Using optical coherence tomography to optimize Mohs micrographic surgery.

Mohs micrographic surgery (MMS) is considered the gold standard for treating high-risk cutaneous basal cell carcinoma (BCC), but is expensive, time-consuming, and can be unpredictable as to how many stages will be required or how large the final lesion and corresponding surgical defect will be. This study is meant to investigate whether optical coherence tomography (OCT), a highly researched modality in dermatology, can be used preoperatively to map out the borders of BCC, resulting in fewer stages of MMS or a smaller final defect. In this prospective study, 22 patients with BCC undergoing surgical excision were enrolled at a single institution. All patients had previously received a diagnostic biopsy providing confirmation of BCC and had been referred to our center for excision with MMS. Immediately prior to performing MMS, OCT was used to map the borders of the lesion. MMS then proceeded according to standard protocol. OCT images were compared to histopathology for agreement. Histopathologic analysis of 7 of 22 MMS specimens (32%) revealed a total absence of BCC, indicating resolution of BCC after previous diagnostic biopsy. This outcome was correctly predicted by OCT imaging in 6 of 7 cases (86%). Nine tumors (9/22, 41%) had true BCC and required a single MMS stage, which was successfully predicted by pre-operative OCT analysis in 7 of 9 cases (78%). The final six tumors (27%) had true BCC and required two MMS stages for complete excision; preoperative OCT successfully predicted the need for a second stage in five cases (5/6, 83.3%). Overall, OCT diagnosed BCC with 95.5% accuracy (Cohen's kappa, κ = 0.89 (p-value = < 0.01) in the center of the lesion. Following a diagnostic biopsy, OCT can be used to verify the existence or absence of residual basal cell carcinoma. When residual tumor is present that requires excision with MMS, OCT can be used to predict tumor borders, optimize surgery and minimize the need for additional surgical stages.

Evaluating the Relationship between Neighborhood-Level Social Vulnerability and Patient Adherence to Ophthalmology Appointments.

PURPOSE: To examine the association between neighborhood-level social vulnerability and adherence to scheduled ophthalmology appointments. METHODS: In this retrospective cohort study, records of all patients ≥18 years scheduled for an ophthalmology appointment between September 12, 2020, and February 8, 2021, were reviewed. Primary exposure is neighborhood-level Social Vulnerability Index (SVI) based on the patient's residential location. SVI is a rank score of 15 social factors into four themes (socioeconomic status, household composition/disability, minority status/language, and housing type/transportation), ranging from 0 to 1.0, with higher ranks indicating greater social vulnerability. The overall SVI score and each theme were analyzed separately as the primary exposure of interest in multivariable logistic regression models that controlled for age, sex, appointment status (new or established), race, and distance from clinic. The primary outcome, non-adherence, was defined as missing more than 25% of scheduled appointments. RESULTS: Of 8,322 patients (41% non-Hispanic Black, 24% Hispanic, 22% non-Hispanic White) with scheduled appointments, 28% were non-adherent. Non-adherence was associated with greater social vulnerability (adjusted odds ratio [aOR] per 0.01 increase in overall SVI = 2.46 [95% confidence interval, 1.99, 3.06]) and each SVI theme (socioeconomic status: aOR = 2.38 [1.94, 2.91]; household composition/disability: aOR = = 1.51 [1.26, 1.81]; minority status/language: aOR = 2.03 [1.55, 2.68]; housing type/transportation: aOR = 1.41 [1.16, 1.73]). CONCLUSION: Neighborhood-level social vulnerability is associated with greater risk of non-adherence to scheduled ophthalmology appointments, controlling for individual characteristics. Multi-level intervention strategies that incorporate neighborhood-level vulnerabilities are needed to reduce disparities in access to ophthalmology care.

Statistical Considerations and Software for Designing Sequential, Multiple Assignment, Randomized Trials (SMART) with a Survival Final Endpoint.

