Risk factors for hospitalisation in Welsh infants with a congenital anomaly.

OBJECTIVES: To investigate risk factor associated with hospitalisation of infants with a congenital anomaly in Wales, UK. DESIGN: A population-based cohort study. SETTING: Data from the Welsh Congenital Anomaly Register and Information Service linked to the Patient Episode Database for Wales and livebirths and deaths from the Office for National Statistics. PATIENTS: All livebirths between 1999 and 2015 with a diagnosis of a congenital anomaly, which was defined as a structural, metabolic, endocrine or genetic defect, as well as rare diseases of hereditary origin. MAIN OUTCOME MEASURES: Adjusted OR (aOR) associated with 1 or 2+ hospital admissions in infancy versus no admissions were estimated for sociodemographic, maternal and infant factors using multinomial logistic regression for the subgroups of all, isolated, multiple and cardiovascular anomalies. RESULTS: 25 523 infants affected by congenital anomalies experienced a total of 50 705 admissions in infancy. Risk factors for ≥2 admissions were younger maternal age ≤24 years (aOR: 1.17; 95% CI 1.06 to 1.30), maternal smoking (aOR: 1.20; 1.10 to 1.31), preterm birth (aOR: 2.52; 2.25 to 2.83) and moderately severe congenital heart defects (aOR: 6.25; 4.47 to 8.74). Girls had an overall decreased risk of 2+ admissions (aOR: 0.84; 0.78 to 0.91). Preterm birth was a significant risk factor for admissions in all anomaly subgroups but the effect of the other characteristics varied according to anomaly subgroup. CONCLUSIONS: Over two-thirds of infants with an anomaly are admitted to hospital during infancy. Our findings identified sociodemographic and clinical characteristics contributing to an increased risk of hospitalisation of infants with congenital anomalies.

Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.

Prostate cancer and antidepressants: A nationwide population-based nested case-control study.

BACKGROUND: We aimed to evaluate the association between antidepressant and prostate cancer by comparing exposures to antidepressants between those with and without prostate cancer. METHODS: A nationwide insurance claims database was used to identify our case subjects. Age- and gender-matched controls were selected at a 1:5 ratio. Conditional logistic regression model was used. RESULTS: 11,515 patients with prostate cancer were identified and matched with 55,373 controls. No increased associations between prostate cancer and most classes of antidepressants were found. However, a positive association with adjusted odds ratios ranged from 1.20 to 1.35 was noted in different doses of imipramine. Nevertheless, this association became statistically insignificant at higher cumulative doses. CONCLUSIONS: Our results indicate that there is no association between mechanistically dissimilar antidepressants and increased hazard for prostate cancer.

Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.

BACKGROUND: Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2. METHODS: We did an open-label, multicentre, dose-escalation, phase 1 study using a 3 + 3 design with planned cohort expansion at the two highest doses below the maximally tolerated dose. The study was done at two centres in France: Institut Gustave Roussy (Villejuif, Val de Marne) and Institut Bergonié (Bordeaux, Gironde). Eligible patients had relapsed or refractory B-cell non-Hodgkin lymphoma or an advanced solid tumour and were older than 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Tazemetostat was administered orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles. The primary endpoint was to establish the maximum tolerated dose or recommended phase 2 dose of tazemetostat, as determined by dose-limiting toxicities, laboratory values, and other safety or pharmacokinetic measures in cycle one according to local investigator assessment. Safety was assessed in patients who received at least one dose of tazemetostat; antitumour activity was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01897571. The phase 1 part of the study is complete, and phase 2 is ongoing. FINDINGS: Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 [33%] of 64 treatment-related events), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and vomiting (six [9%]), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. INTERPRETATION: Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours. FUNDING: Epizyme and Eisai.

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models.

The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. Mol Cancer Ther; 16(5); 850-60. ©2017 AACR.

Increased Intestinal Permeability in Relatives of Patients With Crohn's Disease Is Not Associated With Small Bowel Ulcerations.

