Full Dose SBRT in Combination With Mediastinal Chemoradiation for Locally Advanced, Non-Small Cell Lung Cancer: A Practical Guide for Planning, Dosimetric Results From a Phase 2 Study, and a Treatment Planning Guide for the Phase 3 NRG Oncology LU-008 Trial.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been used with high effectiveness in early-stage non-small cell lung cancer (NSCLC) but has not been studied extensively in locally advanced NSCLC. We conducted a phase 2 study delivering SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes for patients with node-positive locally advanced NSCLC. This manuscript serves as both a guide to planning techniques used on this trial and the subsequent phase 3 study, NRG Oncology LU-008, and to report patient dosimetry and toxicity results. METHODS AND MATERIALS: We initiated a phase 2 multicenter single arm study evaluating SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions with doublet chemotherapy to the involved lymph nodes for patients with stage III or unresectable stage II NSCLC. Patients eligible for adjuvant immunotherapy received up to 12 months of durvalumab. We report a detailed guide for the entire treatment process from computed tomography simulation through treatment planning and delivery. The dosimetric outcomes from the 60 patients who completed therapy on study are reported both for target coverage and normal structure doses. We also report correlation between radiation-related toxicities and dosimetric parameters. RESULTS: Sixty patients were enrolled between 2017 and 2022. Planning techniques used were primarily volumetric modulated arc therapy for SBRT to the primary tumor and conventionally fractionated radiation to the involved nodes, with a minority of cases using dynamic conformal arc technique or static dynamic multileaf collimator intensity modulated radiation therapy. Grade 2 or higher pneumonitis was associated with lung dose V5 Gy > 70% and grade 2 or higher pulmonary toxicity was associated with lung dose V10 Gy > 50%. Only 3 patients (5%) experienced grade 3 or higher pneumonitis. Grade 2 or higher esophagitis was associated with esophageal doses, including mean dose > 20 Gy, V60 Gy > 7%, and D1cc > 55 Gy. Only 1 patient (1.7%) experienced grade 3 esophagitis. CONCLUSIONS: SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes is feasible with planning techniques as described. Radiation-related toxicity on this phase 2 study was low. This manuscript serves as a guideline for the recently activated NRG Oncology LU-008 phase 3 trial evaluating this experimental regimen.

Evidence for a phenotypic switch in corneal afferents after lacrimal gland excision.

Dry eye is a common cause of ocular pain. The aim of this study was to investigate corneal innervation, ongoing pain, and alterations in corneal afferent phenotypes in a mouse model of severe aqueous tear deficiency. Chronic dry eye was produced by ipsilateral excision of the extra- and intraorbital lacrimal glands in male and female mice. Tearing was measured using a phenol thread and corneal epithelial damage assessed using fluorescein. Changes in corneal ongoing ocular pain was evaluated by measuring palpebral opening ratio. Corneal axons were visualized using Nav1.8-Cre;tdTomato reporter mice. Immunohistochemistry was performed to characterize somal expression of calcitonin gene-related peptide (CGRP), the capsaicin sensitive transient receptor potential vanilloid 1 (TRPV1), and activating transcription factor-3 (ATF-3) in tracer labeled corneal neurons following lacrimal gland excision (LGE). LGE decreased tearing, created severe epithelial damage, and decreased palpebral opening, indicative of chronic ocular irritation, over the 28-day observation period. Corneal axon terminals exhibited an acute decrease in density after LGE, followed by a regenerative process over the course of 28 days that was greater in male animals. Corneal neurons expressing CGRP, TRPV1, and ATF3 increased following injury, corresponding to axonal injury and regeneration processes observed during the same period. CGRP and TRPV1 expression was notably increased in IB4-positive cells following LGE. These results indicate that dry eye-induced damage to corneal afferents can result in alterations in IB4-positive neurons that may enhance neuroprotective mechanisms to create resiliency after chronic injury.

Optogenetic Inhibition of Nav1.8 Expressing Corneal Afferents Reduces Persistent Dry Eye Pain.