Sequential, multiple assignment, randomized trial (SMART) designs are appropriate for comparing adaptive treatment interventions, in which intermediate outcomes (called tailoring variables) guide subsequent treatment decisions for individual patients. Within a SMART design, patients may be re-randomized to subsequent treatments following the outcomes of their intermediate assessments. In this paper, we provide an overview of statistical considerations necessary to design and implement a two-stage SMART design with a binary tailoring variable and a survival final endpoint. A chronic lymphocytic leukemia trial with a final endpoint of progression-free survival is used as an example for the simulations to assess how design parameters, including, choice of randomization ratios for each stage of randomization, and response rates of the tailoring variable affect the statistical power. We assess the choice of weights from restricted re-randomization on data analyses and appropriate hazard rate assumptions. Specifically, for a given first-stage therapy and prior to the tailoring variable assessment, we assume equal hazard rates for all patients randomized to a treatment arm. After the tailoring variable assessment, individual hazard rates are assumed for each intervention path. Simulation studies demonstrate that the response rate of the binary tailoring variable impacts power as it directly impacts the distribution of patients. We also confirm that when the first stage randomization is 1:1, it is not necessary to consider the first stage randomization ratio when applying the weights. We provide an R-shiny application for obtaining power for a given sample size for SMART designs.

Computer Vision Syndrome in Undergraduate and Medical Students During the COVID-19 Pandemic.

Purpose: The purpose of this study was to evaluate Computer Vision Syndrome (CVS) in undergraduate and medical students since transitioning to online learning during the COVID-19 pandemic. Patients and Methods: This was a cross-sectional single center survey-based study using a validated CVS questionnaire (CVS-Q). The survey was distributed to 20,080 undergraduate students and 680 medical students at the University of Illinois at Chicago. The primary outcome measures were prevalence of CVS (based on CVS severity score of 6 or more), frequency of CVS and intensity of CVS symptoms. Results: The survey was completed by 2300 undergraduate students (11.4% response rate) and 154 medical students (22.6% response rate). The prevalence of CVS was 77.1% in undergraduate students and 69.1% in medical students. CVS-Q severity scores were highest for headaches and eye dryness, with over half of students reporting worsening of symptoms since March 2020. Increased time spent on online learning (undergraduate: P <0.001, medical: P = 0.018), blue light glasses usage (undergraduate: P <0.001, medical: P = 0.0015), and increased number of device usage were associated with higher CVS severity scores (undergraduate: P <0.001, medical: P = 0.0032). Conclusion: CVS among undergraduate and medical students has increased since the start of the COVID-19 pandemic. More focus should be placed on the management of CVS for students in higher education. Physicians should be cognizant of the consequences of online learning and be proactive about providing advice regarding preventative measures.

Surgical opioid-avoidance protocol: a postoperative pharmacological multimodal analgesic intervention in diverse patient populations.

INTRODUCTION: This study evaluated the effect of a surgical opioid-avoidance protocol (SOAP) on postoperative pain scores. The primary goal was to demonstrate that the SOAP was as effective as the pre-existing non-SOAP (without opioid restriction) protocol by measuring postoperative pain in a diverse, opioid-naive patient population undergoing inpatient surgery across multiple surgical services. METHODS: This prospective cohort study was divided into SOAP and non-SOAP groups based on surgery date. The non-SOAP group had no opioid restrictions (n=382), while the SOAP group (n=449) used a rigorous, opioid-avoidance order set with patient and staff education regarding multimodal analgesia. A non-inferiority analysis assessed the SOAP impact on postoperative pain scores. RESULTS: Postoperative pain scores in the SOAP group compared with the non-SOAP group were non-inferior (95% CI: -0.58, 0.10; non-inferiority margin=-1). The SOAP group consumed fewer postoperative opioids (median=0.67 (IQR=15) vs 8.17 morphine milliequivalents (MMEs) (IQR=40.33); p<0.01) and had fewer discharge prescription opioids (median=0 (IQR=60) vs 86.4 MMEs (IQR=140.4); p<0.01). DISCUSSION: The SOAP was as effective as the non-SOAP group in postoperative pain scores across a diverse patient population and associated with lower postoperative opioid consumption and discharge prescription opioids.

Predictability of the Phenylephrine Test in Congenital Ptosis: Ten Years of Experience.

