Machine Learning Approaches to Predict Hepatotoxicity Risk in Patients Receiving Nilotinib.

Background: Although nilotinib hepatotoxicity can cause severe clinical conditions and may alter treatment plans, risk factors affecting nilotinib-induced hepatotoxicity have not been investigated. This study aimed to elucidate the factors affecting nilotinib-induced hepatotoxicity. Methods: This retrospective cohort study was performed on patients using nilotinib from July of 2015 to June of 2020. We estimated the odds ratio and adjusted odds ratio from univariate and multivariate analyses, respectively. Several machine learning models were developed to predict risk factors of hepatotoxicity occurrence. The area under the curve (AUC) was analyzed to assess clinical performance. Results: Among 353 patients, the rate of patients with grade I or higher hepatotoxicity after nilotinib administration was 40.8%. Male patients and patients who received nilotinib at a dose of ≥300 mg had a 2.3-fold and a 3.5-fold increased risk for hepatotoxicity compared to female patients and compared with those who received <300 mg, respectively. H2 blocker use decreased hepatotoxicity by 11.6-fold. The area under the curve (AUC) values of machine learning methods ranged between 0.61-0.65 in this study. Conclusion: This study suggests that the use of H2 blockers was a reduced risk of nilotinib-induced hepatotoxicity, whereas male gender and a high dose were associated with increased hepatotoxicity.

Stress ulcer prophylaxis versus placebo-a blinded randomized control trial to evaluate the safety of two strategies in critically ill infants with congenital heart disease (SUPPRESS-CHD).

BACKGROUND: Critically ill infants with congenital heart disease (CHD) are often prescribed stress ulcer prophylaxis (SUP) to prevent upper gastrointestinal bleeding, despite the low incidence of stress ulcers and limited data on the safety and efficacy of SUP in infants. Recently, SUP has been associated with an increased incidence of hospital-acquired infections, community-acquired pneumonia, and necrotizing enterocolitis. The objective of this pilot study is to investigate the feasibility of performing a randomized controlled trial to assess the safety and efficacy of withholding SUP in infants with congenital heart disease admitted to the cardiac intensive care unit. METHODS: A single center, prospective, double-blinded, randomized placebo-controlled pilot feasibility trial will be performed in infants with CHD admitted to the cardiac intensive care unit and anticipated to require respiratory support for > 24 h. Patients will be randomized to receive a histamine-2 receptor antagonist (H2RA) or placebo until they are discontinued from respiratory support. Randomization will be performed within 2 strata defined by admission type (medical or surgical) and age (neonate, age < 30 days, or infant, 1 month to 1 year). Allocation will be a 1:1 ratio using permuted blocks to ensure balanced allocations across the two treatment groups within each stratum. The primary outcomes include feasibility of screening, consent, timely allocation of study drug, and protocol adherence. The primary safety outcome is the rate of clinically significant upper gastrointestinal bleeding. The secondary outcomes are the difference in the relative and absolute abundance of the gut microbiota and functional microbial profiles between the two study groups. We plan to enroll 100 patients in this pilot study. DISCUSSION: Routine use of SUP to prevent upper gastrointestinal bleeding in infants is controversial due to a low incidence of bleeding events and concern for adverse effects. The role of SUP in infants with CHD has not been examined, and there is equipoise on the risks and benefits of withholding this therapy. In addition, this therapy has been discontinued in other neonatal populations due to the concern for hospital-acquired infections and necrotizing enterocolitis. Furthermore, exploring changes to the microbiome after exposure to SUP may highlight the mechanisms by which SUP impacts potential microbial dysbiosis of the gut and its association with hospital-acquired infections. Assessment of the feasibility of a trial of withholding SUP in critically ill infants with CHD will facilitate planning of a larger multicenter trial of safety and efficacy of SUP in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03667703. Registered 12 September 2018, https://clinicaltrials.gov/ct2/show/NCT03667703?term=SUPPRESS+CHD&draw=2&rank=1 . All WHO Trial Registration Data Set Criteria are met in this manuscript.

A rare cause of dysphagia due to esophageal intramural pseudodiverticulosis: a case report and review of literature.

