Showing papers in "Critical Reviews in Oncology Hematology in 2005"

Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG).

Abstract: Background: As more and more cancers occur in elderly people, oncologists are increasingly confronted with the necessity of integrating geriatric parameters in the treatment of their patients. Methods: The International Society of Geriatric Oncology (SIOG) created a task force to review the evidence on the use of a comprehensive geriatric assessment (CGA) in cancer patients. A systematic review of the evidence was conducted. Results: Several biological and clinical correlates of aging have been identified. Their relative weight and clinical usefulness is still poorly defined. There is strong evidence that a CGA detects many problems missed by a regular assessment in general geriatric and in cancer patients. There is also strong evidence that a CGA improves function and reduces hospitalization in the elderly. There is heterogeneous evidence that it improves survival and that it is cost-effective. There is corroborative evidence from a few studies conducted in cancer patients. Screening tools exist and were successfully used in settings such as the emergency room, but globally were poorly tested. The article contains recommendations for the use of CGA in research and clinical care for older cancer patients. Conclusions: A CGA, with or without screening, and with follow-up, should be used in older cancer patients, in order to detect unaddressed problems, improve their functional status, and possibly their survival. The task force cannot recommend any specific tool or approach above others at this point and general geriatric experience should be used.

Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation.

Abstract: Post-transplant lymphoproliferative disorders (PTLD) are a well-recognised and potentially fatal complication after solid organ transplantation. They include a spectrum of disorders ranging from benign hyperplasia to invasive malignant lymphoma. The majority of cases are associated with Epstein Barr virus (EBV)-driven tumour formation in B cells and are a consequence of the detrimental effect of immunosuppressive agents on the immune-control of EBV. This review provides an update on the pathogenesis and clinical features of PTLD after solid organ transplantation and discusses recent progress in management. Reduction in immunosuppressive therapy remains a key component of therapy for EBV-positive PTLD and may lead to remission in early disease. Chemotherapy is used when reduced immunosuppression fails to control early disease and as initial therapy for many cases of late disease. Unfortunately, the mortality for PTLD that fails to respond to a reduction in immunosuppression remains high. Newer treatments include manipulation of the cytokine environment, B lymphocyte depleting antibodies and adoptive T cell immunotherapy using allogeneic or autologous EBV-specific cytotoxic T lymphocytes. Although early results appear promising, well-designed clinical trials are needed to assess the efficacy of these novel approaches. EBV vaccination may in the future prove an effective prophylaxis against EBV-driven PTLD but until then, avoiding excessive immunosuppressive therapy may help minimise the risk of PTLD.

Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy.

Abstract: Effective immunosuppression is an essential pre-requisite for successful organ transplantation and improvements in outcome after transplantation have to a large extent been dependent on developments in immunosuppressive therapy. Here we provide an overview of the different immunosuppressive agents currently used in solid organ transplantation. A historical perspective on the development of immunosuppression for organ transplantation is followed by a review of the individual agents, with a focus on their mechanism of action and efficacy. Steroids, anti-proliferative agents (azathioprine and mycophenolate), calcineurin inhibitors (cyclosporine and tacrolimus) and TOR inhibitors (sirolimus and everolimus) are discussed along with both polyclonal and monoclonal antibody preparations. Many of the key clinical trials that underpin current clinical usage of these agents are described and side-effects of the different agents are highlighted. Finally, a number of newer agents still in various stages of clinical development are briefly considered.

