TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4.

Cells released from primary tumors seed metastases to specific organs by a nonrandom process, implying the involvement of biologically selective mechanisms. Based on clinical, functional, and molecular evidence, we show that the cytokine TGFbeta in the breast tumor microenvironment primes cancer cells for metastasis to the lungs. Central to this process is the induction of angiopoietin-like 4 (ANGPTL4) by TGFbeta via the Smad signaling pathway. TGFbeta induction of Angptl4 in cancer cells that are about to enter the circulation enhances their subsequent retention in the lungs, but not in the bone. Tumor cell-derived Angptl4 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries, and facilitates the trans-endothelial passage of tumor cells. These results suggest a mechanism for metastasis whereby a cytokine in the primary tumor microenvironment induces the expression of another cytokine in departing tumor cells, empowering these cells to disrupt lung capillary walls and seed pulmonary metastases.

Fear of happiness through the prism of the dual continua model of mental health.

OBJECTIVE: Two studies were conducted to investigate fear of happiness through the lens of the dual continua model of mental health. METHODS: In Study 1, we examined whether depression (indicator of mental illness) and happiness (indicator of mental health) predicted fear of happiness through a Structural Equation Model. In Study 2, we ran a quasi-experimental design to examine differences in affect (positive and negative), happiness and depression when engaging in either fearless or fearful beliefs of happiness. RESULTS: Fear of happiness was positively and negatively predicted by depression and happiness, respectively. Fearless individuals reported higher positive affect and happiness, and lower negative affect and depression, than fearful individuals. CONCLUSIONS: Fearing happiness might act as a maladaptive self-verifying motive to enhance one's perspective of the world. Given the likelihood of modifying maladaptive cognitive patterns, we highlight different psychological interventions that can address the negative impact of fearful beliefs of happiness.

Effects of School-based Multicomponent Positive Psychology Interventions on Well-being and Distress in Adolescents: A Systematic Review and Meta-analysis.

Multicomponent positive psychology interventions are increasing in the general population but the study of its effectiveness in adolescents is still scarce, especially in the school context. Previous meta-analyses have reported that multicomponent positive psychology interventions increase well-being and reduce distress outcomes. However, the results on these outcomes limit their samples to adult populations. The aim of the current systematic review and meta-analysis is to evaluate and compare the immediate but also long-lasting effects of school-based multicomponent positive psychology interventions aimed at increasing well-being indicators of mental health (i.e., subjective and psychological well-being) and reducing the most common psychological distress indicators (i.e., depression, anxiety, and stress) in adolescents. A total of 9 randomized and non-randomized controlled trials from the searched literature met inclusion criteria for the meta-analysis. The results showed small effects for subjective well-being (g = 0.24), psychological well-being (g = 0.25), and depression symptoms (g = 0.28). Removing low-quality studies led to a slight decrease in the effect sizes for subjective well-being and a considerable increase for psychological well-being and depression symptoms. The relevant moderation analyses had an effect on subjective well-being and depression symptoms. The present systematic review and meta-analysis found evidence for the efficacy of school-based multicomponent positive psychology interventions in improving mental health in the short and long-term. Small effects for subjective well-being, psychological well-being, and depression symptoms were identified. Effects for psychological well-being and depression symptoms remained significant over time. In light of our results, education policy-makers and practitioners are encouraged to include positive practices within the schools' curriculum as effective and easily implemented tools that help to enhance adolescents' mental health. Further research is needed in order to strengthen the findings about school-based multicomponent positive psychology interventions in adolescents.

Changes of liver hemodynamic and elastography parameters in patients with colorectal liver metastases receiving preoperative chemotherapy: "a note of caution".

