Prospective assessment of aneurysmal rupture risk scores in patients with subarachnoid hemorrhage: a multicentric cohort.

PURPOSE: The natural evolution of unruptured intracranial aneurysms (UIA) is indeed difficult to predict at the individual level. OBJECTIVE: In a large prospective multicentric European cohort, we aimed to evaluate whether the PHASES, UCAS, and ELPASS scores in patients with aneurysmal subarachnoid hemorrhage would have predicted a high risk of aneurysmal rupture or growth. METHODS: Academic centers treating patients with intracranial aneurysms were invited to prospectively collect de-identified data from all patients admitted at their institution for a subarachnoid hemorrhage-related to intracranial aneurysmal rupture between January 1 and March 31, 2021 through a trainee-led research collaborative network. Each responding center was provided with an electronic case record form (CRF) which collected all the elements of the PHASES, ELAPSS, and UCAS scores. RESULTS: A total of 319 patients with aneurysmal subarachnoid hemorrhage were included at 17 centers during a 3-month period. One hundred eighty-three aneurysms (57%) were less than 7 mm. The majority of aneurysms were located on the anterior communicating artery (n = 131, 41%). One hundred eighty-four patients (57%), 103 patients (32%), and 58 (18%) were classified as having a low risk of rupture or growth, according to the PHASES, UCAS, and ELAPSS scores, respectively. CONCLUSION: In a prospective study of European patients with aneurysmal subarachnoid hemorrhage, we showed that 3 common risk-assessment tools designed for patients with unruptured intracranial aneurysms would have not identified most patients to be at high or intermediate risk for rupture, questioning their use for decision-making in the setting of unruptured aneurysms.

Role of microRNAs in fluoropyrimidine-related toxicity: what we know.

Although more than half a century has passed since the discovery of fluoropyrimidines, they are still used in the treatment of many types of cancer, and it is estimated that annually two million patients undergo fluoropyrimidine-based chemotherapy. The toxicity resulting from the use of fluoropyrimidines affects about 30-40% of patients, which in some cases may prove to be lethal. The key player in fluoropyrimidine toxicity is DPD activity, and patients with deficits are more likely to develop significant adverse events. In addition to genotyping DPYD variants associated with DPD deficiency, overexpression of miR-27 has also been shown to be a predictive factor for fluoropyrimidine toxicity. This review aims to relate what we know so far about the involvement of miRNA in fluoropyrimidine toxicity and to open new perspectives in this field.

Postprocedural Antiplatelet Treatment after Emergent Carotid Stenting in Tandem Lesions Stroke: Impact on Stent Patency beyond Day 1.

BACKGROUND AND PURPOSE: Postprocedural dual-antiplatelet therapy is frequently withheld after emergent carotid stent placement during stroke thrombectomy. We aimed to assess whether antiplatelet regimen variations increase the risk of stent thrombosis beyond postprocedural day 1. MATERIALS AND METHODS: Retrospective review was undertaken of all consecutive thrombectomies for acute stroke with tandem lesions in the anterior circulation performed in a single comprehensive stroke center between January 9, 2011 and March 30, 2020. Patients were included if carotid stent patency was confirmed at day 1 postprocedure. The group of patients with continuous dual-antiplatelet therapy from day 1 was compared with the group of patients with absent/discontinued dual-antiplatelet therapy. RESULTS: Of a total of 109 tandem lesion thrombectomies, 96 patients had patent carotid stents at the end of the procedure. The early postprocedural stent thrombosis rate during the first 24 hours was 14/96 (14.5%). Of 82 patients with patent stents at day 1, in 28 (34.1%), dual-antiplatelet therapy was either not initiated at day 1 or was discontinued thereafter. After exclusion of cases without further controls of stent patency, there was no significant difference in the rate of subacute/late stent thrombosis between the 2 groups: 1/50 (2%) in patients with continuous dual-antiplatelet therapy versus 0/22 (0%) in patients with absent/discontinued dual-antiplatelet therapy (P = 1.000). In total, we observed 88 patient days without any antiplatelet treatment and 471 patient days with single antiplatelet treatment. CONCLUSIONS: Discontinuation of dual-antiplatelet therapy was not associated with an increased risk of stent thrombosis beyond postprocedural day 1. Further studies are warranted to better assess the additional benefit and optimal duration of dual-antiplatelet therapy after tandem lesion stroke thrombectomy.

