Long-term survival in laparoscopic vs open resection for colorectal liver metastases: inverse probability of treatment weighting using propensity scores

Background

This study compares long-term outcomes between intention-to-treat laparoscopic and open approaches to colorectal liver metastases (CLM), using inverse probability of treatment weighting (IPTW) based on propensity scores to control for selection bias.

Method

Patients undergoing liver resection for CLM by 5 surgeons at 3 institutions from 2000 to early 2014 were analysed. IPTW based on propensity scores were generated and used to assess the marginal treatment effect of the laparoscopic approach via a weighted Cox proportional hazards model.

Results

A total of 298 operations were performed in 256 patients. 7 patients with planned two-stage resections were excluded leaving 284 operations in 249 patients for analysis. After IPTW, the population was well balanced. With a median follow up of 36 months, 5-year overall survival (OS) and recurrence-free survival (RFS) for the cohort were 59% and 38%. 146 laparoscopic procedures were performed in 140 patients, with weighted 5-year OS and RFS of 54% and 36% respectively. In the open group, 138 procedures were performed in 122 patients, with a weighted 5-year OS and RFS of 63% and 38% respectively. There was no significant difference between the two groups in terms of OS or RFS.

Conclusion

In the Brisbane experience, after accounting for bias in treatment assignment, long term survival after LLR for CLM is equivalent to outcomes in open surgery.     

Novel FREM1 mutations expand the phenotypic spectrum associated with manitoba‐oculo‐tricho‐anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome

Loss of function mutations in FREM1 have been demonstrated in Manitoba‐oculo‐tricho‐anal (MOTA) syndrome and Bifid Nose Renal Agenesis and Anorectal malformations (BNAR) syndrome, but the wider phenotypic spectrum that is associated with FREM1 mutations remains to be defined. We screened three probands with phenotypic features of MOTA syndrome. In one severely affected infant who was diagnosed with MOTA syndrome because of bilateral eyelid colobomas, a bifid nasal tip, hydrometrocolpos and vaginal atresia, we found two nonsense mutations that likely result in complete loss of FREM1 function. This infant also had renal dysplasia, a finding more consistent with BNAR syndrome. Another male who was homozygous for a novel stop mutation had an extensive eyelid colobomas, corneopalpebral synechiae, and unilateral renal agenesis. A third male child diagnosed with MOTA syndrome because of corneopalpebral synechiae and eyelid colobomas had a homozygous splice site mutation in FREM1. These cases illustrate that disruption of the FREM1 gene can produce a spectrum of clinical manifestations encompassing the previously described MOTA and BNAR syndromes, and that features of both syndromes may be seen in the same individual. The phenotype of FREM1‐related disorders is thus more pleiotropic than for MOTA and BNAR syndrome alone and more closely resembles the widespread clinical involvement seen with Fraser syndrome. Moreover, our first case demonstrates that vaginal atresia may be a feature of FREM1‐related disorders. © 2013 Wiley Periodicals, Inc.     

Long-term outcome of children treated with rituximab for idiopathic nephrotic syndrome

Background

Rituximab (RTX) has recently showed promising results in the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS).

Methods

This was a retrospective multicenter study of 18 children treated with RTX for SDNS, with a mean follow-up of 3.2 years. RTX was introduced because of side effects or relapses during therapy with immunosuppressive agents. The children received one to four infusions of RTX during the first course of treatment, and subsequent infusions were given due to CD19-cell recovery (CD19?>1 %; 54 % of children) or relapse (41 %), as well as systematically (5 %).

Results

Treatment with RTX maintained sustained remission without relapse in 22 % of patients and increased the duration of remission in all other patients. The time between two successive relapses was 9 months in the absence of re-treatment and 24.5 months when infusions were performed at the time of CD19-cell recovery. At the last follow-up, 44.5 % of patients were free of oral drug therapy. Of those still receiving oral drugs, all doses had been decreased. No serious adverse events occurred.

Conclusion

The results of this retrospective study confirm the efficacy and very good safety of RTX in the treatment of SDNS. The optimal therapeutic protocol seems to be a repeated single infusion at the time of CD19-cell recovery.     

