Background: Afatinib has shown long progression free survival and improvement in quality of life ... more Background: Afatinib has shown long progression free survival and improvement in quality of life in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Although afatinib causes acneiform rash, it can be manageable. Tetracyclines are usually used to treat it; nonetheless, there is no trial that evaluates their prophylactic efficacy on afatinib induced-skin toxicities (AIST).
Revista de investigación clínica; organo del Hospital de Enfermedades de la Nutrición
Effective communication sometimes requires a common language. This is particularly true in scienc... more Effective communication sometimes requires a common language. This is particularly true in science, where communication among health professionals and scientists across national boundaries has become critical because of the rapidity with which new knowledge is acquired. In the modern era, where multinationalism in key medical and scientific discoveries is increasingly common, the language is undoubtedly English. In fact, more than three-quarters of scientific papers today are published in English.
In recent years, the use of diffusion weighted MRI (DW-MRI) has increased for the diagnosis of fo... more In recent years, the use of diffusion weighted MRI (DW-MRI) has increased for the diagnosis of focal liver lesions (FLLs). DW-MRI may help in the differentiation of benign and malignant FLLs by measuring the apparent diffusion coefficient (ADC) values. Unfortunately, liver metastases present different histopathologic features with variable MRI signals within each lesion; this histologic variability explains the intra- and inter-lesion variations of ADC measurements. We present the case of a 64-year-old female with diagnosis of liver metastasis from small cell lung carcinoma admitted to the emergency unit due to symptoms of inappropriate antidiuretic hormone secretion. Quantitative comparison of two liver MRI, on admission and 2-months after transcatheter arterial chemoembolization showed persistence of the hyperintense metastatic lesions with significant difference in the ADC values in the with-in metastatic lesions (p = 0.001) and between normal tissue and liver metastases only at ...
Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness... more Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness. Angiotensin II (ANGII) was initially described as a vasoconstrictor; recent studies have shown its participation in cellular proliferation, vascularisation, and apoptosis. We conducted a prospective study to evaluate the expression of ANGII receptors - AT1 and AT2 - and their relationship with prognosis. We studied 133 tumours from patients with diagnosis of astrocytoma who underwent surgery from 1997 to 2002. AT1 and AT2 were expressed in 52 and 44% of the tumours, respectively, when determined by both reverse transcriptase-polymerase chain reaction and immunohistochemistry. Ten per cent of low-grade astrocytomas were positive for AT1, whereas grade III and IV astrocytomas were positive in 67% (P<0.001). AT2 receptors were positive in 17% of low-grade astrocytomas and in 53% of high-grade astrocytomas (P=0.01). AT1-positive tumours showed higher cellular proliferation and vascular ...
Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the ma... more Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the main causes of death in patients with liver cirrhosis. High Alpha fetoprotein serum levels have been found in 60-70% of patients with Hepatocellular carcinoma; nevertheless, there are other causes that increase this protein. Alpha fetoprotein levels > or =200 and 400 ng/mL in patients with an identifiable liver mass by imaging techniques are diagnostic of hepatocellular carcinoma with high specificity. We analysed the sensitivity and specificity of the progressive increase of the levels of alpha fetoprotein for the detection of hepatocellular carcinoma in patients with liver cirrhosis. Seventy-four patients with cirrhosis without hepatocellular carcinoma and 193 with hepatic lesions diagnosed by biopsy and shown by image scans were included. Sensitivity and specificity of transversal determination of alpha fetoprotein > or = 200 and 400 ng/mL and monthly progressive elevation of alph...
Fibrolamellar Carcinoma (FLC), a subtype of hepatocellular carcinoma (HCC), is a rare primary hep... more Fibrolamellar Carcinoma (FLC), a subtype of hepatocellular carcinoma (HCC), is a rare primary hepatic malignancy. Several aspects of the clinic features and epidemiology of FLC remain unclear because most of the literature on FLC consists of case reports and small cases series with limited information on factors that affect survival. We did a retrospective analysis of the clinical and histological characteristics of FLC. We also determined the rate of cellular proliferation in biopsies of these tumors. We assessed whether these variables were associated with survival. We found 15 patients with FLC out of 174 patients with HCC (8.6%). Between patients with these neoplasms, we found statistically significant survival, age at onset, level of alpha fetoprotein, and an earlier stage of the disease. The 1, 3 and 5 year survival in patients with FLC was of 66, 40 and 26% respectively. The factors associated with a higher survival in patients with FLC were age more than 23 years, feasibilit...