Purpose: The aim of the present study was to investigate the contribution of Nav1.8 expressing corneal afferent neurons to the presence of ongoing pain in lacrimal gland excision (LGE)-induced dry eye. Methods: The proton pump archaerhodopsin-3/eGFP (ArchT/eGFP) was conditionally expressed in corneal afferents using Nav1.8-cre mice. Dry eye was produced by unilateral LGE. Real time place preference was assessed using a three-chamber apparatus. A neutral, unlit center chamber was flanked by one illuminated with a control light and one illuminated with an ArchT activating light. For real-time preference, animals were placed in the neutral chamber and tracked over five 10-minute sessions, with the lights turned on during the second and fourth sessions. In other studies, movement was tracked over three 10-minute sessions (the lights turned on only during the second session), with animals tested once per day over the course of 4 days. A local anesthetic was used to examine the role of ongoing corneal afferent activity in producing place preference. Results: The corneal afferent nerves and trigeminal ganglion cell bodies showed a robust eGFP signal in Nav1.8-cre;ArchT/eGFP mice. After LGE, Nav1.8-cre;ArchT/eGFP mice demonstrated a preference for the ArchT activating light paired chamber. Preference was prevented with pre-application to the cornea of a local anesthetic. Nav1.8-cre;ArchT/eGFP mice with sham surgery and LGE wild-type control mice did not develop preference. Conclusions: Results indicate LGE-induced persistent, ongoing pain, driven by Nav1.8 expressing corneal afferents. Inhibition of these neurons represents a potential strategy for treating ongoing dry eye-induced pain.

Lacrimal gland excision in male and female mice causes ocular pain and anxiety-like behaviors.

Lacrimal gland excision (LGE) induced dry eye produces more severe corneal damage in female mice, yet signs of LGE-induced ocular pain and anxiety in male and female mice have not been characterized. Excision of either the extraorbital gland (single LGE), or both the extraorbital and intraorbital glands (double LGE) was performed in male and female C57BL/6J mice to induce moderate and severe dry eye. Ongoing pain was assessed by quantifying palpebral opening and evoked nociceptive responses after corneal application of capsaicin and menthol. The open-field and plus maze were used to assess anxiety. Single LGE caused a reduction in palpebral opening and an increase in capsaicin and menthol-evoked responses only in female mice. Furthermore, single LGE produced signs of increased anxiety in female but not male mice. Overall, female mice appear more susceptible to signs of ocular pain, irritation, and anxiety in response to aqueous tear deficiency.

Dry eye sensitizes cool cells to capsaicin-induced changes in activity via TRPV1.

Corneal cool cells are sensitive to the ocular fluid status of the corneal surface and may be responsible for the regulation of basal tear production. Previously, we have shown that dry eye, induced by lacrimal gland excision (LGE) in rats, sensitized corneal cool cells to the transient receptor potential melastatin 8 (TRPM8) agonist menthol and to cool stimulation. In the present study, we examined the effect of dry eye on the sensitivity of cool cells to the transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin. Single-unit recordings in the trigeminal ganglion were performed 7-10 days after LGE. At a concentration of 0.3 µM, capsaicin did not affect ongoing or cool-evoked activity in control animals yet facilitated ongoing activity and suppressed cool-evoked activity in LGE animals. At higher concentrations (3 µM), capsaicin continued to facilitate ongoing activity in LGE animals but suppressed ongoing activity in control animals. Higher concentrations of capsaicin also suppressed cool-evoked activity in both groups of animals, with an overall greater effect in LGE animals. In addition to altering cool-evoked activity, capsaicin enhanced the sensitivity of cool cells to heat in LGE animals. Capsaicin-induced changes were prevented by the application of the TRPV1 antagonist capsazepine. With the use of fluorescent in situ hybridization, TRPV1 and TRPM8 expression was examined in retrograde tracer-identified corneal neurons. The coexpression of TRPV1 and TRPM8 in corneal neurons was significantly greater in LGE-treated animals when compared with sham controls. These results indicate that LGE-induced dry eye increases TRPV1-mediated responses in corneal cool cells at least in part through the increased expression of TRPV1. NEW & NOTEWORTHY Corneal cool cells are known to detect drying of the ocular surface. Our study is the first to report that dry eye induced alterations in cool cell response properties, including the increased responsiveness to noxious heat and activation by capsaicin. Along with the changes in cell response properties, it is possible these neurons also function differently in dry eye, relaying information related to the perception of ocular irritation in addition to regulating tearing and blinking.