Guidelines for safe transfer of the brain-injured patient: trauma and stroke, 2019

The location of care for many brain-injured patients has changed since 2012 following the development of major trauma centres. Advances in management of ischaemic stroke have led to the urgent transfer of many more patients. The basis of care has remained largely unchanged, however, with emphasis on maintaining adequate cerebral perfusion as the key to preventing secondary injury. Organisational aspects and training for transfers are highlighted, and we have included an expanded section on paediatric transfers. We have also provided a table with suggested blood pressure parameters for the common types of brain injury but acknowledge that there is little evidence for many of our recommendations. These guidelines remain a mix of evidence-based and consensus-based statements. We have received assistance from many organisations representing clinicians who care for these patients, and we believe our views represent the best of current thinking and opinion. We encourage departments to review their own practice using our suggestions for audit and quality improvement.     

Differential effects of the 3',5'-cyclic adenosine monophosphate and protein kinase C pathways on the response of isolated rat osteoclasts to calcitonin.

Calcitonin (CT) activates both the cAMP and the protein kinase C (PKC) pathways in the kidney cell line LLC-PK1. Although CT also activates cAMP in osteoclasts, its effects on PKC in this cell type are unknown. In order to determine whether the response of osteoclasts to CT also involves the PKC pathway, the effects of activators and inhibitors of PKC on bone resorption and cell surface area were analyzed in isolated rat osteoclasts. As expected, CT inhibited in a dose-dependent manner bone resorption by rat osteoclasts cultured for 24 h on devitalized bovine bone slices and this effect could be mimicked by cAMP. The inhibitory effect of CT could however also be mimicked by phorbol-12,13-dibutyrate (PDBu) and blocked by the PKC inhibitor sphingosine, as well as by the less specific inhibitors H7 and H8, none of which had detectable effects in the absence of CT. No changes in the number of attached osteoclasts were observed under any of these conditions. These results indicate that CT activates PKC in osteoclasts and that this activation, like the activation of cAMP-dependent protein kinase, leads to an inhibition of bone resorption. Quantitative time-lapse videomicroscopy showed that the CT-induced retraction of osteoclasts also involved activation of the PKC pathway and could therefore be induced by phorbol esters. In contrast, (Bu)2 cAMP (1-200 microM) failed to induce rapid cell retraction. It is concluded that, in osteoclasts, CT receptors are coupled to both the cAMP-dependent protein kinase and the PKC pathways. Although these two second messengers can have additive inhibitory effects on bone resorption, only activation of the PKC pathway induces rapid cell retraction. These two effects of calcitonin on osteoclasts are therefore independent and may be functionally unrelated.     

Decreased physiological sensitivity mediated by newly synthesized muscarinic acetylcholine receptors in embryonic chicken heart.

Treatment of chicken embryos in ovo for 8 hr with the muscarinic agonist carbachol results in an 85% reduction in the number of muscarinic acetylcholine receptors ( mAcChoR ) present in atrial membrane homogenates. Subsequent treatment of embryos with the muscarinic antagonist atropine results in a gradual increase in mAcChoR number, which returns to control levels after 14 hr. This recovery of receptor number is blocked by administration of the protein synthesis inhibitor cycloheximide, consistent with previous results in cell culture, which suggested that de novo protein synthesis is required for the recovery of mAcChoR after agonist-induced decreases. Measurements of the negative chronotropic response to applied carbachol with isolated atria show that even after recovery of receptor number to control levels the response to agonist is diminished. The IC50 for carbachol is shifted approximately equal to 10-fold from controls at 20 hr after atropine treatment, but less than 3-fold at 28 hr, with no further change in receptor number occurring over this time. This increase in physiological sensitivity is not blocked by cycloheximide. Receptors at 20 hr have binding constants for agonists and antagonists that are indistinguishable from controls. This implies that there is a defect in coupling of mAcChoR binding to the physiological response when mAcChoR reappear following agonist-mediated decreases in receptor number. Recovery of the ability of mAcChoR to inhibit adenylate cyclase parallels recovery of the beating response--that is, the IC50 is shifted approximately equal to 11-fold from controls at 20 hr after atropine treatment, yet only 3-fold at 28 hr. Thus, newly synthesized mAcChoR exhibit decreased physiological and biochemical responses to muscarinic agonists, suggesting that mAcChoR are initially synthesized in a less active form.     

Common breast cancer risk variants in the post-COGS era: a comprehensive review

Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene–environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of breast cancer and enable implementation of breast cancer screening, prevention or treatment strategies that provide clinical benefit.