Angiotensin II (Ang II) is a main effector peptide in the renin-angiotensin system and participat... more Angiotensin II (Ang II) is a main effector peptide in the renin-angiotensin system and participates in the regulation of vascular tone. It also has a role in the expression of growth factors that induce neovascularisation which is closely associated to the growth of malignant gliomas. We have shown that the selective blockage of the AT1 receptor of angiotensin inhibits tumour growth, cell proliferation and angiogenesis of C6 rat glioma. The aim of this study was to study the effects of the blockage of AT1 receptor on the synthesis of growth factors, and in the genesis of apoptosis in cultured C6 glioma cells and in rats with C6 glioma. Administration of losartan at doses of 40 or 80 mg kg(-1) to rats with C6 glioma significantly decreased tumoral volume and production of platelet-derived growth factor, vascular endothelial growth factor and basic fibroblast growth factor. It also induced apoptosis in a dose-dependent manner. Administration of Ang II increased cell proliferation of c...
Following the success of the EGFR inhibitors a renewed interest in IGF-1R inhibitors has emerged.... more Following the success of the EGFR inhibitors a renewed interest in IGF-1R inhibitors has emerged. IGF-1R overexpression has been identified in several tumour types and protects cancer cells from apoptosis. Currently, several different approaches are being investigated for targeting the IGF-1R, including small-molecule kinase inhibitors, IGF1R monoclonal antibodies, antisense oligonucleotides and RNA interference. To date, it is not clear what factors influence sensitivity to IGF-1R blockade but it is likely that tumours that respond well to treatment will be those where IGF-1R overexpression results in a poor patient prognosis. Initial data show that tumour type may also determine response to therapy with squamous nonsmall cell lung cancers responding well to a IGF-1R monoclonal antibody and chemotherapy. The aim of this study is to elucidate the EGFR and IGF-1R expression profile in a cohort of NSCLC patients and correlate the results to patient clinico-pathological data and prognosis. Methods: EGFR and IGF1R expression were evaluated in 197 NSCLC patients (92 -squamous, 87 -adenocarcinoma, 18 -others) using immunohistochemistry (IHC) analysis. Membraneous staining (% cells × staining intensity) was evaluated by a pathologist and scored as follows: 0 (negative), 1+ (weak), 2+ (moderate) and 3+ (strong). Expression of EGFR and IGF1R were also examined in a panel of cell lines (SKMES1, A549, HCC827, H1819, H1299) and patient samples (10 squamous and 10 adenocarcinomas) using Western Blot analysis. Results: The panel of 6 NSCLC cell lines examined showed variability in IGF-1R expression. In the fresh frozen resected NSCLC tumours IGF-1R was overexpressed relative to matched normal tissues. Furthermore squamous cell carcinomas had higher levels of expression than adenocarcinomas. Immunohistochemistry analysis demonstrated that squamous cell tumours have higher IGF-1R expression levels than adenocarcinomas (3+/2+ Squamous [70/197] versus 3+/2+ Adenocarcinoma 27/197)] p < 0.0001). Patients with squamous cell carcinoma also had higher EGFR expression than those with adenocarcinoma (p = 0.002). Patients with EGFR and IGF-1R overexpression had a poorer survival (p = 0.043). Conclusions: Our findings indicate that while EGFR and IGF-1R expression alone are not independent prognostic markers of survival in NSCLC. Taken together overexpression of both proteins correlates to a poor survival. This subset of patients may benefit from treatments cotargeting IGF-1R and EGFR.
Cancer biomarkers : section A of Disease markers, 2014
Few studies, have evaluated the prognostic impact of the quantification of mRNA expression levels... more Few studies, have evaluated the prognostic impact of the quantification of mRNA expression levels in advanced non-small cell lung cancer (NSCLC). The aim of this work was to quantify mRNA expression levels in peripheral blood through three epithelial markers in patients with stages IIIB and IV in NSCLC. Seventy advanced NSCLC patients and ten healthy controls were included. All patients received platinum-based chemotherapy in first line treatment. Peripheral blood was obtained of each participant and mRNA expression levels present in circulating cells were quantified by molecular techniques (RT-PCR) using three epithelial markers: cytokeratin (CK)-18, CK-19 and Carcinoembryonic-Antigen (CEA). The expression levels were quantified from a standard curve using the cDNA obtained from A549 cells. Registered in ClinicalTrials.gov (NCT01052818). We found a significant statistical correlation between levels of CK-18, CK-19 and CEA mRNA. mRNA expression levels were lower in patients who pres...
Journal of Experimental Therapeutics and Oncology, 2002
This study investigated the effects of chronic administration of thalidomide on three different n... more This study investigated the effects of chronic administration of thalidomide on three different neoplasms of ectodermic origin in rodents: 1) chemically induced tumors of the nervous system of rats by transplacental exposure to ethylnitrosourea; 2) transplanted RPMI-1846 melanoma in hamsters and 3) transplanted C6 glioblastoma in rats. No effects were seen on thalidomide-treated rats on the frequency and time of tumor development induced by ethylnitrosourea. In contrast, a reduction in tumoral growth and mitotic-index was obtained in animals treated with thalidomide in transplanted tumors, melanoma and glioblastoma, when compared with controls (P < 0.001 and 0.025, respectively). These results suggest that, although thalidomide is not a cytotoxic drug for neoplastic cells, it might partially inhibit the tumoral growth through any of its pharmacological actions; by blockage of cell-surface adhesion receptors induction of DNA oxidation, or inhibition of angiogenesis. Further investigations on the use of thalidomide perhaps associated to cytotoxic drugs, for treatment of ectodermic neoplasms seem guaranteed.
