Association between Colonoscopy Sedation Type and Polyp Detection: A Registry-based Cohort Study.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death. Adenomas and serrated polyps are precursors of colorectal cancer, with serrated polyps being more difficult to detect during colonoscopy. The relationship between propofol use and polyp detection remains unclear. The authors investigated the association of propofol-based versus mild-moderate sedation on adenoma and serrated polyp detection during colonoscopy. METHODS: This retrospective cohort study used observational data from the New Hampshire Colonoscopy Registry. Patients aged greater than 50 yr with screening or surveillance colonoscopies between January 1, 2015, and February 28, 2020, were included. Exclusions were diagnostic examinations, no sedation, missing pathology data, and poor bowel preparation. Multivariate logistic regression was used to evaluate differences in polyp detection between propofol and moderate sedation in the full sample while adjusting for covariates. Propensity score adjustment and clustering at the endoscopist level were used in a restricted sample analysis that included endoscopists and facilities with between 5% and 95% propofol sedation use. RESULTS: A total of 54,063 colonoscopies were analyzed in the full sample and 18,998 in the restricted sample. Serrated polyp prevalence was significantly higher using propofol (9,957 of 29,312; 34.0% [95% CI, 33.4 to 34.5%]) versus moderate sedation (6,066 of 24,751; 24.5% [95% CI, 24.0 to 25.1%]) in the full sample and restricted samples (1,410 of 4,661; 30.3% [95% CI, 28.9 to 31.6%] vs. 3,690 of 14,337; 25.7% [95% CI, 25.0 to 26.5%]). In the full sample multivariate logistic regression, propofol was associated with higher neoplasm (adjusted odds ratio, 1.25 [95% CI, 1.21 to 1.29]), adenoma (odds ratio, 1.07 [95% CI, 1.03 to 1.11]), and serrated polyp detection (odds ratio, 1.51 [95% CI, 1.46 to 1.57]). In the restricted sample using inverse probability of treatment weighted propensity score adjustment and clustering at the endoscopist level, an attenuated but statistically significant effect size was observed for serrated polyps (odds ratio, 1.13 [95% CI, 1.07 to 1.19]), but not for adenomas (odds ratio, 1.00 [95% CI, 0.95 to 1.05]) or any neoplastic lesion (odds ratio, 1.03 [95% CI, 0.98 to 1.08]). CONCLUSIONS: Propofol sedation during colonoscopy may be associated with improved detection of serrated polyps, but not adenomas.

Association of Endoscopist Colonoscopy Quality Measures With Follow-Up Colonoscopy Outcomes After Positive Stool Tests (Multitarget Stool DNA or Fecal Immunochemical Test): Retrospective Cross-Sectional Analysis of Data From the New Hampshire Colonoscopy Registry.

INTRODUCTION: Negative colonoscopies following positive stool tests could result from stool test characteristics or from the quality of endoscopist performance. We used New Hampshire Colonoscopy Registry data to examine the association between endoscopist detection rates and polyp yield in colonoscopies performed for positive fecal immunochemical test (FIT) or multitarget stool DNA (mt-sDNA) test to evaluate the degree to which positive stool tests followed by negative colonoscopy ("false positives") vary with endoscopist quality. In addition, we investigated the frequency of significant polyps in the subgroup of highest quality colonoscopies following positive stool tests. METHODS: We compared the frequencies of negative colonoscopies and of specific polyps following positive stool tests across quartiles of endoscopist adenoma detection rate (ADR) and clinically significant serrated polyp detection rate (CSSDR). RESULTS: Our sample included 864 mt-sDNA+ and 497 FIT+ patients. We found a significantly lower frequency of negative colonoscopies following positive stool tests among endoscopists with higher ADR and CSSDR, particularly in the 2 highest quartiles. In addition, detection of any adenoma after a positive stool test for endoscopists in the fourth ADR quartile was 63.3% (FIT+) and 62.8% (mt-sDNA+). Among endoscopists in the fourth CSSDR quartile, sessile serrated lesions were found in 29.2% of examinations following a positive mt-sDNA and in 13.5% following FIT+ examinations. DISCUSSION: The frequency of negative colonoscopies after positive stool tests was significantly higher in examinations performed by endoscopists with low ADR and CSSDR. Our results also suggest a benchmark target of at least 40% for ADR in patients with mt-sDNA+ or FIT+ tests and 20% for sessile serrated lesions in mt-sDNA+ patients.

