Autoimmunity can be associated with cancer and one of the forms of its expression is the developm... more Autoimmunity can be associated with cancer and one of the forms of its expression is the development of antibodies to autologous cellular antigens. The types of cellular proteins which induce autoantibody responses in gastrointestinal malignancies are quite varied and include cellular proteins encoded by mutated normal genes (p53), cellular proteins that are overexpressed and/or aberrantly expressed in malignant tissues (carcinoembryonic antigen), inhibitors of apoptosis (survivin and livin), major components of mucus (mucins), surface receptors of apoptosis (Fas) and nuclear-restricted proteins (double-stranded DNA, single-stranded DNA and Sm family proteins). In the past few years, due to the great clinical interest and the advancement in detection techniques, the above list has grown significantly and a large number of cancer-related antigens, which trigger a specific humoral immune response to the host, have also been identified. The authors review the autoantibodies associated with gastrointestinal malignancies and their clinical implications.
The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and ... more The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.
Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, app... more Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, approved as first line treatment concurrently administrated with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer. One of the most common side effects, rash, is possibly linked to overall and progression-free survival and may serve as a potential surrogate marker. Nevertheless, erlotinib-induced rash is cause of negative impact on patients' quality of life and often can trigger discontinuation of treatment. Adequate and timely management of rash depending on the grade of rash is important for therapy continuation.
Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is c... more Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is considered to be uncommon, it is difficult to evaluate their exact prevalence, mainly because their definition is vast and pathogenic mechanisms are vague. HSR include facial flushing, erythema, pruritus, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Treatment and prevention consists of slowing the infusion rate, steroids, and type 1 and 2 histamine receptor antagonists. Desensitization could allow the small number of patients who experience severe HSR to receive effective therapy for their cancer. Reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitization strategies is still missing. With regard to oxaliplatin, knowledge of its rare but eminent toxicity is paramount, because this drug is widely used in treating colorectal cancer, the second-highest cause of cancer mortality in the United States.
The diagnosis of pancreatic cancer is devastating for patients and their relatives as the inciden... more The diagnosis of pancreatic cancer is devastating for patients and their relatives as the incidence rate is approximately the same as mortality rate. Only a small percentage, which ranges from 0.4% to 4% of patients who have been given this diagnosis, will be alive at five years. At the time of diagnosis, 80% of pancreatic cancer patients have unresectable or metastatic disease. Moreover, the therapeutic alternatives offered by chemotherapy or radiotherapy are few, if not zero. For all these reasons, there is an imperative need of analyzing and understanding the primitive lesions that lead to invasive pancreatic adenocarcinoma. Molecular pathology of these lesions is the key of our understanding of the mechanisms underlying the development of this cancer and will probably help us in earlier diagnosis and better therapeutic results. This review focuses on medical research on pancreatic cancer models and the underlying genetic alterations.
S-1 is an oral fluoropyrimidine that is designed to improve the antitumor activity of 5-fluoroura... more S-1 is an oral fluoropyrimidine that is designed to improve the antitumor activity of 5-fluorouracil (5-FU) concomitantly with an intent to reduce its toxicity. S-1 consists of tegafur, a prodrug of 5-FU combined with two 5-FU biochemical modulators:5-chloro-2,4-dihydroxypyridine (gimeracil or CDHP), a competitive inhibitor of dihydropyrimidine dehydrogenase and oteracil potassium which inhibits phosphorylation of 5-FU in the gastrointestinal tract decreasing serious gastrointestinal toxicities,including nausea, vomiting, stomatitis and diarrhea. Being an oral agent, S-1 offers convenience of administration and prevents complications of central venous access such as infection, thrombosis and bleeding. S-1 has shown efficacy in both gastrointestinal as well non-gastrointestinal malignancies. The authors review the current literature and provide their expert opinion on the incorporation of S-1 in the treatment of solid malignancies [corrected].
