Planning for minimally invasive unicompartmental knee arthroplasty

Unicompartmental knee arthroplasty (UKA) is considered the treatment of choice in patients with single compartment arthritis of the knee at early stages or with osteonecrosis limited to one compartment. However, results in the literature are still controversial and it is a technically difficult procedure. The main goal of UKA is to restore the articular space of the afflicted compartment, without influencing the limb alignment. Selection of patients and pre-operative planning are crucial. The necessity to improve functional results and to reduce immobilization of the patients has led to the development of minimally invasive surgery. Applied to UKA, this approach reduces blood loss and surgical time, causes fewer symptomatic postoperative complications, and permits earlier recovery compared to the traditional incision. The shorter incision makes careful pre-operative planning essential. We briefly review the indications for UKA, the pre-operative clinical and radiological assessment, and the surgical procedure. Proocedings of the Consensus Conference “TSS in hip and knee replacement” (Rapallo, Italy 22–24 June 2006)     

Evaluation of a tiered in vitro testing strategy for assessing the ocular and dermal irritation/corrosion potential of pharmaceutical compounds for worker safety

Introduction: Irritation reactions are a frequently reported occupational illness. The potential adverse effects of pharmaceutical compounds (PCs) on eye and skin can now be assessed using validated in vitro methods.

Objectives: Our overall aim is to reduce animal testing by replacing the historically utilized in vivo test methods with validated in vitro test methods which accurately determine the ocular and dermal irritation/corrosion potential of PCs to inform worker safety within the pharmaceutical space. Bristol–Myers Squibb (BMS) and the Institute for In Vitro Sciences (IIVS) have therefore conceptualized and internally qualified a tiered in vitro testing strategy to inform occupational hazards regarding eye and skin irritation and corrosivity of PCs. For the small scale pre-qualification phase, we paired historical in vivo and newly generated in vitro data for 15 PCs to determine the predictive capacity of in vitro assays already validated for the eye and skin irritation/corrosion endpoints and accepted for certain regulatory submissions. During the post-qualification phase, a group of 24 PCs were subjected exclusively to the developed tiered testing strategy, which is based on three Organisation for Economic Co-operation and Development (OECD) in vitro methods.

Materials and methods: The qualified in vitro testing strategy utilizes the Corrositex^® assay for the corrosivity (OECD TG 435), the Bovine Corneal Opacity and Permeability (BCOP) assay for ocular irritation (OECD TG 437), and the EpiDerm? tissue model-based Skin Irritation Test (SIT) for dermal irritation (OECD TG 439). In the first step, the pH of each PC was determined. For compounds with pH extremes ≥11 or ≤2, the Corrositex^® assay was generally conducted first. For compound(s) that were incompatible with or were negative in the Corrositex^® assay or had pH values between 2 and 11, the BCOP assay and SIT were performed first.

Results: The results of the tiered testing strategy’s qualification phase demonstrated that the BCOP assay is sensitive enough to identify a wide range of eye irritation/corrosion potentials and its over-prediction rate was considered acceptable to inform occupational hazards and ensure the proper handling practices of PCs. The SIT correctly predicted the skin irritation potential of 14 out of the 15 PCs included in the qualification phase, only over-predicting one PC. In the post-qualification phase, four PCs out of four tested were predicted corrosive by the Corrositex^® assay and thus no further testing was needed or conducted. The rest of the PCs were evaluated in the BCOP assay (both neat and as a 20% dilution), with the higher response being used for hazard classification. Four PCs were determined to be severe eye irritants, 1 a moderate irritant, 8 were mild irritants, and 8 were non-irritants. The same set of PCs was evaluated using the SIT and were classified as non-irritants to skin. These results are consistent with the BMS historical in vivo results showing a very low number of PCs as skin irritants.

Conclusions: This tiered in vitro testing strategy, which replaces the use of animal studies, was found to be reasonably accurate in its predictive capacity when compared to historical in vivo results and represents a conservative and reliable platform that can be utilized for the prediction of ocular and dermal irritation/corrosion potential of PCs and for subsequent GHS classification and worker safety hazard communications.     