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy.

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43-57) vs 55 years (IQR 51-62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P = .0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P < .0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P < .0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.

Endoscopist adenomas-per-colonoscopy detection rates and risk for postcolonoscopy colorectal cancer: Data from the New Hampshire Colonoscopy Registry.

BACKGROUND AND AIMS: Adenomas per colonoscopy (APC) may be a better measure of colonoscopy quality than adenoma detection rate (ADR) because it credits endoscopists for each detected adenoma. There are few data examining the association between APC and postcolonoscopy colorectal cancer (PCCRC) incidence. We used data from the New Hampshire Colonoscopy Registry to examine APC and PCCRC risk. METHODS: We included New Hampshire Colonoscopy Registry patients with an index examination and at least 1 follow-up event, either a colonoscopy or a colorectal cancer (CRC) diagnosis. Our outcome was PCCRC defined as any CRC diagnosed ≥6 months after an index examination. The exposure variable was endoscopist-specific APC quintiles of .25, .40, .50, and .70. Cox regression was used to model the hazard of PCCRC on APC, controlled for age, sex, year of index examination, index findings, bowel preparation, and having more than 1 surveillance examination. RESULTS: In 32,535 patients, a lower hazard for PCCRC (n = 178) was observed for higher APCs as compared to APCs of <.25 (reference): .25 to <.40: hazard ratio (HR), .35; 95% confidence interval (CI), .22-.56; .40 to <.50: HR, .31; 95% CI, .20-.49; .50 to <.70: HR, .20; 95% CI, .11-.36; and ≥.70: HR, .19; 95% CI, .09-.37. When examining endoscopists with an ADR of at least 25%, an APC of <.50 was associated with a significantly higher hazard than an APC of ≥.50 (HR, 1.65; 95% CI, 1.06-2.56). A large proportion of endoscopists-one-fifth (32 of 152; 21.1%)-had an ADR of ≥25% but an APC of <.50. CONCLUSIONS: Our novel data demonstrating lower PCCRC risk in examinations performed by endoscopists with higher APCs suggest that APC could be a useful quality measure. Quality improvement programs may identify important deficiencies in endoscopist detection performance by measuring APC for endoscopists with an ADR of ≥25%.

Engineering CD276/B7-H3-targeted antibody-drug conjugates with enhanced cancer-eradicating capability.

CD276/B7-H3 represents a promising target for cancer therapy based on widespread overexpression in both cancer cells and tumor-associated stroma. In previous preclinical studies, CD276 antibody-drug conjugates (ADCs) exploiting a talirine-type pyrrolobenzodiazepine (PBD) payload showed potent activity against various solid tumors but with a narrow therapeutic index and dosing regimen higher than that tolerated in clinical trials using other antibody-talirine conjugates. Here, we describe the development of a modified talirine PBD-based fully human CD276 ADC, called m276-SL-PBD, that is cross-species (human/mouse) reactive and can eradicate large 500-1,000-mm3 triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose. By combining CD276 targeting with judicious genetic and chemical ADC engineering, improved ADC purification, and payload sensitivity screening, these studies demonstrate that the therapeutic index of ADCs can be substantially increased, providing an advanced ADC development platform for potent and selective targeting of multiple solid tumor types.

What do 'false-positive' stool tests really mean? Data from the New Hampshire colonoscopy registry.

