ABSTRACT
BACKGROUND: The equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment. PATIENTS AND METHODS: Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period. RESULTS: Of 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59-1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ. CONCLUSIONS: Final safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/immunology , Breast Neoplasms/mortality , Neoadjuvant Therapy/mortality , Adolescent , Adult , Aged , Biosimilar Pharmaceuticals/administration & dosage , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Docetaxel/administration & dosage , Double-Blind Method , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Middle Aged , Prognosis , Survival Rate , Trastuzumab/administration & dosage , Young AdultABSTRACT
BACKGROUND: This randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC). PATIENTS AND METHODS: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. RESULTS: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). CONCLUSIONS: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Dioxoles/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Tetrahydroisoquinolines/administration & dosage , Adult , Aged , Antineoplastic Agents, Alkylating/adverse effects , Dioxoles/adverse effects , Female , Humans , Middle Aged , Platinum Compounds/therapeutic use , Tetrahydroisoquinolines/adverse effects , TrabectedinABSTRACT
Loss of heterozygosity (LOH) has been shown to be an important prognostic factor in a variety of malignant neoplasm's. Cervical cancer develops as result of multiple genetic alterations. The aim of this study was to analyze presence of LOH in cervical cancer and to identify the correlation between LOH and survival and relapse-free survival time in patients treated with radiotherapy. Studies were performed on tumor specimens and venous blood from 20 patients with cervical cancer (squamous cell carcinoma G2 and G3) in stage II and III (FIGO) treated with radiotherapy. DNA was isolated using organic extraction. Additional microcolumn purification was performed. The fluorescent multiplex polymerase chain reaction (PCR) was used to amplify 10 microsatellite loci included in commercially available human identification kits. Microsatellite marker BAT 26 was amplified in separate PCR reactions. 75% cervical cancers manifested LOH. LOH in BAT 26 analysis (chromosome 2) was present in all these specimens. 60% of the cases showed LOH at one or more of other examined loci (mostly on 3p, 18q21.3, and 11p15.5). Eight of nine cervical cancers in clinical stage III showed LOH. All cases of G3 squamous cell carcinoma of the cervix manifested LOH on 2p. Patients with LOH have worse prognosis for survival and relapse-free survival compared to patients without LOH.
Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/radiotherapy , Loss of Heterozygosity , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/radiotherapy , Adult , Aged , Carcinoma, Squamous Cell/pathology , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 18/genetics , Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, Pair 3/genetics , Female , Humans , Microsatellite Repeats/genetics , Middle Aged , Neoplasm Staging , Polymerase Chain Reaction , Prognosis , Survival Analysis , Survival Rate , Uterine Cervical Neoplasms/pathologySubject(s)
Anticoagulants/therapeutic use , Antineoplastic Agents/therapeutic use , Enoxaparin/therapeutic use , Melanoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carmustine/administration & dosage , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Combined Modality Therapy , Dacarbazine/administration & dosage , Feasibility Studies , Glycosaminoglycans/physiology , Humans , Melanoma/mortality , Melanoma/pathology , Melanoma/radiotherapy , Melanoma/surgery , Neoplasm Staging , Pilot Projects , Radiotherapy, Adjuvant , Remission Induction , Survival Analysis , Tamoxifen/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: Interleukins may stimulate cancer cells growth and contribute to locoregional relapse as well as metastasis. Permanent synthesis and release of these cytokines leads to augmentation of their serum concentration that might be utilized as a marker of immunity status and immune system activation in prognosis and monitoring of the course of cancer. MATERIAL AND METHODS: Therefore, in the present study we assessed the concentration of IL-6, IL-8 and IL-10 in blood serum of breast cancer patients to determine whether it correlates with the disease progression. RESULTS: We showed statistically higher serum concentrations of IL-6, IL-8 and IL-10 in breast cancer patients in comparison with healthy women, which also correlated with clinical stage of breast cancer. CONCLUSIONS: The present study indicates that elevated IL-6, IL-8, and IL-10 serum concentration, are strongly associated with breast cancer and correlate with clinical stage of disease. It was feasible that it can be used to diagnose women with breast cancer and to identify patients with a poor prognosis who may benefit from more aggressive management.