Dominant or recessive mutations in the RYR1 gene causing central core myopathy in Brazilian patients

Central Core Disease (CCD) is an inherited neuromuscular disorder characterized by the presence of cores in muscle biopsy. CCD is caused by mutations in the RYR1 gene. This gene encodes the ryanodine receptor 1, which is an intracellular calcium release channel from the sarcoplasmic reticulum to the cytosol in response to depolarization of the plasma membrane. Mutations in this gene are also associated with susceptibility to Malignant Hyperthermia (MHS).In this study, we evaluated 20 families with clinical and histological characteristics of CCD to identify primary mutations in patients, for diagnosis and genetic counseling of the families.We identified variants in the RYR1 gene in 19/20 families. The molecular pathogenicity was confirmed in 16 of them. Most of these variants (22/23) are missense and unique in the families. Two variants were recurrent in two different families. We identified six families with biallelic mutations, five compound heterozygotes with no consanguinity, and one homozygous, with consanguineous parents, resulting in 30% of cases with possible autosomal recessive inheritance. We identified seven novel variants, four of them classified as pathogenic. In one family, we identified two mutations in exon 102, segregating in cis, suggesting an additive effect of two mutations in the same allele.This work highlights the importance of using Next-Generation Sequencing technology for the molecular diagnosis of genetic diseases when a very large gene is involved, associated to a broad distribution of the mutations along it. These data also influence the prevention through adequate genetic counseling for the families and cautions against malignant hyperthermia susceptibility.Key words: central core disease, RYR1, Next Generation Sequencing     

Prognostic significance of lymphoid infiltration in cerebral malignant gliomas

Data concerning a study on lymphoid infiltration in 61 cerebral malignant gliomas are reported. Lymphoid cellular infiltrates were found in 28 cases (45.9%): 8 (13.1%) with marked and 20 (32.8%) with slight infiltration; the remaining 33 cases (54.1%) did not exhibit lymphoid infiltration. The mean survival time (+/- standard deviation) of patients harboring gliomas with marked lymphoid infiltration was 20.5 (+/-19.9) months, and that of patients with slight lymphoid infiltration in their glioma was 10.3 (+/- 7.5) months; those patients having gliomas without lymphoid cellular infiltrates showed a mean survival time (+/- standard deviation) of 7.2 (+/-6.1) months.     

Initial clinical evaluation of an immunoradiometric assay for CA 19-9 using the NCI serum bank

More than 1,600 coded sera obtained from blood donors and the NCI/Mayo Clinic Serum Bank were analyzed with an improved immunoradiometric assay for the carbohydrate antigenic determinant, CA 19-9. Results indicated that CA 19-9 is elevated in a large fraction of sera (67%) from patients with advanced adenocarcinomas of the upper gastrointestinal (GI) tract, including those with pancreatic, hepatobiliary and gastric carcinomas. Several of these sera had CA 19-9 exceeding 300,000 U/ml. A smaller fraction (18%) of patients with carcinomas of the large bowel had elevated serum CA 19-9 levels, the majority among patients with metastatic disease. In contrast, none of the healthy donors from the serum bank and only 4 of 1,023 of the blood donor specimens (0.4%) had CA 19-9 levels greater than or equal to 40 U/ml. Three of 235 sera (1.3%) from benign disease patients had levels of CA 19-9 in excess of 40 U/ml. These data suggest that the improved CA 19-9 immunoradiometric assay may have clinical utility as a diagnostic adjunct for adenocarcinoma of the upper GI tract and that the assay also may have some value in monitoring patients with advancing colorectal carcinoma, particularly in combination with CEA determinations. Rigorous prospective clinical trials will be necessary to verify these hypotheses.     