We utilized the population-based New Hampshire Colonoscopy Registry to calculate false discovery rates (FDR) and positive predictive values (PPVs) using three 'positive' colonoscopy definitions. Understanding the frequency of meaningful 'true positive' mt-sDNA and Fecal Immunochemical Test (FIT) results can optimize the use of these colorectal cancer (CRC) screening tests. We calculated FDR (positive stool test followed by negative colonoscopy divided by all positive stool tests) and PPV for mt-sDNA and FIT cohorts using the following definitions: 1) DeeP-C Study (CRC, adenomas/serrated polyps ≥ 1 cm, villous/High Grade Dysplasia); 2) < 10 year US Multi-Society Task Force (USMSTF) follow-up: DeeP-C findings & ≥1 sessile serrated polyps (SSPs) < 1 cm (with/without dysplasia) or ≥ 1 tubular adenomas < 1 cm. 3) Clinically Significant: DeeP-C + USMSTF + clinically significant serrated polyps: traditional serrated adenomas, SSPs, hyperplastic polyps (HPs) > 1 cm, and 5-9 mm proximal HPs. The sample included 549 mt-sDNA + and 410 FIT + and patients (mean age 66.4, 43.0% male). Using the most limited definition of positive colonoscopy, DeeP-C, FDR was 71.9% for mt-sDNA + and 81.7% for FIT +. Using the USMSTF definition, FDR decreased substantially: mt-sDNA+:33.2% and FIT+:47.6%. Adding all CSSPs resulted in the lowest FDR: mt-sDNA+:32.2% and FIT+:47.1%. Decreasing FDRs corresponded to increasing PPVs: mt-sDNA+:28.1% and FIT+:18.3% (DeeP-C definition) and mt-sDNA+:67.8% and FIT+:52.9% (DeeP-C + USMSTF + CSSP) (Table 1). FDRs decreased substantially when the definition of positive exams included all significant precancerous findings. These data present a comprehensive understanding of false positive outcomes at colonoscopies following positive stool tests, which to our knowledge is the first such analysis.

Higher Serrated Polyp Detection Rates Are Associated With Lower Risk of Postcolonoscopy Colorectal Cancer: Data From the New Hampshire Colonoscopy Registry.

INTRODUCTION: We used New Hampshire Colonoscopy Registry data to examine the association between postcolonoscopy colorectal cancer (PCCRC) and sessile serrated detection rates (SSLDRs). METHODS: We included patients with either a colonoscopy or a CRC diagnosis in the NH State Cancer Registry. PCCRC was any CRC diagnosed ≥ 6 months after index examination. RESULTS: Of 26,901 patients, 162 were diagnosed with PCCRC. The hazard ratio for PCCRC was lowest for patients whose endoscopists had the highest SSLDR quintile (≥6%) (hazard ratio 0.29; 95% confidence interval 0.16-0.50). DISCUSSION: Endoscopists with higher SSLDRs had lower risks of PCCRC. These data validate SSLDR as a clinically relevant quality measure.

Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer.

Advances in drug treatments for brain metastases of breast cancer have improved progression-free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that of systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: transferrin receptor (TfR) peptide, low-density lipoprotein receptor 1 (LRP1) peptide, albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patterns in vivo. Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P < 0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor, galectin-3, and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other central nervous system (CNS) cancers.In conclusion, drug therapy for brain metastasis needs improvement. We surveyed three transcytotic pathways as potential delivery systems in brain-tropic models and found that albumin has optimal properties. Albumin used a novel endocytic mechanism.

Serrated Polyp Yield at Colonoscopy in Patients with Positive FIT, Positive mt-sDNA, and Colonoscopy Only: Data from the New Hampshire Colonoscopy Registry.

BACKGROUND: Stool-based screening with fecal immunochemical (FIT) or multitarget-stool DNA (mt-sDNA) tests is associated with increased colonoscopy polyp yield. mt-sDNA includes methylated markers, which improve detection of serrated polyps (SP) versus FIT. We compared SP detection in colonoscopies performed for positive FIT or mt-sDNA tests, as well as in colonoscopies without a preceding stool test, using the New Hampshire Colonoscopy Registry, a comprehensive statewide population-based registry. METHODS: Across the three groups, we compared the frequency of clinically relevant SPs (CRSP: sessile SPs, hyperplastic polyps ≥10 mm, and traditional serrated adenomas). We also compared SP size, histology, number, and bulk (combined sizes). RESULTS: Our sample included 560 mt-sDNA+ (age ± SD: 66.5 ± 7.9), 414 FIT+ (age ± SD: 66.3 ± 8.8), and 59,438 colonoscopy-only patients (age ± SD: 61.7 ± 8.0). mt-sDNA+ patients were more likely to have a higher yield of CRSPs and CRSP bulk than FIT+ (P < 0.0001) or colonoscopy-only patients (P < 0.0001). More mt-sDNA+ patients had CRSPs without large adenomas or colorectal cancers (17.9% vs. 9.9% of FIT+ and 8% of colonoscopy-only patients). After adjusting for synchronous large adenomas, colorectal cancers, and other risk factors, mt-sDNA+ patients were more likely (OR, 1.82; 95% CI, 1.18-2.85) than FIT+ patients to have CRSPs. CONCLUSIONS: mt-sDNA+ patients had a higher SP yield than FIT+ or colonoscopy-only patients, particularly in the absence of synchronous large adenomas or colorectal cancer. IMPACT: Our results suggest that screening with mt-sDNA tests could improve colorectal cancer screening by identifying more patients at increased risk from the serrated pathway.