Recognition and processing of cisplatin- and oxaliplatin-DNA adducts

Abstract: The cytotoxicity of platinum compounds is thought to be determined primarily by their DNA adducts. Cisplatin and oxaliplatin are structurally distinct, but form the same types of adducts at the same sites on DNA. However, the DNA adducts are differentially recognized by a number of cellular proteins. For example, mismatch repair proteins and some damage-recognition proteins bind to cisplatin–GG adducts with higher affinity than to oxaliplatin–GG adducts, and this differential recognition of cisplatin- and oxaliplatin–GG adducts is thought to contribute to the differences in cytotoxicity and tumor range of cisplatin and oxaliplatin. A detailed kinetic analysis of the insertion and extension steps of dNTP incorporation in the vicinity of the adduct shows that both DNA polymerase β (pol β) and DNA polymerase η (pol η) catalyze translesion synthesis past oxaliplatin–GG adducts with greater efficiency than past cisplatin–GG adducts. In the case of pol η, the efficiency and fidelity of translesion synthesis in vitro is very similar to that previously observed with cyclobutane TT dimers, suggesting that pol η is likely to be involved in error-free bypass of Pt adducts in vivo. This has been confirmed for cisplatin by comparing the cisplatin-induced mutation frequency in human fibroblast cell lines with and without pol η. Thus, the greater efficiency of bypass of oxaliplatin–GG adducts by pol η may explain the lower mutagenicity of oxaliplatin compared to cisplatin. The ability of these cellular proteins to discriminate between cisplatin and oxaliplatin adducts suggest that there exist significant conformational differences between the adducts, yet the crystal structures of the cisplatin- and oxaliplatin–GG adducts were very similar. We have recently solved the solution structure of the oxaliplatin–GG adduct and have shown that it is significantly different from the previously published solution structures of the cisplatin–GG adducts. Furthermore, the observed differences in conformation provide a logical explanation for the differential recognition of cisplatin and oxaliplatin adducts by mismatch repair and damage-recognition proteins.

Prognostic impact of increasing age and co-morbidity in cancer patients: A population-based approach

Abstract: This large population-based study focuses on the prognostic role of increasing age and co-morbidity in cancer patients diagnosed in the southern Netherlands. Data of patients diagnosed between 1995 and 2002 and recorded in the population-based Eindhoven Cancer Registry were used. Older patients (with serious co-morbidity) with non-small cell lung cancer or prostate cancer underwent surgery less often than younger patients. Elderly with stage III colon cancer, small cell lung cancer, FIGO II or III ovarian cancer or non-Hodgkin's lymphoma (NHL) received (adjuvant) chemotherapy less often, probably because of the higher rate of haematological complications. Administration of adjuvant radiotherapy decreased with age and co-morbidity in patients with rectal cancer, limited small cell lung cancer or breast cancer. In general, elderly did not suffer from more complications than younger patients, except for cardiac complications (colorectal cancer and NHL) and postoperative death (non-small cell lung cancer). For most tumours relative survival was lower for the elderly, except for patients with colon cancer, prostate cancer or indolent NHL. Co-morbidity had an independent prognostic effect, except for tumours with a very poor prognosis. Future prospective studies should investigate whether the guidelines for cancer treatment should be adjusted for elderly with serious co-morbidity.

Hepatocyte growth factor, its receptor, and their potential value in cancer therapies

Abstract: Hepatocyte growth factor plays multiple roles in cancer, by acting as a motility and invasion stimulating factor, promoting metastasis and tumour growth. Furthermore, it acts as a powerful angiogenic factor. The pivotal role of this factor in cancer has indicated HGF as being a potential target in cancer therapies. The past few years have seen rapid progress in developing tools in targeting HGF, in the context of cancer therapies, including development of antagonists, small compounds, antibodies and genetic approaches. The current article discusses the potential value of HGF and its receptor as targets in cancer therapies, the current development in anti-HGF research, and the clinical value of HGF in prognosis and treatment.

Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs.

Abstract: Recent studies have demonstrated that the major Cu influx transporter CTR1 regulates tumor cell uptake of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP), and that the two Cu efflux transporters ATP7A and ATP7B regulate the efflux of these drugs. Evidence for the concept that these platinum (Pt) drugs enter cells and are distributed to various subcellular compartments via transporters that have evolved to manage Cu homeostasis includes the demonstration of: (1) bidirectional cross-resistance between cells selected for resistance to either the Pt drugs or Cu; (2) parallel changes in the transport of Pt and Cu drugs in resistant cells; (3) altered cytotoxic sensitivity and Pt drug accumulation in cells transfected with Cu transporters; and (4) altered expression of Cu transporters in Pt drug-resistant tumors. Appreciation of the role of the Cu transporters in the development of resistance to DDP, CBDCA, and L-OHP offers novel insights into strategies for preventing or reversing resistance to this very important family of anticancer drugs.

