Adoption of Optimal Small (6-9 mm) Colorectal Polyp Resection Technique Over Time.

BACKGROUND: Cold snare polypectomy (CSP) is the preferred resection technique for small (6-9 mm) polyps due to lower rate of incomplete resection compared to cold forceps polypectomy (CFP) and improved safety profile over hot snare polypectomy (HSP). AIMS: To describe resection techniques for small (6-9 mm) polyps and determine factors associated with sub-optimal technique. METHODS: This was retrospective cohort study of colonoscopies performed by gastroenterological and surgical endoscopists from 2012 to 2019 where at least one 6-9 mm polyp was removed. Patient, provider, and procedure characteristics were collected. Univariate and multivariate regression analyses were performed to determine factors associated with sub-optimal technique. RESULTS: In total, 773 colonoscopies where 1,360 6-9 mm polyps removed by 21 endoscopists were included. CSP was used for 1,122 (82.5%), CFP for 61 (4.5%), and HSP for 177 (13.0%). Surgeon specialty was associated with CFP use (aOR 7.81; 95% CI 3.02-20.16). Polyp location in left colon (aOR 1.65; 95% CI 1.17-2.33) and pedunculated morphology (aOR 12.76; 95% CI 7.24-22.50) were associated with HSP. There was a significant increase in overall CSP use from 30.4% in 2012 to 96.8% in 2019. CONCLUSIONS: 82.5% of all 6-9 mm polyps removed from 2012 to 2019 were removed using a cold snare with significant increase in CSP from 2012 to 2019. Differences in how optimal technique was adopted over time based on specialty highlight the need for standardized practice guidelines and quality monitoring.

Risk and subtypes of secondary primary malignancies in diffuse large B-cell lymphoma survivors change over time based on stage at diagnosis.

BACKGROUND: Previous studies have shown an increased risk of secondary primary malignancies (SPMs) after diffuse large B-cell lymphoma (DLBCL) treatment. Whether stage of DLBCL at diagnosis affects the subtypes of SPMs that occur has not been previously described. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients aged >18 years diagnosed with primary DLBCL from 1973 to 2010 and categorized by early stage (ES) (stage I-II) or advanced stage (AS) (stage III-IV) disease. Differences in overall and location-specific SPM incidence by stage and time since diagnosis were assessed in 5-year intervals using a Fine-Gray hazards model. Overall survival was compared using the log-rank test. A Cox proportional hazards model was used to assess differences in survival. RESULTS: In total, 26,038 patients with DLBCL were identified, including 14,724 with ES and 11,314 with AS disease. The median follow-up was 13.3 years. Overall, 13.0% of patients developed SPM, with a higher but nonsignificantly increased risk of SPM development in those who had ES disease compared with those who had AS disease (14% vs 11.6%; P = .14). During the first 5 years after diagnosis, patients who had ES disease had a higher risk of SPM than those who had AS disease, specifically colorectal, pancreas, breast, and prostate SPMs. During the period from 10 to 15 years after diagnosis, patients who had AS disease had a higher risk of SPM than those who had ES disease, specifically hematologic SPMs. Development of SPM was found to significantly increase the risk of death regardless of stage at diagnosis. CONCLUSIONS: In this large, population-based study, distinctly different subtypes and temporal patterns of SPM development were identified based on stage of DLBCL at diagnosis. The current study merits consideration of tailored site-specific and time-specific surveillance for patients with DLBCL according to stage and time interval since diagnosis.

The impact of age at orchiopexy on testicular cancer outcomes.

PURPOSE: To estimate how many boys with UDT must undergo orchiopexy to prevent one case of TC, one death from TC and one exposure to TC treatment beyond radical orchiectomy as compared to being treated at an older age. METHODS: This retrospective study utilized data from a 2007 Swedish study of males who underwent orchiopexy for UDT (Pettersson et al.). TC incidence for boys undergoing orchiopexy for UDT was assessed based on the age at orchiopexy (0-6 years, 7-9 years, 10-12 years, 13-15 years). The incidence of TC in each age cohort was calculated and used to determine the number needed to treat (NNT) for each age group using assumptions based on published TC outcomes. RESULTS: For an index patient ≤ 6 years, 372 boys need to undergo orchiopexy to prevent a single case of TC, 1488 boys to prevent exposure to TC therapy beyond radical orchiectomy, and 5315 boys to prevent a single TC-related death compared to treatment at an older age. CONCLUSION: While there is evidence supporting benefits of early orchiopexy, the NNT to affect TC outcomes is very high. Even those with delayed orchiopexies have low risk for TC poor outcomes. This information can be used when counseling patients and families faced with UDT about the risks related to TC, especially with comorbidities.