Between 30% and 50% of patients with non-small-cell lung cancer (NSCLC) will develop cerebral met... more Between 30% and 50% of patients with non-small-cell lung cancer (NSCLC) will develop cerebral metastases in the course of their illness. As improvements are made in the local brain treatment, the question arises on how to manage patients with NSCLC who have solely stable brain metastatic disease and if treatment should be considered for the primary lung lesion. The present article will review published series of patients with NSCLC and with brain metastases treated with aggressive thoracic management, with either lung tumor resection or thoracic radiation with or without chemotherapy as definitive treatment. We will also assess which prognostic factors may be useful in the identification of the subset of patients who could benefit from this more aggressive approach. For patients treated with surgical resection for the primary lung tumor, median survival ranged from 19 to 27 months, and the 1-, 2-, and 5-year survival reached 56%-69%, 28%-54%, and 11%-24%, respectively. Patients treated with aggressive radiotherapy with or without chemotherapy, achieved a median survival of 15.5-31.8 months, with a 1-year survival of 50%-71%, and a 2-year survival of 16%-60%. Well-selected patients with NSCLC and with exclusively oligometastatic cerebral disease represent a subgroup of patients with stage IV NSCLC that might achieve long-term survival after treatment directed to the brain and lung tumor lesions. Patients with N0 or N1 disease may be selected for surgical thoracic treatment, whereas those with N2 or N3 disease may benefit from combined chemoradiotherapy in the absence of progression after induction chemotherapy.
Because of improved therapeutic results after first-line platinum-based chemotherapy in patients ... more Because of improved therapeutic results after first-line platinum-based chemotherapy in patients with stage IV non-small-cell lung cancer (NSCLC), second-line chemotherapy may be considered for a growing number of patients. Approximately, 10% of patients have an interval time after concluding first-line platinum-based chemotherapy greater than 6 months. These patients may achieve high tumor responses when platinum is again used in second-line treatment. Twenty-three patients experiencing progression following 6 months after concluding platinum-based chemotherapy were managed with second-line treatment with carboplatin combined with gemcitabine or pemetrexed. Overall response, progression-free survival (PFS), and overall survival (OS) after initiation of second-line treatment were calculated for all patients. Median PFS after first-line treatment was 12.6 months (95% confidence interval [95% CI], 10.4-14.7 months). Partial response was achieved in 7 of 23 patients, resulting in an overall response of 30.4% (95% CI, 11.6-49.0). Following initiation of second-line chemotherapy, median PFS was 5.9 months (95% CI, 1-10.9 months) and median OS was 12.5 months (95% CI, 3.5-21.5 months). The 1-year survival rate for all patients was 61.0% (95% CI, 29.5-82.0). Adding these results to those of the 10 previously published trials, 75 of 326 patients, 23%, (95% CI, 18.7-27.3) presented an overall response with the use of second-line platinum-based chemotherapy. The use of platinum combinations as second-line chemotherapy seems to have a place in the management of patients with advanced NSCLC, especially those with an interval time to progression greater than 6 months.
Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2.... more Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. Eli Lilly.
The aim of this study is to determine clinical and histopathological characteristics correlated t... more The aim of this study is to determine clinical and histopathological characteristics correlated to responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer.
Introduction: Previously, we reported the frequency of epidermal growth factor receptor (EGFR) an... more Introduction: Previously, we reported the frequency of epidermal growth factor receptor (EGFR) and KRAS mutations in nonsmallcell lung cancer (NSCLC) patients in Latin America. The EGFR mutation frequency was found between Asian (40%) and Caucasian (15%) populations. Here, we report the updated distribution of NSCLC mutations.
Interactive cardiovascular and thoracic surgery, 2010
We retrospectively reviewed the records of 100 patients with malignant disease and symptomatic pe... more We retrospectively reviewed the records of 100 patients with malignant disease and symptomatic pericardial effusion initially treated with pericardiocentesis at the National Cancer Institute of Mexico between 1985 and 2009. We analyzed predictive factors for recurrence of pericardial effusion by bi- and multivariate analyses. The group comprised 74 women and 26 men. Twenty patients had developed malignant pericardial effusion at the time of primary cancer diagnosis. Recurrence rate after pericardiocentesis was 33%. Progression-free survival for pericardial effusion at one year was 59% (range, 47-71%). Median overall survival (OS) after pericardiocentesis was 40.3+/-7.9 weeks (95% Confidence interval, 24.9-55.7). The sole factor that correlated with increased progression-free survival for pericardial effusion was the presence of bloody pericardial effusion. For OS, multivariate analysis yielded that female gender and presence of pericardial effusion at time of primary malignancy diag...