The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

PURPOSE: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS. EXPERIMENTAL DESIGN: Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models. RESULTS: Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis. CONCLUSIONS: We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.

Using New Hampshire Colonoscopy Registry data to assess United States and European post-polypectomy surveillance guidelines.

BACKGROUND: Our goal was to compare the updated European Society of Gastrointestinal Endoscopy (ESGE) and United States Multi-Society Task Force on Colorectal Cancer (USMSTF) high risk groups in predicting metachronous advanced neoplasia on first follow-up colonoscopy and long-term colorectal cancer (CRC). METHODS: We compared advanced metachronous neoplasia risk (serrated polyps ≥ 1 cm or with dysplasia, advanced adenomas [≥ 1 cm, villous, high grade dysplasia], CRC) on first surveillance colonoscopy in patients with high risk findings according to ESGE versus USMSTF guidelines. We also compared the positive and negative predictive values (PPV, NPV) of both guidelines for metachronous neoplasia. RESULTS: The risk for metachronous neoplasia in our sample (n = 20 458) was higher in the high risk USMSTF (3 year) (13.6 %; 95 %CI 12.3-14.9) and ESGE groups (13.6 %; 95 %CI 12.3-15.0) compared with the lowest risk USMSTF (5.1 %; 95 %CI 4.7-5.5; P < 0.001) and ESGE categories (6.3 %; 95 %CI 6.0-6.7; P < 0.001), respectively. Adding other groups such as USMSTF 5-10-year and 3-5-year groups to the 3-year category resulted in minimal change in the PPV and NPV for metachronous advanced neoplasia. High risk ESGE (hazard ratio [HR] 3.03, 95 %CI 1.97-4.65) and USMSTF (HR 3.07, 95 %CI 2.03-4.66) designations were associated with similar long-term CRC risk (CRC per 100 000 person-years: USMSTF 3-year group 3.54, 95 %CI 2.68-4.68; ESGE high risk group: 3.43, 95 %CI 2.57-4.59). CONCLUSION: Performance characteristics for the ESGE and USMSTF recommendations are similar in predicting metachronous advanced neoplasia and long-term CRC. The addition of risk groups, such as the USMSTF 5-10-year and 3-5-year groups to the USMSTF 3-year category did not alter the PPV or NPV significantly.

Colonoscopy Findings in FIT+ and mt-sDNA+ Patients versus in Colonoscopy-only Patients: New Hampshire Colonoscopy Registry Data.

Few studies compare fecal immunochemical test (FIT) and multi-target stool DNA (mt-sDNA) outcomes in practice. We compared colonoscopy yield following FIT+ or mt-sDNA+ tests to colonoscopies without preceding stool tests in the comprehensive population-based New Hampshire Colonoscopy Registry (NHCR). Outcomes were any neoplasia and an ordered outcome: adenocarcinoma, advanced neoplasia (adenoma/serrated polyp ≥ 1 cm/villous/high-grade dysplasia), nonadvanced neoplasia, or normal. Our total sample included 306 mt-sDNA+ (average age ± SD 67.0 ± 7.9), 276 FIT+ (66.6 ± 8.7), and 50,990 colonoscopy-only patients (61.8 ± 8.1). Among average-risk patients (N = 240 mt-sDNA+, N = 194 FIT+, N = 26,221 colonoscopy only), mt-sDNA+ patients had a higher risk for any neoplasia (67.1%) compared with FIT+ (54.6%, P = 0.00098) or colonoscopy (40.8%, P < 0.0001). Severity of findings and histology subtypes differed across the three groups (P < 0.0001 for both), with a higher yield of advanced findings in mt-sDNA+ patients. In particular, clinically relevant serrated polyps (hyperplastic polyps ≥10 mm/traditional serrated adenomas/sessile serrated polyps) were detected at a higher frequency in mt-sDNA+ patients as compared with FIT+ or colonoscopy-only patients. Even after adjustment, patients with positive mt-sDNA [OR = 2.82; 95% confidence interval (CI), 2.00-4.02] or FIT+ tests (OR = 1.67; 95% CI, 1.19-2.36) were more likely to have histologically more advanced findings than colonoscopy alone. At follow-up colonoscopy, mt-sDNA+ tests were more likely to predict neoplasia than FIT+, largely due to increased detection of serrated polyps. Prevention Relevance: Colorectal cancer screening options include colonoscopy and stool-based tests, including the fecal immunochemical test (FIT) and the multi-target stool DNA (mt-sDNA) test which, if positive, must be followed by a colonoscopy. Assessing "real-world" outcomes of colonoscopies following positive stool tests can inform their clinical use. See related Spotlight, p. 417.

Clinically significant serrated polyp detection rates and risk for postcolonoscopy colorectal cancer: data from the New Hampshire Colonoscopy Registry.

BACKGROUND AND AIMS: Higher adenoma detection rates reduce the risk of postcolonoscopy colorectal cancer (PCCRC). Clinically significant serrated polyps (CSSPs; defined as any sessile serrated polyp, traditional serrated adenoma, large [≥1 cm] or proximal hyperplastic polyp >5 mm) also lead to PCCRC, but there are no data on associated CSSP detection rates (CSSDRs). We used data from the New Hampshire Colonoscopy Registry (NHCR) to investigate the association between PCCRC risk and endoscopist CSSDR. METHODS: We included NHCR patients with 1 or more follow-up events: either a colonoscopy or a colorectal cancer (CRC) diagnosis identified through linkage with the New Hampshire State Cancer Registry. We defined our outcome, PCCRC, in 3 time periods: CRC diagnosed 6 to 36 months, 6 to 60 months, or all examinations (6 months or longer) after an index examination. We excluded patients with CRC diagnosed at or within 6 months of the index examination, with incomplete examinations, or with inflammatory bowel disease. The exposure variable was endoscopist CSSDR at the index colonoscopy. Cox regression was used to model the hazard of PCCRC on CSSDR controlling for age, sex, index findings, year of examination, personal history of colorectal neoplasia, and having more than 1 surveillance examination. RESULTS: One hundred twenty-eight patients with CRC diagnosed at least 6 months after their index examination were included. Our cohort included 142 endoscopists (92 gastroenterologists). We observed that the risk for PCCRC 6 months or longer after the index examination was significantly lower for examinations performed by endoscopists with CSSDRs of 3% to <9% (hazard ratio [HR], .57; 95% confidence interval [CI], .39-.83) or 9% or higher (HR, .39; 95% CI, .20-.78) relative to those with CSSDRs under 3%. CONCLUSIONS: Our study is the first to demonstrate a lower PCCRC risk after examinations performed by endoscopists with higher CSSDRs. Both CSSDRs of 9% and 3% to <9% had statistically lower risk of PCCRC than CSSDRs of <3%. These data validate CSSDR as a clinically relevant quality measure for endoscopists.

Targeted multicolor in vivo imaging over 1,000 nm enabled by nonamethine cyanines.

Recent progress has shown that using wavelengths between 1,000 and 2,000 nm, referred to as the shortwave-infrared or near-infrared (NIR)-II range, can enable high-resolution in vivo imaging at depths not possible with conventional optical wavelengths. However, few bioconjugatable probes of the type that have proven invaluable for multiplexed imaging in the visible and NIR range are available for imaging these wavelengths. Using rational design, we have generated persulfonated indocyanine dyes with absorbance maxima at 872 and 1,072 nm through catechol-ring and aryl-ring fusion, respectively, onto the nonamethine scaffold. Multiplexed two-color and three-color in vivo imaging using monoclonal antibody and dextran conjugates in several tumor models illustrate the benefits of concurrent labeling of the tumor and healthy surrounding tissue and lymphatics. These efforts are enabled by complementary advances in a custom-built NIR/shortwave-infrared imaging setup and software package for multicolor real-time imaging.

Colorectal Neoplasia Detection in Individuals With Positive Multitarget Stool DNA Tests: Data From the New Hampshire Colonoscopy Registry.

BACKGROUND: The US Preventive Services Task Force (USPSTF) includes multitarget stool DNA (mt-sDNA) testing as a colorectal cancer (CRC) screening option in average-risk individuals, but data on colonoscopy outcomes after positive mt-sDNA tests in community settings are needed. AIM: The aim of this study was to investigate colonoscopy outcomes and quality following positive mt-sDNA in the population-based New Hampshire Colonoscopy Registry. METHODS: We compared colonoscopy outcomes and quality between age-matched, sex-matched, and risk-matched patients from 30 endoscopy practices with and without a preceding positive mt-sDNA test. Main outcomes were colonoscopy findings of CRC, advanced noncancerous neoplasia, nonadvanced neoplasia, or normal examination. Quality measures included withdrawal time, bowel preparation quality, examination completion, and percentage of average-risk individuals with normal colonoscopies receiving a USPSTF-recommended 10 year rescreening interval. RESULTS: Individuals with positive mt-sDNA tests (N=306, average age 67.0 y; 61.8% female) were significantly more likely than colonoscopy-only patients (N=918, 66.2 y; 61.8% female) to have CRC (1.3% vs. 0.4%) or advanced noncancerous neoplasia (27.1% vs. 8.2%) (P<0.0001). Neoplasia was found in 68.0% of patients having colonoscopy after a positive mt-sDNA test, (positive predictive value, was 68.0%), versus 42.3% of patients with colonoscopy only (P<0.0001). No significant differences in colonoscopy quality measures were observed between cohorts. CONCLUSIONS: Colonoscopy after a positive mt-sDNA test was more frequently associated with CRC and colorectal neoplasia than colonoscopy alone. Positive mt-sDNA tests can enrich the proportion of colonoscopies with clinically relevant findings. Follow-up recommendations suggest that endoscopists do not inappropriately shorten rescreening intervals in mt-sDNA-positive patients with normal colonoscopy. These findings support the clinical utility of mt-sDNA for CRC screening in community practice.

TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin.

Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon. We identify the protein kinase TNIK as a therapeutic target in LSCC. TNIK is amplified in approximately 50% of LSCC cases. TNIK genetic depletion or pharmacologic inhibition reduces the growth of LSCC cells in vitro and in vivo. In addition, TNIK inhibition showed antitumor activity and increased apoptosis in established LSCC patient-derived xenografts. Mechanistically, we identified the tumor suppressor Merlin/NF2 as a novel TNIK substrate and showed that TNIK and Merlin are required for the activation of focal adhesion kinase. In conclusion, our data identify targeting TNIK as a potential therapeutic strategy in LSCC. SIGNIFICANCE: Targeted therapies have not yet been approved for the treatment of LSCC, due to lack of identification of actionable cancer drivers. We define TNIK catalytic activity as essential for maintaining LSCC viability and validate the antitumor efficacy of TNIK inhibition in preclinical models of LSCC.This article is highlighted in the In This Issue feature, p. 1307.

Colonoscopy Outcomes in Average-Risk Screening Equivalent Young Adults: Data From the New Hampshire Colonoscopy Registry.

INTRODUCTION: Data are needed to further inform the American Cancer Society recommendation to begin colorectal cancer (CRC) screening at age 45. We used the New Hampshire Colonoscopy Registry to compare the prevalence of advanced neoplasia (AN) in an "average-risk screening equivalent" group aged 45-49 years with patients aged 50-54 years and older receiving screening colonoscopy. METHODS: Colonoscopies in adults older than 50 years of age usually have diagnostic indications of varying clinical significance. We combined patients older than 50 years with diagnostic indications (abdominal pain and constipation) expected to yield AN prevalence similar to screening low AN risk and those with a screening indication to form an "average-risk screening equivalent" group. We excluded high-risk indications (e.g., bleeding and anemia), surveillance examinations, and patients with a first-degree family history of CRC, incomplete examinations, and poor bowel preparation. We calculated prevalence/adjusted risks for AN (≥1 cm, villous, high-grade dysplasia, and CRC) and clinically significant serrated polyps (large [≥1 cm] hyperplastic polyps, sessile serrated polyp, traditional serrated adenomas, and proximal hyperplastic polyp ≥ 5 mm). RESULTS: In our sample (n = 40,812), AN prevalence was as follows: <40 years (1.1%), 40-44 years (3.0%), 45-49 years (3.7%), 50-54 years (3.6%), 55-59 years (5.1%), and 60+ years (6.7%) (P < 0.0001 across all groups). The prevalence of both AN and clinically significant serrated polyp was similar in the 45-49 and 50-54 years' age groups. Furthermore, the prevalence of AN increased significantly in the 40-44 group as compared to that in the <40 years group. Adjusted analyses confirmed these results. The diagnostic indications considered to have low risk were not predictive of AN. DISCUSSION: New Hampshire Colonoscopy Registry data, demonstrating an increase in AN risk starting at age 40 and a similar prevalence for individuals aged 45-49 and those ages 50-54, provide clinically useful evidence for optimization of prevention and the age to start screening. However, this is a complex issue involving additional considerations that will need to be addressed.