Rapamycin: an anti-cancer immunosuppressant?

Abstract: Rapamycin and its derivatives are promising therapeutic agents with both immunosuppressant and anti-tumor properties. These rapamycin actions are mediated through the specific inhibition of the mTOR protein kinase. mTOR serves as part of an evolutionarily conserved signaling pathway that controls the cell cycle in response to changing nutrient levels. The mTOR signaling network contains a number of tumor suppressor genes including PTEN, LKB1, TSC1, and TSC2, and a number of proto-oncogenes including PI3K, Akt, and eIF4E, and mTOR signaling is constitutively activated in many tumor types. These observations point to mTOR as an ideal target for anti-cancer agents and suggest that rapamycin is such an agent. In fact, early preclinical and clinical studies indicate that rapamycin derivatives have efficacy as anti-tumor agents both alone, and when combined with other modes of therapy. Rapamycin appears to inhibit tumor growth by halting tumor cell proliferation, inducing tumor cell apoptosis, and suppressing tumor angiogenesis. Rapamycin immunosuppressant actions result from the inhibition of T and B cell proliferation through the same mechanisms that rapamycin blocks cancer cell proliferation. Therefore, one might think that rapamycin-induced immunosuppression would be detrimental to the use of rapamycin as an anti-cancer agent. To the contrary, rapamycin decreases the frequency of tumor formation that occurs in organ transplant experiments when combined with the widely used immunosuppressant cyclosporine compared with the tumor incidence observed when cyclosporine is used alone. The available evidence indicates that with respect to tumor growth, rapamycin anti-cancer activities are dominant over rapamycin immunosuppressant effects.

Overview of monoclonal antibodies in cancer therapy: present and promise

Abstract: After 30 years of development, therapy with monoclonal antibodies has started to realize its promise. Clinical use is most widespread in the field of oncology, where half of the agents approved for routine clinical use are employed and a large number of molecules are currently undergoing clinical trials. In the past 2 years alone, three new compounds-the radiolabeled antibody (131)I-tositumomab and two antibodies targeting growth factor receptors (bevacizumab and cetuximab)-have received FDA approval for indications in oncology. This review summarizes the development of this exciting treatment modality over the last three decades, examines the outcome of treatment with these new antibodies and others available for routine clinical use (i.e. rituximab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, (90)Y-ibritumomab tiuxetan) in standard indications and in experimental settings, and gives a brief outlook on possible future developments.

Management of bone metastases in cancer: A review

Abstract: The presence of bone metastases is indicative of disseminated disease and typically indicates a short-term prognosis in cancer patients. Palliation of symptoms is the primary goal of therapy, with multidisciplinary efforts yielding the best results. New classes of drugs, such as bisphosphonates that significantly increase the time to first skeletal-related event (SRE), represent useful tools for the treatment of bone metastases. While the optimal duration of therapy needs to be defined, there is clinical benefit derived from the use of this class of agents. A potential role for bisphosphonates in the prevention of bone metastases is under current evaluation in clinical trials encompassing different solid tumor types. In combination with ongoing clinical trials, basic research to identify potential novel targets in the tumor cells-bone microenvironment will further define future strategies in the treatment of bone metastases.

Primary non-Hodgkin's lymphoma of the liver.

Abstract: We review the literature on primary hepatic lymphoma (PHL). PHL is a rare malignancy, and constitutes about 0.016% of all cases of non-Hodgkin's lymphoma. It has been reported to occur with increased frequency in patients with chronic hepatitis C infection. Most patients with PHL present with abdominal pain, constitutional symptoms and have hepatomegaly on examination. Imaging studies reveal solitary, or less often, multiple masses in the liver. The predominant histology is B-cell lymphoma, most commonly diffuse large cell type. Most patients are treated with chemotherapy, with some physicians employing a multimodality approach incorporating surgery and radiotherapy with chemotherapy. The prognosis is variable, with good response to early aggressive combination chemotherapy.

Cancer of unknown primary (CUP).