Cervical myelopathy caused by ventrally located atlanto-axial synovial cysts: An open quest for the safest and most effective surgical management. Case series and systematic review of the literature.

OF BACKGROUND DATA: Despite a good understanding of the natural history of spinal synovial cysts (SCs), a widespread agreement regarding their optimal management is still lacking. This is particularly true for SCs occurring at the C1-C2 level, which are rare, but oftentimes lead to a rapidly evolving cervical myelopathy. METHODS: We report a series of 4 patients (M:F ratio=1:1; mean age 63.5 years) presenting with progressive cervical myelopathy secondary to ventrally located C1-C2 SCs. All patients underwent a postero-lateral facet-sparing intradural approach with total excision of the SCs. Functional status was assessed pre- and postoperatively with Nurick scale and the modified Japanese Orthopaedic association grading. Furthermore we conducted a systematic review, following PRISMA guidelines of pertinent literature to contextualize the options for surgical management of such lesions. RESULTS: Complete excision of the SCs was confirmed radiologically and on histological analysis. All measures of functional status improved post-operatively, and no cyst recurrence or need for instrumented fusion were noted during follow up (range from 22 to 88 months). CONCLUSION: Our experience suggests that the facet-sparing intradural approach provides excellent clinical outcomes without causing any C1-C2 instability. This is in keeping with the take home message emerging from our literature review, which confirms that treatment should aim at radical resection of SCs while minimizing the risk of postoperative instability.

Intraoperative imaging for remnant viability assessment in bilateral posterior retroperitoneoscopic partial adrenalectomy in an experimental model.

BACKGROUND: A surgical approach preserving functional adrenal tissue allows biochemical cure while avoiding the need for lifelong steroid replacement. The aim of this experimental study was to evaluate the impact of intraoperative imaging during bilateral partial adrenalectomy on remnant perfusion and function. METHODS: Five pigs underwent bilateral posterior retroperitoneoscopic central adrenal gland division (9 divided glands, 1 undivided). Intraoperative perfusion assessment included computer-assisted quantitative fluorescence imaging, contrast-enhanced CT, confocal laser endomicroscopy (CLE) and local lactate sampling. Specimen analysis after completion adrenalectomy (10 adrenal glands) comprised mitochondrial activity and electron microscopy. RESULTS: Fluorescence signal intensity evolution over time was significantly lower in the cranial segment of each adrenal gland (mean(s.d.) 0·052(0·057) versus 0·133(0·057) change in intensity per s for cranial versus caudal parts respectively; P = 0·020). Concordantly, intraoperative CT in the portal phase demonstrated significantly lower contrast uptake in cranial segments (P = 0·031). In CLE, fluorescein contrast was observed in all caudal segments, but in only four of nine cranial segments (P = 0·035). Imaging findings favouring caudal perfusion were congruent, with significantly lower local capillary lactate levels caudally (mean(s.d.) 5·66(5·79) versus 11·58(6·53) mmol/l for caudal versus cranial parts respectively; P = 0·008). Electron microscopy showed more necrotic cells cranially (P = 0·031). There was no disparity in mitochondrial activity (respiratory rates, reactive oxygen species and hydrogen peroxide production) between the different segments. CONCLUSION: In a model of bilateral partial adrenalectomy, three intraoperative imaging modalities consistently discriminated between regular and reduced adrenal remnant perfusion. By avoiding circumferential dissection, mitochondrial function was preserved in each segment of the adrenal glands. Surgical relevance Preservation of adrenal tissue to maintain postoperative function is essential in bilateral and hereditary adrenal pathologies. There is interindividual variation in residual adrenocortical stress capacity, and the minimal functional remnant size is unknown. New intraoperative imaging technologies allow improved remnant size and perfusion assessment. Fluorescence imaging and contrast-enhanced intraoperative CT showed congruent results in evaluation of perfusion. Intraoperative imaging can help to visualize the remnant vascular supply in partial adrenalectomy. Intraoperative assessment of perfusion may foster maximal functional tissue preservation in bilateral adrenal pathologies and procedures.