Malignancy Trends in HIV-Infected Patients Over the Past 10 Years in a Single-Center Retrospective Observational Study in the United States.

The introduction of antiretroviral therapy (ART) in 1995 had a dramatic impact on the morbidity and mortality of the HIV population, and subsequently, the natural history of cancer has changed. The purpose of our study was to review the prevalence of AIDS-defining malignancies and non-AIDS defining cancers (NADC), taking into consideration racial and gender variations. After the institutional review board approval, the study was conducted as a retrospective chart review of 279 HIV-infected patients who were treated at the Moffitt Cancer Center between January 1, 2000 and December 31, 2010. The demographic characteristics included gender, ethnicity, race, presence or absence of ART, and the type of malignancy reviewed. Of 233 men, 78 (33.5%) had AIDS-defining malignancies. AIDS-related non-Hodgkin lymphoma (NHL) was detected in 49 (21%) patients and Kaposi sarcoma (KS) in 29 (12%) patients. Two-thirds of male patients had NADC, with anal cancer being the most prevalent (8.5%), followed by Hodgkin lymphoma (6%). AIDS-related NHL was also the predominant malignancy for women with a prevalence of 19.5% followed by invasive cervical cancer (ICC) and breast cancer, both with a similar prevalence of 11%. Kaposi sarcoma and anal cancer were equally detected in 2% of women. The prevalence rates of AIDS-defining malignancies among those of white race were 34%, ranging from 21% for NHL to 13% for KS and 1.5% for ICC. Twenty-one (7.7%) patients had anal cancer. AIDS-defining malignancies were found in 36% of patients of black race and 60% had NHL. Non-AIDS-related NHL was the second most common malignancy, followed by breast cancer and anal cancer with a similar prevalence of 6.5%. Of 279 patients, 53% were taking ART; 39.4% were not taking ART; and in 7.5% of the patients, it was unknown if they were taking ART. In the ART era, our study found NADC to be more prevalent than AIDS-defining malignancies with 60% versus 40%, respectively. Non-Hodgkin lymphoma remained the most common AIDS-related malignancy in both genders. Among the patients with NADC, anal cancer was the predominant malignancy. The increasing incidence of some of the NADC is expected as this population is living longer with chronic exposure of viral replication of virus with oncogenic potential such as Human papillomavirus (HPV), Hepatitis B virus (HBV), Epstein-Barr virus (EBV), and Human herpesvirus 8 (HHV-8). Early ART initiation, aggressive vaccination, and judicious cancer screening are the cornerstone of cancer prevention of this growing population.

Poorer Visual Acuity Is Associated with Declines in Cognitive Performance Across Multiple Cognitive Domains: The Maine-Syracuse Longitudinal Study.

OBJECTIVES: Prior studies have found associations between visual acuity (VA) and cognitive function. However, these studies used a limited range of cognitive measures and did not control for cardiovascular disease risk factors (CVD-RFs) and baseline function. The primary objective of this study was to analyze the associations of VA and cognitive performance using a thorough neuropsychological test battery. METHODS: This study used community-dwelling sample data across the sixth (2001-2006) and seventh (2006-2010) waves of the Maine-Syracuse Longitudinal Study (n=655). Wave 6 VA as measured by the Snellen Eye Test was the primary predictor of wave 6 and wave 7 Global cognitive performance, Visual-Spatial Organization and Memory, Verbal Episodic Memory, Working Memory, Scanning and Tracking, and Executive Function. Additionally, VA was used to predict longitudinal changes in wave 7 cognitive performance (wave 6 performance adjusted). We analyzed these relationships with multiple linear and logistic regression models adjusted for age, sex, education, ethnicity, depressive symptoms, physical function deficits in addition to CVD-RFs, chronic kidney disease, homocysteine, continuous systolic blood pressure, and hypertension status. RESULTS: Adjusted for demographic covariates and CVD-RFs, poorer VA was associated with concurrent and approximate 5-year declines in Global cognitive function, Visual-Spatial Organization and Memory, and Verbal Episodic Memory. DISCUSSION: VA may be used in combination with other screening measures to determine risk for cognitive decline. (JINS, 2018, 24, 746-754).