Evolving trends in the management of high-intermediate risk endometrial cancer in the United States.

OBJECTIVE: Gynecologic oncology group protocol 249 (GOG 249) is the contemporary US study that aimed to define the standard of care adjuvant therapy for patients with high-intermediate risk (HIR) endometrial cancer; patients were randomized to pelvic radiation therapy (RT) or vaginal brachytherapy (VBT) with chemotherapy (VBT-C). The preliminary results of GOG 249 were recently presented, yet the management of patients represented in this trial remains controversial. We set out to review US patterns of care for patients meeting eligibility criteria for GOG 249. METHODS: The National Cancer Database (NCDB) was used to identify patients meeting GOG 249 eligibility criteria between 2010 and 2015. The Man-Kendall trend test was used to assess for significant trends over time. RESULTS: We identified 23,015 patients that met study inclusion criteria. Between 2010 and 2015, there was a decline in the use of pelvic RT from 9.8% to 7.5%, although not meeting statistical significance (p = 0.136), and an increase in the use of VBT-C from 4.6% to 7.7% (p = 0.017). Most patients did not receive treatment per either arm of GOG 249, with observation being the most common approach throughout this era, although the percentage of patients observed decreased from 58.1% to 45.8% between 2010 and 2015 (p = 0.003). Further, 21.5% of patients received VBT alone in 2010, increasing to 30.3% by 2015 (p = 0.003). CONCLUSIONS: National practice trends in HIR endometrial cancer reveal that a large number of patients are observed in lieu of receiving adjuvant therapy. Further, the utilization of pelvic RT has declined below utilization of VBT-C, despite a lack of data supporting either improved disease outcomes or toxicity with this experimental regimen on GOG 249.

Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases.

INTRODUCTION: Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. METHODS: We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery. RESULTS: Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0). CONCLUSIONS: Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.

Clinical and laboratory factors contributing to uninterpretable beryllium lymphocyte proliferation tests (BeLPT).

BACKGROUND: The beryllium lymphocyte proliferation test (BeLPT), has become the principal clinical test for detecting beryllium sensitization and chronic beryllium disease. Uninterpretable BeLPT results can occur in a small but significant proportion of tests from poor lymphocyte growth (PG) or over proliferation of lymphocytes (OP). The clinical and laboratory causes of uninterpretable results are not known. METHODS: BeLPT data from the US Department of Energy-supported Former Worker Screening Program were analyzed for a 10-year period. Drivers of uninterpretable BeLPTs were investigated using multivariable models and classification techniques. RESULTS: Three participant attributes were significantly associated with PG, while OP showed no significant associations. Serum lot for the lymphocyte growth medium accounted for 21% of the variation in PG and 16% in OP. CONCLUSION: Serum lots influence the likelihood of having uninterpretable BeLPT. To better understand uninterpretable results and possibly reduce their occurrence, additional laboratory-related factors should be addressed.

Development and validation of a diabetes risk score among two populations.

The purpose of this study was to assess the validity of a practical diabetes risk score amongst two heterogenous populations, a working population and a non-working population. Study population 1 (n = 2,089) participated in a large-scale screening program offered to retired workers to discover previously undetected/incipient chronic illness. Study population 2 (n = 3,293) was part of a Colorado worksite wellness program health risk assessment. We assessed the relationship between a continuous diabetes risk score at baseline and development of diabetes in the future using logistic regression. Receiver operating curves and sensitivity/specificity of the models were calculated. Across both study populations, we observed that participants with diabetes at follow-up had higher diabetes risk scores at baseline than participants who did not have diabetes at follow-up. On average, the odds ratio of developing diabetes in the future was 1.38 (95% CI: 1.26-1.50, p < 0.0001) for study population 1 and 1.68 (95% CI: 1.45-1.95, p-value < 0.0001) for study population 2. These findings indicate that the diabetes risk score may be generalizable to diverse individuals, and thus potentially a population level diabetes screening tool. Minimally-invasive diabetes risk scores can aid in the identification of sub-populations of individuals at risk for diabetes.