ANTECEDENTES: Un abordaje quirúrgico que preserve la función del tejido suprarrenal permite lograr la curación bioquímica, a la vez que evita la necesidad de tratamiento sustitutivo con corticoides de por vida. El objetivo de este estudio experimental fue evaluar el impacto de las técnicas de imagen intraoperatorias en la suprarrenalectomía parcial (partial adrenalectomy, AE) bilateral sobre la perfusión y función del remanente glandular. MÉTODOS: Cinco cerdos fueron sometidos a una división bilateral central de la glándula suprarrenal por retroperitoneoscopia posterior (n = 9, 1 sin dividir). Durante la intervención, la evaluación de la perfusión incluyó la fluorescencia con cuantificación asistida por ordenador (Realidad Aumentada basada en la Fluorescencia, FLuorescence-based Enhanced Reality, FLER), tomografía computarizada (computed tomography, CT), endomicroscopia con laser confocal (confocal laser endomicroscopy, CLE) y un muestreo local de lactato. El análisis de la pieza quirúrgica tras completar la AE (n = 10) incluyó actividad mitocondrial y microscopia electrónica. RESULTADOS: La evolución de la intensidad de la señal de fluorescencia a lo largo del tiempo (ΔI/s) fue significativamente más baja en el segmento craneal de cada una de las glándulas (0,052 ± 0,057 craneal versus 0,133 ± 0,057 caudal, P = 0,02). De forma concordante, la CT intraoperatoria en la fase portal demostró una captación de contraste significativamente más baja en los segmentos craneales (P = 0,03). En la CLE, el contraste de fluoresceína se observó en todos los segmentos caudales, pero solo en el 44% de los segmentos craneales (P = 0,04). Los hallazgos obtenidos en las pruebas de imagen favorables a la perfusión caudal fueron congruentes con niveles significativamente más bajos de lactato capilar a nivel local (11,58 ± 6,53 mmol/L craneal versus 5,66 ± 5,79 mmol/L caudal, P = 0,008). A nivel craneal, la microscopia electrónica mostró más células necróticas (P = 0,03). La actividad mitocondrial (tasas de respiración, especies reactivas de oxígeno y producción de H2 O2 ) no mostraron disparidad entre los diferentes segmentos. CONCLUSIÓN: En un modelo de AE parcial bilateral, las tres modalidades de pruebas de imagen intraoperatorias podrían discriminar de forma consistente una perfusión regular y reducida del remanente suprarrenal. Al evitar una disección circunferencial, se preservó la función mitocondrial en cada segmento de las glándulas suprarrenales.

Stroke Thrombectomy in Patients with COVID-19: Initial Experience in 13 Cases.

We performed a retrospective review in both comprehensive stroke units of a region affected early by the coronavirus disease 2019 (COVID-19) pandemic, between March 1 and April 26, 2020, including patients with COVID-19 who underwent mechanical thrombectomy for ischemic stroke. We identified 13 cases, representing 38.2% of 34 thrombectomies performed during this period. We observed increased mortality and a high incidence of thrombotic complications during hospitalization. Given the high rate of infected patients, systematic use of full personal protection measures seems justified.

A combined single-stage procedure to treat brain AVM.

