Analysis of the concordance in the EGFR pathway status between primary tumors and related metastases of colorectal cancer patients:implications for cancer therapy.

Patients with metastatic Colorectal Cancer (mCRC), in which primary tumors are KRAS mutated, have no response to anti-EGFR therapy. However, less than half of mCRC patients with KRAS wild-type primary tumors respond to anti-EGFR therapy. Other downstream effectors of the EGFR pathway are being analyzed to fine-tune KRAS predictive value. However, as the primary tumor is the tissue of analysis that determines the use of anti-EGFR therapy in advanced disease, a high concordance in the status of these effectors between primary tumors and related metastases is required. We analyzed the concordances of downstream EGFR effectors in tumoral pairs of primaries and related metastases in a series of KRAS wild-type patients. One hundred seventeen tumoral pairs from patients with CRC were tested for KRAS mutational status. The level of concordance in the presence of KRAS mutations was 91% between the primary tumor and related metastases. The 70 pairs with KRAS wild-type primary tumors were further analyzed for BRAF and PIK3CA mutational status and for EGFR, PTEN and pAKT expression, and the number of concordant pairs was 70 (100%), 66 (94%), 43 (61%), 46 (66%) and 36 (54%), respectively. Our findings suggest that the mutational status of KRAS, BRAF and PIK3CA in the primary tumor is an adequate surrogate marker of the status in the metastatic disease. On the other hand, the immunohistochemical analysis of EGFR, PTEN and pAKT showed a much higher degree of discordance between primaries and related metastases.

Irinotecan-cetuximab-bevacizumab as a salvage treatment in heavily pretreated metastatic colorectal cancer patients: a retrospective observational study.

BACKGROUND: The objective was to evaluate the efficacy of irinotecan-cetuximab-bevacizumab in combination as a salvage treatment for heavily pretreated metastatic colorectal cancer patients. METHODS: A total of 39 patients resistant to both oxaliplatin and irinotecan were included in this retrospective study. Treatment consisted of irinotecan 180/m(2) every 14 days, weekly cetuximab standard dose and bevacizumab 5 mg/kg every 14 days. RESULTS: Partial response was observed in 8 patients (20%), stable disease in 24 (61%) and progressive disease in 7 (18%). Overall response rate in KRAS wild type was 6/22 (27%) and in mutated KRAS it was 2/15 (13%). Median time to progression was 8 months (6.4-9.4) and median overall survival 12 months (10.1-13.8). Overall, grade 3-4 adverse events were observed in 24 patients (62%). CONCLUSIONS: This regimen is active and moderately well tolerated in heavily pretreated advanced colorectal patients. However, caution is advisable when interpreting these results, because they run against the findings of two large phase III trials.

Immunohistochemical analysis of tumour regression grade for rectal cancer after neoadjuvant chemoradiotherapy.

AIM: Tumour regression grade (TRG) as defined by Rödel et al. has been used as an independent prognostic factor for rectal carcinoma after preoperative treatment by chemoradiotherapy (CRT). Determination of TRG 2 and 3, semiquantitatively defined as more or less than 50% tumour regression, respectively, does not appear to correlate with prognosis. The purpose of this study was to find an immunohistochemical pattern to permit improved stratification of intermediate responders defined by disease free (DFS) and overall survival (OS). METHOD: Immunohistochemistry of EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), CD133 antibody, p53 antibody and Ki67 antibody was evaluated using tissue microarrays (TMA) on post-treatment surgical specimens from 88 patients. CD133 expression was confirmed in the whole section when available. RESULTS: At a median follow-up of 40 months, TRG was found to be an independent predictor of DFS (P = 0.05) and OS (P = 0.001) but no differences were found between TRG 2 and 3 in terms of DFS (P = 0.74) or OS (P = 0.41). The results of TMA showed an immunohistochemically poor prognostic profile for intermediate responders configured by negativity of CD133 expression. However, when examining CD133 expression in the whole section, there was an intermediate correlation with TMA and the prognostic significance was lost. CONCLUSION: The results did not confirm the value of immunohistochemistry in predicting the prognosis of patients with rectal cancer following neoadjuvant chemoradiotherapy. This questions the accuracy of TMA in detecting CD133 expression in this setting.

Phase II study of a fixed dose-rate infusion of gemcitabine associated with erlotinib in advanced pancreatic cancer.