Prostate Cancer Central Nervous System Metastasis in a Contemporary Cohort.

INTRODUCTION: Central nervous system (CNS) metastasis from prostate cancer (PCA) is a rare event, but one with significant prognostic impact for those affected. There are limited data on its impact in contemporary cohorts treated with modern agents. PATIENTS AND METHODS: A retrospective institutional review was performed to characterize the occurrence/outcome of PCA CNS metastasis on all cases of PCA from 2011 to 2017. A manual chart review was performed to confirm PCA CNS metastases in all cases identified through a diagnostic code screening of the health data. RESULTS: A total of 6596 cases of PCA were identified, with 29 (20 dural and 9 intraparenchymal) confirmed cases of CNS metastases from PCA. The median survival from the time of diagnosis of CNS metastasis was 2.6 months (95% confidence interval, 2.04-10.78 months) and 5.41 months (95% confidence interval, 3.03 months to not reached) for dural and parenchymal metastases, respectively. Among those who developed CNS metastases, approximately 79% of patients had prior exposure to abiraterone and/or enzalutamide, of whom 50% had ≥ 6 months of exposure. Four (0.07%) of the 5841 patients developed CNS metastases prior to the initiation of therapy or on androgen deprivation therapy alone. In contrast, 24 (8.6%) of the 279 patients with 2 or more lines of medical therapy developed CNS metastases. CONCLUSIONS: Our analysis highlights the continued poor prognosis of parenchymal and dural CNS metastases from PCA. CNS metastases in PCA remain a rare event with a 0.4% incidence in this series, but this incidence is considerably increased in patients who receive medical therapy beyond first-line androgen deprivation therapy.

Variation in Toxicity Reporting Methods for Early Phase Lung Cancer Treatment Trials at Oncology Conferences.

INTRODUCTION: Phase I and II trials provide the initial human safety and tolerability data for new drugs. Nevertheless, the methods for presenting toxicity data are not standardized. Clinicians often first encounter these data at professional conferences. We sought to characterize how the burden of adverse events (AEs) is reported at the largest professional conference in clinical oncology. METHODS: We collected toxicity data from all lung cancer-associated phase I and II trial presentations and posters at the American Society for Clinical Oncology annual meetings from 2017 to 2019. We captured the various AE features, including the minimum incidence used for reporting; whether AEs found were treatment emergent or treatment related, grouped by organ system or separated by individual descriptors; whether combined or separated across dose levels when a dose-escalation component was included; and whether dose-limiting toxicities, serious AE, dose-reduction rules, and denominators for laboratory tests were described. RESULTS: A total of 209 trials were analyzed. There was wide variability in toxicity reporting practices. Six different thresholds for reporting AEs of any grade were used. Treatment-related AEs were reported twice as frequently as treatment-emergent AEs. Toxicities were as likely to be reported across dose levels as by dose level. Terms such as dose-limiting toxicity and serious AE were rarely defined. Dose-reduction rules and denominators for laboratory tests were never defined. CONCLUSIONS: Standardization of methods for reporting toxicities could improve the quality and ease of comparability of data on adverse effects in early phase therapeutic trials. A minimal AE data disclosure template is proposed.

Lymph node yield in pediatric, adolescent and young adult Renal Cell Carcinoma - How many are enough?

PURPOSE: Pediatric, adolescent and young adult (PAYA) patients with renal cell carcinoma (RCC) have a high rate of LN involvement, yet data to guide surgical lymph node (LN) management in this group is limited. The objective is to describe a LN yield threshold to quantify the chance of missing occult LN involvement at ≤10% in PAYAs with RCC. MATERIALS & METHODS: The National Cancer Database was queried for patients aged ≤30 y with unilateral, non-metastaticRCC from 2004 to 2013. The probability of a false negative LN sampling was determined on the cohort of patients who had at least one positive LNand ≥ 2 LNs examined. For a given LN yield, the probability that a positive LN exists but none were found was estimated using a beta-binomial model. RESULTS: We identified 112 patients meeting study criteria. Median age was 24 y and median tumor size was 9.5 cm (IQR 5.8-14). The median number of LNs sampled was 7 (IQR 4-12) and the median number of LNs positive was 4 (IQR 2-7). To achieve ≤10% probability of a false-negativeLN sampling, the beta-binomial model estimated that 5 LNs (95% CI4-7) must be sampled. CONCLUSIONS: The desired LN yield to reduce the risk of a false-negativeLN sampling in PAYAs with RCC to ≤10% is 5. This is in keeping with prior studies identifying a LN yield of 6-10 to achieve the same. These data may be used to standardize surgical guidelines when treating PAYAs with renal tumors. LEVEL OF EVIDENCE: II.