Complete resection of brain arteriovenous malformation (AVM) is a surgical challenge, mainly due to risk of intraoperative rupture. The objective of this feasibility study was to analyze complete resection rate at 3 months and clinical outcome at 6 months after treatment of brain AVM by combined single-stage embolization and surgical resection. A retrospective observational study from July 2015 to February 2019 was conducted at the Department of Neurosurgery of Strasbourg University Hospital, France. Decision to treat was taken on the basis of history of AVM rupture, symptomatic AVM, or morphologic risk factors for rupture. Complete resection rate was assessed on postoperative cerebral subtraction angiography at 3 months and clinical outcome at 6 months was evaluated on the modified Rankin Scale (mRS). In the 16 patients treated for symptomatic brain AVM, the rate of complete resection was 75%, resection with residual shunt 18.7%, and incomplete resection with residual nidus 6.3%. Good clinical outcome (mRS=0 or 1) was achieved in 81.3% of patients at 6 months. The transfusion rate was 7.1%. There were procedural complications in 12.5% of patients but no intraoperative ruptures. This combined single-stage procedure allows extensive preoperative embolization of the AVM, facilitating surgical microdissection by identifying the dissection plane and perforating arteries and allowing the operator to work in close contact with the nidus without fear of intraoperative rupture.

Impact of the COVID-19 outbreak on acute stroke pathways - insights from the Alsace region in France.

BACKGROUND AND PURPOSE: To date, no study has attempted to quantify the impact of the COVID-19 outbreak on the incidence and treatment of acute stroke. METHODS: This was a retrospective review of acute stroke pathway parameters in all three stroke units in the Alsace region during the first month of the outbreak (1-31 March 2020), using the similar period from 2019 as a comparator. A secondary detailed analysis of all stroke alerts and stroke unit admissions was performed in the centre with the largest case volume. RESULTS: Compared to the same period in 2019, in March 2020 there were 39.6% fewer stroke alerts and 33.3% fewer acute revascularization treatments [40.9% less intravenous thrombolysis (IVT) and 27.6% less mechanical thrombectomy (MT)]. No marked variation was observed in the number of stroke unit admissions (-0.6%). The proportion of patients with acute revascularization treatments (IVT or MT) out of the total number of stroke unit admissions was significantly lower in March 2020 (21.3%) compared to 2019 (31.8%), P = 0.034. There were no significant differences in time delays or severity of clinical symptoms for patients treated by IVT or MT, nor in the distribution of final diagnosis amongst stroke alerts and stroke unit admissions. CONCLUSION: These results suggest that the overall incidence of stroke remained the same, but fewer patients presented within the therapeutic time window. Increased public awareness and corrective measures are needed to mitigate the deleterious effects of the COVID-19 outbreak on acute stroke care.

Role of pentraxin-3 in risk assessment of patients with metabolic syndrome.

BACKGROUND: Inflammation plays a major role in the development of metabolic syndrome (MetS) and its progression. Recent studies have shown that pentraxin-3 (PTX-3), osteoprogerin (OPG), and tumor necrosis factor-alpha (TNF-α) are key factors in MetS pathophysiology, but evidence for endorsing their clinical use is currently unclear and insufficient. AIM: The study aimed to evaluate the association between the inflammatory biomarkers' levels and the severity of MetS. METHODS: The study was observational, transversal, prospective, cohort, and analytical type. We enrolled 80 patients (M:F = 1, mean age = 55 ± 10.77 years) who met MetS criteria. The study protocol included: medical history, physical examination, 6-min walk test distance (6MWTD), biochemical tests, electrocardiogram, echocardiography, and carotid ultrasonography. We also performed plasmatic measurement of PTX-3, OPG, and TNF-α, in addition to standard biochemical tests. RESULTS: Subjects with severe MetS had higher values of body mass index (BMI) and waist circumference (p < 0.001, p = 0.001). PTX-3 levels were significantly higher in patients with severe MetS (p = 0.03) and the values were not influenced by age or gender. OPG positively correlated with BMI (r = 0.264, p = 0.018). 6MWTD was lower in patients with severe MetS (p = 0.005), whereas CCA-IMT was higher in this group of patients (p = 0.005). In addition, the receiver operating characteristic (ROC) curve analysis for PTX-3 identified a cut-off value of 10.7 ng/dl that differentiates between mild and severe MetS [AUC 0.656; sensitivity =47.1% (95% CI = 36.1%-62.3%); specificity = 78.9% (95% CI = 54.4%-93.9%)]. CONCLUSION: PTX-3 was correlated with the severity of MetS, with other inflammatory parameters and cardiovascular tests. CCA-IMT and 6MWTD are useful in differentiating between mild and severe MetS.

