Connective tissue nevus misdiagnosed as juvenile localized scleroderma.

BACKGROUND: Connective tissue nevi (CTN) are congenital hamartomas caused by excessive proliferation of dermis components. In children, CTN can mimic juvenile localized scleroderma (JLS), an immune mediated skin disorder that requires aggressive immunosuppression. OBJECTIVES: Aim of our study was to describe a series of pediatric patients with CTN misdiagnosed as JLS and the discerning characteristics between the two conditions. METHODS: Retrospective analysis of children referred to our Center during the last two decades for JLS who received a final diagnosis of CTN. Clinical, laboratory, histopathological and instrumental data (MRI and thermography) were collected and compared with those with JLS. RESULTS: Seventeen patients with mean age at onset 4.6 years entered the study. All came to our Center with a certain diagnosis of JLS (n = 15) or suspected JLS (n = 2). The indurated skin lesions were flat and resembled either circumscribed morphea or pansclerotic morphea. In 14 patients (82.4%) they were mainly localized at the lower limbs and in three (17.6%) at the upper limbs. No patient had laboratory inflammatory changes or positive autoantibodies. Skin biopsies confirmed the diagnosis of CTN: non-familial collagenoma in eleven (64.7%), mixed CTN in four (23.5%) and familial CTN in two (11.8%). Mean age at final diagnosis was 9.5 years, with a mean diagnostic delay of 4.8 years (range 1-15 years). Sixteen patients underwent musculoskeletal MRI that was normal in all except two who showed muscle perifascial enhancement. Thermography was normal in all patients. At our first evaluation, eleven patients (64.7%) were on systemic treatment (methotrexate 11, corticosteroids 7, biologics 2), three (17.6%) on topical corticosteroids and three untreated. CONCLUSIONS: CTN can be misdiagnosed as JLS and therefore aggressively treated with prolonged and inappropriate immunosuppression. The absence of inflammatory appearance of the skin lesions, normal instrumental and laboratory findings and the accurate evaluation of skin biopsy are crucial to address the right diagnosis.

Intrasacral meningoceles: Clinical presentation, surgical management, and postoperative outcome: The Giannina Gaslini Hospital's experience.

INTRODUCTION: Intrasacral meningoceles are cysts associated with herniating arachnoid with no nerve root within due to an area of weakness of the dura mater. They are thought to be congenital, but they are usually not symptomatic until adulthood. Surgical treatment is generally indicated in the presence of symptoms. METHODS: We selected cases belonging to the IB category of Nabors et al.'s classification who underwent surgery between 2008 and 2021 at Giannina Gaslini Hospital. Exclusion criteria were prior history of trauma, infections, or operations. Patients' clinical details, associated conditions, surgical techniques, peri- and postoperative complications, and outcomes were collected retrospectively from clinical charts. We compared our series to literature: keywords "intrasacral meningocele" were used on the search engine MEDLINE - Pubmed. RESULTS: We identified 23 cases: 5 of the 14 symptomatic patients had a complete resolution, and 5 had a substantial clinical improvement after surgery. Cyst recurrence and major postoperative complication occurred in none. Among 59 articles considered for evaluation, 50 were excluded and remaining 9 articles underwent full-text analysis. DISCUSSION AND CONCLUSION: The pathogenesis of instrasacral meningoceles is still not completely understood and the spectrum of symptoms is wide. A posterior surgical approach with sacral laminectomy is preferred, although in selected cases it is possible to perform a supplemental anterior approach (sometimes endoscopic). In our surgical series, the largest one published in the literature, a good clinical outcome was achieved in most patients with no cyst's recurrence, pointing out the importance of surgical interruption of communication between cyst and subdural space.

Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

Cetuximab as third-line rechallenge plus either irinotecan or avelumab is an effective treatment in metastatic colorectal cancer patients with baseline plasma RAS/BRAF wild-type circulating tumor DNA: Individual patient data pooled analysis of CRICKET and CAVE trials.

The rechallenge strategy is based on the concept that a subset of patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti-EGFR based-therapy. We performed a pooled analysis of two-phase II prospective trials to determine the role of rechallenge in third-line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third-line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression-free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0-4.9) with median OS (mOS) of 16.9 months (95% CI 11.7-22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7-6.2); mOS was 13.1 months (95% CI 7.3-18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0-5.2); mOS was 18.6 months (95% CI 11.7-25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third-line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments.

BACKGROUND: Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF-V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations. PATIENTS AND METHODS: A prospective discovery cohort including 47 BRAF-V600E-mutant patients treated with BRAFi-anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n= 29). Plasmatic BRAF-V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF-V600E mutations. RESULTS: Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low-BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01). CONCLUSIONS: Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF-V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies.

Clinical efficacy of sequential treatments in KRASG12C-mutant metastatic colorectal cancer: findings from a real-life multicenter Italian study (CRC-KR GOIM).

