Effective Temperatures of a Driven System Near Jamming

Fluctuations in a model of a sheared, zero-temperature foam are studied numerically. Five different quantities that reduce to the true temperature in an equilibrium thermal system are calculated. All five have the same shear-rate dependence, and three have the same value. Near the onset of jamming, the relaxation time is the same function of these three temperatures in the sheared system as of the true temperature in an unsheared system. These results imply that statistical mechanics is useful for the system and provide strong support for the concept of jamming.Comment: 4 pages, 4 postscript figure

Phase II Study of Paclitaxel, Carboplatin, and Cetuximab as First Line Treatment, for Patients with Advanced Non-small Cell Lung Cancer (NSCLC): Results of OPN-017

BackgroundCetuximab has demonstrated synergy with taxanes in preclinical models; as well as single agent activity. We assessed the activity of cetuximab with carboplatin and paclitaxel given on a 4-week schedule, in advanced, chemo-naive non-small cell lung cancer.Patients and MethodsThis phase II, single arm, multi-institution study featured standard dosage of cetuximab 400 mg/m2 day 1, then 250 mg/m2 with paclitaxel (100 mg/m2/wk, for 3 weeks), and carboplatin (area under curve = 6) day 1 of each 28 day cycle. After 4 to 6 cycles, in the absence of disease progression or excess toxicity, cetuximab was continued weekly. Primary end point was response rate.ResultsFifty-three patients (median age 63, 51% male) participated. Response rate was 57% (3 complete response and 27 partial response). At a median follow-up of 12.5 months, the estimated overall survival is 13.8 months (95% CI: 9.08–16.02) with an event-free survival rate of 5.53 months (95% CI: 4.77–7.99), 18.9% remain free from progression at 1 year. Improved survival was associated with female gender, absence of prior radiation, PS 0 and epidermal growth factor receptor expression. Toxicities included rash (28% grade 3), nail changes (3.7% grade 3), hypomagnesemia (7.5% grade 3 and 3.7% grade 4), and neutropenia (25% grade 3 and 13% grade 4) in addition to other typical side effects anticipated with paclitaxel/carboplatin. There were no grade 5 toxicities.ConclusionCombination of cetuximab/paclitaxel/carboplatin in non-small cell lung cancer was well tolerated and clinically active with manageable toxicities. This unique schedule, integrating weekly paclitaxel and cetuximab has not yet been tested in a randomized trial

Force distributions near the jamming and glass transitions

We calculate the distribution of interparticle normal forces $P(F)$ near the glass and jamming transitions in model supercooled liquids and foams, respectively. $P(F)$ develops a peak that appears near the glass or jamming transitions, whose height increases with decreasing temperature, decreasing shear stress and increasing packing density. A similar shape of $P(F)$ was observed in experiments on static granular packings. We propose that the appearance of this peak signals the development of a yield stress. The sensitivity of the peak to temperature, shear stress and density lends credence to the recently proposed generalized jamming phase diagram.Comment: 4 pages, 3 postscript figures;Version 3 replaces figure 1 and removes figure 2 from version 1. Significant rewording of version 1 to emphasize the formation of peak in P(F) when these systems jam along five different routes of the recently proposed jamming phase diagram. Version 2 displayed the incorrect abstrac

Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline

AbstractPurposeTo provide guidance to physicians and patients with regard to the use of external beam radiotherapy, endobronchial brachytherapy, and concurrent chemotherapy in the setting of palliative thoracic treatment for lung cancer, based on available evidence complemented by expert opinion.Methods and MaterialsA Task Force authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors synthesized and assessed evidence from 3 systematic reviews on the following topics: (1) dose fractionation in thoracic external beam radiotherapy (EBRT); (2) clinical utility of initial and salvage endobronchial brachytherapy (EBB); and (3) use of concurrent chemotherapy (CC) with palliative thoracic radiotherapy. Practice guideline recommendations were produced and are contained herein.ResultsStudies suggest that higher dose/fractionation palliative EBRT regimens (eg, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status. As these improvements are associated with an increase in esophageal toxicity, various shorter EBRT dose/fractionation schedules (eg, 20 Gy in 5 fractions, 17 Gy in 2 weekly fractions, 10 Gy in 1 fraction), which provide good symptomatic relief with fewer side effects, can be used for patients requesting a shorter treatment course and/or in those with a poor performance status. No defined role for EBB in the routine initial palliative treatment of chest disease has been demonstrated; however, EBB can be a reasonable option for the palliation of endobronchial lesions causing obstructive symptomatology including lung collapse, or for hemoptysis after EBRT failure. The integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature.ConclusionThis Guideline is intended to serve as a guide for the use of EBRT, EBB, and CC in thoracic palliation of lung cancer outside the clinical trial setting. Further prospective clinical investigations with relevant palliative endpoints into the respective roles of EBB and CC/targeted therapy in the thoracic palliation of lung cancer are warranted, given the current state of the medical literature in these areas

Single-Agent Versus Combination Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer and a Performance Status of 2: Prognostic Factors and Treatment Selection Based on Two Large Randomized Clinical Trials

Purpose:Data from two randomized phase III trials were analyzed to evaluate prognostic factors and treatment selection in the first-line management of advanced non-small cell lung cancer patients with performance status (PS) 2.Patients and Methods:Patients randomized to combination chemotherapy (carboplatin and paclitaxel) in one trial and single-agent therapy (gemcitabine or vinorelbine) in the second were included in these analyses. Both studies had identical eligibility criteria and were conducted simultaneously. Comparison of efficacy and safety was performed between the two cohorts. A regression analysis identified prognostic factors and subgroups of patients that may benefit from combination or single-agent therapy.Results:Two hundred one patients were treated with combination and 190 with single-agent therapy. Objective responses were 37 and 15%, respectively. Median time to progression was 4.6 months in the combination arm and 3.5 months in the single-agent arm (p < 0.001). Median survival times were 8.0 and 6.6 months, and 1-year survival rates were 31 and 26%, respectively. Albumin <3.5 g, extrathoracic metastases, lactate dehydrogenase ≥200 IU, and 2 comorbid conditions predicted outcome. Patients with 0–2 risk factors had similar outcomes independent of treatment, whereas patients with 3–4 factors had a nonsignificant improvement in median survival with combination chemotherapy.Conclusion:Our results show that PS2 non-small cell lung cancer patients are a heterogeneous group who have significantly different outcomes. Patients treated with first-line combination chemotherapy had a higher response and longer time to progression, whereas overall survival did not appear significantly different. A prognostic model may be helpful in selecting PS 2 patients for either treatment strategy

Random Packings of Frictionless Particles

We study random packings of frictionless particles at T=0. The packing fraction where the pressure becomes nonzero is the same as the jamming threshold, where the static shear modulus becomes nonzero. The distribution of threshold packing fractions narrows and its peak approaches random close-packing as the system size increases. For packing fractions within the peak, there is no self-averaging, leading to exponential decay of the interparticle force distribution.Comment: 4 pages, 3 figure

nab-paclitaxel/xarboplatin in vulnerable populations with advanced non-small cell lung cancer: Pooled analysis