BACKGROUND & AIMS: Many first-degree relatives of patients with Crohn's disease (CD) have increased intestinal permeability. Video capsule endoscopy (VCE) is the most sensitive imaging test to identify small bowel mucosal lesions that could indicate subclinical CD. We aimed to estimate the association of increased intestinal permeability with small bowel ulcerations detectable by VCE in healthy first-degree relatives of patients with CD. METHODS: We conducted a cross-sectional study of 223 healthy, asymptomatic first-degree relatives of patients with CD (parents, siblings, and children; 9-45 years old) enrolled at the University of Alberta between 2009 and 2012. Patients were given the lactulose and mannitol test to measure small bowel permeability; we used high-performance liquid chromatography to measure concentrations of lactulose and mannitol in urine samples (increased permeability defined as a ratio of lactulose/mannitol 0.025 or greater). Patients with increased permeability (n = 39) and randomly selected subjects with normal permeability (n = 59) were then examined by VCE for signs of small bowel inflammation and subclinical CD. The prevalence of small bowel lesions was compared among groups. We performed logistic regression analyses to estimate odds ratios for the association of small bowel ulcerations with intestinal permeability. RESULTS: Among 223 first-degree relatives of patients with CD, 30% were found to have increased intestinal permeability; VCE examination found 24% of subjects to have 3 or more small bowel ulcers. Three or more small bowel ulcers were detected in 28% of patients with increased intestinal permeability and 20% of patients with normal intestinal permeability (P = .37). The adjusted odds ratio for the association of 3 or more small bowel ulcers with increased intestinal permeability was 1.5 (95% confidence interval, 0.6-3.8; P = .46). CONCLUSIONS: Thirty percent of healthy, asymptomatic first-degree relatives of patients with CD have increased intestinal permeability. However, a strong association of small bowel ulceration seen on VCE with increased intestinal permeability was not observed.

A proposal: a comprehensive platform to characterize tumors in Chinese and improve success in cancer drug discovery and development.

Cancer is a collection of complex diseases in which cell proliferation and apoptosis are dysregulated due to the acquisition of genetic changes in cancer cells. These genetic changes, combined with the interrelated physiologic adaptations of neo-angiogenesis, recruitment of stromal support tissues, and suppression of immune recognition, are measurable characteristics in tumor gene expression profiles and biochemical pathways. These measures can lead to identification of disease drivers and, ultimately, can be used to assign therapy. With advances in RNA sequencing technologies, the ability to simultaneously measure all genetic and gene expression changes with a single technology is now possible. The ability to create a comprehensive catalog of genotypic and phenotypic changes in a collection of histologically similar but otherwise distinct tumors should allow for a more precise positioning of existing targeted therapies and identification of new targets for intervention.

A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors.

PURPOSE: To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic profile of ispinesib when administered as a 1-h intravenous infusion weekly for three consecutive weeks of a 28 day treatment period to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Thirty patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase at doses ranging from 1-8 mg/m(2)/week. Pharmacokinetic samples, skin punch biopsies, and tumor biopsies (in patients with accessible tumor) were obtained during cycle 1 of treatment. Disease assessment was performed every two treatment cycles. RESULTS: The MTD was defined as 7 mg/m(2) administered as a 1-h infusion weekly for three consecutive weeks of a 28 day schedule. The MTD was exceeded at 8 mg/m(2) due to DLTs of grade 2 (one patient) and grade 3 neutropenia (one patient) that resulted in the inability to administer the Day 15 dose in Cycle 1. The neutrophil nadir occurred at approximately Day 8 with a 3-7 day recovery period. The most common toxicities were nausea, diarrhea, fatigue, and neutropenia. Alopecia, mucositis, and neuropathy were not observed. Stable disease was reported as the best response to treatment in nine patients. CONCLUSION: The recommended dose of ispinesib is 7 mg/m(2) over 1 h weekly for three consecutive weeks of a 28 day treatment cycle.

A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma. METHODS: Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8 mg/m(2). The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48 h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6 weeks. RESULTS: The most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21 days was established as 4 mg/m(2). The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11 months and 6 patients had stable disease for over four cycles. CONCLUSIONS: The recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3 weeks is 4 mg/m(2). The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.

Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer.

PURPOSE: The combination of lapatinib and trastuzumab has been observed to have a synergistic, antiproliferative effect against ErbB2-positive breast cancer cells in vitro. This phase I study assessed the safety, clinical feasibility, optimally tolerated regimen (OTR), pharmacokinetics (PK), and preliminary clinical activity of this combination in patients with ErbB2-positive advanced breast cancer. PATIENTS AND METHODS: Cohorts of three patients with ErbB2-positive advanced breast cancer were treated with escalating doses of lapatinib (750 to 1,500 mg) administered once daily (continuous) in combination with trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) to determine the OTR. Once the OTR was determined, additional patients were enrolled to provide the PK profile of both agents alone and in combination. RESULTS: A total of 54 patients were treated: 27 in the dose-escalation group and 27 in the PK group. Overall, adverse events were mild to moderate in severity, with no drug-related grade 4 events. The most frequent drug-related grade 3 events included diarrhea (17%), fatigue (11%), and rash (6%). The OTR was 1,000 mg lapatinib with standard weekly trastuzumab. One patient had a complete response and seven patients had partial responses. The PK parameters (maximum concentration in plasma and area under the curve) of lapatinib and trastuzumab in combination were not significantly different than when either was administered alone. CONCLUSION: The OTR of the lapatinib/trastuzumab combination was lapatinib 1,000 mg per day with standard weekly trastuzumab. At these doses, the regimen was well tolerated and clinically active in this heavily pretreated ErbB2-positive breast cancer population.

