A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-ß, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort.

JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor ß (PDGFR-ß), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the first clinical study assessing anti-tumor activity of JI-101 in a combinatorial regimen. In the PK cohort, four patients received single agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8, and single agent 200 mg JI-101 on day 15. In the PD cohort, eleven patients received single agent JI-101 at 200 mg twice daily for 28 day treatment cycles. JI-101 was well tolerated as a single agent and in combination with everolimus. No serious adverse events were observed. Common adverse events were hypertension, nausea, and abdominal pain. JI-101 increased exposure of everolimus by approximately 22%, suggestive of drug-drug interaction. The majority of patients had stable disease at their first set of restaging scans (two months), although no patients demonstrated a response to the drug per RECIST criteria. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent may be pursued in a less refractory patient population or in combination with cytotoxic chemotherapy.

Critical illness aspects of heatstroke: A hot topic.

Heatstroke represents the most severe end of the heat illness spectrum, and is increasingly seen in those undergoing exercise or exertion ('exertional heatstroke') and those exposed to high ambient temperatures, for example in heatwaves ('classical heatstroke'). Both forms may be associated with significant thermal injury, leading to organ dysfunction and the need for admission to an intensive care unit. The process may be exacerbated by translocation of bacteria or endotoxin through an intestinal wall rendered more permeable by the hyperthermia. This narrative review highlights the importance of early diagnosis, rapid cooling and effective management of complications. It discusses the incidence, clinical features and treatment of heatstroke, and discusses the possible role of intestinal permeability and advances in follow-up and recovery of this condition. Optimum treatment involves an integrated input from prehospital, emergency department and critical care teams, along with follow-up by rehabilitation teams and, if appropriate, sports or clinical physiologists.

Familial hepatic rupture in vascular Ehlers-Danlos syndrome in pregnancy with atypical thromboses.

This case highlights the importance of genetic testing over fibroblast testing and presents the first published thromboelastometry data in vascular Ehlers-Danlos syndrome.

Simulation of ICD-9 to ICD-10-CM Transition for Family Medicine: Simple or Convoluted?

OBJECTIVE: The objective of this study was to examine the impact of the transition from International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), to Interactional Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), on family medicine and to identify areas where additional training might be required. METHODS: Family medicine ICD-9-CM codes were obtained from an Illinois Medicaid data set (113,000 patient visits and $5.5 million in claims). Using the science of networks, we evaluated each ICD-9-CM code used by family medicine physicians to determine whether the transition was simple or convoluted. A simple transition is defined as 1 ICD-9-CM code mapping to 1 ICD-10-CM code, or 1 ICD-9-CM code mapping to multiple ICD-10-CM codes. A convoluted transition is where the transitions between coding systems is nonreciprocal and complex, with multiple codes for which definitions become intertwined. Three family medicine physicians evaluated the most frequently encountered complex mappings for clinical accuracy. RESULTS: Of the 1635 diagnosis codes used by family medicine physicians, 70% of the codes were categorized as simple, 27% of codes were convoluted, and 3% had no mapping. For the visits, 75%, 24%, and 1% corresponded with simple, convoluted, and no mapping, respectively. Payment for submitted claims was similarly aligned. Of the frequently encountered convoluted codes, 3 diagnosis codes were clinically incorrect, but they represent only <0.1% of the overall diagnosis codes. CONCLUSIONS: The transition to ICD-10-CM is simple for 70% or more of diagnosis codes, visits, and reimbursement for a family medicine physician. However, some frequently used codes for disease management are convoluted and incorrect, and for which additional resources need to be invested to ensure a successful transition to ICD-10-CM.

Squamous non-small cell lung cancer as a distinct clinical entity.

Traditionally, the treatment of lung cancer has been based on histologic type [non-small cell lung cancer (NSCLC) or small cell lung cancer], performance status, and stage of disease. However, more recently, treatment decisions are being made based on molecular and histologic characteristics of the tumor. Specifically, the subclassification of NSCLC as squamous or nonsquamous is important in the context of newer treatments because clinical data have demonstrated differences in the tolerability and activity of these agents. Although progress continues to be made in the treatment of nonsquamous NSCLC, a significant unmet need exists for patients with squamous NSCLC. For both targeted and chemotherapeutic agents, the majority of regulatory approvals and updates to clinical practice guidelines for advanced NSCLC have focused on nonsquamous disease. In addition, because of safety concerns, patients with squamous NSCLC have been excluded from a number of clinical trials of investigational agents, particularly those targeting angiogenesis. This review discusses the importance of histology for treatment selection in NSCLC and summarizes recently completed and ongoing trials of investigational agents in squamous NSCLC. In addition, exciting developments in next-generation sequencing of squamous NSCLC have highlighted differences between squamous and nonsquamous disease and revealed potential new therapeutic targets. Advances in the molecular genetics of squamous NSCLC and implications for therapy will also be reviewed. Although progress in squamous NSCLC has faced limitations, momentum is building toward the identification of more effective treatments for this patient population.

Emerging molecularly targeted therapies in castration refractory prostate cancer.

Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.

Outcomes in 144 patients with colorectal cancer treated in a phase I clinic: the MD Anderson Cancer Center experience.

BACKGROUND: Patients with advanced colorectal cancer have a poor prognosis once standard therapies fail. This retrospective study presents the characteristics and outcomes in 144 patients treated in phase I clinical trials. METHODS: We retrospectively reviewed the clinical outcomes in 144 consecutive patients with colorectal cancer referred to the phase I clinic at MD Anderson. RESULTS: Median age was 60 years (range, 35-86 years). The median number of previous systemic therapies was 4 (range, 1-7). The median PFS with the last line of conventional systemic treatment was 12.3 weeks (95% confidence interval [CI], 11.0-14.4); the median PFS of the best phase I treatment was shorter at 8.1 weeks (95% CI, 7.9-8.7 weeks; log-rank test, P < .0001). In the multivariate analysis that included the RMH score, sex (male vs. female, P = .02; hazard ratio [HR], 1.57), hemoglobin (< 10.5 vs. ≥ 10.5 g/dL; P = .03; HR 1.79), and the RMH score (2-3 vs. 0-1; P < .003; HR, 1.85) were significant predictors of poor survival. CONCLUSION: The PFS of patients with colorectal cancer in phase I treatment was shorter than it was on their last line of conventional systemic treatment. Multivariate analysis confirmed the value of the RMH score for predicting overall survival in patients with colorectal cancer enrolled in phase I studies.

Identification of a metagenome-derived esterase with high enantioselectivity in the kinetic resolution of arylaliphatic tertiary alcohols.

35 metagenome-derived esterases bearing a GGG(A)X motif were screened for activity and enantioselectivity in the hydrolysis of a range of tertiary alcohol acetates. Most of the active esterases showed little or no enantioselectivity in the hydrolysis of the terpinyl acetate, linalyl acetate and 3-methylpent-1-yn-3-yl acetate. However, one esterase showed excellent enantioselectivity (E > 100) in the kinetic resolution of 1,1,1-trifluoro-2-phenylbut-3-yn-2-yl acetate as confirmed by a preparative scale reaction.