PURPOSE: To evaluate the feasibility, toxicity and efficacy of the combination regimen consisting of gemcitabine-FDR infusion plus erlotinib, in ACP patients. METHODS: Forty-two patients with histologically confirmed, locally advanced or metastatic pancreatic cancer were included in this phase II trial. Main objectives were to assess the efficacy and safety of this regimen. Therapeutic regimen consisted of gemcitabine 1,200 mg/m(2) in 120-min infusion on days 1, 8 and 15, plus erlotinib 100 mg orally once daily. Cycles were repeated every 28 days. RESULTS: A total of 160 courses of gemcitabine-FDR erlotinib were administered (median 3.8 courses per patient). The most common grade 3-4 AEs were neutropenia (21%), thrombocytopenia (10%), skin rash (10%) and asthenia (10%). Complete response was achieved in one patient (2%) and 11 (26%) achieved a partial response. Stable disease and progression disease were observed in 11 patients (26%) and 19 (45%), respectively. Median time to progression was 5 months (95%CI: 3.9-5.8 months) and median overall survival was 8 months (95% CI: 5.1-10.8). One-year survival rate was 35%. CONCLUSIONS: A regimen consisting of gemcitabine-FDR infusion plus erlotinib is active and well tolerated in APC patients. However, the results do not justify the conduct of a Phase III trial.

Capecitabine and bevacizumab as first-line treatment in elderly patients with metastatic colorectal cancer.

BACKGROUND: The efficacy and safety of capecitabine and bevacizumab in elderly patients with metastatic colorectal cancer (mCRC) considered unsuitable for receiving first-line chemotherapy with an irinotecan or oxaliplatin-based combination were assessed in a phase II, open, multicentre, uncontrolled study. METHODS: Treatment consisted of capecitabine 1250 mg m(-2) (or 950 mg m(-2) for patients with a creatinine clearance of 30-50 ml min(-1)) twice daily on days 1-14 and bevacizumab (7.5 mg kg(-1)) on day 1 every 3 weeks. RESULTS: A total of 59 patients aged >or=70 years with mCRC were enrolled. In an intention-to-treat analysis, the overall response rate was 34%, with 71% of patients achieving disease control. Median progression-free survival and overall survival were 10.8 months and 18 months, respectively. In all, 32 patients (54%) had grade 3/4 adverse events (AEs), the most common being hand-foot syndrome (19%), diarrhoea (9%) and deep venous thrombosis (7%). Four patients died because of treatment-related AEs. A relationship was detected between creatinine clearance

Spanish Society of Medical Oncology consensus on the use of erythropoietic stimulating agents in anaemic cancer patients

Treatment of anaemia is a very important aspect in the management of cancer patients. In order to carry out a consensus process about the use of erythropoietic stimulating agents (ESAs) in cancer patients, the Spanish Society of Medical Oncology (SEOM) elaborated a working group which coordinated a panel of medical oncology specialists. This working group has reviewed the main issues about the use of ESAs. In addition a consensus meeting was held in Madrid on 25 April 2007. The following conclusions were made: Since ESA treatment increases the haemoglobin (Hb) level and decreases the red blood cell (RBC) transfusion requirements, ESAs should be used within the approved indications in patients undergoing chemotherapy treatment, beginning at a Hb level below 11 g/dl and maintaining it around 12 g/dl, with iron supplements if necessary. Neither increasing the ESA dose in nonresponders nor the use of ESAs in the treatment of chronic cancer-related anaemia is recommended (AU)

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Intra-abdominal desmoplastic small round cell tumour in a 39-year-old man

Desmoplastic small round cell tumor is a very rare neoplasm, that usually appears in children and young adolescents. There is no standard therapy, and responses to chemotherapy are infrequent. Surgery is still the main treatment for this disease. We report the case of a 39 year-old man and briefly summarize the evidence about this tumor (AU)

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A critical role for choline kinase-alpha in the aggressiveness of bladder carcinomas.

