Impact of Simultaneous Circulating Tumor DNA and Tissue Genotyping in the Workup of Stage IV Lung Adenocarcinoma on Quality of Care in an Academic Community Medical Center.

PURPOSE: In patients with metastatic lung adenocarcinoma, evidence-based first-line treatment decisions require analysis of tumors for genomic alterations (GAs). Optimizing the genotyping paradigm may improve the delivery of precision oncology care. Actionable GAs can be identified by analyzing tumor tissue or circulating tumor DNA using liquid biopsy. Consensus guidelines for when to use liquid biopsy have not been established. We evaluated the routine use of liquid biopsy performed simultaneously with tissue testing in patients with newly diagnosed, stage IV lung adenocarcinoma. METHODS: We performed a retrospective study comparing patients who underwent tissue genotyping alone (standard biopsy group) with patients who had simultaneous liquid and tissue genotyping (combined biopsy group). We examined the time to reach a final diagnosis, the need for repeat biopsies, and diagnostic accuracy. RESULTS: Forty two patients in the combined biopsy group and 78 in the standard biopsy group met the inclusion criteria. The standard group had a mean time to diagnosis of 33.5 days, compared with 20.6 days in the combined group (P < .001 by two-tailed t-test). In the combined group, 14 patients did not have sufficient tissue for molecular analysis (30%); however, in 11 (79%) of these patients, liquid biopsy identified a GA that eliminated the need for a second tissue biopsy. In patients who completed both tests, each test found actionable GAs missed by the other. CONCLUSION: Performing liquid biopsy simultaneously with tissue genotyping is feasible in an academic community medical center. Potential advantages of simultaneous liquid and tissue biopsies include shorter time to obtain a definitive molecular diagnosis, reduced need for a repeat biopsy, and improved detection of actionable mutations, although a sequential strategy that saves costs by beginning with a liquid biopsy may be ideal.

A Phase II Open-Label Trial of Binimetinib and Hydroxychloroquine in Patients With Advanced KRAS-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC). METHODS: Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon's 2-stage phase II clinical trial design was used, with an α error of 5% and a power ß of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion. RESULTS: Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met. CONCLUSION: The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068).

Perceptions of and barriers to cancer screening by the sexual and gender minority community: a glimpse into the health care disparity.

PURPOSE: A disparity exists in cancer screening rates for the Sexual and Gender Minority (SGM) community. We sought to understand the perceptions and baseline knowledge of cancer screening among SGM community members. METHODS: Survey administered via social media from June 2018 to October 2018. We asked 31 questions focused on cancer screening, human papillomavirus, emotional distress, and experience with the health care system. Those included were 18 years or older. Cancer screening attitudes and knowledge, as well as perceptions of the health care system were investigated. RESULTS: There were 422 respondents analyzed: 24.6% identified as female, 25.5% as male, 40.1% transgender, and 9.6% as other. 65.4% of the SGM community is not certain what cancer screening to do for themselves. Only 27.3% and 55.7% knew that HPV was a risk factor associated with head and neck cancer and anal cancer, respectively. Half stated their emotional distress prevents them from getting cancer screening. It was identified that process changes in making appointments, comforts during the visit, and formal training for physicians and nurses could increase cancer screening compliance for this community. The transgender population had a trend in more gaps in knowledge of appropriate cancer screening and significant excess emotional distress. CONCLUSION: Gaps in cancer screening knowledge and emotional and financial distress may be responsible for the disparity of lower cancer screening rates for the SGM population and the transgender population may be most at risk. Appreciating the cancer screening concerns of the SGM population can help shape future clinical and institutional approaches to improve health care delivery.

A stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes.

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8-45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov).

Philadelphia Telemedicine Glaucoma Detection and Follow-Up Study: Cataract Classifications Following Eye Screening.

