defects, 2) increased plasma PAI cap found in arteriosclerotic patients is a relatively unspecific phenomenon associated with arterial vessel disease.

IIB von Willebrand's disease: pathogenetic and therapeutic studies.

Infusion of 1-deamino-(8-D-arginine)-vasopressin (DDAVP) into patients with IIB von Willebrand's disease (vWD) has been reported to induce thrombocytopenia. In some families with this disorder thrombocytopenia is present even in the resting state. We have investigated the basis of this chronic thrombocytopenia in one such patient by performing platelet recovery and survival studies. Increased platelet consumption was suggested by a decrease in platelet recovery (40.5%, normal 45%) and mean platelet survival (112 h, normal range 144-224 h). In addition, we have administered test infusions of DDAVP and observed the effect on bleeding time and platelet count. DDAVP caused a decrease in the median platelet count from 86 x 10(9)/l (range 30-221) to 60 x 10(9)/l (range 5-144), the individual decline in the nine subjects ranging from 12% to 84% compared to the pretreatment values. Formation of platelet aggregates was observed in all patients following DDAVP. The bleeding time was prolonged before DDAVP in all patients and lengthened further in two after the infusion. However, partial correction of the bleeding time was seen in three and normalization in one patient following DDAVP infusion. Two IIB vWD patients were treated with virus-inactivated cryoprecipitate (Ristofact). Infusion of cryoprecipitate was followed by rapid appearance of all but the largest vWF multimers in plasma and did not affect the platelet count. The bleeding time was normalized in one patient but remained prolonged in the other. In conclusion, in IIB vWD patients virus-inactivated cryoprecipitate is the treatment of choice in the case of bleeding. Infusion of DDAVP might be effective in a subset of IIB vWD patients that has yet to be characterized.

[Home treatment in hemophilia]. / Die Heimtherapie der Hämophilie.

88 patients with severe haemophilia (66 with haemophilia A without inhibitor, 12 with haemophilia A and inhibitor, 10 with haemophilia B) currently receive comprehensive care at the Vienna haemophilia centre. Data available at the centre and a questionnaire answered by the hemophiliacs were used in order to evaluate the current situation of home care. At present, 62 (70%) out of 88 patients receive home treatment (51 with haemophilia A without inhibitor, 5 patients with haemophilia A and inhibitor and 6 with haemophilia B). For treatment of joint and muscle bleeding mean dosages of 15.3 units/kg body weight of factor VIII concentrate, 17.0 units/kg of factor IX concentrate and 30 units/kg of FEIBA were administered by the hemophiliacs. Children and young patients required higher doses (30 and 17.4 units/kg F VIII, respectively). Two thirds of the bleeding episodes were successfully treated by a single infusion. No severe side effects were observed during home treatment. Home treatment has been widely accepted by the patients. It is regarded as a practical and safe therapy and has improved the life quality of haemophiliac patients.

[Oral anticoagulant therapy--renaissance of an old therapy?]. / Orale Antikoagulantientherapie--Renaissance einer alten Therapie?

Although the antithrombotic potential of oral anticoagulants is undisputed, bleeding complications constitute a serious problem. One of the main causes for these complications has been a lack of standardization of the prothrombin time. The introduction of the International Normalized Ratio (INR) has led to a better standardization of prothrombin time. Thus, the same level of anticoagulation can be reached using different reagents and therefore over- and undercoagulation can be avoided. Furthermore, the benefit/risk ratio can be improved by adapting the intensity of anticoagulation to the indication. The following clinical conditions are established indications for treatment with oral anticoagulants: Prevention of cardiac emboli in acute anterior myocardial infarction with atrial thrombus, in patients with atrial fibrillation with or without mitral valve disease, in patients with prosthetic heart valves and in patients with dilated cardiomyopathy. Furthermore, oral anticoagulants should be given to patients after femoropopliteal bypass. A relatively mild oral anticoagulant treatment (INR 2-3) is sufficient to prevent recurrences of venous thrombosis and pulmonary emboli. The duration of treatment in patients with venous thromboembolism depends on some clinical features and the results of clotting tests which indicate an increased tendency to thrombosis.

Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates.

Recent data published on the prevalence of inhibitors to factor VIII in hemophiliacs on treatment show great variations, with prevalence rates ranging from 3.6 to 14.2%. We have studied the cumulative risk of inhibitor development in a cohort of 62 patients with hemophilia A. All patients were born after 1960, were natives of the Vienna area, had a factor VIII activity of less than 5%, and were treated at least once. Using the method of Cutler and Ederer, the cumulative risk of inhibitor development was found to be 24% at the age of 25 years. Most inhibitors developed between the ages of 3 and 7 years. The current prevalence of F VIII inhibitors in the group of patients studied is 17.5%. It is concluded that prevalence data underestimate the true risk of inhibitor development.

[Right heart failure as a clinical sign of pulmonary artery sarcoma]. / Rechtsherzinsuffizienz als klinisches Zeichen eines Pulmonalarteriensarkoms.

