Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures.

Caregivers' Assessment of the Sensory Processing Patterns Exhibited by Children with Autism in the Gulf Region.

This study explored the nature, prevalence, and developmental profiles of sensory processing disorders among children with autism spectrum disorder (ASD). The participants comprised 119 children with ASD and 30 typically developing children and their parents. The Child Sensory Profile-2 was used to assess the children's sensory processing characteristics.

Behavioral and Neuropsychological Evaluation of Executive Functions in Children with Autism Spectrum Disorder in the Gulf Region.

This study examined the executive functioning abilities and development profiles of children with autism spectrum disorder (ASD). The participants were 119 children with ASD and 30 typically developing children (age range: 6-12 years) who were recruited from three Gulf states. The findings revealed executive functioning deficits in the ASD population when compared to the normative data or to those children without ASD.

A survey of Canadian breast health professionals’ recommendations for high-risk benign breast disease.

The management of high-risk benign breast disease (BBD) is changing because of improvements in radiological and pathological analysis. We sought to determine the current practice recommendations of breast health professionals in managing patients with high-risk BBD. We surveyed members of the Canadian Society of Surgical Oncology, Canadian Association of General Surgeons and Canadian Association of Radiologists.

Outcomes after Surgery for Early Stage Breast Cancer in Women Staged With Preoperative Breast Magnetic Resonance Imaging According to Breast Tissue Density.

Purpose: To determine surgical outcomes and breast cancer disease-free survival outcomes of women with early stage breast cancer with and without use of preoperative breast MRI according to breast tissue density.

Methods: Women with early stage breast cancer diagnosed from 2004 to 2009 were classified into 2 groups: 1) those with dense and heterogeneously dense breasts (DB); 2) those with nondense breasts (NDB) (scattered fibroglandular and fatty replaced tissue). The 2 groups were reviewed to determine who underwent preoperative MRI.

Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier.

Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM.

TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma.

In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients.

Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical data.

Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas.

Combination of PIM and JAK2 inhibitors synergistically suppresses MPN cell proliferation and overcomes drug resistance.

Inhibitors of JAK2 kinase are emerging as an important treatment modality for myeloproliferative neoplasms (MPN). However, similar to other kinase inhibitors, resistance to JAK2 inhibitors may eventually emerge through a variety of mechanisms. Effective drug combination is one way to enhance therapeutic efficacy and combat resistance against JAK2 inhibitors.

Reducing persistent postoperative pain and disability 1 year after breast cancer surgery: a randomized, controlled trial comparing thoracic paravertebral block to local anesthetic infiltration.

Background: The objective of this study was to compare the effect of thoracic paravertebral block (TPVB) and local anesthetic (LA) on persistent postoperative pain (PPP) 1 year following breast cancer surgery. Secondary objectives were to compare the effect on arm morbidity and quality of life.

Methods: Women scheduled for elective breast cancer surgery were randomly assigned to either TPVB or LA followed by general anesthesia.

Improving breast diagnostic services with a Rapid Access Diagnostic and Support (RADS) program.

Background: The diagnostic phase of care is an anxiety-provoking and stressful experience for the potential breast cancer patient. A multidisciplinary team of breast cancer specialists embarked on a new initiative to pilot a Rapid Diagnosis and Support (RADS) Clinic to coordinate the diagnostic workup and nursing support for patients with a high probability of breast cancer.

Methods: Consecutive patients with an initial diagnostic imaging classified as BI-RADS 5 were invited to participate in this 1-year prospective study.

Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors.

Purpose: Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752.

Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting.

Background: In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear.

Methodology/principal Findings: Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ∼250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis.

MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts.

Purpose: Investigate the efficacy and pharmacodynamic effects of MK-1775, a potent Wee1 inhibitor, in both monotherapy and in combination with gemcitabine (GEM) using a panel of p53-deficient and p53 wild-type human pancreatic cancer xenografts.

Experimental Design: Nine individual patient-derived pancreatic cancer xenografts (6 with p53-deficient and 3 with p53 wild-type status) from the PancXenoBank collection at Johns Hopkins were treated with MK-1775, GEM, or GEM followed 24 hour later by MK-1775, for 4 weeks. Tumor growth rate/regressions were calculated on day 28.

Perioperative myocardial ischemia and isolated systolic hypertension in non-cardiac surgery.

Purpose: To determine whether patients with isolated systolic hypertension (ISH) undergoing non-cardiac surgery have a higher incidence of perioperative myocardial ischemia than normotensive patients and hence a greater risk for perioperative adverse events.

Methods: After obtaining Research Ethics Board approval, patients were recruited to either an ISH group (systolic blood pressure [SBP] > 140 mmHg with diastolic blood pressure [DBP] < 90 mmHg) or a normotensive group (SBP < 140 mmHg and DBP < 90 mmHg), according to their resting preoperative blood pressure. The primary outcome was the overall incidence of perioperative myocardial ischemia (PMI) as determined by 48-hr ambulatory Holter monitoring.

EMT is the dominant program in human colon cancer.

Background: Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging.

Methods: We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence.

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors.

Background: Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence.

De novo discovery of a gamma-secretase inhibitor response signature using a novel in vivo breast tumor model.

Notch pathway signaling plays a fundamental role in normal biological processes and is frequently deregulated in many cancers. Although several hypotheses regarding cancer subpopulations most likely to respond to therapies targeting the Notch pathway have been proposed, clinical utility of these predictive markers has not been shown. To understand the molecular basis of gamma-secretase inhibitor (GSI) sensitivity in breast cancer, we undertook an unbiased, de novo responder identification study using a novel genetically engineered in vivo breast cancer model.

Multiplexed measurements of gene signatures in different analytes using the Nanostring nCounter Assay System.

Background: We assessed NanoString's nCounter Analysis System for its ability to quantify gene expression of forty-eight genes in a single reaction with 100 ng of total RNA or an equivalent amount of tissue lysate. In the nCounter System, multiplexed gene expression target levels are directly detected, without enzymatic reactions, via two sequence-specific probes. The individual mRNA is captured with one mRNA target sequence-specific capture probe that is used in a post-hybridization affinity purification procedure.

Comparative expression pathway analysis of human and canine mammary tumors.

Background: Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved.

Regional collaborations as a tool for quality improvements in surgery: a systematic review of the literature.

Background: A systematic review of the literature identifying regional collaborations in surgical practice examining practices related to quality improvement.

Methods: The MEDLINE, EMBASE, and Cochrane Library databases, were searched for published reports of regional collaborations in the surgical community relating to initiatives to enhance quality improvement, quality of care, patient safety, knowledge transfer, or communities of practice.

Results: Seven collaborative initiatives met the inclusion criteria and were included in the systematic review of the evidence.