Bladder cancer is one of the most common causes of death in industrialized countries. New tumor markers and therapeutic approaches are still needed to improve the management of bladder cancer patients. Choline kinase-alpha (ChoKalpha) is a metabolic enzyme that has a role in cell proliferation and transformation. Inhibitors of ChoKalpha show antitumoral activity and are expected to be introduced soon in clinical trials. This study aims to assess whether ChoKalpha plays a role in the aggressiveness of bladder tumors and constitutes a new approach for bladder cancer treatment. We show here that ChoKalpha is constitutively altered in human bladder tumor cells. Furthermore, in vivo murine models, including an orthotopic model to mimic as much as possible the physiological conditions, revealed that increased levels of ChoKalpha potentiate both tumor formation (P< or =0.0001) and aggressiveness of the disease on different end points (P=0.011). Accordingly, increased levels of ChoKalpha significantly reduce survival of mice with bladder cancer (P=0.05). Finally, treatment with a ChoKalpha-specific inhibitor resulted in a significant inhibition of tumor growth (P=0.02) and in a relevant increase in survival (P=0.03).

Prognostic value of carcinoembryonic antigen level in rectal cancer treated with neoadjuvant chemoradiotherapy.

BACKGROUND: The purpose of this study was to identify clinical and pathological parameters to improve prediction of disease-free survival (DFS) and overall survival (OS) in patients treated with neoadjuvant chemoradiotherapy for rectal cancer. METHODS: Between July 1995 and May 2007, 148 patients with primary rectal adenocarcinoma received neoadjuvant chemoradiotherapy followed by mesorectal excision. Preoperative treatment included various protocols, UFT and leucovorin (28%) and oxaliplatin-based chemotherapy (72%). Clinical and pathological variables were evaluated in relation to patient outcomes. RESULTS: Thirteen percent of patients achieved a complete pathologic response. No response or minimal response as defined by Dworak (Tumor Regression Grade 0/1) was observed in 30 patients (20%). At a median follow-up of 37 months, the 3-year DFS and OS were 64% and 83%, respectively. Pre-treatment serum carcinoembryonic antigen (CEA) level

Pancreatic glucagonoma presenting as a pulmonary mass.

Glucagonoma is an uncommon disease, a neuroendocrine tumour that develops from glucagon-producing pancreatic cells. They are usually slow-growing, but generally advanced at diagnosis, and metastatic disease is virtually incurable. Liver is the most common site of metastatic disease. We present the case of a 48-year-old man with a glucagonoma being diagnosed from a pulmonary mass. This case had no liver affection in the whole evolution of the disease, and showed a particularly aggressive course, with very little response to all therapies administered, and a survival from diagnosis of just 16 months.

Pancreatic glucagonoma presenting as a pulmonary mass

Glucagonoma is an uncommon disease, a neuroendocrine tumour that develops from glucagon-producing pancreatic cells. They are usually slow-growing, but generally advanced at diagnosis, and metastatic disease is virtually incurable. Liver is the most common site of metastatic disease. We present the case of a 48-year-old man with a glucagonoma being diagnosed from a pulmonary mass. This case had no liver affection in the whole evolution of the disease, and showed a particularly aggressive course, with very little response to all therapies administered, and a survival from diagnosis of just 16 months (AU)

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Descriptive analysis of clinical factors affecting terminally ill cancer patients.

GOALS OF WORK: To make a descriptive analysis of clinical and laboratories parameters in advanced neoplastic patients. MATERIALS AND METHODS: We interviewed 406 terminally ill cancer patients to study demographic and neoplastic data, 24 graded symptoms, 21 analytical parameters and scales to evaluate general condition, quality of life and independence in daily activities. MAIN RESULTS: An average of 9.3 symptoms per patient were detected and median survival was 26.5 days. Most frequent symptoms were asthenia (96.8%), anorexia (94.8%), weight loss (88.1%) and pain (80.5%). Principal laboratory abnormalities were high blood sedimentation rate (96%), high cytolysis and cholestasis enzyme levels (50-77%), anemia (81.5%), low protein (66%) and low albumin levels (67%). Symptom prevalence was different according to age, gender, primary tumour, location of metastasis, laboratory parameters, performance status, quality of life or independence in daily-living activities. CONCLUSIONS: We should know more frequent symptoms affecting terminal cancer patients and any factor contributing to it to provide more comfort in the final phases of life.

