Showing papers in "Clinical & Translational Oncology in 2007"

Natural products as leads to anticancer drugs.

Abstract: Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as “lead” compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

Molecular biology of neuroblastoma

Abstract: Neuroblastoma is one of the most frequently occurring solid tumours in children, especially in the first year of life, when it accounts for 50% of all tumours. It is the second most common cause of death in children, only preceded by accidents. The most peculiar characteristic of neuroblastoma is its clinical heterogeneity. Approximately half of the cases are classified as high risk, with overall survival rates around 40% despite intensive multimodal therapy. Nevertheless, other subsets of neuroblastomas will undergo spontaneous regression and others will show very slow progression. Despite many advances in the past three decades, neuroblastoma has remained an enigmatic challenge to clinical and basic scientists. Elucidation of the exact molecular pathways of neuroblastoma will enable researchers and clinicians to stratify the disease and adapt therapy to the risk of relapse or progression. This review focuses on recent advances in our understanding of the biology of this complex paediatric tumour. Neuroblastoma is already one of the first examples for the use of tumoral genetic markers as a tool for defining tumour behaviour and to aid clinical staging.

Oxycodone: a pharmacological and clinical review

Abstract: Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma half-life is 3–5 h (half that of morphine) and stable plasma levels are reached within 24 h (2–7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone — which is also a very potent analgesic — and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5–2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3–4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin®) is marketed as 10-, 20-, 40-or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm®) is also available in capsules and oral solution. Side effects are those common to opioids: mainly nausea, constipation and drowsiness. Vomiting, pruritus and dizziness are less common. The intensity of these side effects tends to decrease over the course of time. Oxycodone causes somewhat less nausea, hallucinations and pruritus than morphine.

Yeast on drugs: Saccharomyces cerevisiae as a tool for anticancer drug research.

Abstract: The budding yeast Saccharomyces cerevisiae is being widely used as a model for investigating fundamental processes relevant to all living organisms. Many of these processes are affected by genetic and epigenetic alterations in cancer such as cell cycle progression, DNA replication and segregation, maintenance of genomic integrity and stress responses. Therefore, yeast emerges as an attractive model for anticancer drug research. The genetic tractability of budding yeast, its ease of manipulation and the wealth of functional genomics tools available in this organism makes it ideal for genome-wide analysis of biological functions and chemical screenings. The present review will discuss some of the innovative advantages based on yeast genetics and genomics for antitumour drug target identification and drug discovery.

microRNAs and cancer: role in tumorigenesis, patient classification and therapy.

Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that downregulate gene expression during various crucial cell processes such as apoptosis, differentiation and development. Recent work supports a role for miRNAs in the initiation and progression of human malignancies. Moreover, large high-throughput studies in patients revealed that miRNA profiling has the potential to classify tumours and predict patient outcome with high accuracy. Functional studies, some of which involve animal models, indicate that miRNAs act as tumour suppressors and oncogenes. This review examines the role of miRNAs in the pathogenesis of cancer as well as miRNA-profiling studies performed in human malignancies. Implications of these findings for the diagnosis and treatment of cancer patients are also discussed.

Germ cell tumours of the ovary

Abstract: Germinal cell tumours represent only 2-5% of all cancers of the ovary. However, the characteristics of the tumour and the patients have some special qualities as high rates of healing goes together with a strong desire to keep fertility intact because this condition occurs in female children and adolescent girls. Neither the prognosis nor the treatment of these tumours is homogeneous; the low incidence is the reason it is hard to develop prospective studies for establishing prognostic factors and specific treatments. The introduction of adjuvant chemotherapy into initial surgery has improved the prognosis of these patients. The BEP scheme has proved to be equally efficient and less toxic than PVB, and for this reason it has become the standard scheme despite the fact that no randomised studies have been carried out. The surgical treatment demands the application of the same principles seen in cytoreduction surgery of epithelial cancers of the ovary (maximum possible cytoreduction), though in many cases hysterectomy and double adnexectomy may be obviated. In view of the rarity of these tumours, it is advisable to work within cooperative groups that may have subgroups for the treatment of rare tumours. This will probably be the only way to move forward in the prospective knowledge of prognostic factors for these tumours.