BACKGROUND: New systemic chemotherapy agents have improved prognosis in patients with colorectal liver metastases (CLM), but some of them damage the liver parenchyma and ultimately increase postoperative morbidity and mortality after liver resection. The aims of our study were to determine the degree of hemodynamic and pathological liver injury in CLM patients receiving preoperative chemotherapy and to identify an association between these injuries and postoperative complications after liver resection. METHODS: This is a prospective descriptive study of patients with CLM receiving preoperative chemotherapy before curative liver resection from November 2013 to June 2014. All patients had preoperative elastography and hepatic hemodynamic evaluation. We analyzed clinical preoperative data and postoperative outcomes after grouping the patients by chemotherapy type, development of sinusoidal obstructive syndrome (SOS), and development of major complications. RESULTS: Eleven from the 20 patients included in the study received preoperative oxaliplatin-based chemotherapy (OBC). Nine patients had SOS at pathological analysis and five patients developed major complications. Patients receiving preoperative OBC had higher values of hepatic venous pressure gradient (HVPG) and developed more SOS and major complications. Patients developing SOS had higher values of HVPG and developed more major complications. Patients with major complications had higher values of HVPG, and patients with a HVPG of 5 mmHg or greater had more major complications than those under 5 mmHg (20 vs 80%, p = 0.005). CONCLUSIONS: OBC and SOS impair liver hemodynamics in CLM patients. An increase in major complications after liver resection in these patients develops at subclinical HVPG levels.

[Effectiveness and economic impact of a program of integrated care with telemedicine support on insulin-treated type 2 diabetic patients (Study GITDIABE)]. / Efectividad e impacto económico de un programa de atención integrada con soporte de telemedicina a pacientes diabéticos tipo 2 tratados con insulina (estudio GITDIABE).

AIM: To evaluate if insulin-treated type 2 diabetic patients with blood glucose self-monitoring (DIA), included in a program of integrated management of diabetes mellitus (DM), achieve a better level of metabolic control with telemedicine support than with conventional support, after 12 months follow-up. The impact on the use and cost of healthcare services, pharmaceutical expenditure, and consumption of test strips for blood glucose, was also assessed. DESIGN: A prospective parallel cohorts study. FIELD: Four basic health areas of an integrated healthcare organisation. PARTICIPANTS: The study included 126 DIA patients aged 15 or more years, treated with rapid or intermediate Insulin and blood glucose self-monitoring, grouped into 42 cases and 84 controls, matched according to age, sex, level of metabolic control, and morbidity profile. INTERVENTION: Telematics physician-patient communication and download of blood glucose self-monitoring data through the Emminens eConecta® platform; test strips home delivered according to consumption. Hidden controls with usual follow-up. MAIN MEASUREMENTS: Glycosylated haemoglobin (%HbA1c); perception of quality of life (EuroQol-5 and EsDQOL); cardiovascular risk; use of healthcare resources; consumption of test strips; pharmaceutical and healthcare expenditure. RESULTS: Reduction of 0.38% in HbA1c in the cases (95% CI:-0.89% to 0.12%). No significant differences with regard to any of the activities registered, or any significant change in the quality of life. CONCLUSIONS: The results obtained are similar to other equivalent studies. The profile of the patient is elderly and with multiple morbidities, who still have technological limitations. To surpass these barriers, it would be necessary to devote more time to the training and to the resolution of possible technological problems.

Genes that mediate breast cancer metastasis to the brain.

The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells.

Breast cancers may evade the growth-inhibitory action of TGFbeta by accumulating defects of unknown nature that selectively eliminate cytostatic gene responses. We found the transcription factor C/EBPbeta to be essential for TGFbeta induction of the cell cycle inhibitor p15INK4b by a FoxO-Smad complex and repression of c-MYC by an E2F4/5-Smad complex in human epithelial cells. These cytostatic responses are selectively missing in metastatic breast cancer cells from half of the patients that we tested. The basis for this loss was traced to an excess of the C/EBPbeta inhibitory isoform LIP. We suggest that C/EBPbeta plays a key role in the coordination of TGFbeta cytostatic gene responses, and its malfunction may trigger evasion of these responses in breast cancer.

Liraglutide for the treatment of obesity among patients with hidradenitis suppurativa.