BACKGROUND: The presence of KRASG12C mutation in metastatic colorectal cancer (mCRC) correlates with poor outcome. Although different selective inhibitors are under clinical development, the optimal treatment remains uncertain. Thus, we conducted a retrospective analysis in a large cohort of patients with KRASG12C mCRC treated in 12 Italian oncology units. PATIENTS AND METHODS: Patients with unresectable mCRC harboring KRASG12C mutation receiving a first-line chemotherapy doublet or triplet between 2011 and 2021 were included in the study. Evaluation of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) analysis was carried out. RESULTS: A total of 256/6952 (3.7%) patients with mCRC displayed KRASG12C mutation; of these, 111 met the inclusion criteria. The ORR of first-line therapy was 38.7% (43/111). Median PFS (mPFS) was 9 months [95% confidence interval (CI) 7.5-10.5 months]. After progression, only 62% and 36% of the patients are fit to receive second or third lines of treatment, with limited clinical benefit. Median OS (mOS) was 21 months (95% CI 17.4-24.6 months). In patients receiving first-line triplet chemotherapy, ORR was 56.3% (9/16), mPFS was 13 months (95% CI 10.3-15.7 months) and mOS was 32 months (95% CI 7.7-56.3 months). For irinotecan-based doublets, ORR was 34.5 (10/29), mPFS was 9 months (95% CI 6.4-11.6 months) and mOS was 22 months (95% CI 16.0-28.0 months). With oxaliplatin-based doublets ORR was 36.4% (24/62), mPFS was 7 months (95% CI 4.6-9.4 months) and mOS was 18 months (95% CI, 13.6-22.4 months). CONCLUSION: Patients with KRASG12C-mutant mCRC had a disappointing response to standard treatments. Within the limitations of a retrospective study, these results suggest that first-line chemotherapy intensification with FOLFOXIRI is a valid option in fit patients.

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives.

Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.

Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression.

BACKGROUND: Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. METHODS: We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. RESULTS: The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. CONCLUSIONS: These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.

Evaluating trifluridine + tipiracil hydrochloride in a fixed combination (TAS-102) for the treatment of colorectal cancer.

INTRODUCTION: Despite major progress in treating advanced colorectal cancer (CRC), prognosis in this population after progression on standard treatment remains dismal and the development of new drugs represents an unmet need. Historically, fluoropyrimidines have played a major role in the treatment of metastatic CRC. TAS-102, a novel combination of trifluridine and tipiracil hydrochloride, has demonstrated improvement in overall survival in the refractory CRC setting, with a safe toxicity profile. Areas covered: A literature review of published clinical studies was performed. Herein, the authors review the pharmacological and clinical data of TAS-102 when used in metastatic CRC, both as a single agent as well as in novel combinations under investigation. Expert opinion: The addition of TAS-102 to the therapeutic armamentarium of metastatic CRC is an encouraging breakthrough considering the demonstrated survival benefit and favorable tolerability profile. Combinations with other agents are under clinical investigation in different settings in an attempt to widen its use. To optimize treatment in today's era of molecular oncology, efforts should be focused on understanding primary and secondary resistance mechanisms, along with the identification of potential biomarkers of response.

Symptomatic Venous Thromboembolism and Major Bleeding After Renal Transplantation: Should We Use Pharmacologic Thromboprophylaxis?

BACKGROUND: Venous thromboembolism (VTE) is a major health issue that may result in complications such as post-thrombotic syndrome, pulmonary hypertension, and death. Appropriate thromboprophylaxis in individuals undergoing kidney transplantation remains unclear. The aim of this study was to determine the prevalence of symptomatic VTE and major bleeding within 90 days after renal transplantation (RT). METHODS: This was a retrospective study on consecutive patients undergoing RT at Hospital Privado Córdoba, Argentina, from January 1, 2006, to December 31, 2013. Exclusion criteria were age <18 years and combined organ transplantation. Pharmacologic or mechanical thromboprophylaxis was not used routinely. Symptomatic VTE and major bleeding were documented. RESULTS: A total of 511 RTs were performed; 62 patients received combined organ transplantation, and 8 patients (1.5%) were lost to follow-up. Overall, follow-up was completed on 441 patients, 4 (0.9%) of whom developed deep venous thrombosis and 14 (3%) of whom died. The most frequent causes of death were septic shock and severe hemorrhage. Duration of surgery >4 hours (P = .006) and a history of VTE (P < .001) were associated with VTE. Twenty-three patients (5.2%) had major bleeding, 2 (0.4%) died from bleeding complications, and 17 (3.85%) required a reoperation to control bleeding. CONCLUSIONS: This study shows a low prevalence of symptomatic VTE in patients undergoing RT despite not having used thromboprophylaxis routinely. Major bleeding was significant, and despite the high risk of VTE assigned by the Caprini score, which suggests pharmacologic prophylaxis, our data raise questions about the appropriate prophylaxis for these patients.

