Introduction: Locally advanced non-small cell lung cancer (NSCLC) is highly resistant to chemoradiotherapy, and many cancer patients experience chronic stress. Studies that suggest stimulation of β-adrenergic receptors (β-AR) promotes tumor invasion and therapy resistance. We investigated whether β-AR inhibition with beta-blockers acts as a chemotherapy and radiation sensitizer in vitro and in patients treated with chemoradiation for locally advanced NSCLC. Methods: We investigated the effects of the non-selective beta-blocker propranolol on two human lung adenocarcinoma cell lines (PC9, A549) treated with radiation or cisplatin. We retrospectively evaluated 77 patients with Stage IIIA NSCLC who received induction chemoradiation followed by surgery. Pathological and imaging response, metastatic rate, and survival were analyzed using SPSS v22.0 and PrismGraphpad6. Results: Propranolol combined with radiation or cisplatin decreased clonogenic survival of PC9 and A549 cells in vitro (p < 0.05). Furthermore, propranolol decreased expression of phospho-protein kinase A (p-PKA), a β-adrenergic pathway downstream activation target, in both cell lines compared to irradiation or cisplatin alone (p < 0.05). In patients treated for Stage IIIA NSCLC, 16 took beta-blockers, and 61 did not. Beta-blockade is associated with a trend to improved overall survival (OS) at 1 year (81.3% vs 57.4%, p = 0.08) and distant metastasis-free survival (DMFS) (2.6 years vs. 1.3 years, p = 0.16). Although beta-blocker use was associated with decreased distant metastases (risk ratio (RR) 0.19; p = 0.03), it did not affect primary tumor pathological response (p = 0.40) or imaging response (p = 0.36). Conclusions: β-AR blockade enhanced radiation and cisplatin sensitivity of human lung cancer cells in vitro. Use of beta-blockers is associated with decreased distant metastases and potentially improved OS and DMFS. Additional studies are warranted to evaluate the role of beta-blockers as a chemoradiation sensitizer in locally advanced NSCLC.

Breast cancer subtype, determined by expression of estrogen/progesterone receptor (ER/PR) and human epidermal growth factor receptor (HER)-2, is predictive for prognosis. The importance of subtype to locoregional recurrence (LRR) following neoadjuvant chemotherapy (NAC) is unknown, particularly after adjuvant radiotherapy (RT). We retrospectively identified 160-breast cancer patients registered at Columbia University Medical Center from 1999 to 2012 treated with NAC, surgery and adjuvant RT. Patients were grouped by receptor status: hormone receptor positive (HR+) [(ER or PR+)/HER2−; n = 75], HER2+ (n = 46), or triple-negative (TNBC) [ER (−) PR (−) HER2 (−); n = 36]. The median follow-up was 28 months. 92.0% received an anthracycline-taxane based NAC and 80.4% of HER2+ patients received trastuzumab. All underwent surgical resection followed by RT. 15.6% had a pathologic complete response (pCR): 26% of HER2+, 5% of HR+, and 25% of TN. The actuarial rate of DM was 13.8% for the entire cohort, with equivalent rates by subtypes in non-pCR patients. The overall rate of LRR was 8%. However, the LRR rate was significantly higher for TNBC patients (22.2%) than HER2+ (5.6%) (p = 0.025) or HR+ (3.0%) (p = 0.037) in non-pCR group. In the pCR group, two patients had recurrence; one LRR and one a DM, both had TNBC. All LRR occurred in or near the radiation field. TNBC patients with < pCR to NAC have a significantly higher LRR rate as compared to other subtypes even with surgery and adjuvant RT. Our data support a need to further intensify local therapy in TNBC patients.

Neuronal networks process information in a distributed, spatially heterogeneous manner that transcends the layout of electrodes. In contrast, directed and steerable light offers the potential to engage specific cells on demand. We present a unified framework for adapting microscopes to use light for simultaneous in vivo stimulation and recording of cells at fine spatiotemporal resolutions. We use straightforward optics to lock onto networks in vivo, to steer light to activate circuit elements and to simultaneously record from other cells. We then actualize this 'free' augmentation on both an 'open' two-photon microscope and a leading commercial one. By following this protocol, setup of the system takes a few days, and the result is a noninvasive interface to brain dynamics based on directed light, at a network resolution that was not previously possible and which will further improve with the rapid advance in development of optical reporters and effectors. This protocol is for physiologists who are competent with computers and wish to extend hardware and software to interface more fluidly with neuronal networks.