Subject(s)
Breast Neoplasms/immunology , Interleukin-10/blood , Interleukin-6/blood , Interleukin-8/blood , Adult , Aged , Biomarkers, Tumor/blood , Biomarkers, Tumor/immunology , Breast Neoplasms/blood , Breast Neoplasms/pathology , Female , Humans , Interleukin-10/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Middle Aged , Neoplasm Staging , PrognosisABSTRACT
Coagulopathy and angiogenesis are among the most consistent host responses associated with cancer. These two respective processes, hitherto viewed as distinct, may in fact be functionally inseparable as blood coagulation and fibrinolysis, in their own right, influence tumor angiogenesis and thereby contribute to malignant growth. In addition, tumor angiogenesis appears to be controlled through both standard and non-standard functions of such elements of the hemostatic system as tissue factor, thrombin, fibrin, plasminogen activators, plasminogen, and platelets. "Cryptic" domains can be released from hemostatic proteins through proteolytic cleavage, and act systemically as angiogenesis inhibitors (e.g., angiostatin, antiangiogenic antithrombin III aaATIII). Various components of the hemostatic system either promote or inhibit angiogenesis and likely act by changing the net angiogenic balance. However, their complex influences are far from being fully understood. Targeted pharmacological and/or genetic inhibition of pro-angiogenic activities of the hemostatic system and exploitation of endogenous angiogenesis inhibitors of the angiostatin and aaATIII variety are under study as prospective anti-cancer treatments.
Subject(s)
Hemostasis , Neoplasms/blood supply , Neovascularization, Pathologic/pathology , Animals , HumansABSTRACT
We describe the inhibitory effect of the proteasome inhibitor, lactacystin, on cathepsin A activity in murine melanoma cell lines. In vitro lactacystin metabolite, beta-lactone, at a concentration of 1 microM, significantly suppressed cathepsin A activity in B78 melanoma cell lysates by about 50%. Exposure of three murine melanoma cell lines with different metastatic potential to lactacystin at a concentration of 5 microM for 6 h caused a significant reduction in the carboxypeptidase activity of this enzyme, while the inhibitory activity remained unchanged for at least 12 h. Other proteasome-specific inhibitors, e.g. epoxomicin and N-benzyloxycarbonyl-Ile-Glu(O-tert-Bu)-Ala-leucinal (PSI) at a concentration of 1 microM did not affect cathepsin A activity in melanoma cell line lysates. These data support our previous proposal that lactacystin is not a specific inhibitor of the proteasome. Since cathepsin A is also a tumor-associated enzyme, further research is needed to clarify its role and the significance of its inhibition by lactacystin in tumor biology.
Subject(s)
Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Carboxypeptidases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Melanoma, Experimental/enzymology , Animals , Antibiotics, Antineoplastic/pharmacology , Cathepsin A , Enzyme Inhibitors/pharmacology , Mice , Oligopeptides/pharmacology , Tumor Cells, CulturedABSTRACT
In this paper we present a rare localization of Hodgkin's disease--in the breast. An awareness of such unusual clinical presentation of Hodgkin's disease is important to prevent a delay in diagnosis and treatment.
Subject(s)
Breast Neoplasms/diagnosis , Hodgkin Disease/diagnosis , Breast Neoplasms/pathology , Female , Hodgkin Disease/pathology , Humans , Middle AgedABSTRACT
Blood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor: prothrombin: and factors VII, VIIIc, IX, X, XII, and subunit "a" of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.
Subject(s)
Adenocarcinoma/chemistry , Blood Coagulation Factors/analysis , Neoplasm Proteins/analysis , Pancreatic Neoplasms/chemistry , Adenocarcinoma/blood , Adenocarcinoma/complications , Aged , Endothelium, Vascular/chemistry , Female , Fibrin/analysis , Fibrinogen/analysis , Humans , Immunoenzyme Techniques , Male , Middle Aged , Neoplastic Stem Cells/chemistry , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/complications , Plasminogen Activator Inhibitor 1/analysis , Plasminogen Activator Inhibitor 2/analysis , Protein C/analysis , Protein S/analysis , Prothrombin/analysis , Stromal Cells/chemistry , Thrombophilia/etiology , Thromboplastin/analysisABSTRACT
Malignant melanoma of an unknown primary site remains a diagnostic and therapeutic challenge in clinical practice. With this in mind, we have presented 12 patients with malignant melanoma of an unknown primary site, diagnosed and treated in the Regional Cancer Center in Bialystok. This clinical presentation accounted for 2% of all malignant melanocytic lesions treated in our center during ten year period from 1987 to 1997.