PURPOSE: To assess the predictability of phenylephrine testing for congenital ptosis and review outcomes of Müller's Muscle-conjunctival resection (MMCR) for congenital ptosis across ten years of follow-up. METHODS: In this retrospective case series, all patients who underwent MMCR for congenital ptosis at a single institution between 2010 and 2020 were identified. Exclusion criteria included patients who had not undergone preoperative testing with 2.5% phenylephrine in the superior fornix; patients who underwent revision surgery; and patients who had a broken suture in the early postoperative period. Demographics, margin-reflex distance 1 (MRD1) values pre- and postphenylephrine, millimeters of tissue resected intraoperatively, and final postoperative MRD1 were recorded. RESULTS: A total of 28 patients were included; 19 patients received MMCR and 9 patients received a combined MMCR plus tarsectomy. The amount of tissue resected ranged from 5 to 11 mm. There was no significant difference between median postphenylephrine MRD1 and median final postoperative MRD1 in either surgical group. Neither patient age nor levator function was significantly associated with a change in MRD1 in either group. The addition of a tarsectomy had no bearing on the final MRD1 value. CONCLUSIONS: MMCR is a viable option for patients with congenital ptosis and moderate levator function with a response to phenylephrine. In these patients, MRD1 after 2.5% phenylephrine testing correlates to the final postoperative MRD1 outcome within 0.5 mm.

An Association Between Large Optic Cupping and Total and Regional Brain Volume: The Women's Health Initiative.

PURPOSE: To investigate the relationships between optic nerve cupping and total and regional brain volumes. DESIGN: Secondary analysis of randomized clinical trial data. METHODS: Women 65 to 79 years of age without glaucoma with cup-to-disc ratio (CDR) measurements from the Women's Health Initiative (WHI) Sight Examination study and magnetic resonance imaging (MRI)-based total and regional brain volumes from the WHI Memory Study MRI-1 were included. Large CDR was defined as 0.6 or greater in either eye. Generalized estimating equation models were used to account for intra-brain correlations between the right and left sides. The final analysis was adjusted for demographic and clinical characteristics and for total brain volume (for regional analyses). RESULTS: Final analyses included 471 women, with the mean age ± SD was 69.2 ± 3.6 years; 92.8% of the subjects were white. Of 471 women, 34 (7.2%) had large CDR. Controlling for total brain volume and for demographic and clinical characteristics, lateral ventricle volume was 3.01 cc larger for subjects with large CDR compared to those without large CDR (95% CI = 0.02 to 5.99; P = .048). Furthermore, frontal lobe volume was 4.78 cc lower for subjects with large CDR compared to those without (95% CI = -8.71, -0.84; P = 0.02), and occipital lobe volume was 1.86 cc lower for those with large CDR compared to those without (95% CI = -3.39, -0.3; P =.02). CONCLUSIONS: Our analysis suggests that in women aged 65 years or more, large CDR is associated with lower relative total brain volume and absolute regional volume in the frontal and occipital lobes. Enlarged CDR in individuals without glaucoma may represent a sign of optic nerve and brain aging, although more longitudinal data are needed.

Association between myopia progression and quantity of laser treatment for retinopathy of prematurity.

BACKGROUND: Previous studies found that infants with retinopathy of prematurity (ROP) who were treated for more posterior disease with a greater number of laser spots developed higher myopia. These studies included multiple physicians with variations in laser density. In treatments by a single physician, laser spot count is a better surrogate for area of avascular retina and anterior-posterior location of disease, so that the relationship with myopia can be better assessed. METHODS: Our retrospective study included infants treated with laser for ROP by a single surgeon at a single center. Exclusion criteria were irregularities during laser and additional treatment for ROP. We assessed correlation between laser spot count and change in refractive error over time using a linear mixed effects model. RESULTS: We studied 153 eyes from 78 subjects treated with laser for ROP. The average gestational age at birth was 25.3±1.8 weeks, birth weight 737±248 grams, laser spot count 1793±728, and post-treatment follow up 37±29 months. Between corrected ages 0-1 years, the mean spherical equivalent was +0.4±2.3 diopters; between ages 1-2, it was -1.3±3.2D; and ages 2-3 was -0.8±3.1D. Eyes that received more laser spots had significantly greater change in refractive error over time (0.30D more myopia per year per 1000 spots). None of the eyes with hyperopia before 18 months developed myopia during the follow-up period. CONCLUSIONS: Greater myopia developed over time in infants with ROP treated by laser to a larger area of avascular retina.

Patient Adherence to Immunosuppressive Therapy in Treatment of Chronic Inflammatory Eye Disease.