Metronomic chemotherapy: an antiangiogenic scheduling.

Abstract: Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule.

mTOR signalling in human cancer.

Abstract: Inhibitors of mTOR, the mammalian target of rapamycin, have been extensively studied in clinical trials for cancer treatment Results have been promising, mostly in certain lymphomas, but in solid tumours the results have been generally less encouraging However, recent results, particularly in renal cell carcinoma, have provided renewed interest in the role of mTOR inhibitors in solid tumours A rational, and potentially more successful, development of these agents (ie, RAD001, temsirolimus and AP23573) likely relies in a deeper knowledge of mTOR signalling in cancer, both at the preclinical and clinical levels These would allow a better selection of patients more likely to respond to the use of biologically active doses of the agents and the development of mechanistically based combinations with other agents The goal of this review is to provide an update on the complex signalling of mTOR in cancer and on the biological effects of mTOR inhibitors in cancer cells

Surgical treatment of liver metastases from colorectal carcinoma in elderly patients. When is it worthwhile

Abstract: Background The elderly are under-represented in series of patients operated on for colorectal liver metastases (LM).

Cyclooxygenase-2 (COX-2): a molecular target in prostate cancer.

Abstract: Epidemiological studies provided the first evidence that COX may be involved in the pathogenesis of cancer. In the process of carcinogenesis and in the route of intracellular signalling during carcinogenesis, COX-2 expression may be a universal phenomenon. In general, COX-2 is up-regulated throughout the tumorigenic process, from early hyperplasia to metastatic disease. COX-2 has been reported to be constitutively overexpressed in a variety of malignancies and is frequently constitutively elevated in prostate carcinoma. COX-2 was consistently overexpressed in premalignant lesions such as prostatic intraepithelial neoplasia, and carcinoma. Cases are described with evolution of proliferative inflammatory atrophy of the prostate and prostate carcinoma. The increase of evidence implicating COX-2 in cancer has stimulated clinical trials to investigate the efficacy of selective COX-2 inhibitors in individuals at risk for human cancer. Regarding prostate carcinoma there is much direct or indirect evidence to support the use of COX-2 inhibitors in this disease. Trials using these drugs in familial adenomatous polyposis (FAP) and other patients with a high risk of colorectal carcinoma are ongoing.

Molecular biology of rhabdomyosarcoma

Abstract: Rhabdomyosarcoma (RMS) is one of the most common extracranial solid tumours in children. Embryonal and alveolar subtypes of RMS present completely different genetic abnormalities. Embryonal RMS (eRMS) is characterised by loss of heterozygosity on the short arm of chromosome 11 (11p15.5), suggesting inactivation of a tumour-suppressor gene. In contrast, the majority (80-85%) of the alveolar RMS (aRMS) have the reciprocal chromosomal translocations 't(2;13)(q35;q14) or t(1;13)(p36;q14). t(2;13) appears in approximately 70% of patients with the alveolar subtype. The molecular counterpart of this translocation consists of the generation of a chimeric fusion gene involving the /PAX3/ gene located in chromosome 2 and a member of the fork-head family, /FOXO1/ (formerly /FKHR/), located in chromosome 13. A less frequent variant translocation t(1;13) involves another PAX family gene, /PAX7/, located in chromosome 1 and /FOXO1/ and is present in 10-15% of cases of the alveolar subtype in RMS. Recently, many studies focused on cancer have demonstrated the great potential of the genomic approach based on tumour expression profiles. These technologies permit the identification of new regulatory pathways. Molecular detection of minimal disease by a sensitive method could contribute to better treatment stratification in these patients. In RMS, the advances in the knowledge of the biological characteristics of the tumour are slowly translated into the clinical management of children with this tumour.

Molecular biology of gastric cancer.

Abstract: Despite its decreasing incidence overall, gastric cancer is still a challenging disease. Therapy is based mainly upon surgical resection when the tumour remains localised in the stomach. Conventional chemotherapy may play a role in treating micrometastatic disease and is effective as palliative therapy for recurrent or advanced disease. However, the knowledge of molecular pathways implicated in gastric cancer pathogenesis is still in its infancy and the contribution of molecular biology to the development of new targeted therapies in gastric cancer is far behind other more common cancers such as breast, colon or lung. This review will focus first on the difference of two well defined types of gastric cancer: intestinal and diffuse. A discussion of the cell of origin of gastric cancer with some intriguing data implicating bone marrow derived cells will follow, and a comprehensive review of different genetic alterations detected in gastric cancer, underlining those that may have clinical, therapeutic or prognostic implications.

