Rituximab for the treatment of acute exacerbation of interstitial lung disease associated with connective tissue disease.

BACKGROUND: Acute exacerbation of interstitial lung disease (AE-ILD) is a severe complication with a poor prognosis. No clinical trials have supported the use of rituximab in AE-ILD associated with connective tissue disease. METHODS: We present a series of four cases in which administration of rituximab was associated with appropriate clinical, radiological and functional progress. RESULTS: The four patients were alive 30 days after discharge following their exacerbation. CONCLUSIONS: Given the speed of action, safety and efficacy profile observed for rituximab, we believe that this agent should be further investigated in clinical trials so that it could be included in the daily clinical management of this severe condition.

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer.

BACKGROUND: In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial. PATIENTS AND METHODS: We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). RESULTS: A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤ 50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2- and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤ 50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%. CONCLUSION: Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis. IMPLICATIONS FOR PRACTICE: The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis.

Relationship of immunohistochemical biomarker expression and lymph node involvement in patients undergoing surgical treatment of NSCLC with long-term follow-up.

We try to identify the relationship between immunohistochemical marker expression and lymph node involvement in a cohort of 282 patients followed for 5 years after curative resection for NSCLC. In 189 patients (67%), lymph nodes were unaffected while 93 patients (33%) showed nodal involvement. The expression of 15 molecular markers was determined from each patient by tissue-array immunohistochemistry. Univariate analysis indicated significantly higher expression of E-cadherin, γ-catenin, p27, and p53 in patients with lymph node involvement. In those with unaffected nodes, p16 and Rb were expressed. E-cadherin expression was related to a 50% mortality reduction in patients with node involvement (hazard ratio (HR) 0.5; p = 0.017). c-erbB-2 expression was correlated with a 3.4-fold increase in mortality compared to patients without expression of this marker in subjects without node involvement (HR 3.41; p = 0.017). Multivariate analysis identified c-erbB-2 (HR 2.22; p = 0.089) and p27 (HR 1.44; p = 0.019) as prognostics of mortality while Rb (HR 0.74) indicated a good prognosis. The expression of proteins encoded by oncogenes and tumor suppressor genes was different according to lymph node involvement. The increased mortality related to c-erbB-2 expression in patients with unaffected lymph nodes would suggests a need for adjuvant treatment.

Assessment of Topoisomerase II α status in breast cancer by quantitative PCR, gene expression microarrays, immunohistochemistry, and fluorescence in situ hybridization.

Anthracyclines are frequently used for the treatment of breast cancer and topoisomerase II alpha (TOP2A) is considered to be the molecular target. Numerous studies have evaluated the predictive value of TOP2A using different methodological approaches and inconsistent results have been reported. Indeed, the correlation between techniques for the assessment of TOP2A status has not been well evaluated. In this study, we determined TOP2A status in 61 breast tumor samples by real-time PCR, DNA microarrays, immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH), and then evaluated these results with clinical-pathological features and breast cancer intrinsic subtypes. First, we observed a statistical significant correlation of TOP2A gene expression between real-time PCR and microarrays (Pearson coefficient, 0.816; P < 0.001), and both predicted TOP2A IHC results fairly well (area under the curve > 0.74). In contrast, poor agreement between FISH and IHC data was observed (k: 0.134). Secondly, TOP2A expression was found significantly associated with cell proliferation, and with the highly proliferative Luminal B, Her2-enriched and Basal-like intrinsic subtypes. In conclusion, TOP2A expression in breast cancer was associated with high proliferation and aggressive tumor subtypes and appears to be independent of its amplification status. All of these features should be taken into consideration when assessing the predictive value of TOP2A for anthracycline-based chemotherapy.

Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer.

BACKGROUND: Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS: After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS: Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS: Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.

Abnormal transforming growth factor-beta expression in mesenchymal stem cells from patients with osteoarthritis.

OBJECTIVE: To determine the expression of the genes that code for the isoforms of transforming growth factor-beta (TGF-beta) and TGF-beta receptors (TBR) in mesenchymal stem cells (MSC) from patients with osteoarthritis (OA). METHODS: Total RNA was extracted from primary cultures of MSC and quantitative real-time reverse transcription-polymerase chain reaction was performed to analyze gene expression. RESULTS: MSC from patients with OA showed significantly increased total TGF-beta, TGF-beta1 isoform, TBR-II, and TBR-III mRNA expression compared to controls. CONCLUSION: Our study is the first reporting the gene expression levels of TGF-beta and its isoforms and receptors in patients with OA. These findings might have pathological significance for OA disease.

Utilidad del PSA-Complex en el diagnóstico del carcinoma de próstata / Utility of complexed PSA in the diagnosis of carcinoma of the prostate

OBJETIVOS: Desde el hallazgo del antígeno prostático específico (PSA), como marcador del cáncer de próstata, han sido muchos los intentos de mejorar su eficacia diagnóstica. Uno de ellos ha sido el estudio del comportamiento de las diferentes formas plasmáticas de PSA en su unión a distintas antiproteasas, entre las que destaca la 1-antiquimiotripsina, con la que forma el PSA complex (PSA-c). El objetivo es estudiar la validez del PSA-c para aumentar la especificidad sin variar la sensibilidad, frente al uso del PSA total (PSA-t).MÉTODOS: Entre septiembre de 1998 y marzo de 1999 se tomaron muestras de sangre a 96 pacientes que fueron sometidos a biopsia prostática por sospecha de cáncer de próstata. En estos pacientes se determinó el PSA-c, PSAt (ambos realizados por el Sistema Technicon Immuno 1 de Bayer) y se calculó el PSA-c/PSA-t. RESULTADOS: Se calcularon las curvas ROC y se hallaron los puntos de corte óptimos, para los cuales, ante un valor de sensibilidad semejante (90 por ciento), la especifici dad resultó mayor en el PSA-c (44,6 por ciento [IC 95 por ciento, 32-57]) frente al PSA-t (35,4 por ciento [IC 95 por ciento, 25-49]), y la ratio PSAc/PSA-t (38,5 por ciento[IC 95 por ciento, 27-51]). Para otros valores de sensibilidad el comportamiento del PSA-c fue análogo. CONCLUSIÓN: el PSA-c mejora la especificidad frente al PSA-t y el PSA-c/PSA-t, por lo cual sería posible con su uso una reducción de biopsias innecesarias sin dejar de detectar el mismo número de cánceres de próstata (igual sensibilidad) (AU)