All-trans retinoic acid (ATRA) promotes the endogenous expression of both nerve growth factor (NG... more All-trans retinoic acid (ATRA) promotes the endogenous expression of both nerve growth factor (NGF) and retinoic acid receptor beta (RAR-b). We have previously shown that the administration of ATRA partly reverts the damage induced by diabetic neuropathy (DN). In this investigation, we evaluated the effects of vitamin A, a commercial, inexpensive compound of retinoic acid, on the therapy of DN. A total of 70 rats were randomized into 4 groups. Group A was the control, and groups B, C, and D received a total dose of 60 mg/kg streptozotocin intraperitoneally. When signs of DN developed, groups C and D were treated either with vitamin A (20,000 IU) or with ATRA 25 mg/kg for 60 days. Plasma glucose, contents of NGF, thermal and nociceptive tests, and RAR-b expression were evaluated. All diabetic rats developed neuropathy. The treatment with vitamin A and ATRA reverted similarly the sensorial disturbances, which was associated with increased contents of NGF and RAR-b expression. Our results indicate that the administration of vitamin A has the same therapeutic effect as ATRA on peripheral neuropathy and suggest its potential therapeutic use in patients with diabetes. (Translational Research 2014;164:196-201) Abbreviations: ATRA ¼ all-trans retinoic acid; DN ¼ diabetic neuropathy; NGF ¼ nerve growth factor; RA ¼ retinoic acid; RAR-a ¼ retinoic acid receptor alpha; RAR-b ¼ retinoic acid receptor beta; STZ ¼ streptozotocin
Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neur... more Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neuropathy. All-trans retinoic acid (RA) increases the expression of neural growth factor and its receptor participating in translation pathways. This study evaluates RA as a treatment of diabetic neuropathy: 120 mice were assigned randomly to 4 groups. Group A (n ؍ 30) was taken as control; group B (n ؍ 30) received 50 mg/kg intraperitoneal streptozotocin (STZ); group C (n ؍ 30) received STZ, and after diabetic neuropathy developed, they were treated with subcutaneous RA 20 mg/kg daily during 60 days; and group D (n ؍ 30) only received RA. Plasma glucose, thermosensitive tests, serum, and the nerve contents of NGF were measured in all animals. Evaluation by electron microscopy was performed in search of morphologic changes secondary to neuropathy and nerve regeneration. Diabetic mice had an increased threshold to pain. Treatment with RA in diabetic mice reverted changes in sensitivity as compared with diabetic mice that received placebo (P < 0.001). No differences in pain threshold among controls, RA, and diabetes mellitus (DM) ؉ RA groups were found. Glucose levels were not affected by the treatment with RA. NGF diminished significantly in the sciatic nerve in diabetic mice as compared with controls and with the RA group. Animals with DM ؉ RA had a significant increase of NGF in nerves as compared with the other groups. RA also regressed the ultrastructural changes induced by diabetes that showed increased neural regeneration. RA can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of the increased of NGF concentrations in nerve terminals. (Translational Research 2008;152:31-37) Abbreviations: DM ϭ diabetes mellitus; DRG ϭ dorsal root ganglion; NGF ϭ neural growth
Lung metastasectomy is an area of interest and controversy in surgical oncology. Most of the avai... more Lung metastasectomy is an area of interest and controversy in surgical oncology. Most of the available evidence derives from small cohorts with short follow-up. The aim of this study was to evaluate the oncologic outcomes in an 18-year cohort from a single center. We retrospectively reviewed 398 patients with several malignancies who underwent lung metastasectomy between January 1990 and December 2008. Demographic, clinical, and surgical variables were evaluated. Uni-and multivariate analyses were performed to identify factors associated with overall survival (OS). Mean follow-up was 20 months. Wedge resection was performed in 297 cases and 101 required anatomic resections. In 303 patients the disease-free interval (DFI) was >6 months meanwhile 95 patients had a DFI 6 months. Complete resection was achieved in 351 patients (88.2%). Median OS for all patients was 81.9 months (95% CI, 36.9e126.9). On multivariate analysis, factors associated with a poor overall survival were DFI <6 months (HR, 1.74; 95% CI, 1.24e2.4; p ¼ 0.001) and incomplete resection (HR, 1.58 95% CI, 1.01e2.5; p ¼ 0.0047). Independent prognostic factors associated with better survival were DFI >6 months and complete resection. Size and number of metastases as well as re-do metastasectomy were not associated with worse survival.