Employment in a cohort of cancer patients in Spain. A predictive model of working outcomes

INTRODUCTION: Cancer patients can have problems remaining in employment but the importance of this issue has until now received little attention in Spain. PATIENTS AND METHODS: The study included 347 consecutive cancer patients who were employed at diagnosis. Diagnosis had been confirmed at least 6 months before the interview. Participants completed a questionnaire concerning cancer-related symptoms and work-related factors and clinical details were obtained from their medical records. The study was approved by the Ethical Committee of La Paz Hospital. All patients gave consent to participate. RESULTS: Eighty-five percent of patients were unable to work after diagnosis, but 59% returned to work at the end of treatment. Gender, age, type of worker and type of treatment were independently associated with the ability to work after diagnosis. At the end of treatment these factors were age, education, tumour stage, overall response to the therapy, associated co-morbidity and sequelae of the disease or its treatment. Twenty-one percent noticed changes in their relationship with co-workers and managers, usually in the sense that they tried to be helpful. In a multivariate logistic regression analysis, the strongest predictors for remaining in employment were age, overall response and sequelae of the disease or its treatment. CONCLUSIONS: Cancer survivors in this study encountered some problems in returning to work, mainly linked to the sequelae of their disease and its treatment, rather than to discrimination by employers or colleagues. Prediction of working outcomes is possible to recommend interventions (AU)

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Idiopathic and recurrent thromboembolic phenomena in cancer patients

BACKGROUND: Venous thromboembolism (VTE) is one of the most common complications in cancer patients. It is not only associated with both reduced survival and a high number of recurrences, but an idiopathic VTE also increases the likelihood of a cancer diagnosis. METHODS: Between January 2000 and October 2005 we reviewed the medical history of 88 patients who were admitted to a tertiary hospital and presented both a diagnosis of VTE and any type of tumour. The information collected included the type of tumour, the temporal association between tumour diagnosis and VTE, anticoagulation treatment applied and percentage of recurrences. RESULTS: Ten patients (11.4%) presented the VTE prior to the cancer diagnosis; only half of them underwent a posterior tumour screening routine. Fifteen patients (17%) were diagnosed simultaneously and 71% presented the VTE after the tumour was detected. In 47 patients (53.4%) no risk factors for VTEs were detected. Twenty-nine patients (31.7%) presented a recurrent VTE, mainly during chemotherapy treatment (66%). Less than half of the patients (47.57%) were receiving treatment with low-molecular- weight heparins (LMWH). CONCLUSIONS: Idiopathic VTEs may be the first manifestation of an occult neoplasia, but tumour screening is scheduled in only a few patients. Regarding the high incidence of recurrent VTE in cancer populations, a high percentage is attributed to the underuse of LMWH, whose efficacy in preventing recurrent phenomena is superior to oral dicumarinics (AU)

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Molecular biology of pancreatic cancer

Pancreatic cancer is a leading cause of cancer death. This devastating disease has the horrible honour of close to equal incidence and mortality rates. Late diagnosis and a constitutive resistance to every chemotherapy approach are responsible for this scenario. However, molecular biology tools in cooperation with translational efforts have dissected several secrets that underlie pancreatic cancer. Progressive acquisition of malignant, invasive phenotypes from pre-malignant lesions, recent revelations on core signalling pathways and new targeted designed trials offer a better future for pancreatic cancer patients. This review will summarise recent advances in the molecular biology of pancreatic cancer (AU)

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Employment in a cohort of breast cancer patients.

BACKGROUND: Breast cancer survivors can have problems in returning to work. However, the importance of work to cancer survivors has until recently received little attention. AIMS: To investigate employment- and work-related disability in a cohort of breast cancer patients to identify possible discrimination and other obstacles to remaining in work. METHODS: Questionnaire study of breast cancer patients employed at diagnosis and where diagnosis had been confirmed at least 6 months before the interview. Participants completed a questionnaire concerning cancer-related symptoms and work-related factors and clinical details were obtained from their medical records. RESULTS: The study included 96 consecutive patients with breast cancer aged between 18 and 65 years. In total, 80% of patients were unable to work after diagnosis, but 56% returned to work at the end of treatment. The sequelae of the disease or its treatment and the stage of disease were independently associated with the ability to work after the end of treatment. Only one patient did not tell his/her employers and coworkers about his/her disease. In total, 29% noticed changes in their relation with co-workers and managers, usually in the sense that they tried to be helpful. None reported job discrimination. CONCLUSION: Breast cancer survivors in this study encountered some problems in returning to work, mainly linked to the sequelae of their disease and its treatment rather than to discrimination by employers or colleagues.