Phase I and pharmacokinetic study of lapatinib in combination with capecitabine in patients with advanced solid malignancies.

PURPOSE: This phase I trial (EGF10005) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. RESULTS: Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m(2)/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and alpha-fluoro-beta-alanine, were not meaningfully altered by coadministration. CONCLUSION: Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.

Does the chorda tympani nerve confer general sensation from the tongue?

OBJECTIVE: Patients often complain of numbness of the tongue after otologic procedures; this symptom may occur with or without taste alterations. The purpose of this study was to objectively assess possible changes in the general sensation of the tongue in patients undergoing middle ear surgery. STUDY DESIGN AND SETTING: Thirty-three individuals were included in this prospective controlled clinical study conducted at a tertiary referral center. Fifteen patients underwent middle ear surgery and 18 volunteers served as a control group. Subjects underwent objective tests to assess general sensation of the tongue before and twice after surgery. RESULTS: Forty-seven percent of the patients complained of numbness or tingling of the tongue shortly after surgery. In these patients, a significant reduction in sensitivities to light touch and 2-point discrimination on the operated side were noted at that time (P < 0.01; P < 0.009 respectively). Values returned to baseline on subsequent evaluations. No sensitivity change was noted for the contralateral hemi-tongue. CONCLUSION: Objective changes in the general sensory function of the tongue correlated with post-operative clinical symptoms experienced by patients. The results of this study support the notion that the chorda tympani nerve confers general sensation from the tongue. EBM RATING: A-1b.

A recombinant antibody increases cardiac contractility by mimicking phospholamban phosphorylation.

Many cardiovascular disease states end in progressive heart failure. Changes in intracellular calcium handling, including a reduced activity of the sarcoplasmic reticulum calcium pump (SERCA), contribute to this contractile dysfunction. As the regulatory protein phospholamban can inhibit the calcium pump, we evaluated it as a potential target to improve cardiac function. In this study, we describe a recombinant antibody-based protein (PLN-Ab) that binds to the cytoplasmic domain of phospholamban. Fluorescence resonance energy transfer (FRET) studies suggest that PLN-Ab mimics the effects of phospholamban phosphorylation. PLN-Ab accelerated the decay of the calcium transient when expressed in neonatal rat and adult mouse ventricular cardiac myocytes. In addition, direct injection of adenovirus encoding PLN-Ab into the diabetic mouse heart enhanced contractility when measured in vivo by echocardiography and in ex vivo Langendorff perfused hearts. The PLN-Ab provides a novel therapeutic approach to improving contractility through in vivo expression of an antibody inside cardiac myocytes.

Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016.

The expression of the NH2 terminally truncated ErbB2 receptor (p95ErbB2) in breast cancer correlates with metastatic disease progression compared with the expression of full-length p185ErbB2. We now show that heregulin (HRG), but not EGF, stimulates p95ErbB2 phosphorylation in BT474 breast cancer cells. Furthermore, phospho-p95ErbB2 forms heterodimers with ErbB3, but not EGFR, while p185ErbB2 heterodimerizes with both EGFR and ErbB3. The predilection of p95ErbB2 to heterodimerize with ErbB3 provides an explanation for its regulation by HRG, an ErbB3 ligand. GW572016, a reversible small molecule inhibitor of EGFR and ErbB2 tyrosine kinases, inhibits baseline p95ErbB2 phosphorylation in BT474 cells and tumor xenografts. Inhibition of p95ErbB2, p185ErbB2, and EGFR phosphorylation by GW572016 resulted in the inhibition of downstream phospho-Erk1/2, phospho-AKT, and cyclin D steady-state protein levels. Increased phosphorylation of p95ErbB2 and AKT in response to HRG was abrogated to varying degrees by GW572016. In contrast, trastuzumab did not inhibit p95ErbB2 phosphorylation or the expression of downstream phospho-Erk1/2, phospho-AKT, or cyclin D. It is tempting to speculate that trastuzumab resistance may be mediated in part by the selection of p95ErbB2-expressing breast cancer cells capable of exerting potent growth and prosurvival signals through p95ErbB2-ErbB3 heterodimers. Thus, p95ErbB2 represents a target for therapeutic intervention, and one that is sensitive to GW572016 therapy.