Predictors and Clinical Impact of Delayed Stent Thrombosis after Thrombectomy for Acute Stroke with Tandem Lesions.

BACKGROUND AND PURPOSE: There are very few published data on the patency of carotid stents implanted during thrombectomies for tandem lesions in the anterior circulation. We aimed to communicate our experience of stenting in the acute setting with systematic follow-up of stent patency and discuss predictors and clinical repercussions of delayed stent thrombosis. MATERIALS AND METHODS: We performed a retrospective study of stroke thrombectomies in a single center between January 2009 and April 2018. Patient files were reviewed to extract patient characteristics, procedural details, imaging studies, and clinical information. Predictors of delayed stent thrombosis and clinical outcome at discharge were analyzed using univariate and multivariate analyses. RESULTS: We identified 81 patients treated for tandem lesions: 63 (77.7%) atheromas, 17 (20.9%) dissections, and 1 (1.2%) carotid web. TICI 2b-3 recanalization was achieved in 70 (86.4%) cases. Thirty-five patients (43.2%) were independent (mRS score ≤ 2) at discharge. Among 73 patients with intracranial recanalization and patent stents at the end of the procedure, delayed stent thrombosis was observed in 14 (19.1%). Among 59 patients with patent stents, 44 had further imaging controls (median, 105 days; range, 2-2407 days) and 1 (1.6%) had 50% in-stent stenosis with no retreatment. Stent occlusion rates were 11/39 (28.2%) for periprocedural aspirin treatment versus 3/34 (8.8%) for aspirin and clopidogrel (P = .04). Delayed stent thrombosis was independently associated with higher admission NIHSS scores (OR, 1.1; 95% CI, 1.01-1.28), diabetes (OR, 6.07; 95% CI, 1.2-30.6), and the presence of in-stent thrombus on the final angiographic run (OR, 6.2; 95% CI, 1.4-27.97). Delayed stent thrombosis (OR, 19.78; 95% CI, 2.78-296.83), higher admission NIHSS scores (OR, 1.27, 95% CI, 1.12-1.51), and symptomatic hemorrhagic transformation (OR, 23.65; 95% CI, 1.85-3478.94) were independent predictors of unfavorable clinical outcome at discharge. CONCLUSIONS: We observed a non-negligible rate of delayed stent thrombosis with significant negative impact on clinical outcome. Future studies should systematically measure and report stent patency rates.

Spinal adhesive arachnoiditis following the rupture of an Adamkiewicz aneurysm: Literature review and a case illustration.