Background: Afatinib has shown long progression free survival and improvement in quality of life ... more Background: Afatinib has shown long progression free survival and improvement in quality of life in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Although afatinib causes acneiform rash, it can be manageable. Tetracyclines are usually used to treat it; nonetheless, there is no trial that evaluates their prophylactic efficacy on afatinib induced-skin toxicities (AIST).
Revista de investigación clínica; organo del Hospital de Enfermedades de la Nutrición
Effective communication sometimes requires a common language. This is particularly true in scienc... more Effective communication sometimes requires a common language. This is particularly true in science, where communication among health professionals and scientists across national boundaries has become critical because of the rapidity with which new knowledge is acquired. In the modern era, where multinationalism in key medical and scientific discoveries is increasingly common, the language is undoubtedly English. In fact, more than three-quarters of scientific papers today are published in English.
In recent years, the use of diffusion weighted MRI (DW-MRI) has increased for the diagnosis of fo... more In recent years, the use of diffusion weighted MRI (DW-MRI) has increased for the diagnosis of focal liver lesions (FLLs). DW-MRI may help in the differentiation of benign and malignant FLLs by measuring the apparent diffusion coefficient (ADC) values. Unfortunately, liver metastases present different histopathologic features with variable MRI signals within each lesion; this histologic variability explains the intra- and inter-lesion variations of ADC measurements. We present the case of a 64-year-old female with diagnosis of liver metastasis from small cell lung carcinoma admitted to the emergency unit due to symptoms of inappropriate antidiuretic hormone secretion. Quantitative comparison of two liver MRI, on admission and 2-months after transcatheter arterial chemoembolization showed persistence of the hyperintense metastatic lesions with significant difference in the ADC values in the with-in metastatic lesions (p = 0.001) and between normal tissue and liver metastases only at ...
Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness... more Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness. Angiotensin II (ANGII) was initially described as a vasoconstrictor; recent studies have shown its participation in cellular proliferation, vascularisation, and apoptosis. We conducted a prospective study to evaluate the expression of ANGII receptors - AT1 and AT2 - and their relationship with prognosis. We studied 133 tumours from patients with diagnosis of astrocytoma who underwent surgery from 1997 to 2002. AT1 and AT2 were expressed in 52 and 44% of the tumours, respectively, when determined by both reverse transcriptase-polymerase chain reaction and immunohistochemistry. Ten per cent of low-grade astrocytomas were positive for AT1, whereas grade III and IV astrocytomas were positive in 67% (P<0.001). AT2 receptors were positive in 17% of low-grade astrocytomas and in 53% of high-grade astrocytomas (P=0.01). AT1-positive tumours showed higher cellular proliferation and vascular ...
Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the ma... more Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the main causes of death in patients with liver cirrhosis. High Alpha fetoprotein serum levels have been found in 60-70% of patients with Hepatocellular carcinoma; nevertheless, there are other causes that increase this protein. Alpha fetoprotein levels > or =200 and 400 ng/mL in patients with an identifiable liver mass by imaging techniques are diagnostic of hepatocellular carcinoma with high specificity. We analysed the sensitivity and specificity of the progressive increase of the levels of alpha fetoprotein for the detection of hepatocellular carcinoma in patients with liver cirrhosis. Seventy-four patients with cirrhosis without hepatocellular carcinoma and 193 with hepatic lesions diagnosed by biopsy and shown by image scans were included. Sensitivity and specificity of transversal determination of alpha fetoprotein > or = 200 and 400 ng/mL and monthly progressive elevation of alph...
Fibrolamellar Carcinoma (FLC), a subtype of hepatocellular carcinoma (HCC), is a rare primary hep... more Fibrolamellar Carcinoma (FLC), a subtype of hepatocellular carcinoma (HCC), is a rare primary hepatic malignancy. Several aspects of the clinic features and epidemiology of FLC remain unclear because most of the literature on FLC consists of case reports and small cases series with limited information on factors that affect survival. We did a retrospective analysis of the clinical and histological characteristics of FLC. We also determined the rate of cellular proliferation in biopsies of these tumors. We assessed whether these variables were associated with survival. We found 15 patients with FLC out of 174 patients with HCC (8.6%). Between patients with these neoplasms, we found statistically significant survival, age at onset, level of alpha fetoprotein, and an earlier stage of the disease. The 1, 3 and 5 year survival in patients with FLC was of 66, 40 and 26% respectively. The factors associated with a higher survival in patients with FLC were age more than 23 years, feasibilit...
