Incidental finding of an (11)C-choline PET-positive solitary plasmacytoma lesion.
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Aged↗
Biomedical subjects
E Pasquini
Publications and source records attributed to E Pasquini.
A randomized phase II trial evaluating standard (50 mg/min) versus low (10 mg/min) infusion duration of gemcitabine as first-line treatment in advanced non-small-cell lung cancer patients who are not eligible for platinum-based chemotherapy.
PURPOSE: Gemcitabine is one of the most active drugs against non-small-cell lung cancer (NSCLC). Preclinical data suggested that gemcitabine efficacy could be improved by increasing the dose or by increasing the infusion duration. This study has been designed in order to explore two different approaches of gemcitabine dose intensification in patients with advanced NSCLC. PATIENTS AND METHODS: A total of 121 chemonaive patients with locally advanced or metastatic NSCLC not suitable for a platinum-based chemotherapy were randomly allocated to chemotherapy with gemcitabine 1500 mg/m2 on days 1 and 8 every 3 weeks by standard 30 min intravenous infusion (arm A), or gemcitabine 10 mg/m2/min for 150 min on days 1 and 8 every 3 weeks by intravenous infusion at fixed dose rate (arm B). RESULTS: One hundred and seventeen patients were fully analyzed. No difference in response rate (16.1% versus 9.9%, p=0.28), median time to disease progression (4 months versus 4.5 months, p=0.34) median survival (9.8 months in both arms), and 1-year survival (42.6% versus 39.0% p=0.98) was detected in arms A and B, respectively. No treatment-related deaths occurred. Main hematological toxicities were grade 3-4 neutropenia observed in 17.9% of patients in group A and in 49.2% of individuals in group B (p=0.0002). The incidence of febrile neutropenia was 3.3% in arm A and 0% in arm B (p=0.17). Grade 3-4 thrombocytopenia was more frequently observed in arm B patients (9.9% versus 1.8%, p=0.057). Non-hematological toxicity was similar in both arms, and consisted in grade 1-2 gastrointestinal toxicity observed in 48.2% of patients in arm A and 41.0% in arm B. CONCLUSION: Intensification of standard doses or prolonged infusion schedule did not result in efficacy improvement. Gemcitabine infusion duration does not warrant further investigation in patients with advanced NSCLC.
Aged↗
Pre- and post-dialysis quantitative dosage of thymidine in urine and plasma of a MNGIE patient by using HPLC-ESI-MS/MS.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. The disease is due to a thymidine phosphorylase defect. This enzyme catalyses the phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. For this reason, increased levels of thymidine in plasma and urine are found in MNGIE patients. Haemodialysis can reduce circulating plasma thymidine levels and can be beneficial in some MNGIE patients. We developed a fast analytical method based on HPLC-ESI-MS/MS capable of identifying pyrimidine nucleotides (thymine, cytosine, uracil) and nucleosides (thymidine, citidine, uridine) in plasma and urine after direct dilution of the samples without pre-treatment. In the patient studied, we observed a significant reduction of plasmatic and urinary thymidine levels during and after dialysis. However, we noted a progressive reduction of the initial thymidine level after some dialytic trials. This method will be useful not only for thymidine level follow-up during dialysis in MNGIE patients but also for the improvement of the diagnosis or diagnostic suspect in other pyrimidine defects such as dihydropyrimidine dehydrogenase deficiency, dihydropyrimidinase deficiency and ureidopropionase deficiency.
Adult↗
Genetic and biochemical approach to early prenatal diagnosis in a family with mut methylmalonic aciduria.
Genetic and biochemical prenatal diagnosis was performed at 11 weeks of gestation in a family with a proband affected by mut methylmalonic aciduria (MMA) and homozygotes for the MUT gene c.643G>A (p.Gly215Ser) mutation. Both chorionic villus and amniotic fluid samples were used. The presence of high levels of methylmalonic acid and propionylcarnitine determined by gas chromatography/mass spectrometry and LC/MS/MS analysis, respectively, and the identification of the p.Gly215Ser at a homozygous level in foetal DNA allowed a certain, rapid and early diagnosis. To our knowledge, this is the first mut MMA prenatal diagnosis carried out by genetic and biochemical approach.
Amino Acid Metabolism, Inborn Errors↗
Hyperkalemia after acute metabolic decompensation in two children with vitamin B12-unresponsive methylmalonic acidemia and normal renal function.
