Ancestral Diversity in Pharmacogenomics Affects Treatment for Hispanic/Latine Populations With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: The prevalence of inflammatory bowel disease among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-tumor necrosis factor (TNF) immunogenicity (HLA-DQA1∗05) in a cohort of Hispanic patients of diverse ancestral backgrounds. METHODS: We performed a multicenter, retrospective cohort study comprising 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1∗05; their ancestral origin (European, African, or Amerindian); and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, in exposed patients. RESULTS: NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15, which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15∗4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1∗05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1∗05 in the European allele subset. CONCLUSIONS: These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian/Alaska Native ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1∗05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with inflammatory bowel disease.

Optimizing therapy in primary biliary cholangitis: Alkaline phosphatase at six months identifies one-year non-responders and predicts survival.

BACKGROUND AND AIMS: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response. METHODS: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected. RESULTS: For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82-1.33) vs. 2.37 × ULN (1.72-3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early. CONCLUSIONS: We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria.

Impact of Obesity on Inflammatory Bowel Disease.

PURPOSE OF REVIEW: This review highlights recent work that evaluates the impact of obesity on inflammatory bowel disease (IBD) pathogenesis and management. RECENT FINDINGS: The impact of obesity on IBD prevalence, clinical course, and management, has been studied and described more so in recent years. Studies have shown that obesity increases IBD disease activity, leads to longer hospitalization courses, and increases the likelihood of the development of extraintestinal manifestations. Recent evidence has also suggested that obese IBD patients have a higher frequency of extended steroid treatment and increased use of antibiotics compared to non-obese IBD patients. The effect of obesity on patients with IBD is a topic that has garnered widespread interest in the last decade due to the increasing prevalence of both diseases. To date however, although there are still many unanswered questions. It is quite clear that obesity, and more specifically, visceral adiposity, affects numerous IBD-related outcomes in regard to pathogenesis, extra-intestinal manifestations, response to medical and surgical therapies, hospital length of stay, healthcare-related costs, and health-related quality of life. Future studies should include larger patient populations and evaluate additional factors that are altered in those with obesity including the gut microbiome, dietary patterns, and whether weight loss and/or degree of weight loss impact clinical outcomes.

Increasing uptake of colon cancer screening in a medically underserved population with the addition of blood-based testing.

BACKGROUND: Adherence to colorectal cancer screening in the United States is suboptimal, particularly in medically underserved populations due to significant barriers to care. Unique accessible, low-cost, and non-invasive screening tests for this population could greatly benefit current rates. In this article, we assess patient preference and the impact of offering a blood-based test on screening rates in a cost-free health fair setting from April 2017 to April 2019. METHODS: Participants who met colorectal cancer screening eligibility criteria set forth by the United States Preventive Services Task Force were recommended to attend the colon cancer screening station. Those participants who elected to attend were offered various, accepted screening methods, and if they declined, were offered alternative blood-based testing. Screening rates, test outcomes, and the rate of follow up completion of colonoscopy were measured and compared with historic screening outcomes. RESULTS: Of 1401 participants who were recommended to attend, 640 (45.7%) participants were evaluated at the colon cancer screening station, of whom 460 were eligible for testing. Amongst these, none selected colonoscopy, 30 (6.5%) selected fecal immunochemical testing, and 430 (93.5%) selected blood-based testing. Only 2 participants returned the fecal immunochemical tests. In the blood test cohort, 88 were positive and 20 received a follow up colonoscopy. CONCLUSIONS: Based on this assessment, blood-based testing is an effective method to increase screening rates in medically underserved populations, though efforts to further improve access to follow up colonoscopy are necessary.

Mechanisms of resistance to cyclin-dependent kinase 4/6 inhibitors.

Cyclin-dependent kinase (CDK) 4/6 inhibitors have emerged in the treatment of metastatic hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, most patients will eventually present disease progression, highlighting the inevitable resistance of cancer cells to CDK4/6 inhibition. Several studies have suggested that resistance mechanisms involve aberrations of the molecules that regulate the cell cycle, and the re-wiring of the cell to escape CDK4/6 dependence and turn to alternative pathways. Loss of retinoblastoma function, overexpression of CDK 6, upregulation of cyclin E, overexpression of CDK 7, and dysregulation of several signaling pathways, notably the PI3/AKT/mTOR pathway, have been implicated in the development of resistance to CDK4/6 inhibitors. Overlap with endocrine resistance mechanisms might be possible. Combinational therapeutic strategies should be explored in order to prevent resistance and optimize the management of patients after progression under CDK 4/6 inhibition.

Polypharmacy in Patients with Ovarian Cancer.

OBJECTIVE: Polypharmacy has been associated with morbidity and mortality in patients with cancer. Data about polypharmacy among patients with ovarian cancer are limited. The primary objective of this study was to evaluate polypharmacy in a cohort of patients with ovarian cancer and to assess the evolution of polypharmacy from initial presentation to 2 years posttreatment. A secondary objective was to evaluate differences in polypharmacy between a subset of patients primarily treated in our comprehensive cancer center (CCC) and our safety net hospital (SNH). METHODS: Women treated for ovarian cancer between January 1, 2011, and December 31, 2016, were included. Data were abstracted from the electronic medical record. Medication safety was assessed using the established Anticholinergic Burden (ACB) scale and the Beers criteria. Statistical analyses were performed using paired t tests and Cox proportional hazards models, with significance set at p < .05. RESULTS: The study included 152 patients. The majority of patients had high-grade serous carcinoma. Hypertension was the most common medical problem. The mean number of medications at the time of diagnosis was 3.72. Paired testing demonstrated significant patient-level increases in the number medications at 2 years following initial diagnosis (4.16 vs. 7.01, p < .001). At the CCC, 47.4% of patients met criteria for polypharmacy at diagnosis compared with 19.4% at the SNH (p < .001). By 2 years postdiagnosis, 77.6% of patients at the CCC met criteria for polypharmacy compared with 43.3% at the SNH (p = .001). The use of any medications on the ACB scale (p < .001) increased significantly between initial diagnosis and 2 years for the entire population. Polypharmacy was not a significant predictor of overall survival. CONCLUSION: Polypharmacy worsens as women go through ovarian cancer treatment. Both at initial presentation and at 2 years postdiagnosis, rates of polypharmacy were higher at the CCC. Polypharmacy did not have an effect on survival in this cohort. IMPLICATIONS FOR PRACTICE: Awareness of escalating numbers of medications and potentially adverse interactions is crucial among women with ovarian cancer, who are at high risk for polypharmacy.

