Characteristics and clinical outcomes in young-onset cholangiocarcinoma.

BACKGROUND: While the incidence of cholangiocarcinoma is rising, little is known about young-onset disease. We compared clinical characteristics and outcomes between patients with young-onset cholangiocarcinoma, diagnosed between the ages of 18 and <50 years, and patients with typical-onset cholangiocarcinoma, diagnosed at age 50 years or greater. METHODS: We used the National Cancer Database to identify patients with young-onset cholangiocarcinoma (n = 2520) and typical-onset cholangiocarcinoma (n = 23,826). We compared the frequency of demographic and clinical characteristics between the two groups. We compared overall survival between the two groups using multivariable Cox regression analysis after adjusting for age, gender, race/ethnicity, comorbidity, facility type, tumor location, tumor stage, surgical status, and receipt of radiotherapy, chemotherapy and surgery. RESULTS: When compared to patients with typical-onset disease (median age 68 years), patients with young-onset cholangiocarcinoma (median age 44 years) were more likely to be non-White (35.0% vs. 27.4%, p < 0.01), and had lower overall comorbidity burden. Patients with young-onset disease had a greater proportion of intrahepatic cholangiocarcinoma (56.0% vs. 45.5%, p < 0.001) and stage IV disease (50.5% vs. 43.5%, p < 0.001). Younger patients were more likely than typical-onset patients to receive definitive surgery (30.9% vs. 25.0%, p < 0.001), radiation (27.7% vs. 19.6%, p < 0.001) and chemotherapy (73.1% vs. 50.1%, p < 0.001). In adjusted analyses, patients with young-onset disease had a 15% decreased risk of death, compared with patients with typical-onset disease (HR 0.85 [95% CI 0.80-0.89], p < 0.001). CONCLUSIONS: Patients with young-onset cholangiocarcinoma may represent a demographically and clinically distinct group from those with more typical-onset disease.

Trends in Adjuvant Chemotherapy Use Among Stage III Colon Cancer in Non-Elderly and Low Comorbidity Patients.

BACKGROUND: Adjuvant chemotherapy for stage III colon cancer is underutilized in the United States. The aim of this study was to assess the use of adjuvant chemotherapy in younger and medically fit patients and analyze the socioeconomic factors associated with its utilization. METHODS: Using the National Cancer Database from 2004 to 2015, we selected stage III colon cancer patients between age 18 to 65, Charlson-Deyo Comorbidity Index (CDCI) of 0 or 1, and those that survived at least 12 months after surgery. We then compared patients that underwent surgery only with those that received adjuvant chemotherapy. Multivariable logistic regression analysis was performed to identify variables associated with adjuvant chemotherapy use in the population. Overall survival was estimated by Kaplan-Meier curves. RESULTS: Of the 48,336 patients that met inclusion criteria, 43,315 (90%) received adjuvant chemotherapy. The utilization of adjuvant chemotherapy increased from 87% in 2004 to 91% in 2015. On multivariable regression analysis, the use of adjuvant chemotherapy was lower among males, Non-Hispanic Blacks and Hispanics, low-grade cancer, left-sided tumors, CDCI 1, those who travel ≥ 50 miles, yearly income < $40,227, and uninsured patients. The most common reason for the omission of adjuvant chemotherapy was the patient or caregiver's choice (40% between 2013 and 2015). The 5-year and 10-year overall survival rates were 76.7% and 63.8% respectively, in those who received adjuvant chemotherapy as compared to 65.1% and 49.3% in those who underwent surgery only (P < .001). CONCLUSION: In young and medically fit stage III colon cancer patients, most patients received guideline-compliant care in the United States. However, socioeconomic disparities adversely impacted the use of adjuvant chemotherapy. The patient or caregiver's decision was the most common reason for non-adherence to adjuvant chemotherapy and lead to poor survival outcomes. Emphasis should be placed on developing patient-centered strategies to improve adherence to chemotherapy in all patients.

Racial and Ethnic Differences in Genomic Profiling of Early Onset Colorectal Cancer.

