Citations

Abstract Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).

SummaryAlthough the incidence rate of acute lymphoblastic leukaemia (ALL) is slightly higher in older than in younger adults, response rates to induction chemotherapy and survival rates are poorer. The contribution of disease‐related versus treatment‐related factors remains unclear. We analysed 100 older patients (aged 55–65 years) treated on the UKALLXII/ECOG2993 trial compared with 1814 younger patients (aged 14–54 years). Baseline characteristics, induction chemotherapy course, infections, drug reductions and survival outcomes were compared. There were more Philadelphia‐positive (Ph+) patients in the older group (28% vs. 17%, P = 0·02), and a trend towards higher combined cytogenetic risk score (46% vs. 35%, P = 0·07). The complete remission rate in older patients was worse (73% vs. 93%, P < 0·0001) as was 5‐year overall survival (21% vs. 41%, P < 0·0001) and event‐free survival (EFS) (19% vs. 37%, P < 0·0001). Older patients had more infections during induction (81% vs. 70%, P = 0·05), and drug reductions (46% vs. 28%, P = 0·0009). Among older patients, Ph+ and cytogenetic risk category as well as infection during induction predicted for worse EFS. Poorer outcomes in these patients are partly due to cytogenetic risk, but there is significant morbidity and mortality during induction chemotherapy with frequent delays and drug reductions. New approaches, including better risk stratification and use of targeted therapies, could improve treatment for these patients.

Abstract Purpose: To improve the significance of insulin-like growth factor–binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer. Experimental Design: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts. Results: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS. Conclusion: IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting. Clin Cancer Res; 18(6); 1808–17. ©2012 AACR.

Abstract Patients with severe acute and chronic lung diseases develop derangements in gas exchange that may result in increased levels of CO2 (hypercapnia), the effects of which on human health are incompletely understood. It has been proposed that hypercapnia may have beneficial effects in patients with acute lung injury, and the concepts of “permissive” and even “therapeutic” hypercapnia have emerged. However, recent work suggests that CO2 can act as a signaling molecule via pH-independent mechanisms, resulting in deleterious effects in the lung. Here we review recent research on how elevated CO2 is sensed by cells in the lung and the potential harmful effects of hypercapnia on epithelial and endothelial barrier, lung edema clearance, innate immunity, and host defense. In view of these findings, we raise concerns about the potentially deleterious effects hypercapnia may have in patients with acute and chronic lung diseases.