Prognostic value of sentinel node in oral cancer

AIMS AND BACKGROUND: In stage I oral squamous cell carcinoma, clinical examination and imaging techniques are unable to identify 60-90% of patients at risk of micrometastasis, while the sentinel node biopsy technique allows to avoid the morbidity of elective neck dissection in patients not actually affected by micrometastases. MATERIALS AND METHODS: Forty-one T1-T2N0 patients underwent lymphoscintigraphy after peritumoral injection of human albumin labeled with 99Tc. Focal areas of radiotracer uptake were marked on the skin preoperatively. The sentinel lymph node (SLN) was identified by the combined use of blue dye and gamma probe and subsequently removed. Complete neck dissection was then performed in all patients and the histological findings were compared with those of SLN biopsy. RESULTS: The SLN was identified in 95% of the patients; in four cases (10%) two SLNs were isolated. In 18% of our patients the SLNs were located outside the expected drainage area. When the histology of the negative SLNs was compared with the pathological status of the neck dissection specimens no false negatives were found. Five SLNs in four patients contained micrometastases and were the only positive lymph nodes. CONCLUSIONS: SLN biopsy can be a valuable staging technique in T2 and T2 oral cancer with uninvolved neck in patients whose lymphatic drainage of the neck has not been altered by previous surgery or radiotherapy. It provides reliable detection of micrometastasis, indicating which level(s) should be removed ipsilaterally or contralaterally, and allows the surgeon to accurately plan neck dissection, taking into consideration the pattern of lymphatic drainage of each individual patient. In this way unnecessary neck dissection and its morphofunctional sequelae can be avoided in a considerable number of patients.     

Effects of endoscopic forehead/midface-lift on lower eyelid tension

OBJECTIVE: To evaluate and quantify the increase in lower eyelid tension (stress) after endoscopic forehead/midface-lift in a cohort of patients with normal lower eyelid function preoperatively. METHODS: A prospective nonrandomized study was conducted at a private facial plastic surgery practice and ambulatory surgical center on 22 patients who underwent subperiosteal endoscopic forehead/midface-lift from October 2000 to June 2002. Patients were evaluated preoperatively, 4 to 6 months postoperatively, and approximately 12 months postoperatively. RESULTS: Compared with preoperative lower eyelid tension, there was a 4- to 5-fold increase in lower eyelid tension at 3 and 5 mm of distraction immediately after the operation. Four to 6 months after the operation, lower eyelid tension decreased but was still 2 to 3 times that of preoperative values. Twelve-month measurements for the 15 patients who remained in the study (the other 7 patients were lost to follow-up or refused to have measurements taken) showed that lower eyelid tension was 1.7 to 1.9 times preoperative values. CONCLUSIONS: Our results show that lower eyelid tension increases following endoscopic forehead/midface-lift and that this increased tension is long lasting and quantifiable 12 months after surgery.     

Pitfalls in the clinical and electroencephalographic diagnosis of ceroid lipofuscinosis

Neuronal ceroid lipofuscinosis (NCL) were traditionally classified according to age of onset and clinical features in four main groups. Recently, a combination of clinical, ultra structural and genetics data led to the recognition of eight forms of NCL, providing a more precise framework to classify atypical cases. By the other hand, it was shown that mutations in the same gene could be responsible for a large variety of clinical phenotypes. The objective of this study is to describe two brothers with clinical and electroencephalographic abnormalities characteristic of juvenile NCL, but with ultra structural abnormalities suggestive of late infantile NCL. Electroencephalogram is useful for clinical diagnosis of NCL but it is not helpful in its classification.     

Role of conventional salvage multiple-drug chemotherapy in relapsed and refractory aggressive non-Hodgkin lymphomas

Autologous stem cell transplantation is the standard care for patients with relapsed or refractory aggressive non-Hodgkin lymphomas. Of the patients who are sensitive to second-line chemotherapy, approximately 40-50% are likely to be cured using this approach. The optimal salvage regimen for pre-transplant debulking is controversial and these second-line chemotherapies are particularly important for patients who cannot undergo transplantation for various reasons including age, comorbidity and insufficient stem cell collection. Numerous reports regarding this topic are available. This study evaluated reports published in the last 5 years, focusing on conventional multiple-drug second-line chemotherapies (with or without rituximab), and disregarding single-agent investigational phase-II trials. Results are encouraging, particularly when considering that the more recent and less toxic combinations appear to be equivalent to or even more favourable than previous, more aggressive approaches. Previous results obtained using a combination of mitoxantrone, carboplatin, cytarabine and methylprednisolone, are further updated and included in this study. In conclusion, the most effective conventional chemotherapy currently available for patients with relapsed or refractory non-Hodgkin lymphomas obtains complete remission rates of up to 50-70%; the achievement of a complete remission is the most important factor associated with a better outcome. Although the addition of rituximab is beneficial and safe, it is more effective in patients who have previously not been exposed to this monoclonal antibody. The addition of cycles of salvage chemotherapy to those strictly required for mobilization of peripheral blood stem cells ultimately improves the response rate.