Understanding adverse drug reactions in older adults through drug-drug interactions.

AIMS: The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug-drug interactions (DDIs) in older adults. METHODS: All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate. RESULTS: Amongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%). CONCLUSION: DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly.

Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature.

The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction.

Forearm and hand arteries' aneurysms ­ a case report of bilateral true ulnar artery aneurysm in the hypothenar eminence and systematic review of the literature.

Arterial aneurysms in the forearm, wrist and hand are relatively uncommon. Penetrating injuries, arterial traumas, infections and repetitive microtraumas represent the most frequent cause of these secondary aneurysms or pseudo-aneurysms, while true nontraumaticor infective peripheral aneurysms of the upper extremities are very rarely encountered. Over the last 20 years these have been reported only sporadically, both in adults and children. We describe a case of bilateral true idiopathic saccular artery aneurysms in the hypothenar eminence, treated with excision and arterial continuity restoration by primary end-to-end anastomosis on the left side and conservatively on the right. To our knowledge, no other similar case has been documented to date. Starting from this original case we conducted a systematic review of the literature via PubMed search on peripheral aneurysms of the forearm and hand arteries from 1933 to the present, including specifically true distal ulnar and radial artery aneurysms. Etiology, clinical characteristics and management of these rare pathological entities are extensively discussed.

Anticoagulation therapy for postoperative deep vein thrombosis coupled with pulmonary embolism: a potential trigger for delayed popliteal artery injury presentation after total knee arthroplasty.

OBJECTIVES: A case of delayed popliteal artery injury (PA-INJ) onset after total knee arthroplasty (TKA) in a patient under postoperative anticoagulation therapy is reported. The role of anticoagulation both in late PA-INJ presentation and in PA-INJ management is discussed. REPORT: An obese 76-year-old woman was presented with a common femoral vein thrombosis coupled with pulmonary embolism five days after TKA. She was immediately placed under anticoagulation therapy. Four days later, during physiotherapy-supervised mobilization, she developed a calf haematoma and large retro-articular pseudoaneurysm. Angiography revealed a minor PA-INJ successively treated with a covered stent-graft. CONCLUSIONS: In cases of initially undetected and staunched TKA-related PA-INJs, postoperative anticoagulation therapy may act as a potential trigger for final arterial rupture during mobilization exercises, followed by acute bleeding; in these cases, endovascular management represents an excellent treatment option. Close clinical and instrumental monitoring is strongly recommended after TKA, in patients who imperatively require full-dose anticoagulation therapy.

Arterial entrapment syndrome in the cubital fossa: a rare cause of acute stress-related arterial thrombosis in a patient with brachial artery duplication.

Arterial entrapment syndrome (AES) at elbow level is very rare and to our knowledge no case of AES by lacertus fibrosus in the cubital fossa in presence of brachial artery duplication has been described to date. We describe a rare case of acute arterial thrombosis of one of two brachial arteries highlighted in the cubital fossa which developed after strenuous right elbow flexor muscle activity and hyper-extensions presumably related to AES by lacertus fibrosus at elbow level. A 43-year-old right-handed woman, experienced paleness, coldness and numbness of the right hand, after 8 consecutive hours of gardening. As she worked, her ipsilateral flexor elbow muscles remained in prolonged and inappropriate tension. Clinical examination evidenced the absence of radial artery pulse in the wrist and mild hypothermia in the second and third finger. During surgical exploration two anastomosed brachial arteries were detected in the cubital fossa under the lacertus fibrosus. The lateral superficial brachial artery was occluded. Intraoperative arteriography evidenced brachial artery duplication at the third superior of the arm and normal vascular pattern at the forearm level. In cases of unexplained atypical intermittent upper extremity claudication or acute ischemic symptoms an AES should always be ruled out, particularly when symptoms are exacerbated by strenuous upper extremity activity or when upper limb muscular hypertrophy is evident. In these cases a thorough dynamic clinical and instrumental examination is mandatory to confirm a diagnosis of AES and to avoid possible future ischemic complications.

Real-time analysis of aromatics in combustion engine exhaust by resonance-enhanced multiphoton ionisation time-of-flight mass spectrometry (REMPI-TOF-MS): a robust tool for chassis dynamometer testing.