Hypoxia-inducible factors and cancer.

Abstract: Decreased oxygen availability is a common feature during embryonic development as well of malignant tumours. Hypoxia regulates many transcription factors, and one of the most studied is the hypoxia-inducible factor (HIF). As a consequence of HIF stabilisation, the cell constitutively upregulates the hypoxic programme resulting in the expression of genes responsible for global changes in cell proliferation, angiogenesis, metastasis, invasion, de-differentiation and energy metabolism. Of the three known alpha subunits of HIF transcription factors, HIF-1alpha and HIF-2alpha have been the most studied. Their differential expression and function have been widely discussed, however no clear picture has been drawn on how these two transcription factors differently regulate common and unique target genes. Their role as oncogenes has also been suggested in several studies. In this review we provide an overview of the current knowledge on some of the most important aspects of HIFalpha regulation, its role in tumour angiogenesis and energetic metabolism. We also give an overview of how the modulation of HIF regulating pathways is a potential therapeutic target that may have benefits in the treatment of cancer.

Molecular pathology in sarcomas.

Abstract: Bone and soft tissue sarcomas are an infrequent group of tumours. Their prevalence is 4 in 100,000 people/year, making the disease quite rare. Some of these tumours, such as synovial sarcoma, Ewing tumour and osteosarcoma, are more usual in adolescents or in young adults; there are, though, some neoplasias such as leiomyosarcoma or liposarcoma that are more frequent in patients over 55 years. There are more than a hundred different types of sarcomas from the histological point of view. This is the main limitation at the time of finding major clinic essays on patients with specific types of sarcomas. From the molecular point of view, these neoplasias are grouped into two main types: (a) sarcomas showing specific genetic alterations and relatively simple karyotypes, and translocations which originate gene fusions (e.g., EWS-FLI1 in Ewing tumour); or specific genetic mutations (e.g., c-kit in the gastrointestinal stromal tumour), and (b) sarcomas showing unspecific gene alterations and very complex karyotypes, and very numerous gains and losses. This review describes diverse types of molecular alterations as well, their utility in the clinical domain, as well as implications for the pathologist in translational research in sarcomas.

Molecular determinants of invasion in endometrial cancer.

Abstract: Endometrial carcinoma is the most common gynaecological malignancy in the western world and the most frequent among infiltrating tumours of the female genital tract. Despite the characterisation of molecular events associated with the development of endometrial carcinoma, those associated with the early steps of infiltration and invasion in endometrial cancer are less known. Deep myometrial invasion correlates with more undifferentiated tumours, lymph-vascular invasion, node affectation and decreased global survival. In this review we present an overview of the molecular pathology of myometrial infiltration that defines the initial steps of invasion in endometrial cancer. Down-regulation of E-cadherin as a main player of epithelial to mesenchymal transition, as well as modifications on other molecules involved in cell-cell contacts, render cells with a migratory phenotype. In addition, altered signalling pathways and transcription factors associate with myometrial invasion, histologic grade and metastasis.

PET-CT in clinical oncology.

Abstract: Anatomic imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have been used for many years in clinical oncology. The emergence of positron emission tomography (PET) more than a decade ago was a major breakthrough in the early diagnosis of malignant lesions, as it was based on tumour metabolism and not on anatomy. The merger of both techniques into one thanks to PET-CT cameras has made this technology the most important tool in the management of cancer patients. PET/CT with 18F-FDG is increasingly being used for staging, restaging and treatment monitoring for cancer patients with different types of tumours (lung, breast, colorectal, lymphoma, melanoma, head and neck etc.). At many institutions, PET/CT has replaced separately acquired PET and CT examinations for many oncologic indications. This replacement has occurred despite the fact that only a relatively small number of well designed prospective studies have verified imaging findings against the gold standard of histopathologic tissue evaluation. However, a large number of studies have used acceptable reference standards, such as pathology, imaging and other clinical follow-up findings, for validating PET/CT findings. The impact on the management of patients and the benefits from the information obtained from this anatomo-metabolic procedure justify the term "clinical oncology based on PET-CT" as a new concept to be applied in clinical practice.