Background:Cataracts are a major cause of visual impairment and blindness in the United States and worldwide.Introduction:Risk factors for cataracts include age over 40 years, smoking, diabetes, low socioeconomic status, female sex, steroid use, ocular trauma, genetic factors, and exposure to ultraviolet-B light. Community-based telemedicine vision screenings can be an efficient method for detecting cataracts in underserved populations. The Philadelphia Telemedicine Glaucoma Detection and Follow-Up Study reports the prevalence and risk factors for cataracts in individuals screened and examined for glaucoma and other eye diseases.Materials and Methods:A total of 906 high-risk individuals were screened for glaucoma using telemedicine in seven primary care practices and four Federally Qualified Health Centers in Philadelphia. Participants with suspicious nerves or other abnormalities on fundus photographs, unreadable images, and ocular hypertension returned for an eye examination with an ophthalmologist at the same community location.Results:Of the participants screened through telemedicine, 347 (38.3%) completed a follow-up eye examination by an ophthalmologist. Of these, 267 (76.9%) were diagnosed with cataracts, of which 38 (14.2%) had visually significant cataracts. Participants who were diagnosed with visually significant cataract were more likely to be older (p < 0.001), have diabetes (p = 0.003), and worse visual acuity (p < 0.001).Discussion:Our study successfully detected and confirmed cataracts in a targeted, underserved urban population at high risk for eye disease.Conclusions:Telemedicine programs offer an opportunity to identify and refer individuals who would benefit from continuous follow-up eye care and treatment to improve visual function and quality of life.

Philadelphia glaucoma detection and treatment project: ocular outcomes and adherence to follow-up at a single health centre.

OBJECTIVES: To determine ocular outcomes and factors associated with adherence to ophthalmic follow-up in a medically underserved population at a single health centre in Philadelphia. DESIGN: Retrospective chart review. PARTICIPANTS: Patients from a community glaucoma screening program. METHODS: Chart review was conducted for participants who received a complete eye examination at the Philadelphia District Health Center 5 between January 1, 2012 and May 31, 2014 within the Philadelphia Glaucoma Detection and Treatment Project. Multivariate logistic regression was used to determine factors related to ophthalmic follow-up adherence. RESULTS: A total of 249 participants completed an eye examination (mean age = 57.7 ± 6.9 years). Most were African American (n = 220; 88.4%); female (n = 129; 51.8%). Forty-seven participants (18.9%) received glaucoma-related diagnoses, 20 (8.0%) were prescribed ocular medication, and 26 (10.4%) underwent laser therapy. Ninety (36.1%) attended their recommended follow-up eye examination at the health centre. Glaucoma-related diagnosis (p ≤ 0.001), recommendation of a 4- to 6-week follow-up period (p < 0.001), prescribed eye drops (p < 0.001), or received laser therapy (p = 0.047) were factors most predictive of ophthalmic follow-up adherence. CONCLUSIONS: The collaborative effort of eye care providers and health centres offers an important opportunity to detect, treat, and manage glaucoma and other ocular pathology in medically underserved communities. Having a glaucoma-related diagnosis, initiating treatment, and scheduling regular follow-up visits are the most important factors influencing adherence to follow-up eye appointments.

Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Intraocular Pressure Measurements Found in a Population at High Risk for Glaucoma.

PRECIS: Intraocular pressure (IOP) measurements, when used during telemedicine eye screening alongside nonmydriatic fundus photography, were shown to improve the likelihood of accurate glaucoma and glaucoma-related diagnoses at the follow-up eye examination. PURPOSE: To determine if IOP measurements, used as an adjunct to nonmydriatic fundus photography, are useful in glaucoma telemedicine screening. MATERIALS AND METHODS: A total of 902 high-risk individuals were screened for glaucoma at 7 primary care practices and 4 Federally Qualified Health Centers using telemedicine. Screening at visit 1 included fundus photography, assessing family history of glaucoma, and IOP measurements using a hand-held rebound tonometer. Participants with suspicious nerve findings for glaucoma, IOP>21 mm Hg or other ocular pathologies were invited for a follow-up appointment with an ophthalmologist (visit 2). RESULTS: Of the 902 individuals screened at visit 1, 19.6% (n=177/902) had elevated IOP (>21 mm Hg). Fifteen participants were found to have an IOP>30 mm Hg at visit 1, including 2 with an IOP of >40 mm Hg. Among all who attended visit 2 (n=347), 10.9% had glaucoma and 7.2% had ocular hypertension. For participants having both suspicious nerve findings and IOP>21 mm Hg compared with those with neither, the odds ratio (OR) of being diagnosed with glaucoma was 4.48 (95% CI, 1.50-13.93; P=0.007), whereas for participants with suspicious discs and IOP≤21 mm Hg the OR was 2.04 (95% CI, 0.83-5.53; P=0.15). CONCLUSIONS: In this telemedicine vision screening setting, having a higher IOP at the screening visit increased the likelihood of receiving a final diagnosis of glaucoma. Therefore, this study supports incorporating IOP measurements, using a portable tonometer, into vision screening programs in high-risk populations.

