All-inside repair of meniscal bucket handle tears: a retrospective study at mean 4-years follow-up evaluation.

Bucket-handle tears represent approximately 10% of all meniscal tears. Despite the common treatment is subtotal meniscectomy, repair is technically feasible although complex, and represents a key strategy to avoid severe meniscal tissue loss that could accelerate joint degeneration over time. The aim of this retrospective study was to determine the outcomes of arthroscopically-assisted bucket-handle tear repair, and to identify factors correlating with clinical results. Fifty-four patients affected by meniscal bucket handle tear were included in the present retrospective analysis and evaluated up to mean 4-years follow-up. All patients were treated by arthroscopic-assisted all-inside repair. The primary outcome was considered the need for a re-operation due to failure of meniscal repair. Patients were also evaluated by the following items: KOOS, Lysholm, Tegner, IKDC-subjective and Quadruple-VAS score. Subgroup analysis was performed to identify whether concurrent ACL reconstruction, side of the lesion, age at surgery and time from injury to repair could influence clinical outcome. Ten out 54 patients (18.5%) were considered failed and needed reoperation, mainly within one year from surgery. Overall, there was a significant increase in all clinical scores considered and patients were able to get back to previous sport activity level. Patients with concurrent ACL reconstruction presented a lower risk of failure (p=0.025). Patients with lateral meniscus repair showed better clinical outcome compared to medial meniscus. Timing from injury and age at surgery did not correlated with clinical outcome. Our series showed fair results in bucket handle repair up to middle term evaluation. Concomitant ACL reconstruction was associated with lower failure rate whereas lateral meniscus involvement was associated with higher functional scores at final follow-up evaluation.

Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: an update at 3 year follow-up.

BACKGROUND: Conservative therapies for the treatment of knee degenerative processes are used before resorting to surgery; nonetheless, they may offer only short-term benefits. Encouraging preliminary results have been reported using mesenchymal stem cells (MSCs), either alone or in association with surgery. Among the many sources, adipose tissue has created a huge interest, because of its anti-inflammatory and regenerative properties ascribed to the cells of its stromal vascular fraction. We previously reported the safety and feasibility of autologous micro-fragmented adipose tissue as adjuvant for the surgical treatment of diffuse degenerative chondral lesions at 1 year. Here we present the outcomes of the same cohort of patients evaluated at 3 year follow-up. Micro-fragmented adipose tissue was obtained using a minimal manipulation technique in a closed system. The safety of the procedure was evaluated by recording type and incidence of any adverse event. The clinical outcomes were determined using the KOOS, IKDC-subjective, Tegner Lysholm Knee, and VAS pain scales taken pre-operatively and at 12 and 36 months follow-up. FINDINGS: No adverse events, lipodystrophy cases at the harvesting site nor atypical inflammatory reactions at the joint level were reported. Of the 30 patients previously treated, one was lost, and seven received additional treatments in the period of observation. On average, the 22 patients that had no other treatments in the 3-year period showed that the results observed at 1 year were maintained. Moreover, 41, 55, 55 and 64% of the patients improved with respect to the 1-year follow-up in the Tegner Lysholm Knee, VAS, IKDC-subjective and total KOOS, respectively. CONCLUSION: Our results point to autologous and micro-fragmented adipose tissue injection as an innovative and safe approach for the management of diffuse degenerative knee chondropathy in the mid-term. The procedure is simple, affordable, minimally invasive, and compliant with the regulatory panorama.

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.

Background: Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods: Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results: NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion: This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.

Knee Septic Arthritis after Arthroscopy: Incidence, Risk Factors, Functional Outcome, and Infection Eradication Rate.

Purpose Septic knee arthritis following arthroscopy is a rare but dreaded complication. Definition and management of knee deep infections are quite discussed in literature. In this review, literature regarding infections after knee arthroscopy is analyzed highlighting the incidence, causative bacteria, risk factors as well as clinical outcomes. Methods We performed a review of the literature matching the following key words: "septic arthritis" OR "infection" AND "arthroscopy" AND "knee." Knee arthroscopic procedures, such as debridement, meniscectomy, meniscus repair, synovectomy, microfracture, and lateral release, were considered. Complex procedures, such as ligament reconstruction, fractures, or complex cartilage repair techniques, were not included. Results Thirteen studies were included in this review. Incidence of infection ranged from 0.009 to 1.1% in patients undergoing simple arthroscopic procedures. Staphylococci are the most commonly isolated organisms from postarthroscopy infection. Use of intraoperative intra-articular steroids, smoking, obesity, male sex, diabetes, number of procedures performed during surgery, time of surgery, and tourniquet time of more than 60 minutes have been certified as risk factors for knee infection. Conclusion Postarthroscopy septic arthritis of the knee causes significant morbidity, usually requiring readmission to the hospital, at least one additional operation, and prolonged antibiotic therapy, both intravenous and oral. Prompt diagnosis and treatment are associated with a high success rate. Level of Evidence Level IV, systematic review of I-IV studies.