TITLE: Patient Adherence to Immunosuppressive Therapy for Chronic Inflammatory Eye Disease. PURPOSE: To investigate adherence rates to immunosuppressive therapy (IMT) for treatment of noninfectious inflammatory eye disease (IED), adherence and disease control, and factors associated with nonadherence. METHOD: Retrospective review of medical charts from 2015 to 2020 was conducted on patients with IED at 6 months, 1 and 2 years after initiation of IMT. RESULTS: Of 183 patients, adherence rates at 6 months and 1 year were 70% and 58% by 2 years. Eighty-two percent, 78%, and 65% of patients with disease quiescence were adherent at 6 months, 1 and 2 years, respectively. Adherent patients have 1.86 (95% CI 1.09, 3.20) times greater likelihood for disease control compared to nonadherent. Primary reason for nonadherence was patient self-discontinuation. No specific factors were associated with nonadherence. CONCLUSION: Patients on IMT for IED had steady adherence rates up to 1 year, with decreased adherence at 2 years. Adherence to IMT significantly correlates with disease quiescence.

Association between cognitive function and large optic nerve cupping, accounting for cup-disc-ratio genetic risk score.

PURPOSE: To investigate if accounting for a cup-to-disc ratio (CDR) genetic risk score (GRS) modified the association between large CDR and cognitive function among women. DESIGN: This was a retrospective study using data from the Women's Health Initiative. METHODS: Patients with glaucoma or ocular hypertension were excluded. Large CDR was defined as ≥ 0.6 in either eye. Cognitive function was measured by the Modified Mini-Mental State Examination (3MSE). We used the combined effects from 13 single nucleotide polymorphisms (SNPs) to formulate the GRS for CDR. We used logistic regression to investigate associations between weighted GRS and large CDR, then a linear regression to assess the association between weighted GRS and 3MSE scores, and between weighted GRS, CDR, and 3MSE scores, adjusted for demographic and clinical characteristics. RESULTS: Final analyses included 1,196 White women with mean age of 69.60 ± 3.62 years and 7.27% with large CDR. Mean GRS in women with and without large CDR was 1.51 ± 0.31 vs. 1.41 ± 0.36, respectively (p = 0.004). The odds of large CDR for a one unit increase in GRS was 2.30 (95% CI: (1.22, 4.36), p = 0.011). Adding the CDR GRS in the model with CDR and 3MSE, women with large CDR still had statistically significantly lower 3MSE scores than those without large CDR, yielding a predicted mean difference in 3MSE scores of 0.84 (p = 0.007). CONCLUSIONS: Independent of the CDR GRS, women with large CDR had a lower cognitive function.

Optometrist's perspectives of Artificial Intelligence in eye care.

PURPOSE: The application of artificial intelligence (AI) in diagnosing and managing ocular disease has gained popularity as research highlights the utilization of AI to improve personalized medicine and healthcare outcomes. The objective of this study is to describe current optometric perspectives of AI in eye care. METHODS: Members of the American Academy of Optometry were sent an electronic invitation to complete a 17-item survey. Survey items assessed perceived advantages and concerns regarding AI using a 5-point Likert scale ranging from "strongly agree" to "strongly disagree." RESULTS: A total of 400 optometrists completed the survey. The mean number of years since optometry school completion was 25 ± 15.1. Most respondents reported familiarity with AI (66.8%). Though half of optometrists had concerns about the diagnostic accuracy of AI (53.0%), most believed it would improve the practice of optometry (72.0%). Optometrists reported their willingness to incorporate AI into practice increased from 53.3% before the COVID-19 pandemic to 65.5% after onset of the pandemic (p<0.001). CONCLUSION: In this study, optometrists are optimistic about the use of AI in eye care, and willingness to incorporate AI in clinical practice also increased after the onset of the COVID-19 pandemic.

Imaging and artificial intelligence for progression of age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of severe vision loss. With our aging population, it may affect 288 million people globally by the year 2040. AMD progresses from an early and intermediate dry form to an advanced one, which manifests as choroidal neovascularization and geographic atrophy. Conversion to AMD-related exudation is known as progression to neovascular AMD, and presence of geographic atrophy is known as progression to advanced dry AMD. AMD progression predictions could enable timely monitoring, earlier detection and treatment, improving vision outcomes. Machine learning approaches, a subset of artificial intelligence applications, applied on imaging data are showing promising results in predicting progression. Extracted biomarkers, specifically from optical coherence tomography scans, are informative in predicting progression events. The purpose of this mini review is to provide an overview about current machine learning applications in artificial intelligence for predicting AMD progression, and describe the various methods, data-input types, and imaging modalities used to identify high-risk patients. With advances in computational capabilities, artificial intelligence applications are likely to transform patient care and management in AMD. External validation studies that improve generalizability to populations and devices, as well as evaluating systems in real-world clinical settings are needed to improve the clinical translations of artificial intelligence AMD applications.