BACKGROUND: The rupture of an isolated spinal aneurysm is an exceptional occurrence. It might be responsible for a spinal subarachnoid haemorrhage (SSAH) that in rare cases can be complicated by arachnoiditis. Among the former the adhesive type is the most severe leading to the formation of a cyst and/or a syrinx. PATIENTS AND METHODS: The literature review was performed via a PubMed search using the following keywords. Adhesive arachnoiditis; spinal subarachnoid haemorrhage; spinal arachnoiditis; spinal arachnoid cyst; arachnoid cyst .Thesearch yielded 24 articles. Given the fact that only a few studies had been reported on the subject, we decided to include all studies regarding adhesive arachnoiditis after SAH leading to a descriptive literature review. Furthermore, a case illustration of a 57 year old man harbouring this type of rare pathology is described. RESULTS: Twenty-four case reports were found regarding spinal adhesive arachnoiditis (SAA) following SSAH. Posterior cerebral circulation bleeding (66.7%) most often occurred followed by spinal (9.1%) and anterior cerebral circulation (9.1%) respectively. The mean time between the haemorrhage and the SAA onset was 10 months. A higher predominance of symptomatic thoracic SAA was found. Including the present case, 80% of patients had a laminectomy, 72% had a micro adhesiolysis, and 56% a shunt placement. Cervical and upper thoracic involvement appeared to have a better outcome. CONCLUSION: Although most authors suggested surgical treatment, the long-term outcome remains unclear. Early stage diagnosis and management of this rare and disabling pathology may lead to a better outcome. Larger co-operative studies remain essential to obtain a better understanding of such a rare and complex disease.

Results at 7years after cross-linking procedure in keratoconic patients.

PURPOSE: Long-term evaluation of functional results based on visual acuity, keratometry, spherical equivalent and refractive cylinder in patients with progressive keratoconus treated with corneal collagen cross-linking (CXL). MATERIALS AND METHODS: We studied a group of 114 eyes of 91 consecutive patients treated from 2006 to 2009 by "Epi-off type" CXL. In the preoperative period, all patients had a complete ophthalmologic examination. The inclusion criteria were: patients aged 15 to 54years, with various stages of keratoconus, with a corneal thickness of at least 400µm at the thinnest point. The exclusion criteria were: patients with a corneal thickness of less than 400µm at the thinnest point, with Vogt's striae or herpetic keratitis, dry eye syndrome or aphakia. The patients were then followed at 1, 3 and 6months, and then every year between 1 and 7years postoperatively. RESULTS: There was a decrease in the minimum K and maximum K, respectively 1.6 and 2.0, at 7years postop. (P<0.05). The cylinder decreased from -4.45 D to -3.50 D at 7 years postop (P<0.05). The spherical equivalent decreased by 1.66 D at 7 years (P<0.05). Uncorrected visual acuity increased from an average of 0.78 to 0.679 log MAR (P<0.05) at 7 years postop. The best-corrected visual acuity increased from a mean of 0.64 to 0.52 log Mar (P<0.05) at 7 years postop. CONCLUSIONS: The results of CXL were stable at 7 years in all patients, consisting of reduction of keratometric values and refraction, and improvement in visual acuity.

Low sensitivity of needle aspiration cultures in patients with cellulitis/erysipelas.

PURPOSE: Cellulitis is normally treated without knowledge of the responsible pathogen. Blood cultures are positive in about 2-4 %, and superficial swabs are of no value. Needle aspiration has been proposed with identifying the likely pathogen in up to 29 %, but these studies are of older date and the technique is not widely used. METHODS: We prospectively evaluated the sensitivity of needle aspiration cultures in all patients with erysipelas/cellulitis. Diagnosis was made clinically by the treating physician. Needle aspiration was done with a 1 ml syringe and a 26G needle. The needle was removed and the syringe brought to the microbiological laboratory and analysed according to standard procedures. RESULTS: 95 Patients were seen during a period of 22 month. 4 Patients were excluded, as diagnosis was not confirmed. Cellulitis was present in 10/91 and erysipelas in 81/91 patients. In the first 25 patients with needle aspiration from the margin, none was positive. In 8/66 (12 %) patients where needle aspiration was done at the site of maximum inflammation, the pathogen was identified. 4/8 Cultures were positive for S. aureus, 2/8 for streptococci and 2/8 for other bacteria. In 11/66 (16.6 %) patients, skin colonisation flora was detected. In the subgroup of patients without prior antibiotic treatment and needle aspiration from the site of maximum inflammation, sensitivity was slightly better 8/55 (14.5 %; 95 % CI 7.5-25.8 %). CONCLUSIONS: Needle aspiration culture had a low sensitivity for detecting responsible pathogen in patients with cellulitis/erysipelas. No impact in antibiotic treatment could be observed.