The incidence and mortality of early onset colorectal cancer (EOCRC) is rising; outcomes appear to differ by race and ethnicity. We aimed to assess differences in mutational landscape and gene expression of EOCRC by racial and ethnic groups (non-Hispanic Asian, non-Hispanic Black, non-Hispanic White, White Hispanic) using data from the American Association for Cancer Research Project GENIE (10.2) and University of Texas Southwestern, the latter enriched in Hispanic patients. All statistical tests were 2-sided. Of 1752 EOCRC patients, non-Hispanic Black patients had higher rates of KRAS mutations (60.9%; P = .001, q = 0.015), and non-Hispanic White and non-Hispanic Black patients had higher rates of APC mutations (77.1% and 76.6% among non-Hispanic White and non-Hispanic Black patients, respectively; P = .001, q = 0.015) via the Fisher exact test with Benjamini-Hochberg correction. Using R packages DESeq2 and clusterProfiler, we found that White Hispanic patients had increased expression of genes involved in oxidative phosphorylation (P < .001, q = 0.025). Genomic profiling has the potential to identify novel diagnostics and influence individualized treatment options to address the currently limited prognosis of EOCRC.

Self-reported reasons for colonoscopy among adults aged 45-49 versus 50 years and older from 2010-2018.

BACKGROUND: In May of 2018, the American Cancer Society lowered the age of colorectal cancer (CRC) screening initiation from 50 to 45 years and in October 2020, United States Preventive Services Task Force published draft guidelines also lowering age of screening initiation to 45 years. Evaluating guideline adherence is needed; however, the majority of prior research on cancer screening do not distinguish whether colonoscopy was performed for true screening purposes or for post-symptomatic diagnosis. METHODS: Using data from the National Health Interview Survey between 2010 to mid-2018, we assessed response to the question "What was the MAIN reason you had [last] colonoscopy?" stratified by age (45-49 versus 50+ years). Multivariable logistic regression defined adjusted odds ratios of receiving last colonoscopy for screening controlling for relevant demographic characteristics. To estimate the cost burden of colonoscopy, the proportion of respondents reporting paying out of pocket for their last colonoscopy was assessed. RESULTS: Among 29,074 participants who had undergone a colonoscopy, 44.4 % of those aged 45-50 reported routine procedure as the reason for their most recent colonoscopy, as compared to 82.4 % in the 50+ age group (p < 0.001). Characteristics associated with undergoing colonoscopy as a routine procedure included Black race and male sex for both age cohorts (p < 0.01 for all). Notably, almost half (46.9 %) of participants younger than 50 years paid part of or the full cost of their colonoscopy, as compared to 30.7 % over the age of 50 (p < 0.001). CONCLUSIONS: The majority of adults aged 45-49 self-report that last colonoscopy was not performed for screening, which is unsurprising given guidelines for screening for individuals under 50. As guidelines change, continued surveillance of colonoscopy patterns across age cohorts is needed, and studies should also incorporate reasons for testing.

Racial/Ethnic Disparities and Survival Characteristics in Non-Pancreatic Gastrointestinal Tract Neuroendocrine Tumors.

Background: We studied the effect of race and ethnicity on disease characteristics and survival in gastrointestinal neuroendocrine tumors. Methods: The Surveillance, Epidemiology, and End Results database was used to select patients with non-pancreatic gastrointestinal neuroendocrine tumors diagnosed between 2004 and 2015. Trends in survival were evaluated among three groups: Hispanic, non-Hispanic White, and non-Hispanic Black. Kaplan-Meier and Cox regression methods were performed to calculate overall survival and cause-specific survival after adjusting for patient and tumor characteristics. Results: A total of 26,399 patients were included in the study: 65.1% were non-Hispanic White, 19.9% were non-Hispanic Black, and 15% were Hispanic. Non-Hispanic White patients were more likely to be male (50.0%, p < 0.001), older than 60 years (48.0%, p < 0.001), and present with metastatic disease (17.7%, p < 0.001). Non-Hispanic White patients had small intestine neuroendocrine tumors, while Hispanic and non-Hispanic Black patients had rectum neuroendocrine tumors as the most common primary site. Hispanic patients had better overall survival, while non-Hispanic Black patients had better cause-specific survival versus non-Hispanic White patients. This finding was confirmed on multivariable analysis where Hispanic patients had improved overall survival compared to non-Hispanic White patients (Hazard ratio (HR): 0.89 (0.81-0.97)), whereas non-Hispanic Black patients had better cause-specific survival compared to non-Hispanic White patients (HR: 0.89 (0.80-0.98)). Conclusions: Race/ethnicity is an independent prognostic factor in patients with gastrointestinal neuroendocrine tumors.