Correlation of 68Ga-DOTATATE uptake on PET/CT with pathologic features of cellular proliferation in neuroendocrine neoplasms.

OBJECTIVE: 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) is a useful tool for diagnosing and staging neuroendocrine neoplasms (NEN). Unlike other PET tracers like FDG, the meaningfulness and use of standardized uptake values (SUVs) of 68Ga-DOTATATE is not well-established. This study aimed to determine if a correlation exists between intensity of 68Ga-DOTATATE uptake and markers of cellular proliferation. METHODS: This retrospective study included 79 patients with positive 68Ga-DOTATATE PET/CT and Ki-67 and/or mitotic index (MI) available on pathology report. SUVmax of the most intense lesion and the most intense organ-matched lesion were determined. Demographics and pathology results for Ki-67 and MI were collected from the electronic medical record. Correlations and trends for correlations of SUVmax to Ki-67 and MI were performed using Kruskal-Wallis and Cuzick trend tests. RESULTS: A trend for an association between SUVmax and Ki-67 grade was found; median SUVmax of Ki-67 < 3%, 3-20%, and > 20% was 35.2, 31.8, and 12.8 (p = 0.077), respectively. There was also a trend between SUVmax and Ki-67 categories in organ-matched lesions (p = 0.08). The median organ-matched SUVmax of MI < 2, 2-20, and > 20 lesions was 34.2, 18, and 21.7, respectively, (Cuzick trend test p = 0.066). The median SUVmax for small bowel, pancreatic, and other primary locations was 27.6, 46.9, and 9.3 (p < 0.01), respectively. CONCLUSIONS: The association between 68Ga-DOTATATE SUVmax, histologic grade, and primary site of NEN demonstrates its potential use for prognostication, or potentially as a surrogate for histologic grading when biopsy is not possible.

Tumor volume dynamics and tumor growth rate in ALK-rearranged advanced non-small-cell lung cancer treated with crizotinib.

PURPOSE: The purpose of the study is to investigate volumetric tumor burden dynamics and tumor growth rates in ALK-rearranged advanced NSCLC patients during crizotinib monotherapy. METHODS: The study included 44 ALK-rearranged advanced NSCLC patients treated with crizotinib monotherapy as their initial ALK-directed therapy, who had at least one measurable lung lesion and at least two follow-up CT scans, and experienced tumor volume increase while on crizotinib. The tumor volume (in mm3) of the dominant lung lesion was measured on serial CT scans during therapy for analysis of tumor growth rates after the volume nadir. RESULTS: A total of 231 volume measurements from the nadir to the end of crizotinib therapy or the last follow-up in 44 patients were analyzed in a linear mixed-effects model, fitting time (in months since baseline) as a random effect. When measured from the volume nadir, the tumor growth rate of the logarithm of tumor volume (logeV) was 0.04/month (SE = 0.012, P = 0.0011) in the unadjusted model. When adjusted for the baseline volume (logeV0), the growth rate was again 0.04/month (SE = 0.011, P = 0.0004). When adjusted for clinical variables and logeV0, the growth rate was 0.045/month (SE = 0.012, P = 0.0002), indicating that the tumor growth rate after nadir in this cohort remains very close to 0.04/month regardless of logeV0 or clinical factors. CONCLUSIONS: Tumor volume growth rate after nadir in ALK-rearranged NSCLC patients treated with crizotinib was obtained, providing objective reference values that can inform physicians when deciding to keep their patients on ALK directed therapy with slowly progressing lung cancer.

Identification of a RAS-activating TMEM87A-RASGRF1 Fusion in an Exceptional Responder to Sunitinib with Non-Small Cell Lung Cancer.

PURPOSE: We pursued genomic analysis of an exceptional responder with non-small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. EXPERIMENTAL DESIGN: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9. RESULTS: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A-RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A-RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib. CONCLUSIONS: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.

Impact of MET inhibitors on survival among patients with non-small cell lung cancer harboring MET exon 14 mutations: a retrospective analysis.