Abstract: Carcinoma of unknown primary (CUP) is one of the 10 most frequent cancers worldwide. It constitutes 3-5% of all human malignancies. Patients with CUP present with metastases without an established primary site. CUP manifests as an heterogenous group of mainly epithelial cancers recognised by distinct clinicopathological entities. The diagnostic work-up includes extensive histopathology investigations and modern imaging technology. Nevertheless, the primary tumour remains undetected most of the time. Certain clinicopathological CUP entities are considered as favourable subsets responding to systemic platinum-based chemotherapy or managed by locoregional treatment. These subsets are: the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, peritoneal papillary serous adenocarcinomatosis in females, poorly differentiated neuroendocrine carcinomas, isolated axillary node adenocarcinomas in females or cervical nodal involvement by a squamous cell carcinoma. Patients who belong to the non-favourable subsets have a worse prognosis.

Drug–drug interactions in oncology: Why are they important and can they be minimized?

Abstract: Adverse drug-drug interactions are a major cause of morbidity and mortality. Cancer patients are at particularly high risk of such interactions because they commonly receive multiple medications, including cytotoxic chemotherapy, hormonal agents and supportive care drugs. In addition, the majority of cancer patients are elderly, and so require medications for co-morbid conditions such as cardiovascular, gastrointestinal, and rheumatological diseases. Furthermore, the age-related decline in hepatic and renal function reduces their ability to metabolize and clear drugs and so increases the potential for toxicity. Not all drug-drug interactions can be predicted, and those that are predictable are not always avoidable. However, increased awareness of the potential for these interactions will allow healthcare providers to minimize the risk by choosing appropriate drugs and also by monitoring for signs of interaction. This review considers the basic principles of drug-drug interactions, and presents specific examples that are relevant to oncology.

Cancer incidence after immunosuppressive treatment following kidney transplantation.

Abstract: Cancer incidence is increased in renal transplant recipients due to immunosuppressant treatment that should be maintained to prevent and treat acute rejection. Use of new and very potent immunosuppressants has made it possible to reduce acute rejection incidence and improve renal graft survival, although increase of infections and post-transplant neoplasms have become clearer. On the other hand, renal transplant candidates who remain on dialysis have a greater prevalence of neoplasms than the age-matched general population, either because the neoplasm was the cause of their renal failure (multiple myeloma or kidney or urinary tract cancers) or because their renal disease entails a risk for cancer development (acquired cystic disease or analgesic nephropathy). Practically, all de novo neoplasms have a greater incidence in renal transplant patients. Cutaneous neoplasms are the most prevalent in renal transplant recipients and their incidence increases with transplant time. Post-transplant lymphoproliferative diseases are more frequent in patients who receive greater immunosuppression (antithymocyte/antilymphocyte globulin or OKT3) or are infected de novo by Epstein Barr Virus (EBV) through the transplanted kidney. Kaposi's sarcoma has a high incidence in the renal transplanted population, does not appear in the general population, and is related with Human Herpes Virus 8 (HHV-8) infections. The incidence of tumors in non-functioning native kidneys is especially high in renal transplant due to the presence of acquired cystic disease or analgesic nephropathy. Gold standards of post-transplant de novo renal neoplasm prevention are modulating immunosuppression and avoiding exposure to sunlight and to different oncogenic viruses (EBV, cytomegalovirus, hepatitis B and C viruses).

Role of c-Kit and erythropoietin receptor in erythropoiesis

Abstract: Erythropoiesis is regulated by a number of growth factors, among which stem cell factor (SCF) and erythropoietin (Epo) play a non-redundant function. Viable mice with mutations in the SCF gene (encoded by the Steel (Sl) locus), or its receptor gene c-Kit (encoded by the White spotting (W) locus) develop a hypoplastic macrocytic anemia. Mutants of W or Sl that are completely devoid of c-Kit or SCF expression die in utero of anemia between days 14 and 16 of gestation and contain reduced numbers of erythroid progenitors in the fetal liver. Likewise, Epo and Epo receptor (Epo-R)-deficient mice die in utero due to a marked reduction in the number of committed fetal liver derived erythroid progenitors. Thus, committed erythroid progenitors require both c-Kit and Epo-R signal transduction pathways for their survival, proliferation and differentiation. In vitro, Epo alone is capable of generating mature erythroid progenitors; however, a combined treatment of Epo and SCF results in synergistic proliferation and expansion of developing erythroid progenitors. This review summarizes recent advances made towards understanding the signaling mechanisms by which Epo-R and c-Kit regulate growth, survival, and differentiation of erythroid progenitors alone and cooperatively.

