Purpose FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous-cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically-relevant increases in FGFR1 signaling. Herein, we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in lung cancer. Experimental Design Histologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity, a potent FGFR TKI. A tissue microarray comprised of resected lung tumors was submitted to FGFR1 GCN and mRNA analyses and the results were validated with TCGA lung cancer data. Results 14/58 cell lines exhibited ponatinib sensitivity (IC50 values ≤ 50 nM) that correlated with FGFR1 mRNA and protein expression, but not with FGFR1 GCN or histology. Moreover, ponatinib sensitivity associated with mRNA expression of the ligands, FGF2 and FGF9. In resected tumors, 22% of adenocarcinomas and 28% of SCCs expressed high FGFR1 mRNA. Importantly, only 46% of SCCs with increased FGFR1 GCN expressed high mRNA. Lung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations. Conclusions FGFR1 dependency is frequent across various lung cancer histologies and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN. The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and other solid tumor types.
Adult umbilical cord blood transplantation (CBT) has emerged as an important option for patients lacking matched related (MRD) and matched unrelated donors (MUD). We compared chronic GVHD (cGVHD) incidence, immunosuppression burden and late infections and hospitalizations in consecutive patients undergoing CBT (n=51) versus peripheral blood MUD transplant (n=57) at our center between June 2009 and April 2014. At 3 years post transplantation, the cumulative incidence (CI) of moderate to severe cGVHD was 44% following MUD versus 8% following CBT (P=0.0006) and CI of any cGVHD was 68% following MUD versus 32% following CBT (P=0.0017). Median time to being off immunosuppression among CB patients was 268 days versus not reached among MUD patients (P<0.0001). Late infections and late hospitalized days were reduced in CB patients (P=0.1 and <0.001, respectively). Three-year CI of transplant-related mortality (TRM) and relapse as well as 3-year overall survival (OS) were similar following CB and MUD transplantation. We demonstrate a significantly lower incidence of cGVHD, immunosuppression burden and late complication rate following UCB versus peripheral blood MUD transplant without decreased OS, increased relapse or early TRM. Combined with the rapid availability of UCB, these findings have led our center to move primarily to UCB over peripheral blood MUD when a MRD is not available.
Purpose/Objective(s): Upper extremity lymphedema after axillary lymph node dissection and radiation for breast cancer has been well described and studied. As modern treatment techniques have reduced the incidence of arm lymphedema, breast lymphedema has emerged as a common result of BCT and is associated with poor wound healing, infection and impact on quality of life. Because there is no established tool for its evaluation and quantification, we explored the feasibility of using ultrasound to measure breast lymphedema objectively. We evaluated whether this measure correlated with clinical assessment, treatment factors, and patient-reported outcomes. Materials/Methods: We enrolled 30 women with malignant breast cancer treated with breast conserving surgery, sentinel lymph node biopsy, and breast radiation. Another 10 women with benign disease who had not undergone BCT were sampled as controls. Ultrasound measurements of dermal thickness were performed on the treated breast and untreated breast at the 6:00 position. Post-treatment assessments included physical exam and quality of life DASH questionnaire. We quantified breast lymphedema as the dermal thickness of the affected breast minus the dermal thickness of the unaffected breast. Breast lymphedema was considered present if dermal thickness difference was above the highest-observed value in the benign patients. Results: Mean age ( § SD) was SD 59 § 13 in the malignant group and 46.4 § 17 in the benign group and groups were similar with regard to body mass index. Mean dermal thickness difference was higher in the malignant group compared with the benign group (1.03 mm and 0 mm, respectively). Seventy percent of patients in the malignant group met our definition of breast lymphedema (n = 21) and were more likely to report impact on quality of life pertaining to sexual activity (24% vs 11%), breast sensation (52% vs 16%), sleep quality (33% vs 21%) and confidence (24% vs 5%) than patients without breast lymphedema. Extent of axillary surgery was associated with a 1.29 mm increase in difference in dermal thickness for patients with > = 4 nodes removed (95% CI: -0.22, 2.80). The volume of breast tissue radiated was also positively associated, with every 100cc increase in breast volume radiated associated with a 0.17mm greater dermal thickness difference (95% CI: 0.04, 0.30mm). However, there was no association with percent of breast tissue receiving > 105% of prescribed dose (95%
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