The patients affected by vitamin B12-unresponsive methylmalonic acidemia (MMA) on the long run develop chronic renal disease with interstitial nephropathy and progressive renal insufficiency. The mechanism of nephrotoxicity in vitamin B12-unresponsive MMA is not yet known. Chronic hyporeninemic hypoaldosteronism has been found in many cases of methylmalonic acidemia, hyperkalemia and renal tubular acidosis type 4. We report 2 patients affected by B12-unresponsive methylmalonic acidemia diagnosed at the age of 23 months and 5 years, respectively, with normal glomerular filtration and function. They showed hyporeninemic hypoaldosteronism and significant hyperkalemia requiring sodium potassium exchange resin (Kayexalate) therapy after an episode of metabolic decompensation leading to diagnosis of MMA. In both children, hyporeninemic hypoaldosteronism and hyperkalemia disappeared after 6 months of good metabolic control.
Child, Preschool↗
Successful prenatal molecular diagnosis of carbamyl-phosphate synthetase I deficiency in two at-risk pregnancies.
We report the two first prenatal diagnoses in an Italian family with a proband affected by neonatal carbamyl-phosphate synthetase I deficiency in which molecular analysis identified V457G and Q810R amino acid substitutions. We performed a prenatal diagnosis on genomic DNA isolated from chorionic villus and amniotic fluid samples collected at 13 weeks of gestation. In the first pregnancy, the fetus was compound heterozygous for the mutations and termination of pregnancy was elected. The genetic lesions were also confirmed on genomic DNA isolated from the fetus's liver and skin fibroblasts. A few months later, we performed a second prenatal diagnosis in this family. The second fetus was heterozygous for the wild-type alleles. The pregnancy was continued and a girl was born at 41 weeks of gestation. We have confirmed the wild-type state on the baby's DNA.
Amniocentesis↗
Mutational spectrum in ten Italian patients affected by methylmalonyl-CoA mutase deficiency.
We report seven novel mutations, including three amino acids substitutions (p.Glu286Lys, p.Cys560Tyr, p.Pro615Leu), two nonsense mutations (p.Arg31X, p.Glu 451X), one splicing defect (c.2125-1G >A), one small deletion (c.1758-1759delA) and nine previously described mutations identified in 10 unrelated Italian patients affected by mut MMA.
Adult↗
Phenotypic heterogeneity in two unrelated Danon patients associated with the same LAMP-2 gene mutation.
Danon disease, an X-linked cardioskeletal myopathy caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2), is clinically characterized by cardiomyopathy, myopathy, and variable mental retardation. The pathological hallmark of the disease is the absence of LAMP-2 immunohistochemical staining in muscle. The LAMP-2 gene mutations reported thus far are generally private mutations. We describe two cases of Danon disease with different clinical presentation, in whom we identified the same exon skipping mutation c.928G>A in the LAMP-2 gene. The first patient was affected by an early onset myopathy and hypertrophic cardiomyopathy (HCM) that partially improved with drug treatment. A first muscle biopsy at age 4 months showed markedly increased glycogen, and acid maltase deficiency was ruled out biochemically. A second muscle biopsy, performed at age 3(1/2) years, showed very mild abnormalities. The second child at age 15 years had mild, diffuse muscle weakness and wasting, moderate mental deficiency, and HCM. Two serial biopsies performed at age 8 and 15 years showed similar findings of multiple esterase-positive vacuoles in type I myofibers. In both patients the immunohistochemical study demonstrated the absence of LAMP-2 in skeletal muscle.
Adolescent↗
Efficacy of two different platinum- or anthracycline-containing chemotherapy regimens for the treatment of small cell lung cancer.
The records of 190 consecutive patients referred to our department to be treated for small cell lung cancer were retrospectively evaluated, and the outcomes were compared on the basis of their first-line treatment. 113 patients were treated with 4-6 courses of cyclophosphamide, epidoxorubicin and etoposide (CEVP16), 77 with 4-6 courses of carboplatin and etoposide (CBE). 72 patients had limited disease and 118 extensive disease. Response rates were 58.4% for CEVP16 and 28.6% for CBE (p=0.0001), with no significant difference in the time to progression (255 vs 246 days, p=0.21). Overall survival was 334 days and 212 days, and the 1-year survival rate was 46% and 22.1%, respectively (p=0.0018). In patients with limited disease, overall survival was 434 days and 249 days (p=0.08) in both treatment group respectively and 281 and 208 days in those with extensive disease, respectively (p=0.02). No difference in side effects was observed between the two groups of patients. Our data suggest a role for anthracycline-containing regimens as first-line treatment of small cell lung cancer.
Adult↗
Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV).