BACKGROUND AND AIMS: Hidradenitis suppurativa (HS) is associated with obesity. Weight loss is frequently reflected in an amelioration in the severity of the lesions. Case reports have suggested that liraglutide might improve not only weight but also skin. We aimed to study the effects of liraglutide 3mg in patients with obesity and HS on metabolic and dermatological parameters. METHODS: 14 patients started treatment with liraglutide for 3 months. Severity of the lesions was evaluated using the Hurley Staging System and quality of life with the DLQI (Dermatology Quality Index). RESULTS: There was a significant reduction in BMI (39.3±6.2 vs 35.6±5.8; p=0.002), waist circumference (121.3±19.2 vs 110.6±18.1cm; p=0.01), CRP (4.5±2.2 vs 3±2.1mg/L; p=0.04), homocysteine (16.2±2.9 vs 13.3±3µmol/L; p=0.005) and plasma cortisol (15.9±4.8 vs 12.6±4.5µg/dL; p=0.007). Hurley (2.6±0.5 vs 1.1±0.3; p=0.002) and DLQI (12.3±2.8 vs 9.7±6.9; p=0.04) improved significantly. In multiple regression analysis, weight loss did not correlate with any inflammatory parameter or Hurley. CONCLUSIONS: Liraglutide 3mg is effective and safe among patients with HS and obesity. Long-term studies are mandatory to assess the effects of liraglutide on skin lesions and inflammatory markers among subjects with HS beyond weight loss.

Mediators of vascular remodelling co-opted for sequential steps in lung metastasis.

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.

Effects of liraglutide among patients living with psoriasis and obesity.

BACKGROUND AND AIMS: There is a bidirectional relationship between obesity and psoriasis. Liraglutide has been shown to improve the severity of psoriatic lesions in patients with type 2 diabetes. We aimed to study the effects of liraglutide 3mg in patients with obesity and psoriasis. METHODS: Twenty patients started treatment with liraglutide 3mg for 3 months. Severity of the lesions was evaluated using the Psoriasis Area Severity Index (PASI) and the visual analogue scale of pain (VAS), and quality of life with the Dermatology Quality Index (DLQI). RESULTS: There was a significant reduction in BMI (38.9±5.8 vs. 36.4±5.6; p<0.001), CRP (4.5±2.4 vs. 3±2mg/L; p<0.01), homocysteine (13.3±3.6 vs. 11.9±3µmol/L; p<0.01), ferritin (185.4±142.2 vs. 97.43±114.4ng/mL; p=0.04) and plasma cortisol (12±3.1 vs. 11.6±2.2µg/dL, p=0.04). PASI (10±8.4 vs. 5.1±6; p<0.0001), VAS (4.1±2 vs. 2.3±0.92; p=0.009) and DLQI (12.7±7 vs. 6.4±5.6, p<0.0001) improved significantly. In multiple regression analysis, weight loss did not correlate with any inflammatory parameter or PASI. CONCLUSIONS: Liraglutide 3mg for three months is effective and safe in reducing weight and improving psoriatic lesions among patients with psoriasis and obesity. Besides, there is an improvement in psoriatic lesions regardless of weight loss that deserves further studies.

Moderation effects of loneliness between fatalism and wellbeing during the COVID-19 pandemic.

The COVID-19 pandemic has put more than just our physical health at risk. Due to containment measures, people have become increasingly isolated and have drastically reduced their daily social interactions. Many studies have already shown the negative effects of these measures, including fatalism. However, research linking fatalism during COVID-19 to well-being indicators is still limited. The goal of this study is to examine the relationship between COVID-19-related fatalism and well-being indicators, as well as the role of loneliness in moderating this relationship. Data was collected from 1,036 adults in Peru through an online survey that included the Quality-of-Life Index, the Fatalism Facing COVID-19 Scale, the Loneliness Scale, and the Mood Assessment Scale. Three models were tested using linear regression and ordinary least squares with bias-corrected bootstrapping. The results indicate that fatalism has a negative impact on quality of life and a positive effect on negative affect, and loneliness moderates both relationships, supporting the conclusion that fatalism exacerbates the effect of well-being indicators and negative affect.

