Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.

BACKGROUND: TGF-ß is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-ß blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-ß type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. METHODS: This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m2 over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m2 twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50·4-54·0 Gy in 28-30 fractions). 5-9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m2 on day 1, intravenous fluorouracil 400 mg/m2 on day 1 then 2400 mg/m2 over 46 h, and intravenous oxaliplatin 85 mg/m2 on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. FINDINGS: Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. INTERPRETATION: The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. FUNDING: Eli Lilly via ExIST program, The Providence Foundation.

Role of the Trifluoropropynyl Ligand in Blue-Shifting Charge-Transfer States in Emissive Pt Diimine Complexes and an Investigation into the PMMA-Imposed Rigidoluminescence and Rigidochromism.

Square-planar PtII complexes are of interest as dopants for the emissive layer of organic light-emitting diodes. Herein, the photophysics of three Pt bipyridyl complexes with the strongly e- withdrawing, high-field, 3,3,3-trifluoropropynyl ligand has been investigated. One complex, (phbpy)PtC2CF3 (phbpy = 6-phenyl-2,2'-dipyridyl), has also been characterized by single-crystal X-ray diffraction. All complexes reported are emissive in both RT CH2Cl2 solution (ΦPL = 0.007 to 0.027) and PMMA film (ΦPL = 0.25 to 0.42). The trifluoropropynyl ligand elevates the energy of the MLCT and LL'CT states above that of the IL π-π* state, resulting in IL emission in all cases. The emission energies of the trifluoropropynyl compounds are also blue-shifted relative to the analogous pentafluorophenylethynyl compounds, suggesting that the trifluoropropynyl ligand is one of the most electron-withdrawing alkynyl ligands. Rate constants for radiative and nonradiative deactivation were determined from experimentally determined values of ΦPL and excited-state lifetimes in both solution and PMMA films. The increase in ΦPL upon incorporation into PMMA film (rigidoluminescence) results from a decrease in the rate constant for non-radiative relaxation. Experimental activation energies for excited-state decay in combination with TDDFT are consistent with the rigidoluminescence resulting from an increase in the energy of the non-emissive triplet metal-centered state. Two of the complexes investigated, (Ph2bpy)Pt(C2CF3)2 and (t-Bu2bpy)Pt(C2CF3)2, where t-Bu2bpy = 4,4'-di-tert-butyl-2,2'-dipyridyl and Ph2bpy = 4,4'-diphenyl-2,2'-dipyridyl, exhibit concentration-dependent excimer emission (orange) along with monomer emission (blue), enabling fine-tuning of the emission color. However, excimer emission was absent in cured PMMA films up to the solubility limit for solution processing of (Ph2bpy)Pt(C2CF3)2 in CH2Cl2, demonstrating the diffusional nature of excimer formation.

Ready-JET-Go: Split Flow Accelerates ED Throughput.

PROBLEM: Struggling to keep up with The Centers for Medicare and Medicaid Services out-patient throughput metrics, an adult emergency department serving Burlington and Camden Counties, New Jersey, sought to redefine its care delivery model by adopting the patient segmentation initiatives of the split-flow process of patient care. METHODS: A multidisciplinary team of ED clinicians collaboratively defined the patient segmentation criteria. A joint assessment team approach to patient care was instituted. A 3-pronged approach was adopted to prepare staff for the patient care changes in line with an existing framework specified by the Institute of Medicine. Simulation and queuing analyses were used to estimate the accompanying resource needs. RESULTS: Since implementing split flow, the emergency department has witnessed significant improvements in patient throughput and patient satisfaction, despite a sustained 10% increase in patient volumes after split-flow implementation. The median length of stay for discharged patients and the door-to-diagnostic evaluation time are now down to 112 minutes and 30 minutes, respectively, compared with pre-split-flow values of 192 minutes and 72 minutes, respectively. IMPLICATIONS FOR PRACTICE: Working collaboratively with all stakeholders to define the right patient care delivery model, combined with an understanding of the right resource assignments to optimally support that care delivery model, an emergency department can institute cost-effective changes to realize and sustain significant patient throughput improvements.