Hypersensitivity reactions to antineoplastic agents are defined as unexpected reactions with sign... more Hypersensitivity reactions to antineoplastic agents are defined as unexpected reactions with signs and symptoms inconsistent with known toxicity of antineoplastic drugs. These reactions are uncommon and usually associated with certain antineoplastic categories, such as taxanes, platinum-containing compounds, epipodofyllotoxins, asparaginase, procarbazine and, more rarely, with doxorubicin and 6-mercaptopurine. The mechanisms that are responsible for hypersensitivity reactions are unclear and vary between agents. Symptoms of these reactions range from mild skin rashes to more severe reactions, such as arthralgia, respiratory arrest or even death in some cases. Once hypersensitivity reactions are observed, basic principles that allow their management and possible continuance and completion of the regimen should be followed.
Heat shock proteins (HSP) play an essential role as molecular chaperones by assisting correct hol... more Heat shock proteins (HSP) play an essential role as molecular chaperones by assisting correct holding and folding in human cells. At the same time they present implications in tumor cell proliferation, differentiation, matrix invasion, angiogenesis, metastasis and cell death. They also possess the ability to present tumor molecules to the immune system and elicit an immune response. New agents targeting HSP, as anticancer treatment, are under clinical evaluation. The aim of this review is to explore the role of HSP90 inhibitors as anticancer agents as well as to evaluate the benefit from the use of autologous HSP vaccines in both the adjuvant setting and first-line treatment. The latest evidence regarding the use of geldanamycin analogues or newer water-soluble and synthetics molecules that inhibit the binding of HSP90 to client proteins was reviewed. Immunization using tumor-derived HSP in several cancer types was also evaluated. HSP90 inhibitors represent a promising therapeutic option although further evaluation in larger clinical trials is needed. On the other hand, HSP vaccination has already an established role in our armory against cancer.
Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the ... more Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-κB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.
Autoimmunity can be associated with cancer and one of the forms of its expression is the developm... more Autoimmunity can be associated with cancer and one of the forms of its expression is the development of antibodies to autologous cellular antigens. The types of cellular proteins which induce autoantibody responses in gastrointestinal malignancies are quite varied and include cellular proteins encoded by mutated normal genes (p53), cellular proteins that are overexpressed and/or aberrantly expressed in malignant tissues (carcinoembryonic antigen), inhibitors of apoptosis (survivin and livin), major components of mucus (mucins), surface receptors of apoptosis (Fas) and nuclear-restricted proteins (double-stranded DNA, single-stranded DNA and Sm family proteins). In the past few years, due to the great clinical interest and the advancement in detection techniques, the above list has grown significantly and a large number of cancer-related antigens, which trigger a specific humoral immune response to the host, have also been identified. The authors review the autoantibodies associated with gastrointestinal malignancies and their clinical implications.
The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and ... more The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.
Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, app... more Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, approved as first line treatment concurrently administrated with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer. One of the most common side effects, rash, is possibly linked to overall and progression-free survival and may serve as a potential surrogate marker. Nevertheless, erlotinib-induced rash is cause of negative impact on patients' quality of life and often can trigger discontinuation of treatment. Adequate and timely management of rash depending on the grade of rash is important for therapy continuation.
Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is c... more Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is considered to be uncommon, it is difficult to evaluate their exact prevalence, mainly because their definition is vast and pathogenic mechanisms are vague. HSR include facial flushing, erythema, pruritus, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Treatment and prevention consists of slowing the infusion rate, steroids, and type 1 and 2 histamine receptor antagonists. Desensitization could allow the small number of patients who experience severe HSR to receive effective therapy for their cancer. Reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitization strategies is still missing. With regard to oxaliplatin, knowledge of its rare but eminent toxicity is paramount, because this drug is widely used in treating colorectal cancer, the second-highest cause of cancer mortality in the United States.