Chronic traumatic encephalopathy in an epilepsy surgery cohort: Clinical and pathologic findings.

OBJECTIVE: To determine the occurrence of chronic traumatic encephalopathy (CTE) in young adult patients undergoing epilepsy surgery. METHODS: Ten patients who underwent epilepsy surgery were randomly selected for this retrospective study. The patients were 18-45 years of age, had preoperative neuropsychological evaluation, and had 1 year postoperative follow-up. Microscopic sections from resections were evaluated for the presence of CTE with standard stains and antibodies to tau (clone AT8). RESULTS: The median age at resection was 32.5 years (range 23-43) and the median duration of seizures was 23.5 years (range 3-28). Eight had a history of head injury. Preoperative neuropsychological testing showed mild to moderate cognitive impairment in 8 patients (80%). Pathologic examination in one patient showed focal sparse tau-immunoreactive lesions along descending rami and cortical gyral depths of the resected frontal lobe. Nine patients had no evidence of CTE. All focal cortical resections showed variable subpial and subcortical gliosis commonly identified in patients with chronic seizure disorders. CONCLUSIONS: The present small retrospective observational study suggests that CTE may occur, but appears uncommon, in young adult patients undergoing surgical treatment for drug-resistant focal epilepsy. The significance of these findings requires further investigation to define the relative importance of tau accumulation in younger adult patients with drug-resistant focal epilepsy and cognitive decline.

Evidence on Use of Neuroimaging for Surgical Treatment of Temporal Lobe Epilepsy: A Systematic Review.

IMPORTANCE: Surgery is an effective treatment for drug-resistant focal epilepsy. Neuroimaging studies are considered essential in the diagnostic evaluation of individuals with medically refractory focal seizures being considered for surgical treatment. OBJECTIVES: To review the evidence for the use of neuroimaging studies in the selection of patients with drug-resistant temporal lobe epilepsy for focal cortical resection and discuss the prognostic importance of selected techniques. EVIDENCE REVIEW: Randomized clinical trials, meta-analyses, and clinical retrospective case studies (≥20 patients with ≥1 year of follow-up) were identified using Medical Subject Headings and indexed text terms in EMBASE (1988-November 29, 2014); MEDLINE (1946-December 2, 2014), Cochrane Central Register of Controlled Trials (1991-October 31, 2014), and Cochrane Database of Systematic Reviews (2005-October 31, 2014). Twenty-seven articles describing 3163 patients were included. Neuroimaging techniques analyzed included magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Subpopulations and prognostic factors were identified. FINDINGS: Of the 27 studies evaluated (3163 patients), 7 showed the outcome was more favorable in patients with MRI-identified hippocampal atrophy indicating mesial temporal sclerosis. Five additional studies indicated that the outcome was less favorable in patients with unremarkable MRI studies. There are conflicting findings regarding the prognostic importance of PET-identified focal hypometabolism; however, 2 investigations indicated that the presence of a PET imaging study demonstrating abnormalities in individuals with unremarkable MRI results showed an operative outcome similar to that in patients with mesial temporal sclerosis. The studies assessing SPECT use in temporal lobe epilepsy did not reveal a correlation with outcome. CONCLUSIONS AND RELEVANCE: There is strong evidence that preoperative MRI-identified hippocampal atrophy consistent with mesial temporal sclerosis concordant with the seizure origin in the temporal lobe is a significant factor associated with a favorable outcome. PET studies may be valuable in individuals with unremarkable MRI findings. The current evidence does not support the prognostic importance of SPECT in patients undergoing temporal lobe surgery.

Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults.