Monitoring of minimal residual disease in acute myeloid leukemia

Abstract: Monitoring minimal residual disease (MRD) becomes increasingly important in the risk-adapted management of patients with acute myeloid leukemia (AML). The two most sensitive and quantitative methods for MRD detection are multiparameter flow cytometry (MFC) and real-time polymerase chain reaction (QRT-PCR). Fusion gene-specific PCR in AML is based on the RNA level, and thus in contrast to MFC expression levels rather than cell counts are assessed. For both methods independent prognostic values have been shown. The strong power of MFC has been shown mainly in the assessment of early clearance of the malignant clone. MRD levels in AML with fusion genes have the strongest prognostic power after the end of consolidation therapy. In addition, with QRT-PCR highly predictive initial expression levels can be assessed. With both methods early detection of relapse is possible. So far, validated PCR-based MRD was done with fusion genes that are detectable in only 20-25% of all AML MFC is superior since it is applicable for most AML. However, QRT-PCR is still more sensitive in most cases. Thus, it is desirable to establish new molecular markers for PCR-based studies. Large clinical trials will determine the role and place of immunologic and PCR-based monitoring in the prognostic stratification of patients with AML.

The abbreviated comprehensive geriatric assessment (aCGA): a retrospective analysis

Abstract: Background: A comprehensive geriatric assessment (CGA) is a multidimensional assessment that is designed to detect health problems. A barrier to conducting the CGA is the length of time required to complete the entire assessment. Objective: To understand what items contained in the instruments that make up the CGA could be compiled to construct an abbreviated CGA (aCGA). Design/setting: A retrospective chart review of patients at the H. Lee Moffitt Cancer Center. Participants: Over 500 charts between 1995 and 2001 were reviewed on patients 70 and over. Measurements: Item-to-total correlations and Cronbach's α coefficient were calculated. Construct validity was assessed using a Pearson's product moment correlation coefficient. Results: Fifteen items were compiled to form the aCGA. Cronbach's α was 0.65–0.92 on each instrument of the entire CGA compared to 0.70–0.94 on the aCGA. Correlations ranged from 0.84 to 0.96 for the entire CGA and the aCGA. Conclusion: An aCGA can be helpful in screening for those seniors who would benefit from the entire CGA.

Molecular mechanisms of tumor vascularization.

Abstract: Tumor angiogenesis is a fast growing sub-domain of angiogenesis research and tumor biology. Basic mechanisms have been unraveled and many key players identified. For many years, tumor vascularization was explained solely by the ingrowth of new vessels into the tumor from preexisting one's. However, in recent years, additional mechanisms have been recognized. These include angioblasts recruitment, cooption, vasculogenic mimicry and mosaic vessels. These different mechanisms may exist concomitantly in the same tumor or may be selectively involved in a specific tumor type or host environment. In this article, we will review, in depth, these different mechanisms and also discuss some aspects of anti-angiogenic tumor therapy.

Multi-dysfunctional pathophysiology in ITP.

Abstract: Idiopathic thrombocytopenic purpura (ITP) is an organ-specific autoimmune disorder characterized by a low platelet count and mucocutaneous bleeding. The decrease of platelets is caused by increased autoantibodies against self-antigens, particularly IgG antibodies against GPIIb/IIIa. The production of these autoantibodies by B cells depends on a number of cellular mechanisms that form a network of modulation, with T cells playing a pivotal role in pathophysiology. Delineation of the dysfunction of cellular immunity has recently been attempted. This review will focus on these recent advances applicable to ITP and to highlight how these may translate into novel approaches to treatment in the future. Multi-dysfunction in these networks may include a failure of self-antigen recognition and tolerance, involvement of abnormal cell surface molecules, altered Th1/Th2 cytokine profiles, impaired megakaryocytopoiesis and impaired cell-mediated cytotoxicity. In ITP, multi-step dysfunctions in these networks may take place that finally lead to the occurrence of the disease. Therefore, unveiling these dysfunctions is vital in understanding the pathophysiology of ITP and will finally lead to the development of new therapies to fight the disease.