BACKGROUND: Glycogen storage disease type IV (GSD-IV) is a clinically heterogeneous autosomal recessive disorder due to glycogen branching enzyme (GBE) deficiency and resulting in the accumulation of an amylopectin-like polysaccharide. The typical presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular form of GSD-IV varies in onset (perinatal, congenital, juvenile, or adult) and severity. OBJECTIVE: To identify the molecular bases of different neuromuscular forms of GSD-IV and to establish possible genotype/phenotype correlations. METHODS: Eight patients with GBE deficiency had different neuromuscular presentations: three had fetal akinesia deformation sequence (FADS), three had congenital myopathy, one had juvenile myopathy, and one had combined myopathic and hepatic features. In all patients, the promoter and the entire coding region of the GBE gene at the RNA and genomic level were sequenced. RESULTS: Nine novel mutations were identified, including nonsense, missense, deletion, insertion, and splice-junction mutations. The three cases with FADS were homozygous, whereas all other cases were compound heterozygotes. CONCLUSIONS: This study expands the spectrum of mutations in the GBE gene and confirms that the neuromuscular presentation of GSD-IV is clinically and genetically heterogeneous.
1,4-alpha-Glucan Branching Enzyme↗
Endoscopic treatment of encephaloceles of the lateral wall of the sphenoid sinus.
OBJECTIVE: The suitability of the endoscopic approach for the treatment of an encephalocele of the lateral wall of the sphenoid is discussed. This is a retrospective review of 4 cases diagnosed with temporosphenoidal encephalocele and having a history of CSF leak who were surgically treated using an endoscopic endonasal approach between January 2001 and June 2002 at the Department of Otolaryngology of Sant'Orsola-Malpighi University Hospital and the Department of Neurosurgery at Bellaria Hospital in Bologna. METHODS: Three patients were female between 48 and 73 years of age (mean: 61 years). All patients had suffered from a CSF leak for 5 months to 18 years. None of the patients had a past medical history of head trauma. A fourth patient had undergone a previous microscopic approach for a previously misdiagnosed CSF leak wrongly ascribed to an empty sella. Three patients underwent an ethmoid-pterygo-sphenoidal endoscopic approach (EPSEA), while the patient who had undergone previous microscopic surgery, was treated using a transnasal transsphenoidal endoscopic approach. RESULTS: The follow-up of the patients ranged from 10 to 26 months (mean: 18 months) and no case of a recurrent CSF leak was observed postoperatively. CONCLUSIONS: In our report, the endoscopic approach was a useful tool for the treatment of encephaloceles of the lateral wall of the sphenoid sinus. In skilled hands, this technique permits both the resection of the encephalocele and the subsequent reconstruction of the defect also with a low rate of morbidity.
Aged↗
Structural organization of the human carbamyl phosphate synthetase I gene (CPS1) and identification of two novel genetic lesions.
Carbamyl Phosphate Synthetase I deficiency (CPSID) is a rare autosomal recessive urea cycle disorder usually characterized by potentially lethal neonatal hyperammonemia. The large (5215 bp) CPS1-cDNA, expressed only in liver and epithelial cells of intestinal mucosa, has been cloned. Until now the CPS1 genomic organization was unknown. Taking advantage of the phylogenetic lineage between the CPS1 gene of Homo sapiens and Rattus norvegicus, we determined the intron-exon organization of the human CPS1 gene. Starting from the ATG codon, the CPS I gene is organized in 38 exons spanning from 50bp to 200 bp. We also report the molecular studies on an Italian patient affected by neonatal CPSD. Two novel genetic lesions (c.1370T>G and c.2429A>G) that lead to the novel amino acid substitutions V457G and Q810R, and the known N1406T polymorphism, were detected in the patient's CPS1 RNA and in genomic DNA isolated from peripheral blood lymphocytes. The characterization of the CPS1 genomic organization will allow the identification of the genetic lesions of CPSD patients, the detection of carriers, better genetic counseling and a more certain, less invasive method of prenatal diagnosis.
Amino Acid Substitution↗
Clinical findings and biochemical and molecular analysis of four patients with holocarboxylase synthetase deficiency.
Holocarboxylase synthetase (HLCS) deficiency (HLCSD) is a rare autosomal recessive disorder of biotin metabolism. HLCS catalyzes the biotinylation of the four human biotin-dependent carboxylases. Using the newly available human genomic sequence, we report the map of HLCS genomic structure and the predicted exon/intron boundaries. Moreover, the molecular studies of four patients (two Italians, one Iranian, and one Australian) affected by HLCS deficiency are here reported. The clinical findings, the age of onset, and response to biotin treatment differed between our patients. The diagnosis was made by organic acid analysis and confirmed by enzymatic analysis in three patients. Six mutations in the HLCS gene were identified, including two novel (N511K and G582R) and four known missense mutations (L216R, R508W, V550M, and G581S). Five of the mutations are localized within the HLCS biotin-binding domain, whereas the L216R amino acid change is located in the N-terminal region outside of the putative biotin-binding domain. This mutation, previously reported in a heterozygous state, was detected for the first time in a patient with homozygous status. The patient's severe clinical phenotype and partial responsiveness to biotin support a genotype-phenotype correlation through the involvement of residues of the N-terminal region in a substrate specificity recognition or regulation of the HLCS enzyme.