IMPORTANCE: Classic Purkinje cell cytoplasmic antibody type 1 (PCA-1, or anti-Yo) paraneoplastic cerebellar ataxia has a poor prognosis, yet little has been published otherwise regarding treatment responses and outcomes among patients with autoimmune cerebellar ataxia. OBJECTIVES: To investigate treatment responses and outcomes in adults with autoimmune cerebellar ataxia. DESIGN, SETTING, AND PARTICIPANTS: A cohort study conducted at Mayo Clinic, Rochester, Minnesota, included 118 patients who had ataxia, were 18 years or older, were seropositive for at least 1 neural autoantibody, had received at least 1 immunotherapy or cancer therapy, and had neurologist-reported outcomes documented from January 1, 1989, through December 31, 2013. Data were collected from May 14, 2013, through August 9, 2014, and analyzed from August 9, 2014, through April 27, 2015. Responses to immunotherapy (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunosuppressants) and ambulatory outcomes were compared between different subgroups. Subgroups were classified as paraneoplastic vs nonparaneoplastic disorders; neuronal nuclear and/or cytoplasmic (NNC) antibody positivity vs plasma membrane protein (PMP) antibody positivity; and glutamic acid decarboxylase 65-kDa isoform (GAD65) antibody positivity vs PMP antibody positivity. MAIN OUTCOMES AND MEASURES: Response to therapy and ambulatory ability, with univariate logistic regression and Kaplan-Meier analyses. RESULTS: Inclusion criteria were met by 118 patients. Median age at onset of neurologic symptoms was 58 (range, 27-83) years, and 87 patients (73.7%) were women. Median duration from symptom onset to last follow-up was 25 (range, 2-223) months. Sixty-three patients had paraneoplastic and 55 patients had nonparaneoplastic ataxic disorders. Eighty-one patients were seropositive for NNC antibodies (most commonly PCA-1 [anti-Yo], antineuronal nuclear antibody type 1 [anti-Hu], and GAD65 antibody); 22 patients, for neural PMP receptor or ion channel antibodies (most commonly targeting P/Q- or N-type voltage-gated calcium channels); and 15 patients, for antibodies from both categories. Neurologic improvements occurred in 54 patients (with a robust change in ambulatory ability in 22) attributable to immunotherapy; univariate regression analysis revealed that improvements were significantly more common among patients with nonparaneoplastic disorders (P = .03) and those with exclusively PMP antibodies (P = .02). Kaplan-Meier analyses revealed that progression to wheelchair dependence occurred significantly faster among patients with NNC antibody positivity only (P = .02), although those with GAD65 autoimmunity progressed to wheelchair dependence at a rate similar to those with PMP autoimmunity (P = .92). CONCLUSIONS AND RELEVANCE: Although autoimmune ataxia is usually severe, treatment responses can be gratifying, particularly in patients with nonparaneoplastic disorders and in those harboring autoantibodies directed against GAD65 or neural PMPs.

Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study.

The renin-angiotensin system is a key regulator of blood pressure (BP), with inhibitors of angiotensin-converting enzyme (ACE) used clinically to treat hypertension and other cardiovascular conditions. ACE2 is a newly identified member of this system, which converts angiotensin II to angiotensin, and of which the occurrence in plasma has not been investigated. The aim of this study was to determine the heritability of circulating ACE, ACE2, and neprilysin (NEP), which may also be a regulator of BP, in a family study, and to determine covariates that contribute to the variation in plasma activity. ACE, ACE2, and NEP activities were measured in plasma from 534 subjects in the Leeds Family Study using selective fluorogenic substrates. Genetic factors accounted for 24.5%, 67%, and 22.7% of the phenotypic variation in circulating ACE, ACE2, and NEP, respectively. ACE insertion/deletion polymorphism and other measured covariates accounted for 23.8% of variance in circulating ACE. High-density lipoprotein cholesterol was a significant determinant of circulating ACE2. Measured covariates accounted for 17.3% of variation in circulating NEP. ACE and NEP were associated with systolic and diastolic BP in univariate analyses; however, only ACE was independently associated with systolic and diastolic BP after accounting for covariates and shared childhood household.

A small molecule antagonist of the alpha(v)beta3 integrin suppresses MDA-MB-435 skeletal metastasis.

INTRODUCTION: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The alpha(v)beta3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the alpha(v)beta3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. MATERIALS AND METHODS: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100 mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. RESULTS AND CONCLUSIONS: IC50 for S247 adhesion to alpha(v)beta3 or alpha(IIB)beta3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 microM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50% of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the alpha(v)beta3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that alpha(v)beta3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.