Apoptosis regulators as targets for cancer therapy

Abstract: Apoptosis serves to remove excess or damaged cells and its dysregulation may lead to a number of pathological disorders including cancer. Studies during the last 20 years have unravelled much of the molecular mechanisms that control apoptosis. Whether a cell dies in response to diverse apoptotic stimuli, including DNA-damaging agents, is determined largely by interactions between proteins of the Bcl-2 family. A death signal is transmitted through the BH3-only proteins to Bax and Bak which in turn permeabilise the outer mitochondrial membrane allowing the release of apoptogenic factors, which triggers activation of cell-death-promoting caspases. These proteolytic enzymes are tightly controlled by members of the inhibitor of apoptosis (IAP) family. Activation of the caspase cascade via cell death receptors also represents a key apoptotic pathway in both normal and tumour cells. Basic knowledge of these apoptosis regulators provides the basis for novel therapeutic strategies aimed at promoting tumour cell death or enhancing susceptibility to apoptotic inducers. This review focuses on these strategies.

Molecular biology of cervical cancer.

Abstract: Cervical cancer is a virus-induced disease that is caused by the integration of high-risk infecting human papillomaviruses (HPV) in the host genome. For this reason, the carcinogenesis process of cervical cancer is associated to the expression of the viral oncogenic proteins E6 and E7. These proteins are capable of inactivating p53 and pRb, which induces a continuous cell proliferation with the increasing risk of accumulation of DNA damage that eventually leads to cancer. Moreover, cervical cancer can be prevented by prophylactic HPV vaccines; their molecular characteristics and mechanism of action are reviewed. Ultimately, new molecular targets for cervical cancer like proteasome, the EGFR family and IGF family are exposed.

Molecular biology of bladder cancer.

Abstract: Bladder cancer is a major cause of health expenses and it presents formidable clinical challenges. Two types of tumors have been identified, papillary and non-papillary. The former are mainly characterized by FGFR3 and chromosome 9 alterations and a low frequency of Tp53 alterations. The latter are characterized by a high frequency of alterations in genes in the p53 and Rb pathways. Chromosome 9 alterations, specially in 9q, are crucial to bladder cancer development and occur in both types of tumors. Progression of some superficial tumors (mainly TaG3 and T1G3) to high-grade, invasive, carcinomas provides evidence of some overlap between the two pathways. Distinct gene expression profiles have been identified in superficial and invasive tumors. The stage is now ready for the clinical application of this knowledge.

Docetaxel-induced interstitial pneumonitis following non-small-cell lung cancer treatment

Abstract: Interstitial pneumonitis has been described infrequently following administration of docetaxel, used alone or in combination with other chemotherapeutic agents or concurrent irradiation, for non-small-cell lung cancer (NSCLC). This toxicity is of special relevance in NSCLC, as clinical severity and differential diagnosis may be especially challenging. It seems to be due to type I and type IV hypersensitivity reactions to the drug. Clinical and radiographic features are nonspecific and diagnosis is made by exclusion. The rate of grade III-IV docetaxel-induced pneumonitis, ranging from 7 to 47%, depends on several factors, including total dose, chemotherapy schedule and especially concomitant docetaxel treatment with gemcitabine and radiotherapy. Although the usual outcome is cure, it sometimes eventually progresses to pulmonary fibrosis despite steroid treatment. This toxicity must be taken into account when planning treatment strategies for NSCLC in order to reduce its rate and to achieve prompt diagnosis and treatment.

Telomerase and telomere dynamics in ageing and cancer: current status and future directions.

