The time to onset and overall analgesic efficacy of rofecoxib 50 mg: a meta-analysis of 13 randomized clinical trials

OBJECTIVE: To determine the time to onset of analgesia of rofecoxib based on a patient-level meta-analysis of randomized, placebo-controlled, postoperative oral surgery pain studies. METHODS: A search on MEDLINE and of Merck data on file was conducted to identify studies that met the inclusion criteria. Meta-analysis inclusion criteria required that patients were treated with a single oral dose of rofecoxib 50 mg when they experienced moderate or severe pain after surgical extraction of > or = 2 third molars; study design involved patient randomization, double-blinding, and matching placebo, and onset data from individual patients were available. The meta-analysis of time to onset also required that studies used the two-stopwatch method. Eleven studies fulfilled the onset criteria and included patients who received a single dose of rofecoxib 50 mg (N = 1220) or placebo (N = 483). These studies were analyzed to determine time to onset of analgesia, time to perceptible pain relief, percentage of patients achieving onset of analgesia, and duration of analgesia. Six of the 11 studies included a nonselective nonsteroidal anti-inflammatory drug (N = 303) and were included in the onset meta-analysis for comparison. The meta-analysis of overall efficacy also required that data on total pain relief scores over 8 hours were available. Over-all effectiveness of analgesia was based on analysis of 13 studies involving 1330 rofecoxib patients and 570 placebo patients on the endpoints of total pain relief scores over 8 hours and patient global assessment of response to therapy at 24 hours. Eight of the 13 studies with a nonselective nonsteroidal anti-inflammatory drug comparator (N = 391) were included for the efficacy meta-analysis. RESULTS: Patient demographics and baseline characteristics were similar across treatment groups in each study. Median time to onset of analgesia for rofecoxib was 34 minutes (95% CI, 31-38 minutes), significantly faster than placebo, which did not achieve onset within the 4 hours the assessment was conducted (P < 0.001). Duration of analgesia for rofecoxib 50 mg was > 24 hours. Rofecoxib achieved a greater mean total pain relief score over 8 hours than placebo (17.4 versus 4.4; P < 0.001) and a greater patient response rate on patient global assessment of response to therapy at 24 hours than placebo (73% versus 16%; P < 0.001). Outcomes were similar between the rofecoxib group and the nonselective nonsteroidal anti-inflammatory drug group. CONCLUSION: In this meta-analysis of over 1200 rofecoxib-treated patients, a single dose of rofecoxib 50 mg demonstrated a rapid onset of analgesia in approximately half an hour combined with sustained effectiveness, supporting its use as a treatment of acute pain.     

Preoperative MRI of the Breast (POMB) Influences Primary Treatment in Breast Cancer: A Prospective,Randomized, Multicenter Study

Background

Breast magnetic resonance imaging (MRI) has shown high sensitivity in determining tumor extent, multifocality, and occult contralateral breast cancer. Low specificity, unnecessary mastectomies, and costs are arguments against MRI. The purpose of this study was to determine whether preoperative breast MRI would affect primary surgical management, reduce reexcision/reoperation procedures, and influence the choice of neoadjuvant treatment in patients with newly diagnosed breast cancer.

Methods

This prospective, randomized, multicenter study included 440 breast cancer patients younger than aged 56 years from three, Swedish, large-volume breast units. Patients were randomly allocated on a 1:1 basis to either preoperative staging with breast MRI (n = 220) or no breast MRI (n = 220) (control group). Treatment planning of all patients was discussed at multidisciplinary team conferences.

Results

In patients randomized to the MRI group, who had an observed higher percentage of planned breast-conserving surgery (BCS) compared with the control group, a change from suggested breast conservation to mastectomy occurred in 23 of 153 (15 %) patients. Breast MRI provided additional information in 83 of 220 (38 %) patients, which caused a change in treatment plan in 40 (18 %). The breast reoperation rate was significantly lower in the MRI group: 11 of 220 (5 %) versus 33 of 220 (15 %) in the control group (p < 0.001). The number of mastectomies, axillary reoperations, and the number of patients receiving neoadjuvant chemotherapy after definitive treatment did not differ significantly between the groups.

Conclusions

Preoperative staging with breast MRI in women younger than age 56 years altered the treatment plan in 18 % of the patients. Although a higher MRI-related conversion rate from breast conservation to mastectomy was found, the final numbers of mastectomies did not differ between the two groups. The breast reoperation rate in the MRI group was significantly reduced.     

Surgical strategy for primary hyperparathyreoidism with thyroid hemiagenesis

Background

Thyroid hemiagenesis is a rare congenital anomaly, and still more rarely associated with primary hyperparathyroidism (pHPT). Due to the embryologic pathways of the thyroid and parathyroid glands, it remains unclear whether or not thyroid hemiagenesis may be linked to ipsilateral parathyroid agenesis, and consequently, surgical strategy for thyroid hemiagenesis associated pHPT (THAP) does not only depend on preoperative localization but also on the thyroid anomaly.

