Natural Language Processing-Assisted Literature Retrieval and Analysis for Combination Therapy in Cancer.

PURPOSE: Despite advances in molecular therapeutics, few anticancer agents achieve durable responses. Rational combinations using two or more anticancer drugs have the potential to achieve a synergistic effect and overcome drug resistance, enhancing antitumor efficacy. A publicly accessible biomedical literature search engine dedicated to this domain will facilitate knowledge discovery and reduce manual search and review. METHODS: We developed RetriLite, an information retrieval and extraction framework that leverages natural language processing and domain-specific knowledgebase to computationally identify highly relevant papers and extract key information. The modular architecture enables RetriLite to benefit from synergizing information retrieval and natural language processing techniques while remaining flexible to customization. We customized the application and created an informatics pipeline that strategically identifies papers that describe efficacy of using combination therapies in clinical or preclinical studies. RESULTS: In a small pilot study, RetriLite achieved an F1 score of 0.93. A more extensive validation experiment was conducted to determine agents that have enhanced antitumor efficacy in vitro or in vivo with poly (ADP-ribose) polymerase inhibitors: 95.9% of the papers determined to be relevant by our application were true positive and the application's feature of distinguishing a clinical paper from a preclinical paper achieved an accuracy of 97.6%. Interobserver assessment was conducted, which resulted in a 100% concordance. The data derived from the informatics pipeline have also been made accessible to the public via a dedicated online search engine with an intuitive user interface. CONCLUSION: RetriLite is a framework that can be applied to establish domain-specific information retrieval and extraction systems. The extensive and high-quality metadata tags along with keyword highlighting facilitate information seekers to more effectively and efficiently discover knowledge in the combination therapy domain.

Oxidative Phosphorylation Is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer.

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.

Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer.

PURPOSE: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. EXPERIMENTAL DESIGN: Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. RESULTS: Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%) and PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), and ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody-drug conjugate targets LIV-1 and B7-H3. CONCLUSIONS: Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.

Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer.

PURPOSE: Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA approved for HER2-overexpressing/amplified (HER2+) breast cancer. In this preclinical study, we explored the efficacy of neratinib in combination with inhibitors of downstream signaling in HER2+ cancers in vitro and in vivo. EXPERIMENTAL DESIGN: Cell viability, colony formation assays, and Western blotting were used to determine the effect of neratinib in vitro. In vivo efficacy was assessed with patient-derived xenografts (PDX): two breast, two colorectal, and one esophageal cancer (with HER2 mutations). Four PDXs were derived from patients who received previous HER2-targeted therapy. Proteomics were assessed through reverse phase protein arrays and network-level adaptive responses were assessed through Target Score algorithm. RESULTS: In HER2+ breast cancer cells, neratinib was synergistic with multiple agents, including mTOR inhibitors everolimus and sapanisertib, MEK inhibitor trametinib, CDK4/6 inhibitor palbociclib, and PI3Kα inhibitor alpelisib. We tested efficacy of neratinib with everolimus, trametinib, or palbociclib in five HER2+ PDXs. Neratinib combined with everolimus or trametinib led to a 100% increase in median event-free survival (EFS; tumor doubling time) in 25% (1/4) and 60% (3/5) of models, respectively, while neratinib with palbociclib increased EFS in all five models. Network analysis of adaptive responses demonstrated upregulation of EGFR and HER2 signaling in response to CDK4/6, mTOR, and MEK inhibition, possibly providing an explanation for the observed synergies with neratinib. CONCLUSIONS: Taken together, our results provide strong preclinical evidence for combining neratinib with CDK4/6, mTOR, and MEK inhibitors for the treatment of HER2+ cancer.

Incidence of nausea and vomiting after intragastric balloon placement in bariatric patients - A systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis was performed to examine the rates of nausea and vomiting along with other common side effects reported from different subtypes of intragastric balloons (IGBs) placed in obese adults. METHODS: The online databases of Pubmed, Cochrane Database, and Web of Science were searched to include studies conducted from 09/31/2012 to 09/31/2017 in English using keywords to identify articles relevant to this study. Two independent reviewers performed a full text review to ensure quality of studies and report rates of primary end point of interest: nausea and vomiting post IGB placement. RESULTS: Ten studies fulfilled the inclusion criteria. The treatment group's sample size comprised of 688 patients and adverse events' sample size comprised of 938 patients. We evaluated rates of nausea and vomiting of four subtypes of IGB systems: Elipse, Obalon, ORBERA, and ReShape and calculated meta-analytic rates based on adverse events' sample size. Total 564 patients reported experiencing nausea which provided a meta-analytic rate of 63.33% (95% CI 61.49%-65.16%), and 507 patients reported experiencing vomiting which resulted in a meta-analytic rate of 55.29% (95% CI 53.59%-56.99%). The ORBERA balloon system had the highest rates of nausea and vomiting compared to other balloon systems. CONCLUSIONS: Based on the findings from previous studies scrutinizing side effects of different types of IGB offered on the market, it has been concluded that nausea and vomiting are very common side effects post gastric balloon placement.