Autoimmunity can be associated with cancer and one of the forms of its expression is the developm... more Autoimmunity can be associated with cancer and one of the forms of its expression is the development of antibodies to autologous cellular antigens. The types of cellular proteins which induce autoantibody responses in gastrointestinal malignancies are quite varied and include cellular proteins encoded by mutated normal genes (p53), cellular proteins that are overexpressed and/or aberrantly expressed in malignant tissues (carcinoembryonic antigen), inhibitors of apoptosis (survivin and livin), major components of mucus (mucins), surface receptors of apoptosis (Fas) and nuclear-restricted proteins (double-stranded DNA, single-stranded DNA and Sm family proteins). In the past few years, due to the great clinical interest and the advancement in detection techniques, the above list has grown significantly and a large number of cancer-related antigens, which trigger a specific humoral immune response to the host, have also been identified. The authors review the autoantibodies associated with gastrointestinal malignancies and their clinical implications.
The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and ... more The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.
Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, app... more Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, approved as first line treatment concurrently administrated with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer. One of the most common side effects, rash, is possibly linked to overall and progression-free survival and may serve as a potential surrogate marker. Nevertheless, erlotinib-induced rash is cause of negative impact on patients' quality of life and often can trigger discontinuation of treatment. Adequate and timely management of rash depending on the grade of rash is important for therapy continuation.
Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is c... more Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is considered to be uncommon, it is difficult to evaluate their exact prevalence, mainly because their definition is vast and pathogenic mechanisms are vague. HSR include facial flushing, erythema, pruritus, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Treatment and prevention consists of slowing the infusion rate, steroids, and type 1 and 2 histamine receptor antagonists. Desensitization could allow the small number of patients who experience severe HSR to receive effective therapy for their cancer. Reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitization strategies is still missing. With regard to oxaliplatin, knowledge of its rare but eminent toxicity is paramount, because this drug is widely used in treating colorectal cancer, the second-highest cause of cancer mortality in the United States.
The diagnosis of pancreatic cancer is devastating for patients and their relatives as the inciden... more The diagnosis of pancreatic cancer is devastating for patients and their relatives as the incidence rate is approximately the same as mortality rate. Only a small percentage, which ranges from 0.4% to 4% of patients who have been given this diagnosis, will be alive at five years. At the time of diagnosis, 80% of pancreatic cancer patients have unresectable or metastatic disease. Moreover, the therapeutic alternatives offered by chemotherapy or radiotherapy are few, if not zero. For all these reasons, there is an imperative need of analyzing and understanding the primitive lesions that lead to invasive pancreatic adenocarcinoma. Molecular pathology of these lesions is the key of our understanding of the mechanisms underlying the development of this cancer and will probably help us in earlier diagnosis and better therapeutic results. This review focuses on medical research on pancreatic cancer models and the underlying genetic alterations.
S-1 is an oral fluoropyrimidine that is designed to improve the antitumor activity of 5-fluoroura... more S-1 is an oral fluoropyrimidine that is designed to improve the antitumor activity of 5-fluorouracil (5-FU) concomitantly with an intent to reduce its toxicity. S-1 consists of tegafur, a prodrug of 5-FU combined with two 5-FU biochemical modulators:5-chloro-2,4-dihydroxypyridine (gimeracil or CDHP), a competitive inhibitor of dihydropyrimidine dehydrogenase and oteracil potassium which inhibits phosphorylation of 5-FU in the gastrointestinal tract decreasing serious gastrointestinal toxicities,including nausea, vomiting, stomatitis and diarrhea. Being an oral agent, S-1 offers convenience of administration and prevents complications of central venous access such as infection, thrombosis and bleeding. S-1 has shown efficacy in both gastrointestinal as well non-gastrointestinal malignancies. The authors review the current literature and provide their expert opinion on the incorporation of S-1 in the treatment of solid malignancies [corrected].