Proton Therapy Reduces Normal Tissue Dose in Extended-Field Pelvic Radiation for Endometrial Cancer.

PURPOSE: We dosimetrically compared pencil beam scanning (PBS) proton therapy and intensity-modulated radiation therapy (IMRT) for pelvic and para-aortic lymph node disease in endometrial carcinoma and present acute toxicities associated with extended-field PBS. PATIENTS AND METHODS: Twenty-five patients with locally advanced endometrial malignancies were enrolled in an image-guided registry study. Seven of these patients were treated with PBS, and 18 patients were treated with IMRT. Organs at risk included pelvic bone marrow (PBM), small bowel (SB), large bowel (LB), rectum, bladder, and kidneys. The IMRT and PBS dosimetric parameters were compared using Wilcoxon rank-sum tests. RESULTS: Compared with IMRT PBM dose-volume histograms, PBS resulted in significantly lower dose volumes from 0 to 26.0 Gy (P < .05) and higher dose volumes from 33.9 to 42.9 Gy (P < .05). Overall, PBS resulted in 22% lower median PBM volume irradiated to 10 Gy (RBE) (PBS 71.3% versus IMRT 93.4%, P < .001) and 14% lower median volume irradiated to 20 Gy (RBE) (PBS 65.1% versus IMRT 79.4%, P < .001). Compared with IMRT, PBS also significantly reduced SB dose volumes from 0 to 27.5 Gy, LB dose volumes from 0 to 31.6 Gy, bladder dose volumes from 0 to 27.3 Gy, and rectal dose volumes from 0 to 7.6 Gy (all P < .05). However, PBS resulted in higher rectal dose volumes compared with IMRT from 26.0 to 48.4 Gy. Grade 3+ hematologic toxicities were present in 2 (11%) IMRT-treated patients and no PBS-treated patients. No grade 3+ gastrointestinal or genitourinary toxicities were present in either treatment group. CONCLUSION: In endometrial carcinoma, extended-field PBS is clinically feasible, resulting in statistically significant dose reduction to PBM as well as SB, LB, and bladder in the lower dose regions.

Saturation mutagenesis reveals manifold determinants of exon definition.

To illuminate the extent and roles of exonic sequences in the splicing of human RNA transcripts, we conducted saturation mutagenesis of a 51-nt internal exon in a three-exon minigene. All possible single and tandem dinucleotide substitutions were surveyed. Using high-throughput genetics, 5560 minigene molecules were assayed for splicing in human HEK293 cells. Up to 70% of mutations produced substantial (greater than twofold) phenotypes of either increased or decreased splicing. Of all predicted secondary structural elements, only a single 15-nt stem-loop showed a strong correlation with splicing, acting negatively. The in vitro formation of exon-protein complexes between the mutant molecules and proteins associated with spliceosome formation (U2AF35, U2AF65, U1A, and U1-70K) correlated with splicing efficiencies, suggesting exon definition as the step affected by most mutations. The measured relative binding affinities of dozens of human RNA binding protein domains as reported in the CISBP-RNA database were found to correlate either positively or negatively with splicing efficiency, more than could fit on the 51-nt test exon simultaneously. The large number of these functional protein binding correlations point to a dynamic and heterogeneous population of pre-mRNA molecules, each responding to a particular collection of binding proteins.