Resonance-enhanced multiphoton ionisation time-of-flight mass spectrometry (REMPI-TOF-MS) is a robust method for real-time analysis of monocyclic and polycyclic aromatic hydrocarbons in complex emissions. A mobile system has been developed which enables direct analysis on site. In this paper, we utilize a multicomponent calibration scheme based on the analytes' photo-ionisation cross-sections relative to a calibrated species. This allows semi-quantification of a great number of components by only calibrating one compound of choice, here toluene. The cross-sections were determined by injecting nebulised solutions of aromatic compounds into the TOF-MS ion source with the help of a HPLC pump. Then, REMPI-TOF-MS was implemented at various chassis dynamometers and test cells and the exhaust of the following vehicles and engines investigated: a compression ignition light-duty (LD) passenger car, a compression ignition LD van, two spark ignition LD passenger cars, 2 two-stroke mopeds, and a two-stroke engine of a string gas trimmer. The quantitative time profiles of benzene are shown. The results indicate that two-stroke engines are a significant source for toxic and cancerogenic compounds. Air pollution and health effects caused by gardening equipment might still be underestimated.

Localized superficial femoral vein thrombosis coupled with iatrogenic arteriovenous fistulas presenting as pulmonary emboli.

INTRODUCTION: 'Localized' femoral vein thrombosis (FVT) is a relatively rare condition usually associated with traumas, external compression or iatrogenic etiologies and the consequence can be pulmonary embolism. REPORT: This is the case of a 46-year-old woman who presented with pulmonary emboli secondary to 'localized' superficial FVT, coupled with post-puncture arteriovenous fistulas (AVFs), two days after trans-femoral vein radio-frequency cardiac ablation. After placing a temporary IVC-filter, the AVFs were sutured directly while the residual FVT was treated conservatively. DISCUSSION: Close local monitoring and adequate medical and surgical management are mandatory to avoid possible dangerous complications, also in apparently 'low-risk' iatrogenic AVFs.

Update on low molecular weight heparins at the beginning of third millennium. Focus on reviparin.

BACKGROUND: This review provides an outline of the main pharmacological and clinical features of low molecular weight heparins (LMWHs) and a wider description of reviparin. The basic pharmacological properties of LMWHs are compared with those of unfractionated heparin, showing clear advantages of the former, mainly as for pharmacokinetic profile. DESIGN: Consequently LMWHs are characterized by a more predictable behaviour. A key issue is the lack of "bioequivalence": LMWHs are in fact distinct chemical entities, with typical pharmacological and clinical profile for each agent. Therefore, they are not reciprocally interchangeable. The efficacy and safety of reviparin, a second generation LMWH, has been evaluated in many clinical trials as both thrombosis prevention and treatment. Reviparin use is documented in general and orthopaedic surgery. In patients undergoing abdominal surgery reviparin resulted more effective and better tolerated than unfractionated heparin (UFH). In total hip replacement patients, reviparin compared favourably with enoxaparin, showing the same efficacy but better safety. In patients who undergone total hip replacement, also the long-term, out of hospital prevention of deep vein thrombosis (DVT) has been proven. CONCLUSIONS: The comparison with acenocoumarol demonstrated that reviparin was more effective in preventing DVT recurrences and far better tolerated than oral anticoagulant treatment. Reviparin was also effective and well tolerated in immobilised patients following leg injury with plaster casts or braces applications. Positive results were also obtained in the treatment of venous thromboembolism in well-designed studies on large patient populations. In this indication reviparin compared favourably with iv UFH. As for the use in cardiology patient, reviparin is at present the only approved LMWH for the prevention of acute thrombotic events in patients undergoing percutaneous transluminal coronary angioplasty.

Application of modern online instrumentation for chemical analysis of gas and particulate phases of exhaust at the European Commission heavy-duty vehicle emission laboratory.

The European Commission recently established a novel test facility for heavy-duty vehicles to enhance more sustainable transport. The facility enables the study of energy efficiency of various fuels/scenarios as well as the chemical composition of evolved exhaust emissions. Sophisticated instrumentation for real-time analysis of the gas and particulate phases of exhaust has been implemented. Thereby, gas-phase characterization was carried out by a Fourier transform infrared spectrometer (FT-IR; carbonyls, nitrogen-containing species, small hydrocarbons) and a resonance-enhanced multiphoton ionization time-of-flight mass spectrometer (REMPI-TOFMS; monocyclic and polycyclic aromatic hydrocarbons). For analysis of the particulate phase, a high-resolution time-of-flight aerosol mass spectrometer (HR-TOF-AMS; organic matter, chloride, nitrate), a condensation particle counter (CPC; particle number), and a multiangle absorption photometer (MAAP; black carbon) were applied. In this paper, the first application of the new facility in combination with the described instruments is presented, whereby a medium-size truck was investigated by applying different driving cycles. The goal was simultaneous chemical characterization of a great variety of gaseous compounds and particulate matter in exhaust on a real-time basis. The time-resolved data allowed new approaches to view the results; for example, emission factors were normalized to time-resolved consumption of fuel and were related to emission factors evolved during high speeds. Compounds could be identified that followed the fuel consumption, others showed very different behavior. In particular, engine cold start, engine ignition (unburned fuel), and high-speed events resulted in unique emission patterns.