DEVELOPMENT OF SYNTHETIC GROWTH CHARTS FOR ROMANIAN POPULATION.

There are no new national growth references for the Romanian population and the current recommendations for short stature evaluation is the use of the Swiss growth charts developed based on a longitudinal study.The aim of the present paper is to present the new synthetic growth references for Romanian children. MATERIAL AND METHODS: We used local Romanian data from 9 studies with information on height and weight obtained between 1999 and 2016. Based on their plausibility and methodology six studies were selected for generating the National Synthetic Growth References for Romanian Children based on the specific methodology described previously. The selected studies included 8407 subjects measured in schools/kindergartens. Age is reported in years covering a range from 3-18 years. Height and weight were measured at a precision of 0.1 cm and 0.1 kg. All children were measured at normal temperature, in light clothes, without footwear. RESULTS: We present the charts and tables with the common centiles for height, weight and body mass index for boys and girls. CONCLUSION: We suggest synthetic growth references based upon recent growth data from 6 different Romanian regions as new National Growth Charts for Romanian children.

Adjusting dento-alveolar morphology with orthodontic mini-implants (miniscrews). A clinical case report.

Mini-implants are increasingly popular for creating skeletal anchorage in clinical orthodontics. The aim of this article is to present and discuss the clinical uses, benefits and drawbacks of the miniscrew implants used to reorder and adjust the dento-alveolar morphology of the overerupted maxillary molars. The loss of the lower premolars and molars very often leads to overeruption of the opposing maxillary teeth, combined with insufficient space for prosthetic restorations. The available treatment options are either a significant reduction of the maxillary teeth, often associated with endodontic treatment, or a complex orthodontic treatment. In the previous years, different cases of orthodontic intrusion with mini-implants were described. In this report, the authors describe a case of a young patient who needed a maxillary molar intrusion in order to get sufficient prosthetic space for an implant supported fixed restoration in the third quadrant. This treatment type preserved maximum tooth structures and allowed a successful mandibular restoration.

[The neurogenic mechanisms of ocular inflammation and their modulation under local treatment with indomethacin]. / Mecanisme neurogene ale inflamatiei oculare si modularea lor sub tratament local cu indometacin.

Neurogenic modulation of the inflammation is an essential mechanism of initiate and conditionate an inflammatory reaction. SP, NKA and NKB--neurokinins are involved in the modulation of the local ocular inflammation initiated by the surgical perforating trauma of the anterior pole. They determine the increase of vascular permeability and the breakdown of the aqueous-humor-blood barrier by direct action on the endothelial vascular receptors and by indirect mechanism (releases prostaglandins). This effect is demonstrated by the increase of the blue Evans concentration in the aqueous-humor after local application of SP, NKA and NKB in a dose-dependent manner. Local treatment with non-steroidal-antiinflammatory drugs like Indomethacin stabilizes the aqueous-humor-blood barrier, by diminishing the local effect of neurokinins. By increasing the vascular permeability SP, NKA and NKB make an important linkage by which the nervous system mediators contribute to the modulation of eye inflammatory responses whose intimate mechanisms are not entirely known yet.

Dissolution and in vivo evidence of differences in reference products: impact on development of generic drugs.