BACKGROUND: Esophageal intramural pseudodiverticulosis is an uncommon, idiopathic disorder characterized by multiple small outpouchings protruding from the esophageal lumen. Esophageal intramural pseudodiverticulosis is associated with conditions such as gastroesophageal reflux disease and diabetes mellitus, as well as emergent complications including pneumomediastinum. The most common presenting symptom is dysphagia with associated esophageal stricture formation. While the pathogenesis of EIP has yet to be determined, it is important to bring awareness to this unique disease with distinctive diagnostic findings and treatment options. CASE PRESENTATION: In this case, we present a 62-year-old woman who suffered from dysphagia, an inability to tolerate a regular diet, and unintentional weight loss for several years prior to her diagnoses. She was diagnosed by esophagram and esophagogastroduodenoscopy to have esophageal intramural pseudodiverticulosis, complicated by severe stricture formation. Following treatment with sequential dilatation and maintenance H2-blocker therapy, she achieved significant symptomatic improvement. CONCLUSIONS: This case highlights the importance of accurate identification and treatment of an uncommon cause of dysphagia, esophageal intramural pseudodiverticulosis. Treatment includes dilatational therapy, as successfully demonstrated in our patient. Furthermore, treatment is focused on optimizing medical management, as demonstrated in our patient with the addition of an H2-blocker for GERD, or addressing potentially serious underlying causes, such as carcinoma, with surgery.

An Herbal H2 Blocker in Melasma Treatment.

BACKGROUND: Melasma is a skin pigmentation disorder that remains resistant to available therapies. The exact cause of melasma is unknown. Histamine is an inflammatory factor. Its involvement in pigmentation is obscure. The aim of this study is to introduce an herbal antihistamine H2 receptor which is effective in these disorders. METHODS: This is a review study by searching the electronic databases and also Persian Medicine books, from 2000 to 2018 by the keywords such as H2 antagonist, H2 blocker and melasma. RESULTS: According to the researched studies, histamine can induce melanogenesis and melasma after a series of stages in the body. Also, Histamine, through receptors 2, triggers melasma. Therefore, it can be said that antihistamine H2 receptor can be effective in melasma. Considering chemical antihistamine, H2 receptors have side effects, such as digestive problems, H2 antagonists can be used in the treatment of diseases such as dyspepsia but they have multiple complications. On the other hand, there is an herbal H2 antagonist that can be useful for melasma due to having some special properties. CONCLUSION: Herbal H2 blockers should be noted in melasma treatment along with the topical drugs.

Risk factors associated with the incidence and time to onset of lapatinib-induced hepatotoxicity.

PURPOSE: Although lapatinib-induced hepatotoxicity can cause severe clinical complications in patients, the factors affecting hepatotoxicity have rarely been investigated. The purpose of this study was to investigate risk factors for hepatotoxicity and time to lapatinib-induced hepatotoxicity. METHODS: This retrospective study was performed on metastatic breast cancer patients treated with lapatinib. Various factors were evaluated for hepatotoxicity and time to hepatotoxicity, including sex, age, body weight, height, body surface area, underlying disease, smoking history, start dose of lapatinib, status of liver metastasis, and concomitant drugs. RESULTS: Among 159 patients, the percentage of patients with hepatotoxicity after lapatinib initiation was 57.9% (n = 92). Multivariate analysis showed that concomitant use of H2 blockers increased the incidence of hepatotoxicity by 2.3-fold. Patients who received CYP3A4 inducers had 3.1 times higher risk of hepatotoxicity incidence; the attributable risks of H2 blockers and CYP3A4 inducers were 56.7% and 68.1%, respectively. Use of H2 blockers increased the hazard of time to hepatotoxicity by 1.8-fold compared to non-use of H2 blockers. CONCLUSIONS: Our study demonstrated that concomitant use of H2 blockers and CYP3A4 inducers was associated with lapatinib-induced hepatotoxicity. Close liver function monitoring is recommended, especially in patients receiving H2 blockers or CYP3A4 inducers.

Are prophylactic anti-reflux medications effective after esophageal atresia repair? Systematic review and meta-analysis.