Assessment of a Machine Learning Model Applied to Harmonized Electronic Health Record Data for the Prediction of Incident Atrial Fibrillation.

Importance: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and its early detection could lead to significant improvements in outcomes through the appropriate prescription of anticoagulation medication. Although a variety of methods exist for screening for AF, a targeted approach, which requires an efficient method for identifying patients at risk, would be preferred. Objective: To examine machine learning approaches applied to electronic health record data that have been harmonized to the Observational Medical Outcomes Partnership Common Data Model for identifying risk of AF. Design, Setting, and Participants: This diagnostic study used data from 2 252 219 individuals cared for in the UCHealth hospital system, which comprises 3 large hospitals in Colorado, from January 1, 2011, to October 1, 2018. Initial analysis was performed in December 2018; follow-up analysis was performed in July 2019. Exposures: All Observational Medical Outcomes Partnership Common Data Model-harmonized electronic health record features, including diagnoses, procedures, medications, age, and sex. Main Outcomes and Measures: Classification of incident AF in designated 6-month intervals, adjudicated retrospectively, based on area under the receiver operating characteristic curve and F1 statistic. Results: Of 2 252 219 individuals (1 225 533 [54.4%] women; mean [SD] age, 42.9 [22.3] years), 28 036 (1.2%) developed incident AF during a designated 6-month interval. The machine learning model that used the 200 most common electronic health record features, including age and sex, and random oversampling with a single-layer, fully connected neural network provided the optimal prediction of 6-month incident AF, with an area under the receiver operating characteristic curve of 0.800 and an F1 score of 0.110. This model performed only slightly better than a more basic logistic regression model composed of known clinical risk factors for AF, which had an area under the receiver operating characteristic curve of 0.794 and an F1 score of 0.079. Conclusions and Relevance: Machine learning approaches to electronic health record data offer a promising method for improving risk prediction for incident AF, but more work is needed to show improvement beyond standard risk factors.

Metaphylactic Antibiotic Treatment to Prevent the Transmission of Corynebacterium bovis to Immunocompromised Mouse Offspring.

Current methods for eradicating Corynebacterium bovis, such as depopulation, embryo transfer, and cesarean rederivation followed by cross fostering, are expensive, complex, and time-consuming. We investigated a novel method to produce immunocompromised offspring free of C. bovis from infected NOD. Cg-PrkdcscidIl2rgtm1Wgl/SzJ (NSG) breeding pairs. Adult NSG mice were infected with C. bovis, paired, and randomly assigned to either a no-antibiotic control group (NAB, n = 8) or a group that received amoxicillin-clavulanic acid (0.375 mg/mL) in their drinking water for a mean duration of 7 wk (AB group, n = 7), spanning the time from pairing of breeders to weaning of litters. The AB group also underwent weekly cage changes for 3 wk after pairing to decrease intracage C. bovis contamination, whereas the NAB mice received bi-weekly cage changes. Antibiotics were withdrawn at the time of weaning. All litters (n = 7) in the AB group were culture- and qPCR-negative for C. bovis and remained negative for the duration of the study, whereas all litters in the NAB group (n = 6) remained C. bovis positive. A single adult from each breeding pair was sampled at weaning and at 5 and 10 wk after weaning to confirm the maintenance of (NAB) or to diagnose the reemergence (AB) of C. bovis infection. By the end of the study, C. bovis infection had returned in 3 of the 7 (43%) tested AB adults. Our data suggest that metaphylactic antibiotic use can decrease viable C. bovis organisms from adult breeder mice and protect offspring from infection. However, using antibiotics with frequent cage changing negatively affected breeding performance. Nevertheless, this technique can be used to produce C. bovis-free NSG offspring from infected adults and may be an option for salvaging infected immunocompromised strains of mice that are not easily replaced.

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study.