Angiotensin II (Ang II) is a main effector peptide in the renin-angiotensin system and participat... more Angiotensin II (Ang II) is a main effector peptide in the renin-angiotensin system and participates in the regulation of vascular tone. It also has a role in the expression of growth factors that induce neovascularisation which is closely associated to the growth of malignant gliomas. We have shown that the selective blockage of the AT1 receptor of angiotensin inhibits tumour growth, cell proliferation and angiogenesis of C6 rat glioma. The aim of this study was to study the effects of the blockage of AT1 receptor on the synthesis of growth factors, and in the genesis of apoptosis in cultured C6 glioma cells and in rats with C6 glioma. Administration of losartan at doses of 40 or 80 mg kg(-1) to rats with C6 glioma significantly decreased tumoral volume and production of platelet-derived growth factor, vascular endothelial growth factor and basic fibroblast growth factor. It also induced apoptosis in a dose-dependent manner. Administration of Ang II increased cell proliferation of c...
Following the success of the EGFR inhibitors a renewed interest in IGF-1R inhibitors has emerged.... more Following the success of the EGFR inhibitors a renewed interest in IGF-1R inhibitors has emerged. IGF-1R overexpression has been identified in several tumour types and protects cancer cells from apoptosis. Currently, several different approaches are being investigated for targeting the IGF-1R, including small-molecule kinase inhibitors, IGF1R monoclonal antibodies, antisense oligonucleotides and RNA interference. To date, it is not clear what factors influence sensitivity to IGF-1R blockade but it is likely that tumours that respond well to treatment will be those where IGF-1R overexpression results in a poor patient prognosis. Initial data show that tumour type may also determine response to therapy with squamous nonsmall cell lung cancers responding well to a IGF-1R monoclonal antibody and chemotherapy. The aim of this study is to elucidate the EGFR and IGF-1R expression profile in a cohort of NSCLC patients and correlate the results to patient clinico-pathological data and prognosis. Methods: EGFR and IGF1R expression were evaluated in 197 NSCLC patients (92 -squamous, 87 -adenocarcinoma, 18 -others) using immunohistochemistry (IHC) analysis. Membraneous staining (% cells × staining intensity) was evaluated by a pathologist and scored as follows: 0 (negative), 1+ (weak), 2+ (moderate) and 3+ (strong). Expression of EGFR and IGF1R were also examined in a panel of cell lines (SKMES1, A549, HCC827, H1819, H1299) and patient samples (10 squamous and 10 adenocarcinomas) using Western Blot analysis. Results: The panel of 6 NSCLC cell lines examined showed variability in IGF-1R expression. In the fresh frozen resected NSCLC tumours IGF-1R was overexpressed relative to matched normal tissues. Furthermore squamous cell carcinomas had higher levels of expression than adenocarcinomas. Immunohistochemistry analysis demonstrated that squamous cell tumours have higher IGF-1R expression levels than adenocarcinomas (3+/2+ Squamous [70/197] versus 3+/2+ Adenocarcinoma 27/197)] p < 0.0001). Patients with squamous cell carcinoma also had higher EGFR expression than those with adenocarcinoma (p = 0.002). Patients with EGFR and IGF-1R overexpression had a poorer survival (p = 0.043). Conclusions: Our findings indicate that while EGFR and IGF-1R expression alone are not independent prognostic markers of survival in NSCLC. Taken together overexpression of both proteins correlates to a poor survival. This subset of patients may benefit from treatments cotargeting IGF-1R and EGFR.
Cancer biomarkers : section A of Disease markers, 2014
Few studies, have evaluated the prognostic impact of the quantification of mRNA expression levels... more Few studies, have evaluated the prognostic impact of the quantification of mRNA expression levels in advanced non-small cell lung cancer (NSCLC). The aim of this work was to quantify mRNA expression levels in peripheral blood through three epithelial markers in patients with stages IIIB and IV in NSCLC. Seventy advanced NSCLC patients and ten healthy controls were included. All patients received platinum-based chemotherapy in first line treatment. Peripheral blood was obtained of each participant and mRNA expression levels present in circulating cells were quantified by molecular techniques (RT-PCR) using three epithelial markers: cytokeratin (CK)-18, CK-19 and Carcinoembryonic-Antigen (CEA). The expression levels were quantified from a standard curve using the cDNA obtained from A549 cells. Registered in ClinicalTrials.gov (NCT01052818). We found a significant statistical correlation between levels of CK-18, CK-19 and CEA mRNA. mRNA expression levels were lower in patients who pres...
Journal of Experimental Therapeutics and Oncology, 2002
This study investigated the effects of chronic administration of thalidomide on three different n... more This study investigated the effects of chronic administration of thalidomide on three different neoplasms of ectodermic origin in rodents: 1) chemically induced tumors of the nervous system of rats by transplacental exposure to ethylnitrosourea; 2) transplanted RPMI-1846 melanoma in hamsters and 3) transplanted C6 glioblastoma in rats. No effects were seen on thalidomide-treated rats on the frequency and time of tumor development induced by ethylnitrosourea. In contrast, a reduction in tumoral growth and mitotic-index was obtained in animals treated with thalidomide in transplanted tumors, melanoma and glioblastoma, when compared with controls (P < 0.001 and 0.025, respectively). These results suggest that, although thalidomide is not a cytotoxic drug for neoplastic cells, it might partially inhibit the tumoral growth through any of its pharmacological actions; by blockage of cell-surface adhesion receptors induction of DNA oxidation, or inhibition of angiogenesis. Further investigations on the use of thalidomide perhaps associated to cytotoxic drugs, for treatment of ectodermic neoplasms seem guaranteed.