The WHO List of International Comparator Pharmaceutical Products (CPP) For Equivalence Assessment of Interchangeable Multi-Source (Generic) Products will address an important issue in developing new generic drugs because it will identify the 'correct' reference product. This list will reduce unnecessary clinical studies in jurisdictions requiring new generics to be compared with brand products sold locally. Eventually, by employing the CPP, there will be a world-wide standard for brand and generic drugs, assuring the same level of quality internationally. The strategy of a single global reference is meritorious, but there are several hurdles to overcome. Most important is that the same brand may differ in dissolution and/or bioavailability in various jurisdictions, including some drugs with a narrow therapeutic index like phenytoin. Several examples are provided in this manuscript. This issue of regional differences has relevance, not only to the WHO list, but also to the matter of how safety and efficacy was established for that product in the first place. Normally, phase III clinical studies are conducted on a product manufactured in a single site, set to one standard. If the product differs in bioavailability in different jurisdictions, one is left with the question: 'which product has remained true to the original formulation?' Alternatively, if safety and efficacy is maintained with all formulations, then one is faced with the question: 'are the criteria currently employed for bioequivalence unnecessarily restrictive?'

A thousand points of light or just dim bulbs? Radiolabeled antibodies and colorectal cancer imaging.

Radioimmunoscintigraphy (RIS) is coming into its own as an imaging modality in clinical oncology. Early experience with indium-111-labeled intact murine monoclonal antibodies (MoAbs) in colorectal cancer suggested that RIS images hepatic metastases poorly. Moreover, an antimurine immune response was frequently provoked, precluding multiple follow-up RIS studies in individual patients due to reticuloendothelial sequestration of the radioimmunoconjugate before tumor targeting could occur. Recent trials of technetium-99m-labeled antibody fragments and human MoAbs have demonstrated significant improvement in imaging efficacy, and repeated or serial imaging is possible because of the absence of associated immunogenicity. RIS is demonstrably more sensitive than conventional diagnostic modalities (CDM) such as computed tomography (CT) for detection of extrahepatic abdominal and pelvic colorectal carcinoma and is complementary to CDM in imaging liver metastases. In a surgical decision-making analysis comparing CT, RIS (IMMU-4 99mTc-Fab'; CEA-Scan), and CT plus RIS in patients with recurrent or metastatic colorectal cancer, CT plus RIS improved correct prediction of resectability by 40% and correct prediction of unresectability by 100% compared with CT alone. At the present time, RIS used in combination with CDM contributes an incremental improvement in diagnostic accuracy in colorectal cancer patients with known or suspected recurrent disease. Basic and clinical research currently in progress promises to yield agents and methods that provide rapid high-resolution imaging, high tumor-to-background ratios in all organs at risk for tumor recurrence or metastasis, negligible immunogenicity and toxicity, and a significant further improvement in the accuracy of clinical decision making in oncology patients.

Unfiltered sulfur colloid and sentinel node biopsy for breast cancer: technical and kinetic considerations.

BACKGROUND: There are few clinical data on technical limitations and radiocolloid kinetics related to sentinel lymph node (SLN) biopsy for breast cancer. METHODS: In 70 clinical node-negative patients, unfiltered 99mTc sulfur-colloid was injected peritumorally and cutaneous hot spots were mapped with a gamma probe. SLN biopsy was performed followed by axillary lymph node dissection. Missed radioactive nodes (nodes not under hot spots) were removed from axillary lymph node dissection specimens and submitted separately. RESULTS: At least one hot spot was mapped in 69 patients (98%) and SLNs were retrieved in 62 (89%). No radiolabeled nodes were found in five (7%) and only nodes not under hot spots were retrieved in three patients (4%). Residual nodes not under hot spots were retrieved in 17 patients (24%) in whom at least one SLN specimen had been found. Diffuse radioactivity around the radiocolloid injection site impeded identification of all radiolabeled nodes during SLN biopsy, and was responsible for one of two false negatives (20 node-positive patients; false-negative rate 10%). Hot spot radioactivity, number of radiolabeled nodes, and nodal radioactivity did not change with time interval from radiocolloid injection to surgery (0.75-6.25 hours). CONCLUSIONS: Although SLN localization rate is high, intraparenchymal injection may predispose to failure of radiocolloid migration, failure to identify SLNs because of high radiation background, and false-negative outcomes. Alternative routes of radiocolloid administration should be explored.