Osteopontin expression and its relationship with prognostic factors in diffuse large B-cell lymphoma.

The aim of this study is to explore the expression of osteopontin (OPN) and its relationship with prognostic factors and survival in diffuse large B cell lymphoma (DLBCL). A tissue microarray was performed for immunohistochemical evaluation. Contingency tables were analyzed for trends; chi-square test was used to determine differences between groups. Univariate and multivariate Cox proportional hazards-regression analyses were performed to evaluate the impact of prognostic factors on survival. Expression of OPN was observed in 28%. It was different in non-germinal center DLBCL (P=0.04). The mean overall survival (OS) was lower in patients with positive OPN expression (19.762; CI 95% 14.269-25.255) it was not significant (P=0.123). It is not possible to establish a clear relationship between the expression by immunohistochemistry of osteopontin and a poor prognosis but it would be important to complement the analysis with other techniques as PCR or NGS that allow us to assess the influence of the isoforms and post-translational modifications of OPN on the biological behavior of DLBCL. Our findings indicate that OPN expression could be associated with a more aggressive variant of lymphoma: non-germinal center DLBCL.

Molecular Epidemiology of ALK Rearrangements in Advanced Lung Adenocarcinoma in Latin America.

OBJECTIVE: Latin American countries are heterogeneous in terms of lung cancer incidence and exposure to potential carcinogens. We evaluated the frequency and clinical characteristics of ALK rearrangements (ALKr) in Latin America. METHODS: A total of 5,130 lung cancer patients from 10 Latin American countries were screened for inclusion. ALKr detection was performed by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to assess method variability. Demographic and clinicopathologic characteristics were analyzed. RESULTS: Among the 5,130 patients screened, 8.4% (n = 433) had nonevaluable FISH tests. Evaluable FISH analyses revealed positive ALKr in 6.8% (320/4,697) of the study population, which included patients from 9 countries. ALKr distribution for each country was: Mexico 7.6% (79/1,034), Colombia 4.1% (10/242), Argentina 6.0% (153/2,534), Costa Rica 9.5% (13/137), Panama 4.4% (5/114), Uruguay 5.4% (2/37), Chile 8.6% (16/185), Venezuela 8.9% (13/146), and Peru 10.8% (29/268). RT-PCR showed high positive (83.6%) and negative (99.7%) predictive values when compared to the gold standard FISH. In contrast, IHC only showed a high negative predictive value (94.6%). CONCLUSIONS: Although there is a clear country and continental variability in terms of ALKr frequency, this difference is not significant and the overall incidence of ALKr in Latin America does not differ from the rest of the world.

Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus.

Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.

A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer.

Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m(2) as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m(2)) or cisplatin (50 mg/m(2)) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were 163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.

The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer.

OBJECTIVES: In non-small cell lung cancer (NSCLC), the association between common EGFR mutations (Del EX19/L858R) with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been well established. However, this has not been investigated for rare EGFR mutations or their impact on treatment response and outcome to EGFR TKIs (primary objective) and chemotherapy (secondary objective). MATERIALS AND METHODS: In an observational prospective cohort, we analyzed 188 NSCLC patients from Mexico, Colombia and Costa Rica with EGFR mutations. As a first line of treatment, 66.5% received platinum-based chemotherapy. All patients received TKIs in first-line treatment or after progression to chemotherapy. The clinical-pathological characteristics as well as the f of common and rare EGFR mutations associated with treatment response were analyzed. RESULTS: Of all patients, 79.5% had common and 20.5% had rare EGFR mutations. Lepidic and acinar adenocarcinomas were associated with common EGFR mutations (p=0.010). Patients with common EGFR mutations had higher response rates to EGFR-TKIs than those who had rare EGFR mutations (63.8 vs 32.4%, p<0.001). Women had increased progression-free survival (PFS) to EGFR-TKIs than men (16.4 vs 9.5 months, p=0.02). The median PFS and overall survival (OS) were better in patients with common EGFR mutations (15.5 vs 3.9 months, p<0.001; and 37.3 vs 17.4 months, p<0.001) respectively. CONCLUSION: Our findings suggested that only patients with rare EGFR mutations could receive platinum-based chemotherapy as a first-line treatment, due to their low response rates and short PFS in response to EGFR-TKIs. Consequently, EGFR-TKIs could be reserved as a second- or third-line treatment. In patients with EGFR mutations, women have better PFS to EGFR-TKIs than men, and rare EGFR mutations are more frequent in high grade adenocarcinomas than in low grade tumors.

Angiotensin II stimulates cyclooxygenase-2 mRNA expression in renal tissue from rats with kidney failure.

We have shown increased cyclooxygenase-2 (COX-2) expression in rats with kidney failure. Increased angiotensin II concentration, hypertension, and renal mass reduction have been described during development of kidney failure. Thus we explored each of these mechanisms, because any one of them could be responsible for COX-2 induction. Kidney failure increased systolic blood pressure from 104 +/- 5 to 138 +/- 2 mmHg, urinary PGE(2) from 74 +/- 17 to 185 +/- 25 ng/24 h, and COX-2 expression from 0.06 +/- 0.04 to 0.17 +/- 0.03 arbitraty units (AU). Treatment of the rats with ramipril or losartan prevented the increase in blood pressure, urinary PGE(2), and COX-2 expression in the rats with kidney failure. Infusion of angiotensin II increased blood pressure from 101 +/- 6 to 132 +/- 6 mm Hg, urinary PGE(2) excretion from 62 +/- 15 to 155 +/- 17 ng/24 h, and COX-2 expression from 0.23 +/- 0.01 to 1.6 +/- 0.3 AU. When the angiotensin II-infused rats were treated with nitrendipine, blood pressure decreased from 132 +/- 6 to 115 +/- 2 mm Hg, and urinary PGE(2) excretion decreased from 152 +/- 18 to 97 +/- 12 ng/24 h, whereas COX-2 expression was 1.6 +/- 0.7 and 1.7 +/- 0.5 AU for rats with and without nitrendipine. Blood pressure of the rats with renal pole resection was similar to that in sham rats (97 +/- 7 and 91 +/- 4 mmHg, respectively), whereas COX-2 expression was increased in rats with renal pole resection, from 0.06 +/- 0.04 to 0.12 +/- 0.03 AU. We suggest that in kidney failure, the increase in angiotensin II concentration regulates COX-2 expression, thereby increasing prostaglandin synthesis, which contributes to the development of kidney failure.