Introduction: Despite improvements in the treatment of advanced non-small cell lung cancer (NSCLC), certain patient populations remain underrepresented in clinical trials. Many patients have benefited from platinum doublets, including Methods: To better understand outcomes in these patient populations, we performed a pooled analysis using data from the ABOUND clinical trial program (ABOUND.SQM, ABOUND.PS2, ABOUND.70+) and the key phase III trial of Results: Median progression-free survival (PFS) ranged from 4.1 months in patients with ECOG PS 2 (95% CI, 2.04-5.09 months) to 7.7 months in patients with diabetes (95% CI, 5.88-10.12 months). PFS for elderly patients and patients with renal impairment was 6.9 months each (95% CI, 6.01-7.98 months and 4.47-9.79 months, respectively). Median overall survival (OS) was 18.2 months (95% CI, 10.94-28.22 months), 17.4 months (95% CI, 14.59-20.14 months), and 16.1 months (95% CI, 14.09-18.50 months) in patients with renal impairment, patients with diabetes, and elderly patients, respectively. Patients with ECOG PS 2 exhibited the shortest median OS: 5.6 months (95% CI, 3.98-11.37 months). Overall response rates were 56.9%, 54.6%, 45.9%, and 29.4% in patients with diabetes, elderly patients, patients with renal impairment, and patients with ECOG PS 2, respectively. Most treatment-related adverse events were hematologic. The most common grade 3/4 hematologic adverse events in patients with renal impairment, elderly patients, patients with diabetes, and patients with poor performance status included neutropenia, anemia, and thrombocytopenia. Conclusions: Although survival data in patients with ECOG PS 2 were notably inferior to the other cohorts, our findings are consistent with those previously reported in the population-specific studies of the ABOUND trials and lend additional support for the use o

SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study).

BackgroundS1400B is a biomarker-driven Lung-MAP substudy evaluating the phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (sqNSCLC).MethodsEligible patients had tumoral phosphatidylinositol-4,5-biphosphate 3 kinase catalytic subunit alpha (PIK3CA) alterations by next-generation sequencing and disease progression after at least one line of platinum-based therapy. Patients received 4-mg taselisib orally daily. The primary analysis population (PAP) was a subset of patients having substitution mutations believed to be associated with clinical benefit of PI3K inhibitors. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival and duration of response.ResultsTwenty-six patients treated with taselisib comprised the full evaluable population (FEP); 21 patients comprised the PAP. Median age for patients in the FEP was 68 years (range: 53-83 years), 19 were male (73%). The study was closed for futility at interim analysis with one responder in the PAP (5% response rate, 95% confidence interval [CI]: 0%-24%). Two possibly treatment-related deaths (one respiratory failure, one cardiac arrest) were observed; one patient had grades 4 and 11 had grade 3 adverse events. Median progression-free survival and overall survival in the PAP group were 2.9 months (95% CI: 1.8-4.0 mo) and 5.9 months (95% CI: 4.2-7.8 mo), respectively. These numbers were nearly the same in the FEP.ConclusionsStudy S1400B evaluating taselisib in PIK3CA-altered sqNSCLC failed to meet its primary endpoint and was closed after an interim futility analysis. The trial is unique in cataloguing the diversity of PIK3CA mutations in sqNSCLC

Jamming at Zero Temperature and Zero Applied Stress: the Epitome of Disorder

We have studied how 2- and 3- dimensional systems made up of particles interacting with finite range, repulsive potentials jam (i.e., develop a yield stress in a disordered state) at zero temperature and applied stress. For each configuration, there is a unique jamming threshold, $\phi_c$, at which particles can no longer avoid each other and the bulk and shear moduli simultaneously become non-zero. The distribution of $\phi_c$ values becomes narrower as the system size increases, so that essentially all configurations jam at the same $\phi$ in the thermodynamic limit. This packing fraction corresponds to the previously measured value for random close-packing. In fact, our results provide a well-defined meaning for "random close-packing" in terms of the fraction of all phase space with inherent structures that jam. The jamming threshold, Point J, occurring at zero temperature and applied stress and at the random close-packing density, has properties reminiscent of an ordinary critical point. As Point J is approached from higher packing fractions, power-law scaling is found for many quantities. Moreover, near Point J, certain quantities no longer self-average, suggesting the existence of a length scale that diverges at J. However, Point J also differs from an ordinary critical point: the scaling exponents do not depend on dimension but do depend on the interparticle potential. Finally, as Point J is approached from high packing fractions, the density of vibrational states develops a large excess of low-frequency modes. All of these results suggest that Point J may control behavior in its vicinity-perhaps even at the glass transition.Comment: 21 pages, 20 figure

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

Introduction Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. Methods A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). Results As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. Conclusions The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC