Anatomical location of colorectal neoplasia in patients with positive stool tests (mt-sDNA or FIT): Data from the New Hampshire Colonoscopy Registry.

Background And Aims: Data comparing the location of polyp yield in patients with positive stool tests can aid screening test selection. We conducted a cross sectional analysis of New Hampshire Colonoscopy Registry data to compare the location, left versus right side of the colon, of neoplasia detected on colonoscopy following a mt-sDNA+ or FIT+ test as compared to a reference group having colonoscopy without a stool test.

Methods: Our outcomes were advanced lesions (adenoma and/or serrated polyp, including cancer), advanced adenomas (AA), or advanced serrated polyps (ASP), stratified by location.

A CSF-1R inhibitor both prevents and treats triple-negative breast cancer brain metastases in hematogenous preclinical models.

Unlabelled: Brain metastasis is a common and serious complication of metastatic triple-negative breast cancer (TNBC) with few effective treatments. Here, we evaluated the effect of targeting the brain tumor microenvironment via the myeloid colony-stimulating factor-1 receptor (CSF-1R) pathway using the small molecule inhibitor BLZ945. Studies were conducted in two TNBC hematogenous brain-tropic models, 4T1-BR5 and 231-BR, with endpoints of prevention of brain metastasis formation and treatment of established brain metastasis.

IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia.

We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.

Adenoma Detection Rates Calculated Using All Examinations Are Associated With Lower Risk for 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) risk and an adenoma detection rate (ADR) which was calculated using examinations with all indications, as compared with ADR restricted to only screening examinations.

Methods: Our cohort study included New Hampshire Colonoscopy Registry patients with an index examination and at least 1 follow-up event, either a colonoscopy or a CRC diagnosis. Our outcome, PCCRC, was any CRC diagnosed ≥6 months after an index examination.

Anatomical Distribution of Polyps Is Different for Men and Women With Positive Stool Tests.

Background And Aim: Our goal was to inform endoscopist practice by exploring how the odds of advanced neoplasia in the right and left colon differ between men and women with and without prior positive stool tests.

Methods: Our primary outcome was advanced lesions (advanced adenomas, advanced serrated polyps, and/or colorectal cancer) found during colonoscopy. We used logistic regression to compare adjusted outcome odds by colon location (left or right), patient sex, and screening cohort.

Association Between Smoking Status and Prevalence of Advanced Outcomes in Patients With and Without Positive Stool Test Prior to Colonoscopy: Data from the New Hampshire Colonoscopy Registry.

Background And Aims: Our goal was to examine the association between smoking status (current, former, and never) and prevalence of advanced findings in patients with colonoscopy after a positive multi-target stool DNA test (mt-sDNA), patients with colonoscopy after a positive Fecal Immunochemical Test (FIT), and patients with colonoscopy only (no prior stool test).

Methods: Our main outcome was prevalence of advanced lesions (any colorectal cancer (CRC), advanced adenoma, or advanced serrated polyp). We also looked at advanced adenomas and advanced serrated polyps separately.

Targeting c-MYC and gain-of-function p53 through inhibition or degradation of the kinase LZK suppresses the growth of HNSCC tumors.

The worldwide annual frequency and lethality of head and neck squamous cell carcinoma (HNSCC) is not improving, and thus, new therapeutic approaches are needed. Approximately 70% of HNSCC cases have either amplification or overexpression of , which encodes the kinase LZK. Here, we found that LZK is a therapeutic target in HNSCC and that small-molecule inhibition of its catalytic function decreased the viability of HNSCC cells with amplified .

Which is the better polyp detection metric: adenomas per colonoscopy or adenoma detection rate? A simulation modeling study.

We compared the ability of adenoma detection rate (ADR) and adenoma per colonoscopy (APC) to assess endoscopist detection, using statistical principles and simulations. We simulated a population of endoscopists and patients to compare the ability of ADR versus APC for capturing true endoscopist ability (TEA). We compared these rates with and without adjustment for patient and exam factors using multivariable models, and adjustment for imprecision due to low volume using empirical Bayes (shrinkage).

Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth.

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by ) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified . A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules.

Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.

We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.

Metastatic organotropism in small cell lung cancer.

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies.

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.

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.

Analysis of Nanoparticles' Potential to Induce Autoimmunity.

Autoimmune responses are characterized by the presence of antibodies and lymphocytes specific to self or so-called autoantigens. Among such autoantigens is DNA; therefore, screening for antibodies recognizing single- and/or double-stranded DNA is commonly used to detect and classify autoimmune diseases. While autoimmunity affects both sexes, females are generally more affected than males, which is recapitulated in some animal models.

Distinct uptake and elimination profiles for trastuzumab, human IgG, and biocytin-TMR in experimental HER2+ brain metastases of breast cancer.

Background: The aim of this study is an improved understanding of drug distribution in brain metastases. Rather than single point snapshots, we analyzed the time course and route of drug/probe elimination (clearance), focusing on the intramural periarterial drainage (IPAD) pathway.

Methods: Mice with JIMT1-BR HER2+ experimental brain metastases were injected with biocytin-TMR and either trastuzumab or human IgG.

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-mm triple-negative breast cancer xenografts at doses 10- to 40-fold lower than the maximum tolerated dose.

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.

Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment.

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.

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.

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.

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.

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.