Control Across Scales by Positive and Negative Feedback

Feedback is a key element of regulation, as it shapes the sensitivity of a process to its environment. Positive feedback upregulates, and negative feedback downregulates. Many regulatory processes involve a mixture of both, whether in nature or in engineering. This article revisits the mixed-feedback paradigm, with the aim of investigating control across scales. We propose that mixed feedback regulates excitability and that excitability plays a central role in multiscale neuronal signaling. We analyze this role in a multiscale network architecture inspired by neurophysiology. The nodal behavior defines a mesoscale that connects actuation at the microscale to regulation at the macroscale. We show that mixed-feedback nodal control provides regulatory principles at the network scale, with a nodal resolution. In this sense, the mixed-feedback paradigm is a control principle across scales.

Outcomes of Saudi Arabian Patients With Nasopharyngeal Cancer Treated With Primarily Neoadjuvant Chemotherapy Followed by Concurrent Chemoradiotherapy

Purpose Nasopharyngeal cancer (NPC) is the most common head and neck cancer in Saudi Arabia. This study reports the locoregional disease control and survival outcomes in patients with NPC treated in King Abdulaziz University Hospital. Methods Patients treated for NPC between June 2007 and October 2014 were retrospectively reviewed. Demographic information, clinicopathologic variables, and chemotherapy data were collected and analyzed. Cumulative survival and disease control rates were calculated by Kaplan-Meier product-limit actuarial method. Results Thirty-nine patients with NPC were reviewed. Thirty-five (90%) patients received definitive radiotherapy (RT) and four (10%) had palliative RT. Mean prescribed dose for definitive RT was 68 Gy (range, 60 to 70.2 Gy), delivered with mean doses per fraction of 1.9 Gy (range, 1.8 to 2.1 Gy). After a median follow-up of 15 months (range, 1 to 84 months), 22 (63%) patients who underwent definitive RT were disease free and 13 (37%) were still with disease. During this period, seven (18%) patients died of the disease; five (13%) of them received definitive RT. After 2 years’ follow-up, the actuarial estimate rates were: 85.7% for local control, 91.4% for nodal control, and 85.7% for distant control. Conclusion Our study showed a disease with clinical behavior similar to what has been observed in East and Southeast Asia. Further it explored the neoadjuvant chemotherapy approach in treating NPC with results that are comparable to literature. However, little is known about the molecular pathogenesis of this disease in this region, and further research integrating clinical and molecular biomarkers is required.

E1308: Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC).

LBA6006 Background: HPV+ patients (pts) in E2399 obtained a 2-yr 95% survival and 86% PFS after IC and 70Gy chemoradiation. We hypothesized reduced-dose IMRT (54Gy, 23% reduction) in HPV+ OPSCC pts could maintain high LR control and 85% 2-yr PFS in pts with cCR to IC. Methods: Pts with resectable stage III/IVa,b HPV+ OPSCC received IC q3 weeks x 3 with paclitaxel 90mg/m2 days (D) 1,8,15, cisplatin 75mg/m2 D1, and standard cetuximab (Cetux) weekly schedule. IC response determined IMRT dose independently at primary and involved nodes: IMRT 54Gy/27 if cCR vs. 69.3Gy/33 if <cCR. Cetux was continued during IMRT. Primary endpoint was 2-yr PFS. Results: 90 pts were enrolled (80 analyzable). Med FU is 23.3 months (mo). Tumor and Nodal stage: T4-10%, T3-17%, T2-50%, and T1-23%; N0,1-16%, N2a,b-54%, N2c-31%. Med age 57yrs. 46% never smoked and 84% not current smokers. IC and C-IMRT was well tolerated: 96% received all 3-cycles of IC. 71% had cCR. 62 pts (78%) received reduced-dose Cetux-IMRT. For all reduced IMRT pts, 23mo PFS is 84%, primary site LC 94%, nodal control 95%, and distant 92%. Post-treatment neck dissection was positive for tumor in 4/8 reduced dose IMRT pts compared to 1/3 pts treated with std dose. One late grade 3 toxicity occurred in 1 reduced-dose pt: hypomagnesemia at 30mo. Conclusions: IC + reduced-dose Cetux-IMRT produced high tumor control rates. Late toxicities were minimal. Low dose pts achieved 84% PFS at 23mo and 95% 2-yr survival. Pts with <10yrs smoking, T1-3 and N0-2b disease achieved 96% PFS. Further studies of reduced-dose IMRT in chemoresponsive HPV+ pts are warranted. Clinical trial information: NCT01084083. [Table: see text]