Methods

Including the present case report, a total of nine cases with THAP retrieved from the literature were reviewed. Seven of nine cases had thyroid hemiagenesis on the left side, three out of nine showed a parathyroid adenoma on the contralateral side to the thyroid hemiagenesis.

Conclusions

Based on these cases, it can be concluded that the embryologic pathways of the thyroid and parathyroid glands are different, and in cases of THAP, parathyroid exploration should follow standard recommendations for pHPT surgery.     

Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis.

BACKGROUND: The objective of the present study was to elucidate possible relationships between four polymorphisms of the TGF-beta1 gene (-800G>A; -509C>T; Leu10Pro; Arg25Pro) and stage, histological activity grade and progression rate of liver fibrosis, classified according to the METAVIR-score. METHODS: Three study groups, i.e. 48 patients with hepatic fibrosis (26 with known duration of hepatitis C virus infection), 47 patients with non-fibrotic diseases and 50 healthy blood donors, were analyzed for TGF-beta1 polymorphisms using ARMS-PCR and sequence analysis. The concentrations of total TGF-beta1 in plasma and of hyaluronan, P-III-NP and activities of transminases in serum were measured. RESULTS: The presence of proline at codons 10 and/or 25 was associated with a faster progression of fibrosis than other polymorphisms. Patients with the genotype (25)ArgPro developed fibrosis significantly faster (0.23 units/year) than those having (25)ArgArg (0.08 units/year). Similarly, the fibrosis progression rate of patients with genotypes (10)LeuPro and (10)ProPro was almost three times as fast as of those having genotype (10)LeuLeu. Stage and histological activity grade of fibrosis in (25)ArgPro in comparison to (25)ArgArg were higher. Also (10)LeuPro showed a higher average stage of fibrosis than (10)LeuLeu. The TGF-beta1 plasma concentrations of patients with hepatic fibrosis were not significantly different between carriers of (25)ArgArg and (25)ArgPro genotypes. The frequency of the genotype (25)ArgPro in liver fibrotic patients was about three times that of the control group whereas the frequency distribution of the genotype (25)ArgArg tended to lower frequency in the fibrosis group. TGF-beta1-promoter polymorphisms did not show any correlation with stage, grade or progression of liver fibrosis. CONCLUSION: Our results indicate that the heterozygous ArgPro of codon 25 predicts significantly faster fibrotic progression of chronic hepatitis C than the homozygous (25)ArgArg genotype. The homozygous LeuLeu genotype of codon 10 showed a slow progression of fibrosis.     

Novel DCC variants in congenital mirror movements and evaluation of disease-associated missense variants

Congenital mirror movements (CMM) are involuntary movements of one side of the body that mirror intentional movements of the other side. Heterozygous missense, frameshift and nonsense variants and small intragenic deletions in DCC cause CMM, isolated agenesis of the corpus callosum (ACC) or both. We report here the clinical phenotype and natural history of ten individuals with CMM carrying five different monoallelic DCC variants, including the missense variant p.(Trp273Arg), two duplications, one deletion and one deletion-insertion; all are novel and absent from databases. We re-evaluated the 15 known disease-associated DCC missense variants by determining minor allele frequency (MAF) and pathogenicity using four in silico tools combining previous pathogenicity scores and the ACMG/AMP standards and guidelines and classified them in three groups. Group I contains three DCC missense variants that are rather unlikely to be associated with a higher risk to CMM and/or ACC. The five variants in group II may represent susceptibility factors to altered midline crossing in the central nervous system. Group III includes seven variants absent in publically available databases and representing possible pathogenic alleles, with four predicted to have a severe impact on protein function. Based on this data and the variable expressivity and incomplete penetrance present in heterozygous carriers of a DCC variant, classification and clinical interpretation of missense variants is challenging in the absence of evidence of pathogenicity originated from functional studies. Evaluation of missense variants by MAF and a weighted combination of several computational algorithms is recommended.     