Does single-port laparoscopic sleeve gastrectomy result in improved short-term perioperative outcomes compared to conventional multi-port laparoscopic sleeve gastrectomy?

A best evidence topic in bariatric surgery was written according to a structured protocol. The question asked whether single-port laparoscopic sleeve gastrectomy produces better short-term perioperative outcomes compared to the conventional multi-port laparoscopic sleeve gastrectomy in the treatment of morbid obesity. A Pubmed search generated 82 papers, 6 of which represented the best evidence to answer the clinical question. Of the 6, 1 paper was an updated analysis of the same patient cohort. The evidence on this subject is good. Five papers were level III, nonrandomized studies, 2 of which were prospective and 3 were retrospective cohort studies. The sixth paper was a level II, randomized, prospective study. We conclude that single-port laparoscopic sleeve gastrectomy results in less use of postoperative analgesia and better cosmetic satisfaction compared to multi-port laparoscopic sleeve gastrectomy in the short-term. The two groups showed comparable results in terms of mean operative time, mean hospitalization, and percentage excess weight loss. There was no difference in rate of postoperative complications including trocar site incisional hernia, staple line leaks, and bleeding.

Poland syndrome with extracorporeal intercostal liver herniation and thoracic myelomeningocele.

Poland syndrome is characterized by hypoplastic unilateral chest wall structures. These chest wall deformities may be associated with upper extremity anomalies. The association of Poland syndrome with either intercostal liver herniation or a spinocerebral deformity has been described, but there is no report of both findings encountered simultaneously. This is the first report of a newborn child with Poland syndrome associated with an intercostal liver segment herniation and thoracic myelomeningocele with features of an Arnold-Chiari II cerebral malformation.

Laparoscopic cystogastrotomy by ultrasonic dissection after pylorus-preserving pancreaticoduodectomy.

BACKGROUND AND OBJECTIVES: Symptomatic pancreatic pseudocysts can be drained using open, endoscopic, and laparoscopic techniques. Little is written on the role of laparoscopic drainage techniques after major abdominal operations. We describe a case of laparoscopic cystgastrotomy after pancreaticoduodenecomy. CASE REPORT: A 55-year-old female with a prior history of open pylorus-preserving pancreaticoduodenectomy presented with multiple symptomatic pancreatic pseudocysts in the setting of alcohol-induced chronic pancreatitis. METHODS: After preoperative planning with contrast-enhanced computed tomography, the patient successfully underwent laparoscopic cystgastrotomy with ultrasonic dissection. CONCLUSION: This case report illustrates that laparoscopic cystenteric drainage of pancreatic pseudocysts can be performed safely after major open abdominal operations. Further investigation is needed.

Noninvasive mechanical ventilation in patients with chronic obstructive pulmonary disease and severe hypercapnic neurological deterioration in the emergency room.

OBJECTIVES: The objective of this study was to assess the effectiveness of noninvasive motion ventilation (NIMV) in patients with chronic obstructive pulmonary disease (COPD), having infectious exacerbation and severe hypercapnic neurological dysfunction in the emergency room. DESIGN: This is a prospective interventional study. SETTING: The study setting was the emergency room at the Military Hospital in Guayaquil, Ecuador. PATIENTS: A total of 24 patients were studied. Twelve patients had acute exacerbation of their chronic obstructive pulmonary disease: they presented at the emergency room with severe neurological dysfunction, with a Glasgow Coma Scale (GCS) score of less than 8 and a pH of less than 7.25. These patients were compared with 12 controls who were being treated with invasive mechanical ventilation (IMV), who were then matched according to their GCS scores, pH status, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and age. INTERVENTIONS: We evaluated the effectiveness and safety of applying a ventilatory strategy based on a biphasic positive airway pressure protocol in the emergency room. MEASUREMENTS AND RESULTS: The pH, PCO2, and GCS scores, measured during the first 3 h, were predictors of success for the application of NIMV treatment (P<0.05). Mortality was 33.3 and 16.7% for the IMV and the NIMV groups, respectively (P=0.01). Days of IMV were 5.60+/-1.2 versus 3.6+/-1.1 for NIMV (P=0.006). Days of hospitalization were 11.1+/-4.7 for the IMV group and 6.5+/-1.9 for the NIMV group (P=0.001). The cumulative survival rates at 6 months were 71.4 and 80% for the IMV and NIMV groups, respectively (P=0.80). CONCLUSION: We consider that severe neurological dysfunction and pH of less than 7.25 do not constitute absolute contraindications to the use of NIMV. This kind of management can be implemented in the emergency room with favorable results.