Between 30% and 50% of patients with non-small-cell lung cancer (NSCLC) will develop cerebral met... more Between 30% and 50% of patients with non-small-cell lung cancer (NSCLC) will develop cerebral metastases in the course of their illness. As improvements are made in the local brain treatment, the question arises on how to manage patients with NSCLC who have solely stable brain metastatic disease and if treatment should be considered for the primary lung lesion. The present article will review published series of patients with NSCLC and with brain metastases treated with aggressive thoracic management, with either lung tumor resection or thoracic radiation with or without chemotherapy as definitive treatment. We will also assess which prognostic factors may be useful in the identification of the subset of patients who could benefit from this more aggressive approach. For patients treated with surgical resection for the primary lung tumor, median survival ranged from 19 to 27 months, and the 1-, 2-, and 5-year survival reached 56%-69%, 28%-54%, and 11%-24%, respectively. Patients treated with aggressive radiotherapy with or without chemotherapy, achieved a median survival of 15.5-31.8 months, with a 1-year survival of 50%-71%, and a 2-year survival of 16%-60%. Well-selected patients with NSCLC and with exclusively oligometastatic cerebral disease represent a subgroup of patients with stage IV NSCLC that might achieve long-term survival after treatment directed to the brain and lung tumor lesions. Patients with N0 or N1 disease may be selected for surgical thoracic treatment, whereas those with N2 or N3 disease may benefit from combined chemoradiotherapy in the absence of progression after induction chemotherapy.
Because of improved therapeutic results after first-line platinum-based chemotherapy in patients ... more Because of improved therapeutic results after first-line platinum-based chemotherapy in patients with stage IV non-small-cell lung cancer (NSCLC), second-line chemotherapy may be considered for a growing number of patients. Approximately, 10% of patients have an interval time after concluding first-line platinum-based chemotherapy greater than 6 months. These patients may achieve high tumor responses when platinum is again used in second-line treatment. Twenty-three patients experiencing progression following 6 months after concluding platinum-based chemotherapy were managed with second-line treatment with carboplatin combined with gemcitabine or pemetrexed. Overall response, progression-free survival (PFS), and overall survival (OS) after initiation of second-line treatment were calculated for all patients. Median PFS after first-line treatment was 12.6 months (95% confidence interval [95% CI], 10.4-14.7 months). Partial response was achieved in 7 of 23 patients, resulting in an overall response of 30.4% (95% CI, 11.6-49.0). Following initiation of second-line chemotherapy, median PFS was 5.9 months (95% CI, 1-10.9 months) and median OS was 12.5 months (95% CI, 3.5-21.5 months). The 1-year survival rate for all patients was 61.0% (95% CI, 29.5-82.0). Adding these results to those of the 10 previously published trials, 75 of 326 patients, 23%, (95% CI, 18.7-27.3) presented an overall response with the use of second-line platinum-based chemotherapy. The use of platinum combinations as second-line chemotherapy seems to have a place in the management of patients with advanced NSCLC, especially those with an interval time to progression greater than 6 months.
Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2.... more Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. Eli Lilly.
The aim of this study is to determine clinical and histopathological characteristics correlated t... more The aim of this study is to determine clinical and histopathological characteristics correlated to responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer.
Introduction: Previously, we reported the frequency of epidermal growth factor receptor (EGFR) an... more Introduction: Previously, we reported the frequency of epidermal growth factor receptor (EGFR) and KRAS mutations in nonsmallcell lung cancer (NSCLC) patients in Latin America. The EGFR mutation frequency was found between Asian (40%) and Caucasian (15%) populations. Here, we report the updated distribution of NSCLC mutations.
Interactive cardiovascular and thoracic surgery, 2010
We retrospectively reviewed the records of 100 patients with malignant disease and symptomatic pe... more We retrospectively reviewed the records of 100 patients with malignant disease and symptomatic pericardial effusion initially treated with pericardiocentesis at the National Cancer Institute of Mexico between 1985 and 2009. We analyzed predictive factors for recurrence of pericardial effusion by bi- and multivariate analyses. The group comprised 74 women and 26 men. Twenty patients had developed malignant pericardial effusion at the time of primary cancer diagnosis. Recurrence rate after pericardiocentesis was 33%. Progression-free survival for pericardial effusion at one year was 59% (range, 47-71%). Median overall survival (OS) after pericardiocentesis was 40.3+/-7.9 weeks (95% Confidence interval, 24.9-55.7). The sole factor that correlated with increased progression-free survival for pericardial effusion was the presence of bloody pericardial effusion. For OS, multivariate analysis yielded that female gender and presence of pericardial effusion at time of primary malignancy diag...