Outcomes and cost of lung cancer patients treated surgically or medically in Catalunya: cost-benefit implications for lung cancer screening programs.

Lung cancer screening programs with computed tomography of the chest reduce mortality by more than 20%. Yet, they have not been implemented widely because of logistic and cost implications. Here, we sought to: (1) use real-life data to compare the outcomes and cost of lung cancer patients with treated medically or surgically in our region and (2) from this data, estimate the cost-benefit ratio of a lung cancer screening program (CRIBAR) soon to be deployed in our region (Catalunya, Spain). We accessed the Catalan Health Surveillance System (CHSS) and analysed data of all patients with a first diagnosis of lung cancer between 1 January 2014 and 31 December 2016. Analysis was carried forward until 30 months (t = 30) after lung cancer diagnosis. Main results showed that: (1) surgically treated lung cancer patients have better survival and return earlier to regular home activities, use less healthcare related resources and cost less tax-payer money and (2) depending on incidence of lung cancer identified and treated in the program (1-2%), the return on investment for CRIBAR is expected to break even at 3-6 years, respectively, after its launch. Surgical treatment of lung cancer is cheaper and offers better outcomes. CRIBAR is estimated to be cost-effective soon after launch.

Time to Review Authorisation and Funding for New Cancer Medicines in Europe? Inferences from the Case of Olaratumab.

The potential benefits of early patient access to new medicines in areas of high unmet medical need are recognised, but uncertainties concerning effectiveness, safety and added value when new medicines are authorised, and subsequently funded based on initial preliminary data only, have important implications. In 2016 olaratumab received accelerated conditional approval from both the European Medicines Agency and the US Food and Drug Administration for the treatment of soft-tissue sarcoma, based on the claims of a substantial reduction in the risk of death with an 11.8-month improvement in median overall survival in a phase II trial in combination with doxorubicin vs. doxorubicin alone. The failure to confirm these benefits in the post-authorisation pivotal trial has highlighted key concerns regarding early access and conditional approvals for new medicines. Concerns include potentially considerable clinical and economic costs, so that patients may have received suboptimal treatment and any money spent has foregone the opportunity to improve access to effective treatments. As a result, it seems reasonable to reconsider current marketing authorisation models and approaches. Potential pathways forward include closer collaboration between regulators, pharmaceutical companies and payers to enhance the generation of rapid and comparative confirmatory trials in a safe and fair manner, with minimal patient exposure as required to achieve robust evidence. Additionally, it may be time to review early access systems, and to explore new avenues regarding who should pay or part pay for new treatments whilst information is being collected as part of any obligations for conditional marketing authorisation. Greater co-operation between countries regarding the collection of data in routine clinical care, and further research on post-marketing data analysis and interpretation, may also contribute to improved appraisal and continued access to new innovative cancer treatments.

[Prediction of prognosis of patients with pancreatic adenocarcinoma with curative intent resection by means of histologic grade and pathologic N stage]. / Predicción del pronóstico de los pacientes con adenocarcinoma pancreático resecado con intención curativa mediante el grado histológico y el estadio N patológico.