Rigosertib Induces Mitotic Arrest and Apoptosis in RAS-Mutated Rhabdomyosarcoma and Neuroblastoma.

Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NBs) have a poor prognosis despite multimodality therapy. In addition, the current standard of care for these cancers includes vinca alkaloids that have severe toxicity profiles, further underscoring the need for novel therapies for these malignancies. Here, we show that the small-molecule rigosertib inhibits the growth of RMS and NB cell lines by arresting cells in mitosis, which leads to cell death. Our data indicate that rigosertib, like the vinca alkaloids, exerts its effects mainly by interfering with mitotic spindle assembly. Although rigosertib has the ability to inhibit oncogenic RAS signaling, we provide evidence that rigosertib does not induce cell death through inhibition of the RAS pathway in RAS-mutated RMS and NB cells. However, the combination of rigosertib and the MEK inhibitor trametinib, which has efficacy in RAS-mutated tumors, synergistically inhibits the growth of an RMS cell line, suggesting a new avenue for combination therapy. Importantly, rigosertib treatment delays tumor growth and prolongs survival in a xenograft model of RMS. In conclusion, rigosertib, through its impact on the mitotic spindle, represents a potential therapeutic for RMS.

Increased risk of metachronous large serrated polyps in individuals with 5- to 9-mm proximal hyperplastic polyps: data from the New Hampshire Colonoscopy Registry.

BACKGROUND AND AIMS: Because data on metachronous risk for patients with index proximal 5- to 9-mm hyperplastic polyps (HPs) are limited, the clinical significance of these polyps is unclear. Conversely, published data suggest that sessile serrated polyps (SSPs), traditional serrated adenomas (TSAs), and large (≥1 cm) HPs are high-risk lesions requiring close surveillance. We used data from the New Hampshire Colonoscopy Registry (NHCR) to examine the risk of metachronous large SPs and advanced neoplasias (ANs) in patients with 5- to 9-mm proximal HPs. METHODS: We included adults with at least 1 polyp resected at index colonoscopy and a surveillance examination 12 months or more after index. Outcomes were risk for metachronous large (≥1 cm) SPs and ANs (≥1 cm, villous elements, high-grade dysplasia, or colorectal cancer [CRC]). Individuals were hierarchically stratified by the most significant index SP. The risks for adults with proximal 5- to 9-mm HPs at index examination were compared with individuals with index findings of large (≥1 cm) HPs or any SSPs or TSAs, nonsignificant HPs (<1 cm in rectosigmoid or <5 mm anywhere in colon), high-risk adenomas (AAs or ≥3 adenomas, no SPs), and low-risk adenomas (no SPs). We present absolute and adjusted risks of metachronous polyps from a regression model that included age, sex, body mass index, smoking, previous polyp history, family history of CRC, year of diagnosis, endoscopist SP detection rates, and months to surveillance examination. RESULTS: A total of 8560 NHCR participants were included (44.8% women; average age, 59.0 years; standard deviation, 9.1). Similar to those with large HPs or any SSPs/TSAs at index examination (odds ratio, 7.63; 95% confidence interval, 4.78-12.20), individuals with proximal 5- to 9-mm HPs had an elevated risk for metachronous large SPs (odds ratio, 4.77; 95% confidence interval, 2.54-8.94) as compared with adults with low-risk conventional adenomas. CONCLUSIONS: NHCR data suggest that similar to adults with large HPs or any SSPs or TSAs at index examination, individuals with index 5- to 9-mm HPs proximal to the sigmoid are at an increased risk for metachronous large SPs. These novel data suggest that close surveillance intervals may be appropriate for patients with 5- to 9-mm proximal HPs.