Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

Background: The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors.

Methods: Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter.

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

Background: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity.

Patients And Methods: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study.

Clinical impact of checkpoint inhibitors as novel cancer therapies.

Immune responses are tightly regulated via signaling through numerous co-stimulatory and co-inhibitory molecules. Exploitation of these immune checkpoint pathways is one of the mechanisms by which tumors evade and/or escape the immune system. A growing understanding of the biology of immune checkpoints and tumor immunology has led to the development of monoclonal antibodies designed to target co-stimulatory and co-inhibitory molecules in order to re-engage the immune system and restore antitumor immune responses.

A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer.

Purpose: To determine the maximum tolerated dose (MTD) of the combination of linsitinib (OSI-906), a dual inhibitor of IGFR and IR tyrosine kinase activity, and everolimus as treatment for patients with refractory metastatic colorectal cancer (mCRC).

Methods: Eligible adult patients with refractory mCRC, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate end-organ function received escalating doses of OSI-906 and everolimus in a 3 + 3 design. Treatment continued until disease progression or unacceptable toxicity, with response evaluations every 8 weeks.

[Clinical application of ROLL technique in non-breast diseases. Complementary use after PET-CT study].

Objective: The aim of this study was to evaluate the usefulness of ROLL technique (Radioguided Occult Lesion Localization) as a verification method of suspicious lesions not related to breast disease found in PET-CT studies.

Material And Methods: We retrospectively evaluated 9 patients diagnosed of cancer or with suspected tumor disease who showed hypermetabolic lymph nodes in (18)F-FDG PET-CT. Subjects underwent diagnostic testing for evaluation of treatment response in lymphoma (3), suspected recurrence in other tumors (3) or biopsy guide (3).

Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor.

Purpose: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment.

Patients And Methods: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib.

Phase I dose-escalation studies of SNX-5422, an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumours.

Background: Orally administered SNX-5422, a novel, selective prodrug of the Heat shock protein 90 (Hsp90) inhibitor SNX-2112, was investigated in two sequential phase I studies to determine the safety, maximum tolerated doses (MTDs) and pharmacokinetic profile of SNX-5422.

Methods: Using a dose-escalation design, 3-6 adults with advanced solid tumours received SNX-5422 every-other-day (QOD) or once-daily (QD) 3weeks on/1week off or QD continuously, with disease assessments every 8 weeks. Single-dose and steady-state pharmacokinetic parameters of SNX-2112 were determined.

Histopathological Study of the Lungs of Mice Receiving Human Secretory IgA and Challenged with Mycobacterium tuberculosis.

Background: Humoral and cellular immune responses are associated with protection against extracellular and intracellular pathogens, respectively. In the present study, we evaluated the effect of receiving human secretory immunoglobulin A (hsIgA) on the histopathology of the lungs of mice challenged with virulent Mycobacterium tuberculosis.

Methods: The hsIgA was purified from human colostrum and administered to Balb/c mice by the intranasal route prior to infection with M.

Targeting PI3 kinase in cancer.

The PI3K/Akt/mTOR pathway is the most frequently known activated aberrant pathway in human cancers. Pathologic activation can occur at multiple levels along the signaling pathway by a variety of mechanisms, including point mutations, amplifications, and inactivation of tumor suppressor genes. This pathway is also a known resistance pathway, as it can be activated by both receptor tyrosine kinases and other oncogenes.

Accumulation of extracellular hyaluronan by hyaluronan synthase 3 promotes tumor growth and modulates the pancreatic cancer microenvironment.

Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells.

Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma.

Purpose: This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.

Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors.

Purpose: LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation.

Levels of immune cells in transcendental meditation practitioners.

Context: Relationships between mind and body have gradually become accepted. Yogic practices cause modulation of the immune system. Transcendental meditation (TM) is a specific form of mantra meditation.

A Phase I cardiac safety and pharmacokinetic study of tivozanib hydrochloride in patients with advanced solid tumors.

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib's effects on the QTc interval in patients with advanced solid tumors were assessed. Patients received 1.

Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436).

Purpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship.

Experimental Design: Dabrafenib was administered orally once, twice (BID), or three times daily (TID).

A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.

Background: Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.

A phase I/II study of lenalidomide in combination with sunitinib in patients with advanced or metastatic renal cell carcinoma.

Background: This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide plus sunitinib in metastatic renal cell carcinoma (RCC) patients.

Patients And Methods: Patients with histologically confirmed, metastatic RCC were treated with 10 mg/day lenalidomide plus 37.5 mg/day sunitinib, orally in 21-day cycles.

Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies.

Background: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.

Methods: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000.

Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6.

Background: The most common spinocerebellar ataxias (SCA)--SCA1, SCA2, SCA3, and SCA6--are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset.

Methods: We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort.

A phase I dose escalation study of oral c-MET inhibitor tivantinib (ARQ 197) in combination with gemcitabine in patients with solid tumors.

Background: Tivantinib (ARQ 197) is an orally available, non-adenosine triphosphate competitive, selective c-MET inhibitor. The primary objective of this study was to evaluate the safety, tolerability and to establish the recommended phase II dose (RP2D) of tivantinib and gemcitabine combination.

Patients And Methods: Patients with advanced or metastatic solid tumors were treated with escalating doses of tivantinib (120-360 mg capsules) in combination with gemcitabine (1000 mg/m(2) weekly for 3 of 4 weeks).

Focal nodular hyperplasia within accessory liver: imaging findings at computed tomography and magnetic resonance imaging.

Accessory liver tissue is a rare but probably underreported entity that may harbor the same spectrum of pathology as that of the parent organ. The rarity and aberrant locations of such lesions cause confusion and may lower diagnostic confidence despite otherwise classic radiographic appearances. Focal nodular hyperplasia (FNH) is the most common non-hemangiomatous benign hepatic tumor, but to our knowledge, ectopic FNH has been reported only once before in the gastroenterology literature.

Serum uric acid and risk of dementia in Parkinson's disease.

Objective: Low serum uric acid (UA) levels have been associated with a worse cognitive function later in life and also with a higher risk and faster progression of Parkinson's disease (PD). Here we studied whether serum UA levels and the genetic variants related to its variability are associated with the presence of dementia in a cohort of patients with PD.

Methods: The study included 343 PD patients, which were examined for the presence of dementia according to the MDS Task Force criteria (level 1).

Leptomeningeal carcinomatosis as only pathological finding at FDG-PET/CT in case of tumor marker elevation in breast cancer.

Leptomeningeal carcinomatosis is an infrequent disease and although its treatment is palliative, earlier diagnosis will lead to prolonged survival and improve functional outcome. Whole-body FDG-PET allows the entire spinal cord to be examined noninvasively, so close attention should be paid to the spinal canal, since these lesions can easily be mistaken for physiologic uptake, sometimes there is no clinical suspicion and may occur without concurrent active cancer. We present a female patient with a history of carcinoma of the breast, who presented an elevation of serum tumor marker CA 15-3.