OBJECTIVES: Although dramatic responses to MET inhibitors have been reported in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC), the impact of these treatments on overall survival in this population is unknown. METHODS: We conducted a multicenter retrospective analysis of patients with METex14 NSCLC to determine if treatment with MET inhibitors impacts median overall survival (mOS). Event-time distributions were estimated using the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox models were fitted to estimate hazard ratios. RESULTS: We identified 148 patients with METex14 NSCLC; the median age was 72; 57% were women and 39% were never smokers. Of the 34 metastatic patients who never received a MET inhibitor, the mOS was 8.1 months; those in this group with concurrent MET amplification had a trend toward worse survival compared to cancers without MET amplification (5.2 months vs 10.5 months, P = 0.06). Of the 27 metastatic patients who received at least one MET inhibitor the mOS was 24.6 months. A model adjusting for receipt of a MET inhibitor as first- or second-line therapy as a time-dependent covariate demonstrated that treatment with a MET inhibitor was associated with a significant prolongation in survival (HR 0.11, 95% CI 0.01-0.92, P = 0.04) compared to patients who did not receive any MET inhibitor. Among 22 patients treated with crizotinib, the median progression-free survival was 7.4 months. DISCUSSION: For patients with METex14 NSCLC, treatment with a MET inhibitor is associated with an improvement in overall survival.

Use of targeted next generation sequencing to characterize tumor mutational burden and efficacy of immune checkpoint inhibition in small cell lung cancer.

BACKGROUND: Clinically-available biomarkers to identify the fraction of patients with small cell lung cancer (SCLC) who respond to immune-checkpoint inhibitors (ICIs) are lacking. High nonsynonymous tumor mutational burden (TMB), as assessed by whole exome sequencing, correlates with improved clinical outcomes for patients with SCLC treated with ICIs. Whether TMB as assessed by targeted next generation sequencing (NGS) is associated with improved efficacy of ICIs in patients with SCLC is currently unknown. Here we determined whether TMB by targeted NGS is associated with efficacy of ICIs in patients with SCLC. METHODS: We collected clinicopathologic data from patients with relapsed or refractory SCLC which underwent targeted NGS with TMB assessment by the Dana-Farber Cancer Institute OncoPanel platform. The relationship between TMB and clinical outcomes after treatment with ICIs was investigated. RESULTS: Among the 52 patients treated with ICIs, we found no significant difference in the objective response rate (ORR) between patients with a TMB above the 50th percentile ("TMB high") and those with a TMB at or below the 50th percentile ("TMB low"). The median progression-free survival (mPFS) and median overall survival (mOS) were significantly longer in patients with a high TMB compared to those with a low TMB (mPFS: 3.3 versus 1.2 months, HR: 0.37 [95% CI: 0.20-0.69], P < 0.01; mOS: 10.4 versus 2.5 months, HR: 0.38 [95% CI: 0.19-0.77], P < 0.01). The one-year PFS and OS rates improved with increasing mutational load when TMB was divided into tertiles. CONCLUSIONS: These findings show that targeted NGS, a readily available clinical diagnostic test, can be used to identify patients with SCLC who are most likely to benefit from treatment with immune checkpoint inhibitors.

Success of genomic profiling of non-small cell lung cancer biopsies obtained by trans-thoracic percutaneous needle biopsy.

PURPOSE: Genomic profiling for personalized targeted therapy has become standard of care. We report the success of genomic profiling of non-small cell lung cancer (NSCLC) obtained by trans-thoracic needle biopsy (TTNB) in a single center experience. MATERIALS AND METHODS: Patients with NSCLC who underwent TTNB for genomic were identified. Pathology specimens were evaluated for tumor adequacy and then analyzed for selected exons of epidermal growth factor receptor, KRAS, BRAF, PIK3CA, and ERBB2. ALK rearrangements were detected with fluorescence in situ hybridization and/or immunohistochemistry. Technical success was recorded and the factors affecting successful profiling were evaluated. Complications (pneumothorax, hemorrhage, and admission) were recorded. Comparison of yield and complications were done between the two groups (core biopsy and fine needle aspiration only group). Utility of PET-CT to guide the needle track for optimized yield was assessed in a subset of patients. RESULTS: Between December 6, 2009, and December 30, 2016, 765 patients with NSCLC underwent TTNB. Five-hundred and seventy-seven of 765 (75%) of all TTNB were profiled, for genomic analysis. Five-hundred and eight of 577 (88%) were successfully profiled. The number of samples obtained ranged from 1 to 10 (1 to 2 cm, 18 to 20 G). Lesions biopsied ranged in size from 0.6 to 16 cm. No statistically significant difference was observed in the incidence of pneumothorax between two groups (P = 0.26). PET guidance was not found to be statistically significant ( P = 0.79) in the overall yield. CONCLUSION: Computed tomographic guided TTNB is a safe and efficacious technique for genomic profiling, enables the acquisition of sufficient tissue for genetic mutation analyses allowing for personalized therapy with an acceptable complication rate.