A 43 year-old female patient was admitted on account of severe dyspnoea of several months' duration and thrombocytopenia. The clinical symptomatology was compatible with pulmonary embolism, but no source of embolization was found and heparin therapy did not lead to clinical improvement. Angiography of the pulmonary artery revealed multiple filling defects. Symptoms improved after treatment with cortisone and so a malignant process was assumed. The patient died from right ventricular failure before the diagnosis could be established. At autopsy a sarcoma of the pulmonary artery, obviously originating from the pulmonary trunk was found. Thrombocytopenia most probably resulted from consumption of platelets by a mechanism corresponding to the Kasabach-Merritt syndrome. The difficulties in the diagnosis of pulmonary artery sarcomas are discussed and the 69 previously published cases are reviewed.

[Use of genetic technics in medical diagnosis exemplified by hemophilia A]. / Anwendung gentechnischer Methoden in der medizinischen Diagnostik am Beispiel der Hämophilie A.

Recent years have seen the rapid development of molecular probes for the detection of defective human genes. These react either directly with the gene in question or with a DNA sequence which lies in close proximity to the gene and which exhibits polymorphism. In the case of haemophilia A two probes were found that belong to the latter category. We have used one of these probes to test its usefulness in the detection of carriers of haemophilia A. For these tests DNA was isolated from blood cells, but can, in principle, be obtained just as easily from other cells or tissues. The results of tests on several families show that the gene technological method is much more precise and sensitive than conventional methods used so far to detect carriers. In all cases a clear assertion was possible as to whether or not the person in question was a carrier of haemophilia A. The method should be applicable to prenatal diagnosis.

Thromboembolism in patients with prosthetic heart valves. An adequately controlled intense anticoagulant therapy and its influence on the occurrence of thromboembolism in relation to valve type.

This study was designed to evaluate the efficacy of carefully controlled treatment with oral anticoagulants in patients with different mechanical heart valve prostheses. One hundred eighty-one patients with various types of prosthetic valves (mitral 89, aortic 87, combined 5) received oral anticoagulation aiming at Thrombotest (TT) values between 5% and 12%. Median follow-up was 46 months; 80.8% of all TT determinations were below 12%. The thromboembolic rate was 0.25%/year in patients with aortic valve replacement (AVR) and 4.87%/year in patients with mitral valve replacement (MVR). There was a strikingly lower incidence of thromboembolism with newer types of valves (Björk-Shiley convex-concave) in the mitral position under exactly the same intensity and stability of anticoagulant treatment. Clinically overt valve occlusion could be almost completely prevented (0.12%/year) in prostheses at both sites. Severe hemorrhage occurred at a rate of 1.71%/year and fatal bleeding at a rate of 0.37%/year. Our results indicate that carefully controlled anticoagulation is effective in the reduction of thromboembolic complications at a reasonable risk of bleeding.

Acquired thrombasthenia due to GPIIb/IIIa-specific platelet autoantibodies.

An otherwise healthy woman developed a hemorrhagic diathesis with fluctuating clinical symptoms and laboratory findings, but without thrombocytopenia, over 8 years. In periods of bad clinical condition, a platelet defect, characteristic of thrombasthenia, was found. In contrast to classic thrombasthenia, electrophoresis of the patient's platelet membranes revealed normal amounts of glycoproteins IIb alpha, IIb beta, and IIIa in the normal positions. Monoclonal antibodies, specific for GPIIIa and GPIIb/IIIa, respectively, bound normally to the P1A1-positive platelets from the patient. Although no antibody and no platelet function inhibitor were evident in the autologous plasma, an IgG1 antibody that was bound to the patient's platelets and was directed against GPIIb/IIIa could be demonstrated. After elution from the patient's platelets, this antibody immunoprecipitated GPIIb (both subunits), IIIa, and a 200-kilodalton (kd) band (probably undissociated GPIIb/IIIa complex) from solubilized normal platelets, but did not react with thrombasthenic platelets. Adding the eluate from the patient's platelets to normal platelet-rich plasma immediately caused concentration-dependent inhibition of adenosine diphosphate (ADP)-induced and collagen-induced aggregation and also strong inhibition of ADP-stimulated fibrinogen binding. Because it was very unlikely from the patient's medical history that the antibody was caused by alloimmunization, the hemorrhagic diathesis must be interpreted as acquired thrombasthenia due to an anti-GPIIb/IIIa autoantibody.

Platelet-associated immunoglobulins IgG, IgM, IgA and complement C3c in chronic idiopathic autoimmune thrombocytopenia: relation to the sequestration pattern of 111indium labelled platelets.

Levels of platelet-associated immunoglobulins (PAIg) IgG, IgM, IgA and complement C3c were related to parameters of 111Indium-labelled platelet kinetics in 17 patients with chronic idiopathic autoimmune thrombocytopenia (cAITP). Elevated levels of PAIg/C3c were found in 14 patients (82%) (PAIgG n = 13, PAIgM n = 11, PAIgA n = 1, PAC3c n = 5). Only PAIgG correlated with platelet counts (RS = -0.71, p less than 0.01). Mean platelet life span (MLS) was shortened in all patients (median 12.0 h, range 0.3-45.6 h) and correlated with the platelet counts (RS = 0.49, p less than 0.05). MLS was correlated with PAIgG (RS = -0.52, p less than 0.05), but not with PAIgM, PAIgA, or PAC3c. The site of sequestration was splenic in 10 patients and splenic-hepatic in 7 patients. Although no significant correlation between either site of platelet sequestration and any of the investigated PAIg/C3c was demonstrable, platelets coated with higher PAIgG levels were more readily sequestrated in the spleen, while elevations of PAC3c were found in 4 out of 7 patients with hepatic involvement.