Abstract: This review will focus on the clinical utilities of telomerase for human cancer diagnosis and prognosis. Much attention has been focused on control of telomerase activity in early and late stage tumours. Telomerase stabilisation may be required for cells to escape replicative senescence and to proliferate indefinitely. Because of a very strong association between telomerase and malignancy, both clinicians and pathologists expect this molecule to be a useful diagnostic and prognostic marker and a new therapeutic target. These data have greatly inspired the development of various strategies to target telomere and telomerase for cancer therapy. Finally, evidence is now emerging that G-quadruplex ligands produce rapid senescence and selective cell death. A summary of recent experimental works with new small molecules as potential inhibitors of telomerase is presented.

Aromatase inhibitors and male breast cancer.

Abstract: The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels.

Assessment of functional status, symptoms and comorbidity in elderly patients with advanced non-small-cell lung cancer (NSCLC) treated with gemcitabine and vinorelbine.

Abstract: The incidence and prevalence of comorbid conditions in lung cancer patients increase with age. The aim of the study was to determine response and tolerability with the biweekly combination gemcitabine–vinorelbine in elderly non-small-cell lung cancer (NSCLC) patients. In order to characterise the population included in the study well and assess the results achieved properly, an evaluation of the functional status, comorbidity and survival was performed. Between June 2001, and December 2003, 59 untreated advanced NSCLC patients over the age of 70 years entered the study. Treatment consisted of gemcitabine 1750 mg/m2 and vinorelbine 30 mg/m2 on day 1 every two weeks. The response was evaluated every f ive cycles (RECIST guidelines). Comorbidity was evaluated according to the Charlson and Kaplan Feinstein scales. To measure functional status, activities of daily living (ADL) and instrumental ADL (IADL) were considered. Median age was 74; ECOG performance status was <2 in 59.3%; no dependence in ADL or IADL was found in 24.8% and 42.4% of patients, respectively. A total of 381 courses were administered. Grade 3–4 neutropenia was present in 6.8% of these courses and correlated with IADL. Objective response was 22% (95% CI 12–32). Mean global survival and cause-specific survival were 29 weeks (95% CI 19.9–38.1) and 32 weeks (95% CI 23.4–40.8) respectively. Comorbidity displayed no close correlation with functional status, but comorbidity according to the Kaplan Feinstein index correlated with IADL. Performance status, ADL, IADL and weight loss were significantly related to survival in multivariate analysis. This biweekly combination is feasible in elderly lung cancer patients with a high burden of comorbidity and dependence. Toxicity is acceptable, whereas response rate and survival fall in the range of active regimens. ADL and IADL indices allow the identification of elderly patients with a worse prognosis.

Treatment of peritoneal carcinomatosis from ovarian cancer. Present, future directions and proposals.

Abstract: Peritoneal carcinomatosis, considered years ago as a final stage of unresectable cancer, can now be managed with curative intention by means of a radical cytoreductive surgical procedure with associated peritonectomy and intraperitoneal chemotherapy, as described by Sugarbaker. Malignant neoplasms such as mesothelioma and pseudomyxoma peritonei, ovarian and colon cancer nowadays are experiencing some new therapeutical approaches. Higher survival rates can be reached in ovarian cancer, which is commonly diagnosed in the presence of peritoneal carcinomatosis, using an optimal cytoreductive radical surgery with intraperitoneal chemotherapy. An actualised review of the treatment of advanced ovarian cancer and a proposal of a national multicentre protocol for the treatment of peritoneal carcinomatosis from ovarian cancer has been performed by a group of Spanish surgeons and oncologists dedicated to a therapeutical approach to this pathology.

New screening method for lung cancer by detecting volatile organic compounds in breath.

Abstract: Lung cancer is a frequent cause of cancer-related deaths in the world. There is no valid screening process and this limits its detection to the late stages, with consequently high mortality rates. Volatile organic compounds (VOC) are chemical compounds (mainly the products of cell catabolism) found as gases in the human breath. Different methods have been developed to analyse VOCs and to compare them in healthy subjects and lung cancer patients. In this review, we summarise the different techniques used to analyse VOC. Many reports have been published with promising results similar to those achieved with accepted screening methods such as mammography. These methods show good perspectives on lung cancer screening.