Subject(s)
Bone Neoplasms/secondary , Bone Neoplasms/therapy , Gastrointestinal Neoplasms/secondary , Gastrointestinal Neoplasms/therapy , Head and Neck Neoplasms/secondary , Head and Neck Neoplasms/therapy , Lung Neoplasms/secondary , Lung Neoplasms/therapy , Melanoma/secondary , Melanoma/therapy , Skin Neoplasms/pathology , Adult , Aged , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Skin Neoplasms/surgeryABSTRACT
The anthracyclines are among the most active and useful anticancer agents, but they are also the most common chemotherapeutics associated with the development of congestive heart failure. Twenty seven to sixty percent of patients with anthracycline-induced cardiomyopathy die of congestive cardiac failure. The paper presents the pathomechanisms of anthracycline-induced cardiotoxicity and perspectives on prevention of congestive heart failure resulting from anthracycline chemo-therapy.
Subject(s)
Antibiotics, Antineoplastic/adverse effects , Heart Failure/chemically induced , Adult , Child , Drug Monitoring , Humans , Neoplasms/drug therapy , Risk FactorsSubject(s)
Blood Coagulation/drug effects , Polymers/pharmacology , Sulfonic Acids/pharmacology , Thrombosis/drug therapy , Adenosine Diphosphate/pharmacology , Administration, Oral , Animals , Anticoagulants/pharmacology , Arterioles/drug effects , Arterioles/pathology , Collagen/pharmacology , Disease Models, Animal , Fibrinolytic Agents/pharmacology , Humans , Injections, Intravenous , Lasers/adverse effects , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/pathology , Partial Thromboplastin Time , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effects , Platelet Count/drug effects , Prothrombin Time , Rats , Rats, Wistar , Thrombin Time , Thrombosis/etiology , Thrombosis/prevention & controlABSTRACT
Several lysosomal proteases including cathepsins B, D, H and L have been found to play a role in the metastasis of tumor cells. However, up to now no information on the role of cathepsin A, a lysosomal multifunctional peptidase, in the proliferative, invasive, and metastatic potential of malignant tumors has been available. In the present study we compared the activity of cathepsin A in lysates of 34 human melanocytic tumors: primary (n = 12) and metastatic (n = 5) malignant melanoma, dysplastic pigmented nevi (n = 6) and pigmented nevi without evidence of dysplastic melanocytes (n = 11). The carboxypeptidase activity of cathepsin A was assayed at pH 5.0 with its specific substrate Cbz-Phe-Ala. The amount of released C-terminal alanine was measured by the ninhydrin method. We found that lysates of primary malignant melanoma lesions exhibited significantly higher cathepsin A activity than lysates of dysplastic and normal pigmented nevi. The cathepsin A activity in lysates of metastatic lesions of malignant melanoma was significantly higher than in primary focus lysates. It seems that cathepsin A may play a role in malignant transformation and metastatic dissemination of malignant melanoma.
Subject(s)
Carboxypeptidases/metabolism , Melanoma/enzymology , Cathepsin A , Humans , Melanoma/secondaryABSTRACT
Immunohistochemistry was applied to AMeX-fixed tissue sections of 12 adenocarcinomas of the stomach (seven intestinal adenocarcinomas and five diffuse carcinomas), 12 adenocarcinomas of the pancreas (nine ductal adenocarcinomas and three signet ring carcinomas), and 12 squamous cell carcinomas of the larynx obtained at surgical resection to examine the possibility of extravascular activation of blood coagulation in cancer tissues by exploring the in loco patterns of distribution of fibrinogen, a final product of blood coagulation, fibrin, and a by-product of coagulation reactions (prothrombin fragment 1+2). Gastric, pancreatic, and laryngeal cancers exhibited fibrinogen antigen in abundance throughout the tumor stroma. Fibrin was detected along the edges of nests of carcinoma cells and at the host-tumor interface. Prothrombin fragment 1+2 was present in the blood vessels in areas of neoangiogenesis at the host-tumor interface (gastric and pancreatic cancer tissues) and on the tumor cell bodies (pancreatic and laryngeal cancer tissues). The presence of prothrombin fragment 1+2 in cancer tissues appears to be a good indicator of coagulation activation and thrombin generation at the tumor burden.