CDK4/6 and aromatase inhibitors as first-line treatment in metastatic high-grade neuroendocrine carcinoma of the breast: A case report.

Key Clinical Message: There is no consensus regarding the therapeutic approach of breast neuroendocrine carcinomas (NECs). As most NECs are hormone receptor positive and HER-2 negative, we suggest that endocrine-based strategies may play a leading role. Here, we report a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium. Abstract: Primary neuroendocrine neoplasms of the breast constitute a rare entity. They are characterized by predominant neuroendocrine differentiation and are further divided into well-differentiated neuroendocrine tumors and poorly differentiated (high-grade) neuroendocrine carcinomas (NECs). Regarding their therapeutic approach, there are no standardized guidelines. Herein, we present the first case ever reported, concerning a female patient with de novo metastatic breast NEC who received hormonal therapy, a combination of a CDK4/6 inhibitor palbociclib with letrozole and triptorelin, as first-line treatment with significant clinical and radiological response. As most NECs are estrogen receptor and/or progesterone receptor positive and HER-2 negative, we suggest that hormonal therapy may play a leading role even in the first-line setting. The present report provides a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium of breast NECs.

'Counterfeit deviance' revisited.

BACKGROUND: The field has seen a renewed interest in exploring the theory of 'counterfeit deviance' for persons with intellectual disability who sexually offend. The term was first presented in 1991 by Hingsburger, Griffiths and Quinsey as a means to differentiate in clinical assessment a subgroup of persons with intellectual disability whose behaviours appeared like paraphilia but served a function that was not related to paraphilia sexual urges or fantasies. Case observations were put forward to provide differential diagnosis of paraphilia in persons with intellectual disabilities compared to those with counterfeit deviance. The brief paper was published in a journal that is no longer available and as such much of what is currently written on the topic is based on secondary sources. METHOD: The current paper presents a theoretical piece to revisit the original counterfeit deviance theory to clarify the myths and misconceptions that have arisen and evaluate the theory based on additional research and clinical findings. The authors also propose areas where there may be a basis for expansion of the theory. RESULTS: The theory of counterfeit deviance still has relevance as a consideration for clinicians when assessing the nature of a sexual offence committed by a person with an intellectual disability. Clinical differentiation of paraphilia from counterfeit deviance provides a foundation for intervention that is designed to specifically treat the underlying factors that contributed to the offence for a given individual. DISCUSSION: Counterfeit deviance is a concept that continues to provide areas for consideration for clinicians regarding the assessment and treatment of an individual with an intellectual disability who has sexually offended. It is not and never was an explanation for all sexually offending behavior among persons with intellectual disabilities.

Combining Pentoxifylline With Vedolizumab for Crohn's Disease: Results of a Randomised, Placebo-controlled Pilot Study.

BACKGROUND AND AIMS: The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn's disease [CD] is safe and improves response compared with VDZ monotherapy. METHODS: Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect. RESULTS: Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred. CONCLUSIONS: VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study.

The changing treatment of metastatic her2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been historically associated with an aggressive disease course with common distant metastasis and poor prognosis. HER2-targeting therapies have significantly changed treatment and drastically improved outcomes for this group of patients. However, primary or acquired resistance to anti-HER2 regimens leads almost universally to disease progression, often with difficult to treat central nervous system (CNS) metastases. The current review summarized the existing therapeutic options for HER2-positive metastatic disease in the first, second and further line setting. Furthermore, novel agents currently under development were presented, which have demonstrated encouraging results in heavily pretreated patients or specific subgroups, such as HR-positive/HER2-positive tumors and CNS disease.

Truncated Variants of Gaussia Luciferase with Tyrosine Linker for Site-Specific Bioconjugate Applications.

Gaussia luciferase (Gluc)-with its many favorable traits such as small size, bright emission, and exceptional stability-has become a prominent reporter protein for a wide range of bioluminescence-based detection applications. The ten internal cysteine residues crucial to functional structure formation, however, make expression of high quantities of soluble protein in bacterial systems difficult. In addition to this challenge, the current lack of structural data further complicates the use of Gluc for in vitro applications, such as biosensors, or cellular delivery, both of which rely heavily on robust and reproducible bioconjugation techniques. While Gluc is already appreciably small for a luciferase, a reduction in size that still retains significant bioluminescent activity, in conjunction with a more reproducible bioorthogonal method of chemical modification and facile expression in bacteria, would be very beneficial in biosensor design and cellular transport studies. We have developed truncated variants of Gluc, which maintain attractive bioluminescent features, and have characterized their spectral and kinetic properties. These variants were purified in high quantities from a bacterial system. Additionally, a C-terminal linker has been incorporated into these variants that can be used for reliable, specific modification through tyrosine-based bioconjugation techniques, which leave the sensitive network of cysteine residues undisturbed.