Hypersensitivity reactions to antineoplastic agents are defined as unexpected reactions with sign... more Hypersensitivity reactions to antineoplastic agents are defined as unexpected reactions with signs and symptoms inconsistent with known toxicity of antineoplastic drugs. These reactions are uncommon and usually associated with certain antineoplastic categories, such as taxanes, platinum-containing compounds, epipodofyllotoxins, asparaginase, procarbazine and, more rarely, with doxorubicin and 6-mercaptopurine. The mechanisms that are responsible for hypersensitivity reactions are unclear and vary between agents. Symptoms of these reactions range from mild skin rashes to more severe reactions, such as arthralgia, respiratory arrest or even death in some cases. Once hypersensitivity reactions are observed, basic principles that allow their management and possible continuance and completion of the regimen should be followed.
Heat shock proteins (HSP) play an essential role as molecular chaperones by assisting correct hol... more Heat shock proteins (HSP) play an essential role as molecular chaperones by assisting correct holding and folding in human cells. At the same time they present implications in tumor cell proliferation, differentiation, matrix invasion, angiogenesis, metastasis and cell death. They also possess the ability to present tumor molecules to the immune system and elicit an immune response. New agents targeting HSP, as anticancer treatment, are under clinical evaluation. The aim of this review is to explore the role of HSP90 inhibitors as anticancer agents as well as to evaluate the benefit from the use of autologous HSP vaccines in both the adjuvant setting and first-line treatment. The latest evidence regarding the use of geldanamycin analogues or newer water-soluble and synthetics molecules that inhibit the binding of HSP90 to client proteins was reviewed. Immunization using tumor-derived HSP in several cancer types was also evaluated. HSP90 inhibitors represent a promising therapeutic option although further evaluation in larger clinical trials is needed. On the other hand, HSP vaccination has already an established role in our armory against cancer.
Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the ... more Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-κB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.
Autoimmunity can be associated with cancer and one of the forms of its expression is the developm... more Autoimmunity can be associated with cancer and one of the forms of its expression is the development of antibodies to autologous cellular antigens. The types of cellular proteins which induce autoantibody responses in gastrointestinal malignancies are quite varied and include cellular proteins encoded by mutated normal genes (p53), cellular proteins that are overexpressed and/or aberrantly expressed in malignant tissues (carcinoembryonic antigen), inhibitors of apoptosis (survivin and livin), major components of mucus (mucins), surface receptors of apoptosis (Fas) and nuclear-restricted proteins (double-stranded DNA, single-stranded DNA and Sm family proteins). In the past few years, due to the great clinical interest and the advancement in detection techniques, the above list has grown significantly and a large number of cancer-related antigens, which trigger a specific humoral immune response to the host, have also been identified. The authors review the autoantibodies associated with gastrointestinal malignancies and their clinical implications.
The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and ... more The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.
Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, app... more Erlotinib is a tyrosine kinase inhibitor with anti epidermal growth factor receptor activity, approved as first line treatment concurrently administrated with gemcitabine for locally advanced unresectable or metastatic pancreatic cancer. One of the most common side effects, rash, is possibly linked to overall and progression-free survival and may serve as a potential surrogate marker. Nevertheless, erlotinib-induced rash is cause of negative impact on patients' quality of life and often can trigger discontinuation of treatment. Adequate and timely management of rash depending on the grade of rash is important for therapy continuation.
Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is c... more Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is considered to be uncommon, it is difficult to evaluate their exact prevalence, mainly because their definition is vast and pathogenic mechanisms are vague. HSR include facial flushing, erythema, pruritus, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Treatment and prevention consists of slowing the infusion rate, steroids, and type 1 and 2 histamine receptor antagonists. Desensitization could allow the small number of patients who experience severe HSR to receive effective therapy for their cancer. Reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitization strategies is still missing. With regard to oxaliplatin, knowledge of its rare but eminent toxicity is paramount, because this drug is widely used in treating colorectal cancer, the second-highest cause of cancer mortality in the United States.
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