Importance: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. Objective: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. Design, Setting, and Participants: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. Interventions: SRS and WBRT for small cell lung cancer brain metastases. Main Outcomes and Measures: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. Results: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Conclusions and Relevance: Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.

Inferior outcomes and treatment disparities in elderly patients with classical Hodgkin lymphoma: a national cancer data base analysis.

Elderly patients with classical Hodgkin lymphoma (cHL) are understudied and poorly defined. The National Cancer Data Base was queried for adults with cHL diagnosed 2004-2013: 22,547 age 18-39, 12,841 age 40-59, and 10,873 age ≥60 were identified. Two-year overall survival (OS) was 97%, 91%, and 65% for the three age cohorts, respectively (p < .0001). Elderly patients age ≥60 had greater advanced comorbidity scores, stage III-IV disease, and lymphocyte-depleted histology. Elderly patients were treated less with chemotherapy, radiotherapy for stage I-II disease, and at academic/research centers (p < .001). There was improved OS in elderly patients who received chemotherapy and/or radiotherapy and were treated at academic/research centers. This largest analysis of elderly cHL demonstrates that patients ≥60 are distinct from those 40-59. Age ≥60 should be a stratification in future trials and merit distinct studies. Improving the poor rate of treatment delivery and directing care to academic centers may improve outcomes.

Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes.

Aldehyde dehydrogenase (ALDH) activity is not only a valuable marker for cancer cells with stem-like features, but also plays a vital role in drug resistance and disease progression in many tumors including melanoma. However, the precise role of ALDH activity in patient prognosis remains unclear. In this study, using the Cancer Genome Atlas (TCGA) RNA-sequencing expression data, we analyzed gene expression of ALDH isozymes in melanoma tumors to define the expression patterns and the prognostic and predictive values of these enzymes. We found that ALDH1A1 and ALDH1A3 had both higher and broader expression ranges in melanoma patients, and that ALDH1A3 expression correlated with better overall survival in metastatic melanoma. Further, stratification of the TCGA cohorts by the mutational subtypes of melanoma specifically revealed that expression of ALDH1A3 correlated with better prognosis in metastatic BRAF-mutant melanoma while expression of ALDH1A1 correlated with better prognosis in BRAF wild-type melanoma. Gene set enrichment analysis (GSEA) of these cohorts identified upregulation in oxidative phosphorylation, adipogenesis, and fatty acid metabolism signaling in ALDH1Alo patients, suggesting BRAF/MEK inhibitor resistance in that subset of patients. On the other hand, GSEA of ALDH1A3hi cohorts revealed upregulation in glycolysis, hypoxia and angiogenesis, suggesting BRAF/MEK inhibitor sensitivity in that subset of patients. Gene expression analysis using pre-treatment tumor samples supports high ALDH1A3 expression before BRAF/MEK inhibitor treatment as predictive of better treatment response in BRAF-mutant melanoma patients. Our study provides evidence that high ALDH1A3 mRNA expression is not only a prognostic marker but also a predictive marker for BRAF/MEK inhibitor treatment response in BRAF-mutant metastatic melanoma patients.

How many lymph nodes are enough? Assessing the adequacy of lymph node yield for staging in favorable histology wilms tumor.

PURPOSE: Current investigational priorities in the treatment of favorable histology Wilms tumor (FHWT) center on accurate staging and risk-stratification. The extent of lymph node (LN) sampling has not been clearly defined; its importance cannot be overstated as it guides adjuvant therapy. The identification of a minimum LN yield to minimize the risk of harboring occult metastatic disease could help development of surgical guidelines. This study focuses on using the beta-binomial distribution to estimate the risk of occult metastatic disease in patients with FHWT. MATERIALS & METHODS: The National Cancer Database was queried for patients with unilateral FHWT from 2004 to 2013. Data were used to characterize nodal positivity for patients who underwent surgery and had ≥1 positive LN and ≥2 LNs examined. The probability of missing a positive LN (i.e., false negative) for a given LN yield was calculated using an empirical estimation and the beta-binomial model. Patients were then stratified by tumor size. RESULTS: 422 patients met study criteria. To limit the chance of missing a positive LN to ≤10%, the empirical estimation and beta-binomial model estimated that 6 and 10 LNs needed to be sampled, respectively. Tumor size did not influence the result. Internal validation showed little variation to maintain a false negative rate ≤ 10%. CONCLUSIONS: Using mathematical modeling, it appears that the desired LN yield in FHWT to reduce the risk of false-negative LN sampling to ≤10% is between 6 and 10. The current analysis represents an objective attempt to determine the desired surgical approach to LN sampling to accurately stage patients with FHWT. LEVEL OF EVIDENCE: II.