An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking

Microvillus inclusion disease (MVID) is a rare intestinal enteropathy with an onset within a few days to months after birth, resulting in persistent watery diarrhea. Mutations in the myosin Vb gene (MYO5B) have been identified in the majority of MVID patients. However, the exact pathophysiology of MVID still remains unclear. To address the specific role of MYO5B in the intestine, we generated an intestine-specific conditional Myo5b-deficient (Myo5b^fl/fl;Vil-CreERT2) mouse model. We analyzed intestinal tissues and cultured organoids of Myo5b^fl/fl;Vil-CreERT2 mice by electron microscopy, immunofluorescence, and immunohistochemistry. Our data showed that Myo5b^fl/fl;Vil-CreERT2 mice developed severe diarrhea within 4 d after tamoxifen induction. Periodic Acid Schiff and alkaline phosphatase staining revealed subapical accumulation of intracellular vesicles in villus enterocytes. Analysis by electron microscopy confirmed an almost complete absence of apical microvilli, the appearance of microvillus inclusions, and enlarged intercellular spaces in induced Myo5b^fl/fl;Vil-CreERT2 intestines. In addition, we determined that MYO5B is involved not only in apical but also basolateral trafficking of proteins. The analysis of the intestine during the early onset of the disease revealed that subapical accumulation of secretory granules precedes occurrence of microvillus inclusions, indicating involvement of MYO5B in early differentiation of epithelial cells. By comparing our data with a novel MVID patient, we conclude that our mouse model completely recapitulates the intestinal phenotype of human MVID. This includes severe diarrhea, loss of microvilli, occurrence of microvillus inclusions, and subapical secretory granules. Thus, loss of MYO5B disturbs both apical and basolateral trafficking of proteins and causes MVID in mice.Microvillus inclusion disease (MVID) is a rare intestinal enteropathy with autosomal recessive inheritance, which was first described in 1978 (1). MVID patients cannot take up any nutrients and are often completely dependent on parenteral nutrition. The disease is characterized by villus atrophy, (partial) loss of microvilli on the apical plasma membrane of intestinal epithelial cells, and accumulation of intracellular vesicles/vacuoles, containing apical proteins and microvilli (2, 3). In addition, some studies also show mislocalization of apical and basolateral proteins, occasional crypt hyperplasia, and villus fusion (4–6).In the great majority of patients, MVID is caused by mutations in MYO5B, encoding the motorprotein, myosin Vb (5). In two patients, mutations in syntaxin 3 (STX3) caused a variant form of MVID (7). More than 41 unique mutations along the different regions in MYO5B have been identified in MVID patients, including deletions and nonsense, missense, and splice-site mutations (8–10). MYO5B is coding for the actin-based myosin 5b motor protein, which regulates apical membrane trafficking (5, 11). MYO5B functions as a homodimer and has three functional domains: an N-terminal motor domain, a calmodulin-binding domain, and a C-terminal tail, which binds cargo through association with the small GTPases RAB8A and/or RAB11A (12, 13). Altered expression of myosin Vb affects the apical membrane trafficking mechanism in epithelial cells, causing mislocalization of apical brush border proteins, such as villin (vil), CD10, or alkaline phosphatase (ALP) in the cytoplasm of duodenal enterocytes (2, 3, 5), and an increased apical localization of transferrin receptor (5, 14).Although mouse models mimicking certain features of MVID have previously been described, such as Rab8 (15), Cdc42 (16, 17), and Rab11a knockout (KO) mice (18, 19), no mutations in the coding regions of those genes have been reported in human MVID patients. Current in vitro models to study apical trafficking and polarization-associated diseases such as MVID are the parental Caco2 cell line, Caco-BBE, and LS174 W4 cells, in which polarization can be induced in vitro (4, 8, 12, 20). Although valuable knowledge about the function of MYO5B in polarization was gained in these models, the direct relevance of the colon cancer cell lines for the disease is questionable, and diverging results have been obtained with knockdown of MYO5B in the parental Caco2 cells compared with the more polarized Caco-BBE cells (8, 12, 20). As such, we here present an inducible MVID mouse model that recapitulates the genetic defects in man, which allows analysis of the role of MYO5B in a physiological setting and the sequence of events in MVID pathophysiology.     

Systematic identification and stratification of help-seeking school-aged youth with mental health problems: a novel approach to stage-based stepped-care

We investigated whether a novel visitation model for school-aged youth with mental health problems based on a stage-based stepped-care approach facilitated a systematic identification and stratification process without problems with equity in access. The visitation model was developed within the context of evaluating a new transdiagnostic early treatment for youth with anxiety, depressive symptoms, and/or behavioural problems. The model aimed to identify youth with mental health problems requiring an intervention, and to stratify the youth into three groups with increasing severity of problems. This was accomplished using a two-phase stratification process involving a web-based assessment and a semi-structured psychopathological interview of the youth and parents. To assess problems with inequity in access, individual-level socioeconomic data were obtained from national registers with data on both the youth participating in the visitation and the background population. Altogether, 573 youth and their parents took part in the visitation process. Seventy-five (13%) youth had mental health problems below the intervention threshold, 396 (69%) were deemed eligible for the early treatment, and 52 (9%) had symptoms of severe mental health problems. Fifty (9%) youth were excluded for other reasons. Eighty percent of the 396 youth eligible for early treatment fulfilled criteria of a mental disorder. The severity of mental health problems highlights the urgent need for a systematic approach. Potential problems in reaching youth of less resourceful parents, and older youth were identified. These findings can help ensure that actions are taken to avoid equity problems in future mental health care implementations.