Tumour cells resistance in cancer therapy

Abstract: Resistance to chemotherapeutic drugs presents a big caveat for cancer treatment. In this review we will describe the molecular mechanisms involved in chemoresistance, discussing the mechanisms of resistance related to tumour microenvironment, as well as their intracellular mechanisms. Chemoresistance can also appear as a consequence to treatments with new anticancer drugs. In this sense, we will exemplify this type of resistance discussing mechanisms of action of epidermal growth factor receptor (EGFR) inhibitors. We conclude that the main problem of chemoresistance is due to its pleiotropic and multifactorial nature.

Molecular biology of thyroid cancer initiation.

Abstract: Thyroid cancers stand out among solid tumours because many of the tumour-initiating genetic events have been identified. Mutations leading to constitutive activation of MAP kinase effectors-the tyrosine receptor kinase RET and the intracellular signalling effectors RAS and BRAF-are essential for the pathogenesis of papillary thyroid carcinoma (PTC). Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3-kinase (PI3K)/AKT effectors-PTEN and PI3KCa-are essential for the pathogenesis of follicular thyroid carcinoma (FTC). Besides this strong relationship between the histological phenotype and the pathway predominantly activated, the nature of the genetic event seems to determine the biological behaviour of the tumour and the ultimate clinical outcome of the patient. In this review we will summarise and discuss the main genetic events related to thyroid cancer initiation, the contribution of genomics and the convenience of using a new molecular classification of thyroid cancer, complementary to the clinicopathological classification. This may help us to predict more faithfully the clinical outcome of patients with thyroid cancer and to select more appropriately candidates for targeted therapies.

Clinical outcome in patients with intramedullary spinal cord metastases from lung cancer.

Abstract: Intramedullary spinal cord metastases (ISCM) are uncommon and present with rapidly progressing neurological deficits. The objective of this study was to determine the rate, duration of neurological response and survival after radiation therapy. We have retrospectively reviewed the clinical outcome of six cases with a diagnosis of ISCM from primary lung cancer, non-small cell (NSCLC) (n=3) and small cell (SCLC) (n=3). Total radiation dose ranged from 27 Gy/5 fr to 40 Gy/20 fr. Ambulation was preserved in 3 patients and partially recovered in one. Five out of the six patients (83%) showed improvement in neurological signs/symptoms with a mean duration of 17.2 days (max: 40 days; min: 6 days). Median survival time was 5 months (confidence interval (CI) 95%: 0-12) for NSCLC and 5 months (CI 95%: 4-6) for SCLC. Although radiation response rate is high, the interval free of neurological progression is very short. A therapeutic approach should be considered for each individual.

Incidence of radiation-induced leukoencephalopathy after whole brain radiotherapy in patients with brain metastases.

Abstract: Introduction Whole brain radiation therapy (WBRT) remains a recommended treatment for patients with brain metastases in terms of symptom palliation, especially when extracranial systemic disease is present. The aim of the study was to determine the clinical correlation between pre-existing leukoaraiosis and posterior leukoencephalopathy secondary to WBRT.

Weekly docetaxel with concomitant radiotherapy in patients with inoperable oesophageal cancer.

Abstract: To evaluate the efficacy and tolerability of weekly docetaxel concurrent with radiotherapy in inoperable oesophageal cancer patients Thirty-four oesophageal cancer patients with co-morbid medical conditions, locally advanced tumours (T4) or advanced age (older than 75 years) received docetaxel (20 mg/m2 weekly) plus concurrent radiotherapy (2 Gy daily, to a total dose of 66 Gy) Twenty-two patients (64%) were stage III, 19 of whom had T4 tumours Twenty-seven patients (79%) completed the planned chemoradiotherapy treatment Nine patients (26%) achieved a complete response and 8 (24%) achieved a partial response, for an overall response rate of 50% Median survival was 6 months, and 1-year survival was 35% Patients with T4 tumours had significantly shorter survival than other patients: 5 months for T4 tumours vs 11 months for T1–3 (p=004) Grade 3–4 oesophagitis occurred in 6 patients (17%) There were two treatment-related deaths due to radiation pneumonitis Docetaxel plus concurrent radiotherapy is active in poor-prognosis oesophageal cancer patients, with a lower incidence of severe oesophagitis than with cisplatin-based chemoradiotherapy regimens This schedule can be considered, especially in patients with non-T4 tumours who are not candidates for oesophageal resection