Subject(s)
Adenocarcinoma/chemistry , Biomarkers/blood , Carcinoma, Squamous Cell/chemistry , Gastrointestinal Neoplasms/chemistry , Peptide Fragments/biosynthesis , Prothrombin/biosynthesis , Adenocarcinoma/blood supply , Adenocarcinoma/complications , Blood Coagulation , Carcinoma, Squamous Cell/blood supply , Carcinoma, Squamous Cell/complications , Fibrin/biosynthesis , Gastrointestinal Neoplasms/blood supply , Gastrointestinal Neoplasms/complications , Immunohistochemistry , Laryngeal Neoplasms/blood , Laryngeal Neoplasms/chemistry , Laryngeal Neoplasms/complications , Neovascularization, Pathologic , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/chemistry , Pancreatic Neoplasms/complications , Stomach Neoplasms/blood , Stomach Neoplasms/chemistry , Stomach Neoplasms/complications , Stromal Cells/pathologyABSTRACT
Platelet-induced thrombin generation time (PITT) is a newly developed global coagulation assay in which a small amount of partially anticoagulated platelet-rich plasma (PRP) is rotated in a disc-shaped cuvette within the light beam of a photometer. The time intervals from onset of rotation until aggregation and coagulation of the sample are registered. The aim of our study was to compare platelet activation with generation of thrombin during rotation of PRP in PITT system. Aliquots of PRP were taken before, 1, 3, and 8 min after the onset of rotation as well as at the beginning of aggregation and shortly before coagulation. Thrombin activity was measured with chromogenic substrate S-2238. We have also measured the level of generated prothrombin activation fragment 1+2 (F1+2), which reflects the concentration of liberated thrombin. Platelet activation was assayed by means of platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG) concentration and registration of the aggregation. The concentrations of the F1+2, PF4, beta-TG increased very slowly from the beginning of the test until aggregation occurred. From the start of aggregation, the levels of F1+2 rose rapidly. In contrast to the F1+2 measurements, thrombin activity has not been detected from onset of rotation until the end of the test. Only trace thrombin activity was detectable just after the plasma sample had been clotted in the cuvette. Our results demonstrate that there exists a close relationship between platelet activation and thrombin generation. Viable platelets, which adhered to the cuvette walls, form an active template on which thrombin can be generated from prothrombin.
Subject(s)
Platelet Activation/physiology , Thrombin Time , Thrombin/physiology , Adult , Humans , MaleABSTRACT
The purpose of the study was to evaluate the effectiveness of recombinant human erythropoetin (r-HuEPO) treatment in patients suffering from anemia in the course of Hodgkin's disease (HD). 6 patients suffering from HD (4 of nodular sclerosis type II (NS II) and 2 of nodular sclerosis type I (NS I)) were treated with r-HuEPO for 10 weeks. All patients suffering from the NS II of HD exhibited an increase in the level of Hb by more than 2 g/dl after 10 weeks of r-HuEPO therapy whereas patients suffering from the NS I subtype of HD did not benefit from such treatment.
Subject(s)
Anemia/drug therapy , Erythropoietin/therapeutic use , Hodgkin Disease/complications , Adult , Anemia/etiology , Female , Hemoglobins/analysis , Hodgkin Disease/pathology , Humans , Male , Neoplasm Staging , Pilot Projects , Recombinant Proteins , Treatment OutcomeABSTRACT
The blood coagulation mechanism may support tumor progression by several mechanisms including promotion of cell proliferation and angiogenesis. Immunohistochemical procedures were applied to AMeX-fixed sections of twelve cases of squamous cell carcinoma of the larynx obtained at surgical resection to determine the presence and distribution of tissue factor (TF), tissue factor pathway inhibitor (TFPI), other coagulation factors, fibrinogen, and fibrin in situ. TF antigen was present in normal squamous epithelial cells and tumor cells, predominantly in immature tumor cells in the vicinity of the host-tumor interface. Tumor cells stained also for factors VII and X. Staining for TFPI antigen was demonstrated in the connective tissue stroma adjacent to the tumor, in microvascular endothelial cells, and in normal squamous epithelial cells. Fibrinogen and factor XIIIa were distributed throughout the tumor connective tissue stroma. Fibrin (thrombin-cleaved fibrinogen) was detected at the host-tumor interface and along the margins of tumor nodules. Tumor cells in carcinoma of the larynx express a functional, TF-initiated pathway of blood coagulation. Interpretation of these findings together with the results of clinical trials of inhibitors of TF-induced coagulation activation versus effects of inhibitors of TF expression suggest novel approaches to the experimental therapy of laryngeal carcinoma.
Subject(s)
Carcinoma/metabolism , Laryngeal Neoplasms/metabolism , Lipoproteins/biosynthesis , Thromboplastin/biosynthesis , Blood Coagulation , Carcinoma/blood supply , Humans , Laryngeal Neoplasms/blood supply , Neovascularization, PathologicABSTRACT
The case of chylomicronaemia syndrome complicating clinical course of type-1 hyperlipoproteinaemia and insulin-dependent diabetes is described. The patient required hypoglycaemic and lipid-lowering therapy.