Preselection of Lung Cancer Cases Using FGFR1 mRNA and Gene Copy Number for Treatment With Ponatinib.

INTRODUCTION: Preclinically, high epidermal growth factor receptor 1 (FGFR1) messenger RNA (FGFR1-MRNA) and FGFR1 amplification (FGFR1-AMP) predicted sensitivity to fibroblast growth factor receptor inhibitors in non-small-cell lung cancer and small-cell lung cancer cell lines. KRAS mutations did not preclude sensitivity. PATIENTS AND METHODS: Metastatic EGFR- and ALK-negative lung cancers were screened for FGFR1-MRNA by in-situ hybridization (ISH) and FGFR1-AMP by silver in-situ hybridization (SISH). Patients with positive findings were offered ponatinib, a multi-kinase inhibitor of FGFR1-4. Differences in overall survival (OS) between cohorts were assessed by the log-rank test. Association of FGFR1 positivity with clinicopathologic features were assessed by Fisher exact test and Kruskal-Wallis rank sum test. RESULTS: A total of 171 cases were prescreened: 9 (7.3%) of 123 SISH+; 53 (42.1%) of 126 ISH+; and 6 cases concordantly positive for SISH and ISH. SISH+ cases had fewer coincident KRAS mutations (P = .03) than SISH- cases, and ISH+ cases had worse OS (P = .020) than ISH- cases. Data distributions suggested a distinct higher positivity cut point for FGFR1 ISH (≥ 20%), occurring in 29 (23%) of 126 cases, was associated with small-cell lung cancer histology (P = .022), soft tissue metastases (P = .050) and shorter OS (P = .031). Four patients received ponatinib on study: All ISH+ by the initial cut point, 2 of 4 by higher cut point, 1 of 4 SISH+. Tolerability was poor. The best response for the 2 higher ISH cases was stable disease and progressive disease for the 2 lower ISH cases. CONCLUSION: Elevated FGFR1-MRNA is more common than FGFR1-AMP and associated with worse OS. Higher FGFR1 mRNA expression may be associated with a specific phenotype and is worthy of further exploration. Ponatinib's poor tolerance suggests further fibroblast growth factor receptor exploration in ISH+ cases should utilize more selective FGFR1 inhibitors.

ROS1 Gene Rearrangements Are Associated With an Elevated Risk of Peridiagnosis Thromboembolic Events.

INTRODUCTION: This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. METHODS: Venous and arterial TEEs within ±365 days of diagnosis of ROS1+, ALK+, EGFR+, or KRAS+ advanced NSCLC at five academic centers in the United States and China were captured (October 2002-April 2018). The primary endpoint was incidence of TEE in ROS1+ compared to anaplastic lymphoma kinase (ALK)+, EGFR+, and KRAS+ NSCLC within ±90 days of diagnosis. Logistic regression was used to assess if the odds of TEE differed among oncogene drivers. RESULTS: Eligible data from 95 ROS1+, 193 ALK+, 300 EGFR+, and 152 KRAS+ NSCLC patients were analyzed. The incidence rate of TEE was 34.7% (n = 33), 22.3% (n = 43), 13.7% (n = 41), and 18.4% (n = 28), respectively. In univariate analysis, the odds of a TEE in ROS1+ NSCLC were higher than ALK+, EGFR+, and KRAS+ cohorts. In multivariable analysis, the odds of a TEE were significantly higher for ROS1+ compared to EGFR+ and KRAS+ cohorts, the odds ratio (OR) was 2.44, with a 95% confidence interval of 1.31-4.57 (p = 0.005), and OR: 2.62, with a 95% confidence interval of 1.26-5.46 (p = 0.01), respectively. Although numerically superior, the odds for a TEE with ROS1+ compared to ALK+ was not statistically significant (OR: 1.45, p = 0.229). Overall survival was not significantly different in patients with or without TEE within ±90 days of diagnosis in the overall study cohort or within each molecular group. CONCLUSIONS: The risk of peridiagnostic TEEs is significantly elevated in patients with advanced ROS+ NSCLC compared to EGFR+ and KRAS+ cases. TEE risk may be similarly elevated in ALK+ NSCLC.