BACKGROUND AND OBJECTIVE: Pancreatic cancer has the poorest prognosis of any common gastrointestinal malignancy, with a 5-year overall survival of less than 5%. A better knowledge of prognostic factors related to this neoplasia might help improve the survival of these patients. We evaluated the prognostic significance of different factors in both overall survival and tumor recurrence in patients with pancreatic adenocarcinoma who had undergone pancreatic resection with curative intent. PATIENTS AND METHOD: All patients with pancreatic adenocarcinoma submitted to surgical resection in our unit from January 1995 to February 2005 were evaluated. Twenty-three pre-surgical, therapeutic, and histopathologic variables were analyzed. Univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) analyses were performed to select independent prognostic factors. RESULTS: Ninety-four patients were evaluated. The median age of patients was 63 years and 53% were woman. The probability of overall survival was 63% at 1 year, 18% at 3 years, and 8% at 5 years, with a median survival of 18 months. Univariate analysis identified performance of adjuvant therapy, histologic grade, percentage of involved-resected lymph nodes, pathologic N stage, and pathologic TNM stage as variables associated with overall survival. On the other hand, the probability of tumor recurrence was 52% at 1 year, 83% at 3 years, and 91% at 5 years, with a median time to tumor recurrence of 12 months. Predictive variables of tumor recurrence in the univariate analysis were preoperative N stage, preoperative TNM stage, postoperative CA 19.9 serum concentration, histological grade, percentage of involved-resected lymph nodes, pathologic N stage and pathologic TNM stage. Multivariate analysis identified histological grade and pathologic N stage as independent predictive factors of both overall survival (histologic grade: HR=2.341 [CI 95%, 1.342-4.098; p=0.003]; pathologic N stage: HR=2.242 [1.213-4.149; p=0.01]) and tumor recurrence (histological grade: HR=1.742 [CI 95%, 1.121-3.086; p=0.05]; pathologic N stage: HR=2.096 [1.089-4.032; p=0.027]). CONCLUSIONS: The histological grade and pathologic N stage predict the prognosis of patients with pancreatic adenocarcinoma after surgical resection.

Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial.

This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)°C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events ≥ 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile.

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29.

Is there a genetic signature for liver metastasis in colorectal cancer?

Even though liver metastasis accounts for the vast majority of cancer deaths in patients with colorectal cancer (CRC), fundamental questions about the molecular and cellular mechanisms of liver metastasis still remain unanswered. Determination of gene expression profiles by microarray technology has improved our knowledge of CRC molecular pathways. However, defined gene signatures are highly variable among studies. Expression profiles and molecular markers have been specifically linked to liver metastases mechanistic paths in CRC. However, to date, none of the identified signatures or molecular markers has been successfully validated as a diagnostic or prognostic tool applicable to routine clinical practice. To obtain a genetic signature for liver metastasis in CRC, measures to improve reproducibility, to increase consistency, and to validate results need to be implemented. Alternatives to expression profiling with microarray technology are continuing to be used. In the recent past, many genes codifying for proteins that are directly or indirectly involved in adhesion, invasion, angiogenesis, survival and cell growth have been linked to mechanisms of liver metastases in CRC.

Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer.

PURPOSE: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor is overexpressed in pancreatic cancer, and in vitro studies have shown that epidermal growth factor receptor inhibitors can overcome radio- and chemoresistance. The aim of the study was to determine whether the addition of gefitinib to RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC) was feasible and safe. METHODS AND MATERIALS: Eighteen patients with pathologically proven LAPC, based on major vascular invasion based on helical computed tomography (CT) and endoscopic ultrasound, were entered into the study. The targeted irradiated volume included the tumor and 2-cm margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cm(3) of planning tumor volume were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150, and 200 mg/m(2)/day of gemcitabine in a 2-h infusion over Weeks 1, 2, 3, 4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers was also performed to evaluate a possible antiangiogenic effect. RESULTS: There were no dose-limiting toxicities. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. The median (95% confidence interval [CI]) progression-free survival was 3.7 (95% CI = 1.9-5.5) months, and the median overall survival was 7.5 (95% CI = 5.2-9.9) months. No significant reduction of vascular endothelial growth factor and interleukin-8 was observed after treatment. CONCLUSION: Our results support that the combination of gefitinib, RT, and gemcitabine has an acceptable toxicity but with modest activity in LAPC.

FAS/FAS ligand ratio: a marker of oxaliplatin-based intrinsic and acquired resistance in advanced colorectal cancer.

PURPOSE: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs. Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown. PATIENTS AND METHODS: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses. RESULTS: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P=0.0001; 0.07 versus 0.14 ng/mL; P=0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11 ng/mL; P=0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001). CONCLUSIONS: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.