Primary cardiac osteosarcoma

Primary cardiac neoplasms are an infrequent disease, as most of the tumors arising in the heart are metastatic. Between the malignant tumors, sarcomas are the most frequent ones, accounting for at least 95% of them. We report the case of a 70-year old woman, diagnosed of primary cardiac osteosarcoma arising in the left atrium. Although complete excision of the tumor was performed, the disease relapsed and subsequently developed metastatic disease. In this paper, we also review briefly the management of this rare disease and the therapeutic options (AU)

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Study of the prevalence of tumour-related asthenia in Spanish cancer patients.

INTRODUCTION: Asthenia is the most prevalent symptom in oncological patients but it is underestimated by the majority of healthcare professionals. The aim of the present study is to estimate the prevalence of tumour-related asthenia in the Spanish population, while defining the associated factors. METHODS: An epidemiological, multicentre, cross-sectional study was conducted in oncology services from Spain, including 712 cancer patients (58.4+/-13.5 years). RESULTS: 42.5% patients showed asthenia. This prevalence appeared to be tumour-related (p<0.05) and increased among patients with a more advanced stage of disease or with a worsening of performance status (p<0.001). The prevalence of asthenia increased in the presence of the following factors: chemotherapy (in the past: 52.1% vs. 31.0%; at the time of the study: 46.1% vs. 38.2%), symptomatic treatment (in the past: 60.4% vs. 39.8%; at the time of the study: 61.3% vs. 38.6%), present interferon treatment (100%), anaemia (59.7% vs. 31.3%), dehydration/waterelectrolyte imbalance (58.3% vs. 41.6%), respiratory failure (61.4% vs. 39.7%), liver disease (59.5% vs. 41.3%), malnutrition (76.1% vs. 38.7%), pain (57.7% vs. 27.0%), anxiety (56.1% vs. 38.6%), depression (57.9% vs. 40.0%) and sleep disturbances (51.1% vs. 39.4%). A multivariate logistic regression showed that a model including performance status, patient circumstance, chemotherapy, anaemia, pain and anxiety correctly diagnosed asthenia in 70.9% of cases. CONCLUSIONS: The physiopathology of tumour-related asthenia remains relatively unknown, despite its high prevalence and considerable quality of life impact. Determining factors related to asthenia in clinical practice can favour the use of concrete treatments and improve the conditions of cancer patients.

El enfermo terminal y su familia / No disponible

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Study of the prevalence of tumour-related asthenia in Spanish cancer patients

INTRODUCTION: Asthenia is the most prevalent symptom in oncological patients but it is underestimated by the majority of healthcare professionals. The aim of the present study is to estimate the prevalence of tumour-related asthenia in the Spanish population, while defining the associated factors. METHODS: An epidemiological, multicentre, cross-sectional study was conducted in oncology services from Spain, including 712 cancer patients (58.4+/-13.5 years). RESULTS: 42.5% patients showed asthenia. This prevalence appeared to be tumour-related (p<0.05) and increased among patients with a more advanced stage of disease or with a worsening of performance status (p<0.001). The prevalence of asthenia increased in the presence of the following factors: chemotherapy (in the past: 52.1% vs. 31.0%; at the time of the study: 46.1% vs. 38.2%), symptomatic treatment (in the past: 60.4% vs. 39.8%; at the time of the study: 61.3% vs. 38.6%), present interferon treatment (100%), anaemia (59.7% vs. 31.3%), dehydration/waterelectrolyte imbalance (58.3% vs. 41.6%), respiratory failure (61.4% vs. 39.7%), liver disease (59.5% vs. 41.3%), malnutrition (76.1% vs. 38.7%), pain (57.7% vs. 27.0%), anxiety (56.1% vs. 38.6%), depression (57.9% vs. 40.0%) and sleep disturbances (51.1% vs. 39.4%). A multivariate logistic regression showed that a model including performance status, patient circumstance, chemotherapy, anaemia, pain and anxiety correctly diagnosed asthenia in 70.9% of cases. CONCLUSIONS: The physiopathology of tumour-related asthenia remains relatively unknown, despite its high prevalence and considerable quality of life impact. Determining factors related to asthenia in clinical practice can favour the use of concrete treatments and improve the conditions of cancer patients (AU)

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