IL-6 and IL-8 Are Linked With Myeloid-Derived Suppressor Cell Accumulation and Correlate With Poor Clinical Outcomes in Melanoma Patients.

We sought to identify tumor-secreted factors that altered the frequency of MDSCs and correlated with clinical outcomes in advanced melanoma patients. We focused our study on several of the many factors involved in the expansion and mobilization of MDSCs. These were identified by measuring circulating concentrations of 13 cytokines and growth factors in stage IV melanoma patients (n = 55) and healthy controls (n = 22). Based on these results, we hypothesized that IL-6 and IL-8 produced by melanoma tumor cells participate in the expansion and recruitment of MDSCs and together would be predictive of overall survival in melanoma patients. We then compared the expression of IL-6 and IL-8 in melanoma tumors to the corresponding plasma concentrations and the frequency of circulating MDSCs. These measures were correlated with clinical outcomes. Patients with high plasma concentrations of either IL-6 (40%) or IL-8 (63%), or both (35%) had worse median overall survival compared to patients with low concentrations. Patients with low peripheral concentrations and low tumoral expression of IL-6 and IL-8 showed decreased frequencies of circulating MDSCs, and patients with low frequencies of MDSCs had better overall survival. We have previously shown that IL-6 is capable of expanding MDSCs, and here we show that MDSCs are chemoattracted to IL-8. Multivariate analysis demonstrated an increased risk of death for subjects with both high IL-6 and IL-8 (HR 3.059) and high MDSCs (HR 4.265). Together these results indicate an important role for IL-6 and IL-8 in melanoma patients in which IL-6 potentially expands peripheral MDSCs and IL-8 recruits these highly immunosuppressive cells to the tumor microenvironment. This study provides further support for identifying potential therapeutics targeting IL-6, IL-8, and MDSCs to improve melanoma treatments.

Detection of oligoprogressive disease in oncogene-addicted non-small cell lung cancer using PET/CT versus CT in patients receiving a tyrosine kinase inhibitor.

OBJECTIVES: In oncogene-addicted non-small cell lung cancer (NSCLC), oligoprogressive disease (OPD) can be treated with local ablative therapy (LAT) to prolong benefit from tyrosine kinase inhibitors (TKIs). A comparison of PET/CT vs. CT for the detection of OPD at first extra central nervous system (eCNS) progression was performed to determine which modality was more sensitive for OPD detection. MATERIALS AND METHODS: Patients with metastatic EGFR-MT, ALK + or ROS-1+ NSCLC on a relevant TKI from 2010 to 2016 were identified. Scan methodology at first eCNS progression (index scan) was noted and progression was categorized as OPD (≤ 4 lesions) or non-OPD (> 4 lesions). RESULTS: Of the 67 analyzable patients (EGFR-MT = 37, ALK+ = 28, ROS1+ = 2), OPD was detected in 81.3% (26/32) by PET/CT vs. 68.6% (24/35) by CT (p = 0.363). Of these, 17/26(65.4%) in PET/CT and 5/24(20.8%) in CT group had LAT (p = 0.004). Among patients receiving an alternate modality scan within 6 weeks of the index scan that showed first eCNS progression, 91.7% (11/12) had CT prior to index PET/CT, 75% (6/8) had post-index PET/CT showing further progression, whereas 0% (0/5) had post-index CT showing further progression. Time to progression (TTP), Post-progression TKI benefit (TTP2) and overall survival (OS) were longer in the PET/CT-detected group (p = 0.001, p = 0.032, and p = 0.01, respectively). In both PET/CT (N = 26) and CT-detected (N = 24) OPD subgroups, TTP2 and OS were longer in those that received LAT (65.4% [17/26] and 20.8% [5/24]) versus those that did not, although the difference was not statistically significant. CONCLUSION: PET/CT demonstrated a non-significant trend to detect more eCNS OPD and a significantly higher rate of OPD suitable for LAT than CT. Peri-progression alternate modality scans were also consistent with PET/CT being more sensitive. A prospective randomized study is required to assess the long-term impact of PET/CT vs CT in oncogene-addicted NSCLC patients on TKI therapy.