Heat shock induces the expression of pro-inflammatory cytokines in human Achilles tendon tenocytes.

The aim of our study is to investigate the behaviour of healthy and tendinopathic human tenocytes after a heat shock. After we harvested tendinopathic and healthy human tendon samples, we split tenocytes into 4 groups: 3 groups were submitted to heat shock, followed by different periods of post-heating (2, 4 and 20 h). The other group represents our negative control. The target genes were analysed using Real Time PCR. IL-1ß and IL-6 expression were significantly increased in tendinopathic samples after heat shock. COL1 and COL3 expression were increased in non-stimulated tendinopathic tenocytes, but their levels significantly decreased after heat shock (p less than 0.01). COL3 levels increase in healthy samples after 20 h post-heating (p less than 0.01). COL1 and COL3 decreased after heat shock as a sign of the failure of repair mechanisms in tendinopathic tendons. Heat shock in in vitro models was insufficient to trigger pro-inflammatory cytokines in healthy human tenocytes.

Surgical treatment of sacral chordoma: survival and prognostic factors.

INTRODUCTION: Sacral chordoma is a rare low-to-intermediate grade malignant tumour. The mainstay of treatment is still surgery with en bloc and wide resection margins, which can grant the best chances of a long-term control or cure of this disease. The first aim of this paper is to collect data about survival, time to local recurrence and metastasis among patients affected by sacral chordoma and primarily treated with surgery. The second aim is to analyze the influence of level resection, tumor volume and surgical margins on local recurrence. MATERIALS AND METHODS: The study population was composed of 14 patients treated with sacral chordoma resection at the National Tumour Institute of Naples-Pascale (Italy) from January 2000 to June 2013. The median follow-up was 84 months (range 24-132 months). The follow-up was characterized by: standard radiographs, MRI, and a CT scan of the chest annually. Time to recurrence or metastasis was calculated from the date of resection to the date of diagnosis of first recurrence or metastasis. RESULTS: Out of all the patients, six died (42.86 %) during the follow-up; 6 (42.86 %) had local recurrence; 4 (28.57 %) had metastasis. At univariate analysis wide surgical margins (R0) were associated with increased survival up to a local recurrence (OR = 0.0286; 95 % CI = 0.0014-0.5739; P = 0.026); the level of resection (OR = 3.33; 95 % CI = 0.3619-30.7025; P = 0.592) and tumour volume (P = 1) did not show a statistically significant correlation. DISCUSSION: Based on our experience, we hope all patients to be treated by surgery, the only good standard treatment of this disease. The resection should result in margins as wide as possible. For these reasons, it is essential for this disease to be treated in highly specialized centres because only a complete surgery can offer a chance to care for these patients. CONCLUSIONS: Solid survival at long-term follow-up can be achieved by a surgical resection performed with wide margins.

Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest.

BACKGROUND: Early tumor shrinkage (ETS) and depth of response (DoR) predict overall survival (OS) in first-line trials of chemotherapy ± anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC). These associations and the predictive accuracy of response measurements for survival parameters were investigated in the phase III TRIBE trial of FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev. PATIENTS AND METHODS: A landmark approach was adopted to define the assessable population. The distribution of RECIST response rate, ETS and DoR was compared in the two arms. Associations between response measurements and progression-free survival (PFS), post-progression survival (PPS) and OS were tested by univariate and multivariate Cox models. Prediction performance of each factor was estimated by C-index. RESULTS: A significantly higher percentage of patients in the FOLFOXIRI plus bev arm achieved ETS ≥20%, when compared with the control arm (62.7% versus 51.9%, P = 0.025). Also the DoR was significantly higher in the triplet plus bev arm (43.4% versus 37.8%, P = 0.003). Both ETS and DoR were associated with PFS, PPS and OS at the univariate analyses and in the multivariate models stratified for other prognostic variables. Both ETS and DoR were able to predict survival as accurately as RECIST response. CONCLUSION: FOLFOXIRI plus bev improves ETS and DoR when compared with FOLFIRI plus bev. Achieving rapid and deep tumor shrinkage consistently delays tumor progression and prolongs survival in patients treated with first-line chemotherapy plus bev. ETS is a promising and valuable end point for clinical trials' design deserving further investigation.

CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion.

OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

Whole body cholesterol metabolism is impaired in Huntington's disease.

We previously reported impaired cholesterol biosynthesis in rodent Huntington Disease (HD) models and HD patients' fibroblasts and post mortem brains. We also found that plasma levels of 24S-hydroxycholesterol (24OHC), the brain specific elimination product of cholesterol considered a marker of brain cholesterol turnover, were significantly reduced in HD patients at any disease stage. In the present study we analysed by mass spectrometry the fasting plasma levels of cholesterol, its biosynthetic precursors lanosterol and lathosterol, of the whole-body elimination products 27-hydroxycholesterol and of brain 24OHC in a cohort of premanifest and HD patients at different disease stages. We found that the cholesterol precursors lanosterol and lathosterol (both index of whole body cholesterol synthesis), the levels of the bile acid precursor 27-hydroxycholesterol, and of the brain specific 24OHC, were all significantly reduced in manifest HD patients, suggesting that whole-body and brain cholesterol homeostasis are both impaired in HD.

EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders.

OBJECTIVES: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. CONCLUSION: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.

EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias.

OBJECTIVES: These EFNS guidelines on the molecular diagnosis of channelopathies, including epilepsy and migraine, as well as stroke, and dementia are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. SEARCH STRATEGY: To collect data about planning, conditions, and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The best level of evidence for genetic testing recommendation (B) can be found for a small number of syndromes, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, severe myoclonic epilepsy of infancy, familial recurrent hemorrhages, familial Alzheimer's disease, and frontotemporal lobar degeneration. Good practice points can be formulated for a number of other disorders. CONCLUSION: These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in our article will allow improved recommendation with an increased level of evidence.

EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

Decreased diffusivity in the caudate nucleus of presymptomatic huntington disease gene carriers: which explanation?

BACKGROUND AND PURPOSE: The neostriatum is known to be affected in HD. In this work, our aim was to determine whether microstructural and volumetric alterations occur in the neostriatum of presymptomatic HD gene carriers and in patients with early-stage HD. MATERIALS AND METHODS: We studied a group of 15 presymptomatic gene carriers who were far from the estimated symptom onset (16% probability of developing the disease within 5 years), a group of 9 patients with early symptomatic HD, and 2 groups of age-matched controls. Volumetric MR imaging and DWIs were acquired, and statistical analyses were performed on the volumes of the caudate nucleus and putamen and on the corresponding MD measurements. RESULTS: Neostriatal volumes were significantly smaller in both presymptomatic HD gene carriers and symptomatic patients with respect to controls. However, whereas the diffusivity in the caudate nucleus was increased in the symptomatic patients, it was decreased in the presymptomatic gene carriers. CONCLUSIONS: Altered diffusivity and reduced volume of the caudate nucleus in presymptomatic HD gene carriers indicate that the neostriatum is affected well before the onset of symptoms. The observed initial decrease and subsequent increase of MD might be related to the combined effect of increased oligodendroglial population, putatively a developmental abnormality, and incipient neurodegeneration.

EFNS guidelines on the molecular diagnosis of mitochondrial disorders.

OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.

EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer.

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m(-2) and oxaliplatin 85 mg m(-2) on day 1 plus capecitabine 2000 mg m(-2) per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3-4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4-82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.

Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.

The search for cerebral biomarkers of Huntington's disease: a review of genetic models of age at onset prediction.

The mutation causing Huntington's disease is an expanded CAG trinucleotide repeat number beyond 35 in the 5' translated region of the gene. The mutation penetrance varies widely and depends on the CAG expansion length, the low pathological triplet range (36-41) showing a very low penetrance, possibly associated with late ages at onset. No research has so far yielded biomarkers for accurately predicting either age at onset or disease progression in at risk individuals. Specific markers able to follow-up mutation carrier subjects from the pre-symptomatic stages of life are crucial for testing experimental neuroprotective preventive therapies. Nevertheless, the factor accounting for the largest percentage of age at onset variation is the expanded repeat number within the gene. Over the years, this factor has helped in setting up models for genetically predicting age at onset. Once available for practical application in clinics, such models allowed phenotype-genotype correlations that were hitherto inconceivable. In this review, we discuss how these genetic models have been applied in clinical practice and comment on their potential value in searching for cerebral biomarkers of disease onset and severity and in designing trials of therapeutic drugs.