Impacts of the Pandemic on Social Determinants of Health in an Academic Emergency Department.

INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic caused significant disruptions in daily life. Given the role that social determinants of health play in the overall well-being of individuals and populations, we wanted to determine the effects of the COVID-19 pandemic on our patient population in the emergency department (ED). METHODS: We adapted the Centers for Medicare and Medicaid Services social risk assessment to assess changes to participants' social situations throughout the COVID-19 pandemic from January 2020-February 2021. The survey was administered within the ED to individuals selected by a convenience sample of patients who were stable enough to complete the form. RESULTS: We received 200 (66%) responses from the 305 patients approached. Worsened food access was reported by 8.5% (17) of respondents, while 13.6% (27) reported worsened food concern since the onset of the COVID-19 pandemic. The odds of worsened food access were higher among non-Whites (adjusted odds ratio [aOR] 19.17, 95% confidence interval [CI] 3.33-110.53) and females (aOR 9.77, CI 1.51-63.44). Non-Whites had greater odds of worsened food concern (aOR 15.31, CI 3.94-59.54). Worsened financial difficulty was reported by 24% (48) of respondents. The odds of worsened financial difficulty were higher among females (aOR 2.87, 95% CI 1.08-7.65) and non-Whites (aOR 10.53, CI 2.75-40.35). CONCLUSION: The COVID-19 pandemic has worsened many of the social determinants of health found within communities. Moreover, vulnerable communities were found to be disproportionately affected as compared to their counterparts. Understanding the challenges faced by our patient populations can serve as a guide on how to assist them more comprehensively.

A cross-sectional study of a prototype carcinogenic human papillomavirus E6/E7 messenger RNA assay for detection of cervical precancer and cancer.

PURPOSE: To evaluate carcinogenic human papillomavirus (HPV) mRNA for E6 and E7 mRNA detection on clinical specimens to identify women with cervical precancer and cancer. EXPERIMENTAL DESIGN: We evaluated a prototype assay that collectively detects oncogenes E6/E7 mRNA for 14 carcinogenic HPV genotypes on a sample of liquid cytology specimens (n=531), masked to clinical data and to the presence of HPV genotypes detected by PGMY09/11 L1 consensus primer PCR assay. RESULTS: We found an increasing likelihood of testing positive for carcinogenic HPV E6/E7 mRNA with increasing severity of cytology (P(Trend) < 0.0001) and histology (P(Trend) < 0.0001), with 94% of cervical intraepithelial neoplasia grade 3 (CIN3) histology cases (46 of 49) and all five cancer cases testing positive for carcinogenic HPV E6/E7 mRNA. Overall, fewer specimens tested positive for carcinogenic HPV E6/E7 mRNA than for carcinogenic HPV DNA (P<0.0001, McNemar's chi(2) test), especially in women with

Antiandrogen blocks estrogen-induced masculinization of the song system in female zebra finches.

Song behavior and the neural song system that serves it are sexually dimorphic in zebra finches. In this species, males sing and females normally do not. The sex differences in the song system include sex differences in the proportion of neurons that express androgen receptors, which is higher in specific brain regions of males. Estradiol (E2) administered in early development profoundly masculinizes the song system of females, including the proportion of neurons expressing androgen receptors. We examined whether or not the expression of these androgen receptors was causally related to the E2-induced masculinization of this system by co-administering Flutamide, which blocks androgen action at the receptor, along with E2 at hatching. E2 alone had its usual masculinizing effect on the female song system, measured in adulthood: increasing the size of song nuclei, the size of neurons in HVC, RA, and 1MAN, and the number of neurons in HVC. E2's masculinizing action, however, was significantly diminished on all measures by co-administering Flutamide. Indeed, females receiving both E2 and Flutamide were never significantly more masculine than controls on any measure. Flutamide alone had no effect. Our results strongly suggest that the activation of androgen receptors is necessary for the E2-induced masculinization of the song system in females.