Skin cancer and immunosuppression.

Abstract: All immunosuppressive treatments, either pharmacological or physical, have the potential to impair the skin immune system network of cells and cytokines, thus leading to an increased incidence of skin cancer. Since skin cancer in transplant recipients may show uncommon clinical features and have an unusually aggressive course, transplant patients should be strictly followed up by experienced dermatologists in order to diagnose and treat properly any skin cancer in an early phase. Importantly, due to the fact that sun exposure increases immunosuppression in the skin, patients should be clearly informed about the additional risk of sun exposure and the preventive measures to be taken.

Predicting drug response and toxicity based on gene polymorphisms.

Abstract: The sequencing of the human genome has allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphims (SNP), which may play an important role in the expression level and activity of the corresponding proteins. When these polymorphisms occur at the level of drug metabolising enzymes or transporters, the disposition of the drug may be altered and, consequently, its efficacy may be compromised or its toxicity enhanced. Polymorphisms can also occur at the level of proteins directly involved in drug action, either when the protein is the target of the drug or when the protein is involved in the repair of drug-induced lesions. There again, these polymorphisms may lead to alterations in drug efficacy and/or toxicity. The identification of functional polymorphisms in patients undergoing chemotherapy may help the clinician prescribe the optimal drug combination or schedule and predict with more accuracy the response to these prescriptions. We have recorded in this review the polymorphisms that have been identified up till now in genes involved in anticancer drug activity. Some of them appear especially important in predicting drug toxicity and should be determined in routine before drug administration; this is the case of the most common variations of thiopurine methyltransferase for 6-mercaptopurine and of dihydropyrimidine dehydrogenase for fluorouracil. Other appear determinant for drug response, such as the common SNPs found in glutathione S-transferase P1 or xereoderma pigmentosum group D enzyme for the activity of oxaliplatin. However, confusion factors may exist between the role of gene polymorphisms in cancer risk or overall prognosis and their role in drug response.

Telomerase: regulation, function and transformation.

Abstract: Work from several laboratories over the past decade indicates that the acquisition of constitutive telomerase expression is a critical step during the malignant transformation of human cells. Normal human cells transiently express low levels of telomerase, the ribonucleoprotein responsible for extending and maintaining telomeres, and exhibit telomere shortening after extended passage, whereas most cancers exhibit constitutive telomerase expression and maintain telomeres at stable lengths. These observations establish a direct connection between immortalization and stabilization of telomere structure. However, recent work suggests that telomerase also contributes to cancer development beyond its role in maintaining stable telomere lengths. In this review, we summarize recent observations that support the concept that telomerase plays multiple roles in facilitating human cell transformation.

Cancer of the prostate.

Abstract: Prostate carcinoma, with about 190,000 new cases occurring each year (15% of all cancers in men), is the most frequent cancer among men in northern and western Europe. Causes of the disease are essentially unknown, although hormonal factors are involved, and diet may exert an indirect influence; some genes, potentially involved in hereditary prostate cancer (HPC) have been identified. A suspect of prostate cancer may derive from elevated serum prostate-specific antigen (PSA) values and/or a suspicious digital rectal examination (DRE) finding. For a definitive diagnosis, however, a positive prostate biopsy is requested. Treatment strategy is defined according to initial PSA stage, and grade of the disease and age and general conditions of the patient. In localized disease, watchful waiting is indicated as primary option in patients with well or moderately differentiated tumours and a life expectancy

Cancer of the penis.

Abstract: Cancer of the penis is rare in Europe, accounting for less than 0.5% of all cancers. Phimosis and poor hygiene are strong risk factors whereas neonatal circumcision is a contributing factor in the prevention of this disease. More than 95% of penile carcinomas are squamous cell carcinomas. Early disease (stage I-II) is curable in most patients, who can be treated by conventional penile amputation or, in selected cases, by organ preserving techniques, including Moh's micrographic surgery, laser ablation or radiation therapy (external-beam, brachytherapy). For more advanced primary tumours, penile amputation is required. Survival of patients with penile cancer is strongly related to the presence and extent of nodal metastases. Bilateral inguinal lymphadenectomy is recommended for palpable lymph nodes that persist 3 or more weeks after removal of the primary tumour and a course of antibiotic therapy. In patients with proven inguinal lymph node metastases, bilateral ileoinguinal dissection should be performed. When the nodes are clinically negative, "prophylactic" inguinal lymphadenectomy may be a reasonable approach in patients with invasive tumours (T2 or greater), high grade tumours, or tumours exhibiting vascular invasion. The role of chemotherapy, as adjuvant and neoadjuvant or primary treatment in metastatic disease, needs to be further explored in prospective clinical trials.

Incidence and risk factors for cancer after liver transplantation

Abstract: De novo tumors (DNT) are a serious complication after orthotopic liver transplantation (OLT), showing a higher overall incidence ranging from 4.7% to 15.7% in non-selected series. Skin cancer (SC) is the most frequent malignancy observed, ranging from 6% to 70% of the tumors observed, followed by post-transplant lymphoproliferative disorders (PTLD) (4.3–30%). Different immunosuppressive protocols do not seem to influence DNT appearance. Colon and upper aerodigestive cancer after OLT seems to be more prone to develop when there are associated risk factors, such as primary sclerosing cholangitis (PSC) and alcoholic liver cirrhosis (ALC). Some risk factors, such as age, smoking, alcohol and others seem to play a role in higher risk for malignancy, but the presence of a long-term immunosuppressive state, more than the specific regimen used, is the basis for this higher incidence. Ethnic and demographic factors are also important variables influencing the heterogeneity of the results, especially influencing Kaposi's sarcoma and skin tumors.

Treatment concepts of acute promyelocytic leukemia

Abstract: In the past, acute promyelocytic leukemia (APL) was associated with a high risk of early mortality resulting from severe coagulopathy, frequently inducing fatal cerebral hemorrhage. With the introduction of the differentiating agent all-trans retinioc acid (ATRA) APL has changed to the best curable subtype of acute myeloid leukemia (AML). With ATRA and chemotherapy approximately 70-80% of patients with newly diagnosed APL achieve long-term remission and are probably cured. PML/RARalpha, the molecular fusion transcript of the specific translocation t(15;17) represents not only the target for ATRA but also permits a precise diagnosis and provides a marker for the identification of minimal residual or recurrent disease (MRD). During the last decade, substantial progress has been made with regard to the recognition of prognostic factors and the optimization of the combination of ATRA and chemotherapy. Remaining questions are the role of arsenic and of ara-C in first line therapy of APL as well as the indication of maintenance therapy in the individual patient. Several treatment options exist for patients with APL who have relapsed after ATRA and chemotherapy. Approximately 50% of the patients in first relapse can achieve long-lasting second remission and might be cured with salvage regimens. Currently, arsenic compounds and transplantation procedures seem to be the most promising options in relapsed disease. The role of CD33 antibodies has to be determined in future studies. Refining the molecular monitoring of MRD by quantitative RT-PCR, better elucidation of the biologic mechanisms, and the identification of prognostic factors might be helpful to make further progress in the treatment of APL.