Development and validation of a new MRI simulation technique that can reliably estimate optimal in vivo scanning parameters in a glioblastoma murine model.

BACKGROUND: Magnetic Resonance Imaging (MRI) relies on optimal scanning parameters to achieve maximal signal-to-noise ratio (SNR) and high contrast-to-noise ratio (CNR) between tissues resulting in high quality images. The optimization of such parameters is often laborious, time consuming, and user-dependent, making harmonization of imaging parameters a difficult task. In this report, we aim to develop and validate a computer simulation technique that can reliably provide "optimal in vivo scanning parameters" ready to be used for in vivo evaluation of disease models. METHODS: A glioblastoma murine model was investigated using several MRI imaging methods. Such MRI methods underwent a simulated and an in vivo scanning parameter optimization in pre- and post-contrast conditions that involved the investigation of tumor, brain parenchyma and cerebrospinal fluid (CSF) CNR values in addition to the time relaxation values of the related tissues. The CNR tissues information were analyzed and the derived scanning parameters compared in order to validate the simulated methodology as a reliable technique for "optimal in vivo scanning parameters" estimation. RESULTS: The CNRs and the related scanning parameters were better correlated when spin-echo-based sequences were used rather than the gradient-echo-based sequences due to augmented inhomogeneity artifacts affecting the latter methods. "Optimal in vivo scanning parameters" were generated successfully by the simulations after initial scanning parameter adjustments that conformed to some of the parameters derived from the in vivo experiment. CONCLUSION: Scanning parameter optimization using the computer simulation was shown to be a valid surrogate to the in vivo approach in a glioblastoma murine model yielding in a better delineation and differentiation of the tumor from the contralateral hemisphere. In addition to drastically reducing the time invested in choosing optimal scanning parameters when compared to an in vivo approach, this simulation program could also be used to harmonize MRI acquisition parameters across scanners from different vendors.

Safety of Programmed Death-1 Pathway Inhibitors Among Patients With Non-Small-Cell Lung Cancer and Preexisting Autoimmune Disorders.

Purpose Although programmed death (PD)-1 pathway inhibitors are now used in nearly all patients with advanced non-small-cell lung cancer (NSCLC), the large number of patients with NSCLC and concurrent autoimmune disease (AID) have been universally excluded from immunotherapy clinical trials. Therefore, the safety of PD-1 and PD-ligand 1 (PD-L1) inhibitors in patients with NSCLC and underlying AID is currently unknown. Methods As part of a multi-institutional effort, we retrospectively collected clinicopathologic data from patients with NSCLC and a history of AID who received monotherapy with either a PD-1 or a PD-L1 (herein referred to as PD-[L]1) inhibitor. Qualifying AIDs included but were not limited to: rheumatologic, neurologic, endocrine, GI, and dermatologic conditions. Results We identified 56 patients with NSCLC and an AID who received a PD-(L)1 inhibitor. At the time of treatment initiation, 18% of patients had active AID symptoms and 20% were receiving immunomodulatory agents for their AID. A total of 55% of patients developed an AID flare and/or an immune-related adverse event (irAE). Exacerbation of the AID occurred in 13 patients (23% of the whole cohort), four of whom required systemic corticosteroids. Immune-related adverse events occurred in 21 patients (38%). Among irAEs, 74% were grade 1 or 2 and 26% were grade 3 or 4; eight patients required corticosteroids for irAE management. PD-(L)1 therapy was permanently discontinued in eight patients (14%) because of irAEs. The overall response rate to immunotherapy in this population was 22%. Conclusion In patients with NSCLC with AID treated with a PD-(L)1 inhibitor, exacerbation of AID occurred in a minority of patients. The incidence of irAEs was similar to reported rates in clinical trials where patients with AID were excluded. Adverse events were generally manageable and infrequently led to permanent discontinuation of immunotherapy.