All-trans retinoic acid (ATRA) promotes the endogenous expression of both nerve growth factor (NG... more All-trans retinoic acid (ATRA) promotes the endogenous expression of both nerve growth factor (NGF) and retinoic acid receptor beta (RAR-b). We have previously shown that the administration of ATRA partly reverts the damage induced by diabetic neuropathy (DN). In this investigation, we evaluated the effects of vitamin A, a commercial, inexpensive compound of retinoic acid, on the therapy of DN. A total of 70 rats were randomized into 4 groups. Group A was the control, and groups B, C, and D received a total dose of 60 mg/kg streptozotocin intraperitoneally. When signs of DN developed, groups C and D were treated either with vitamin A (20,000 IU) or with ATRA 25 mg/kg for 60 days. Plasma glucose, contents of NGF, thermal and nociceptive tests, and RAR-b expression were evaluated. All diabetic rats developed neuropathy. The treatment with vitamin A and ATRA reverted similarly the sensorial disturbances, which was associated with increased contents of NGF and RAR-b expression. Our results indicate that the administration of vitamin A has the same therapeutic effect as ATRA on peripheral neuropathy and suggest its potential therapeutic use in patients with diabetes. (Translational Research 2014;164:196-201) Abbreviations: ATRA ¼ all-trans retinoic acid; DN ¼ diabetic neuropathy; NGF ¼ nerve growth factor; RA ¼ retinoic acid; RAR-a ¼ retinoic acid receptor alpha; RAR-b ¼ retinoic acid receptor beta; STZ ¼ streptozotocin
Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neur... more Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neuropathy. All-trans retinoic acid (RA) increases the expression of neural growth factor and its receptor participating in translation pathways. This study evaluates RA as a treatment of diabetic neuropathy: 120 mice were assigned randomly to 4 groups. Group A (n ؍ 30) was taken as control; group B (n ؍ 30) received 50 mg/kg intraperitoneal streptozotocin (STZ); group C (n ؍ 30) received STZ, and after diabetic neuropathy developed, they were treated with subcutaneous RA 20 mg/kg daily during 60 days; and group D (n ؍ 30) only received RA. Plasma glucose, thermosensitive tests, serum, and the nerve contents of NGF were measured in all animals. Evaluation by electron microscopy was performed in search of morphologic changes secondary to neuropathy and nerve regeneration. Diabetic mice had an increased threshold to pain. Treatment with RA in diabetic mice reverted changes in sensitivity as compared with diabetic mice that received placebo (P < 0.001). No differences in pain threshold among controls, RA, and diabetes mellitus (DM) ؉ RA groups were found. Glucose levels were not affected by the treatment with RA. NGF diminished significantly in the sciatic nerve in diabetic mice as compared with controls and with the RA group. Animals with DM ؉ RA had a significant increase of NGF in nerves as compared with the other groups. RA also regressed the ultrastructural changes induced by diabetes that showed increased neural regeneration. RA can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of the increased of NGF concentrations in nerve terminals. (Translational Research 2008;152:31-37) Abbreviations: DM ϭ diabetes mellitus; DRG ϭ dorsal root ganglion; NGF ϭ neural growth
Lung metastasectomy is an area of interest and controversy in surgical oncology. Most of the avai... more Lung metastasectomy is an area of interest and controversy in surgical oncology. Most of the available evidence derives from small cohorts with short follow-up. The aim of this study was to evaluate the oncologic outcomes in an 18-year cohort from a single center. We retrospectively reviewed 398 patients with several malignancies who underwent lung metastasectomy between January 1990 and December 2008. Demographic, clinical, and surgical variables were evaluated. Uni-and multivariate analyses were performed to identify factors associated with overall survival (OS). Mean follow-up was 20 months. Wedge resection was performed in 297 cases and 101 required anatomic resections. In 303 patients the disease-free interval (DFI) was >6 months meanwhile 95 patients had a DFI 6 months. Complete resection was achieved in 351 patients (88.2%). Median OS for all patients was 81.9 months (95% CI, 36.9e126.9). On multivariate analysis, factors associated with a poor overall survival were DFI <6 months (HR, 1.74; 95% CI, 1.24e2.4; p ¼ 0.001) and incomplete resection (HR, 1.58 95% CI, 1.01e2.5; p ¼ 0.0047). Independent prognostic factors associated with better survival were DFI >6 months and complete resection. Size and number of metastases as well as re-do metastasectomy were not associated with worse survival.
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Papers by Oscar Arrieta