Germ cell tumours of the testis

Abstract: Cancer of the testis is a relatively rare disease, accounting for about 1% of all cancers in men. Cryptorchidism is the only confirmed risk factor for testicular germ cell tumour. The majority of GCT are clinically detectable at initial presentation. Any nodular, hard, or fixed area discovered in the testis, must be considered neoplastic until proved otherwise. The appropriate surgical procedure to make the diagnosis is a radical orchidectomy through an inguinal incision. Many GCT produce tumoural markers (AFP, HCG, LDH), who are useful in the diagnosis and staging of disease; to monitor the therapeutic response and to detect tumour recurrence. In 1997 a prognostic factor-based classification for the metastatic germ cell tumours was developed by the IGCCCG: good, intermediate and poor prognosis, with 5-year survival of 91, 79 and 48%, respectively. GCT of the testis is a highly table, often curable, cancer. Germ cell testicular cancers are divided into seminoma and non-seminoma types for treatment planning because seminomatous testicular cancers are more sensitive to radiotherapy. Seminoma (all stages combined) has a cure rate of greater than 90%. For patients with low-stage disease, the cure approaches 100%. For patients with non-seminoma tumours, the cure rate is >95% in stages I and II; it is ∼70% with standard chemotherapy and resection of residual disease, if necessary, in stages III and IV. Minimum guidelines for clinical, biochemical, and radiological follow-up have been reported by ESMO in 2001.

Gene expression arrays in cancer research: methods and applications.

Abstract: During the last 5 years, the number of papers describing data obtained by microarray technology increased exponentially with about 3000 papers in 2003. Undoubtedly, cancer is by far the disease that received most of the attention as far as the amount of data generated. As array technology is rather new and highly dependent on bioinformatics, mathematics and statistics, a clear understanding of the knowledge and information derived from array-based experiments is not widely appreciated. We shall review herein some of the issues related to the construction of DNA arrays, quantities and heterogeneity of probes and targets, the consequences of the physical characteristics of the probes, data extraction and data analysis as well as the applications of array technology. Our goal is to bring to the general audience, some of the basics of array technology and its possible application in oncology. By discussing some of the basic aspects of the methodology, we hope to stimulate criticism concerning the conclusions proposed by authors, especially in the light of the very low degree of reproducibility already proven when commercially available platforms were compared . Regardless of its pitfalls, it is unquestionable that array technology will have a great impact in the management of cancer and its applications will range from the discovery of new drug targets, new molecular tools for diagnosis and prognosis as well as for a tailored treatment that will take into account the molecular determinants of a given tumor. Hence, we shall also highlight some of the already available and promising applications of array technology on the day-to-day practice of oncology.

Coping and psychological well being in families of elderly cancer patients

Abstract: This article reviews research directions on elderly cancer patients and the consequences of their disease for their partners and families. In a systematic review of the research literature, five research directions were identified: first, the relationship between the family and the etiology of the disease; second, the importance of the family as a source of social support; third, family caregivers as second order patients and the moderating role of psychological factors; fourth, cancer as a challenge for the family and fifth, ways of providing social and psychological support for the families of patients including examples for intervention programs. It is shown that the assumption of a "psychogenic" etiology may inhibit adaptive processes. Depending on its quality, social support can trigger adaptive coping in the patients. Elderly patients seem to be ambivalent in their attitudes towards social support because they may feel hindered with respect to their autonomy. Distress among family members is sometimes very similar to the distress experienced by patients. Several studies have shown that distress is differentially influenced by disease-related, personal and interpersonal factors as well as social resources. Interpersonal factors seem to have a specific impact on the adaptive capacities of patients and their family members. Open communication, a "healthy" family cohesion and adaptive competence seem to positively influence patients' coping. Support programs which actively include family members seem to be effective in reducing the distress of patients and their relatives. Some conclusions will be drawn including a discussion of future research directions.

The molecular pathogenesis of acute myeloid leukemia

Abstract: The description of the molecular pathogenesis of acute myeloid leukemias (AML) has seen dramatic progress over the last years. Two major types of genetic events have been described that are crucial for leukemic transformation: alterations in myeloid transcription factors governing hematopoietic differentiation and activating mutations of signal transduction intermediates. These processes are highly interdependent, since the molecular events changing the transcriptional control in hematopoietic progenitor cells modify the composition of signal transduction molecules available for growth factor receptors, while the activating mutations in signal transduction molecules induce alterations in the activity and expression of several transcription factors that are crucial for normal myeloid differentiation. The purpose of this article is to review the current literature describing these genetic events, their biological consequences and their clinical implications. As the article will show, the recent description of several critical transforming mutations in AML may soon give rise to more efficient and less toxic molecularly targeted therapies of this deadly disease.