PURPOSE: Gastroesophageal reflux after surgical repair of esophageal atresia (EA) can be associated with complications, such as esophageal stricture. Recent guidelines recommend prophylactic anti-reflux medication (PARM) after EA repair. However, the effectiveness of PARM is still unclear. The aim of this study was to review evidence surrounding the use of PARM in children operated for EA. METHODS: We performed a systematic review and meta-analysis. We searched Medline, EMBASE, and the Cochrane Databases from inception until the end of 2016 for comparative studies of PARM versus no PARM (control). Primary outcome was postoperative esophageal stricture. Quality of evidence was assessed using GRADE system. RESULTS: We identified four observational studies that focused on esophageal stricture as an outcome. A total of 362 patients were included in meta-analysis. There was no significant difference in esophageal stricture rates between PARM and control (OR = 1.14; 95% CI = 0.61-2.13; p = 0.68; I2 = 38%). The quality of the evidence was very low, due to lack of precision as a consequence of small study sizes. CONCLUSIONS: Our results indicate that PARM does not reduce the incidence of esophageal stricture after EA repair. Future well-controlled prospective studies are needed to obtain higher quality evidence.

The Utility of the Reflux Symptom Index for Diagnosis of Laryngopharyngeal Reflux in an Allergy Patient Population.

BACKGROUND: Laryngopharyngeal reflux (LPR) is associated with asthma, vocal cord dysfunction, cough, postnasal drainage, and throat irritation. The Reflux Symptom Index (RSI) is a clinical tool to predict the presence of LPR, but a threshold RSI score has never been validated for the diagnosis of LPR in an allergic patient population. OBJECTIVE: To identify the optimal threshold RSI score predictive of LPR in an allergy clinic population. METHODS: The 9-question RSI questionnaire was administered to 84 patients in the Kaiser Permanente San Diego Allergy Department. The patient's allergist (who was blinded to the patient's RSI responses) was asked to determine whether the patient had symptoms consistent with LPR. Each subject's RSI score was then compared with a corresponding physician-based diagnosis. After determining the correlation between the subject's RSI score and physician-diagnosed LPR/supraesophageal reflux, a cutoff level above which LPR/supraesophageal reflux would be highly suspected was calculated on the basis of most optimal balance of sensitivity and specificity determined via a receiver-operating curve analysis. RESULTS: Thirty of the 84 patients (36%) were diagnosed with LPR. The mean RSI score for the group without LPR was 18.3 ± 9.8 (out of 45 possible), while the LPR group's mean was 25.0 ± 8.3 (P < .01). The optimal RSI score cutoff was determined to be 19. An abbreviated questionnaire was also generated using 6 of the RSI questions found to be significantly different between patients with and without LPR. CONCLUSIONS: An RSI score of 19 appears to represent the best threshold for predicting LPR in an allergy clinic patient population.

Risk factors for suboptimal drug concentration of posaconazole oral suspension in patients with hematologic malignancy.

Absorption of posaconazole oral suspension is influenced by several factors including diet, medications, and mucosal integrity. However, there are few prospective data about which is the most important modifiable factor in routine clinical practice. We prospectively analyzed clinical risk factors associated with low posaconazole trough concentrations in 114 patients receiving anticancer chemotherapy due to acute myeloid leukemia or myelodysplastic syndrome who received posaconazole oral suspension. In multivariate analyses, risk factors for drug level<500ng/mL included low calorie intake, mucositis≥grade 2, H2 blocker famotidine and proton-pump inhibitor. The only significant risk factor for drug level<700ng/mL was famotidine use (adjusted relative risk, 3.18; 95% confidence interval, 1.07-9.11; P=0.038). In conclusion, medication of H2 blocker famotidine should be cautious in patients with hematologic malignancy receiving posaconazole suspension.

Molecular modelling studies on 2-substituted octahydropyrazinopyridoindoles for histamine H2 receptor antagonism.