The MKK6-p38 MAPK pathway prolongs the cardiac contractile calcium transient, downregulates SERCA2, and activates NF-AT.

OBJECTIVE: Our goal was to determine if the MKK6-p38 MAPK pathway regulates cardiac intracellular calcium ([Ca(2+)](i)). We also tested if MKK6 might influence expression of SERCA2, a calcium regulatory molecule involved in relaxation, and the activity of nuclear factor of activated T-cells (NF-AT), a calcium-regulated transcription factor that participates in pathological responses to pressure-overload. METHODS: Neonatal rat ventricular myocytes were transfected with MKK6(Glu), an activator of p38 MAPK. Green fluorescent protein (GFP) was used as transfection marker and [Ca(2+)](i) was evaluated via indo-1. SERCA2 expression was assayed via Northern and Western techniques. The activity of the rat SERCA2 gene promoter and NF-AT-dependent gene expression were monitored with reporter genes. Myocyte contractility was regulated by electrical pacing. RESULTS: MKK6(Glu) prolonged decay of the contractile calcium transients, downregulated SERCA2 expression, and reduced the activity of the rat SERCA2 gene promoter. Diastolic [Ca(2+)](i) in myocytes pacing at 1-2 Hz was dramatically increased by MKK6(Glu). NF-AT-dependent gene expression was activated by MKK6(Glu) and by pacing of contractions in a synergistic manner. Overexpression of SERCA2 mitigated the effects of MKK6(Glu) on [Ca(2+)](i) and NF-AT. CONCLUSIONS: The MKK6(Glu)-p38 MAPK pathway prolongs the decay phase of the cardiac contractile calcium by downregulating SERCA2, increasing diastolic [Ca(2+)](i) which activates NF-AT. The ability of SERCA2 over-expression to reduce NF-AT activity represents a potential novel therapeutic effect of SERCA2 that should be further considered in the development of cardiac gene therapy strategies.

Regulatory approvals of pediatric oncology drugs: previous experience and new initiatives.

PURPOSE: To review the Food and Drug Administration (FDA) experience with approvals of new drugs for pediatric oncology and to discuss new regulatory initiatives directed at pediatric oncology. METHODS: A retrospective review of FDA archival documents and the published literature. RESULTS: More than 100 drugs have been approved by the Division of Oncology Drug Products of the FDA for the treatment of malignancies. Only 15 have pediatric use information in their labeling, which is less than 50% of the drugs commonly used in the treatment of pediatric malignancies. In the past 20 years, there have been six submissions to the FDA for pediatric oncology indications. To illustrate principles of the approval process, each submission is discussed. CONCLUSION: Potential reasons for a lack of New Drug Application submissions for pediatric oncology include the small pediatric oncology market compared with the adult oncology market and perceived barriers to performing studies in children. Reasons for failure to approve pediatric indications include small numbers of patients, lack of appropriate controls, and failure to demonstrate patient benefit. Approval criteria include the use of controlled trials, prospective data collection, and disease-appropriate end points. Regulatory initiatives to promote pediatric therapeutic development and product labeling are discussed.

Phase I study of perillyl alcohol in patients with refractory malignancies.

We treated 21 patients in a dose-finding and pharmacokinetic study of the monoterpene perillyl alcohol with the drug given orally in 3 divided doses on a chronic basis. The average number of days that patients remained on study was 48 (range 11-172). Fatigue and low-grade nausea were dose limiting. Using this schedule, a starting dose of 1.6 g/m2 with escalation to 2.1 g/m2 as tolerated is recommended. Two major metabolites were detectable and the mean peak plasma concentrations were 383 microM for perillic acid and 27 microM for dihydroperillic acid. The peak plasma concentration and the metabolite half-life were 2 h and 1 h post ingestion for perillic acid, and 4 h and 2.4 h for dihydroperillic acid, respectively. Stabilization of disease was observed in one of the 16 patients evaluable for response. Many of the gastrointestinal side effects that were poorly tolerated on a chronic basis may be partly related to the soybean oil base used in the current formulation. Further development of perillyl alcohol on this schedule would be facilitated by reformulation of the capsule.