The human histamine H2 receptor (hH2HR) is a G-protein coupled receptor protein with seven transmembrane (TM)-spanning helices primarily involved in regulation of gastric acid secretion. Antagonists targeting hH2HR are useful in the treatment of hyperacidic conditions such as peptic ulcers, gastresophageal reflux disease and gastrointestinal bleeding. We have previously reported the antagonism of 2-substituted pyrazinopyridoindoles at the human histamine H1 receptor and mode of binding of these compounds at the hH1HR using in silico methods. Interestingly, some of the compounds in the series also showed promising activity towards hH2HR that prompted us to investigate the mode of binding of these compounds at hH2HR. In the absence of the crystal structure of hH2HR a homology model has been constructed using multiple sequence alignment, using the X-ray crystal structures of Turkey ß1-adrenergic receptor (tß1AR), Human histamine H1 receptor (hH1HR), Human ß2-adrenergic receptor (hß2AR) and Human D3 dopamine receptor (hD3R). The important residues for binding were depicted in TMIII, TMV, TMVI and TMVII by the homology modelled hH2HR for 2-substituted pyrazinopyridoindoles. A comparative study for deducing the selectivity regarding the binding towards hH1HR and hH2HR has been carried out, which may be useful in designing of selective hH1HR/hH2HR antagonists in these classes of compounds.

Prophylactic effect of H2 blocker for anastomotic stricture after esophageal atresia repair.

BACKGROUND: Anastomotic stricture is the main complication after esophageal atresia (EA) repair. In this study, we assessed the efficacy of long-term prophylactic H2 blocker treatment in preventing stricture. METHODS: Twenty-seven patients who had undergone primary repair for EA (Gross type C) were reviewed retrospectively. The patients were analyzed in two groups: the H2 blocker group (n = 13), in which the patients were treated with prophylactic H2 blocker; and the control group (n = 14), in which they were not. To assess anastomotic stricture, contrast esophagography was performed and the number of patients who required balloon dilatation was recorded. RESULTS: Five patients (18.5%) required postoperative balloon dilatation within 1 year of primary repair. There was no difference in dilatation rate between the two groups. In the H2 blocker group, however, anastomotic stricture improved significantly in the late postoperative period relative to that in the early postoperative period. In contrast, in the control group, anastomotic stricture did not improve after a long postoperative period. The incidence of gastroesophageal reflux was 55.6%. Postoperative gastroesophageal reflux was a predisposing factor for balloon dilatation in the control group, but not in the H2 blocker group. CONCLUSIONS: Long-term treatment with prophylactic H2 blocker may prevent anastomotic stricture caused by gastroesophageal reflux in the late postoperative period after EA repair.

Clinical Study of Perforated Duodenal Ulcer

PURPOSE: There has been considerable controversy about whether acid reduction surgery is a definitive surgical treatment for perforated duodenal ulcer with numerous methods having been described. The controversy has increased with the development of the Proton Pump inhibitor and the discovery of Helicobacter Pylori (HP), because the recurrence and morbidity have been shown to decrease with simple closure followed by a good medical therapy against HP and the ulcer. This study is an evaluation of simple closure as an alternative treatment of perforated duodenal ulcer. METHODS: This retrospective study reviewed the records of 288 patients with surgically-treated ulcer perforation. After 62 patients were excluded, 128 patients treated with simple closure were compared with 98 patients treated with definitive surgery. In the simple closure group, we compared 50 patients treated with Proton Pump inhibitor and 78 patients treated with H2 blocker. Also, the influence of various factors such as age, delayed operation, size of ulcer perforation, operative methods, associated diseases, and complications were analyzed to evaluate recurrence, morbidity and mortality. RESULTS: After mean follow up for 53.7 months, 56.6% of patients treated with simple closure had fewer post operative complications and a lower recurrence rate compared with definitive surgery. The infection rate by HP of 81.6% in our study was similar to that of other studies. Some factors as age (>60), duration of symptoms (>24 hours), size of ulcer perforation (>10 mm), associated disease and operative time showed an influence on the mortality. CONCLUSION: Recent advances in the treatment of perforated peptic ulcer such as the development of the Proton Pump inhibitor and the discovery of HP have shown that after simple closure, an adequate medical treatment of ulcer can effectively decrease the recurrence rate, morbidity and mortality.