Acidosis↗
Genetic analysis in nine unrelated Italian patients affected by OTC deficiency: detection of novel mutations in the OTC gene.
Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder due to a defect of the mithocondrial enzyme ornithine transcarbamylase (OTC). Genetic analysis in nine unrelated Italian patients affected by OTCD (one male patient and eight female manifesting carriers) led to the detection of three novel mutations and six previously reported mutations in the OTC gene. The analysis was performed by direct sequencing of OTC cDNA, OTC exons, and intron-exon boundaries and enzymatic restriction analysis on the patients' genomic DNA and total RNA isolated from peripheral blood lymphocytes. In the male patient the new mutation S132P due to the nucleotide change c.394T>C was identified. In a manifesting carrier the nucleotide change c.292G>A that leads to the novel amino acid substitution E98K was identified; this mutation is close to the OTC protein's carbamyl phospate binding site. In another manifesting carrier the OTC cDNA analysis revealed the normally spliced transcript and an aberrant transcript with an insertion of two nucleotides (c.77-78insAG). In the patient's genomic DNA we identified a new transvertion IVS1-3C>G at the heterozygous state; this nucleotide change generates a new splice acceptor site in intron 1 that induces an RNA splicing defect. This insertion causes a frame shift in OTC cDNA ORF and leads to a premature stop codon. The previously described mutations N161S, R141Q, T178M, R92X, A208T, M268T were identified in the other six manifesting carriers.
Alleles↗
Two new mutations in children affected by partial biotinidase deficiency ascertained by newborn screening.
Mutation analysis performed on DNA from 6 Italian patients with partial biotinidase deficiency ascertained by newborn screening allowed the identification of two new mutations, c1211C > T (T404I) and a single base deletion c594delC. All patients were compound heterozygous for the D444H amino acid substitution showing that this mutation is also common in Italian patients affected by partial biotinidase deficiency.
Amidohydrolases↗
3-Hydroxy-3-methylglutaric aciduria in an Italian patient is caused by a new nonsense mutation in the HMGCL gene.
3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). Up to now only a few mutations have been reported in the HMGCL gene. We report the first Italian patient, a female who presented metabolic acidosis at 3 days of age and then 3 months later. Analysis of urinary organic acids showed the excretion of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. A defect of HMGCL activity was suspected and then confirmed on cultured skin fibroblasts. Brain RM showed a diffuse mild abnormality of cerebral white matter in the periventricular regions, and the single voxel proton MRI spectroscopy showed abnormal peaks. In the patient's full-length HMGCL-cDNA a new c286C > T transition that leads to the stop codon Q96X was detected at the homozygous level. This mutation, that gives rise to a truncated protein, was confirmed in the patient's and also her parents' genomic DNA. The severe genetic lesion identified in the patient, which is in contrast with the mild clinical phenotype, stresses the importance of early diagnosis and therapy in HMGCL deficiency.
Brain↗
Combination chemotherapy of carboplatin and gemcitabine against solid tumors: a phase I trial.
BACKGROUND: Some trials have suggested that the combination of gemcitabine and platinum compounds can have a synergistic effect on several solid tumors, but, at present, the data concerning carboplatin-gemcitabine combinations are not sufficient to allow the planning of phase II trials. The present phase I trial was planned to define the maximum tolerated dose and the dose-limiting toxicity of a carboplatin-gemcitabine combination. METHODS: Thirty-two patients with advanced, pretreated solid tumors were treated with carboplatin on day 1 and gemcitabine on days 1, 8, and 15 every 28 days. The starting doses of carboplatin and gemcitabine were 3.5 mg/ml per min (area under the curve; AUC), and 600 mg/m2, respectively. The doses of the two agents were alternately increased to 4, 4.5, and 5 mg/ml per min and to 800 and 960 mg/m2, respectively. At each dose level, three patients were initially enrolled. If one of them experienced grade IV hematological toxicity or grade III-IV nonhematological toxicity (with the exception of alopecia), an additional three patients were enrolled at the same dose level. If two or more patients experienced grade IV hematological toxicity or grade III-IV non-hematological toxicity (with the exception of alopecia), the maximum tolerated dose was considered to have been reached, and the dose below this was recommended for further studies. All patients were evaluated weekly for toxicity and after every two courses of chemotherapy for response. RESULTS: Dose-limiting toxicity was hematological, and the maximum tolerated doses were 4.5 mg/ml per min for carboplatin and 800 mg/m2 for gemcitabine. The activity of the carboplatin/gemcitabine combination was encouraging, with a 21.9% response rate (7/32), three complete disease regressions, and a median time to progression of 30 weeks. The gemcitabine doses of day 15 or days 8 and 15 were omitted for hematological toxicity in 57 (50%) and 17 (14.9%) courses of chemotherapy, while no courses of chemotherapy were delayed for grade III-IV hematological or nonhematological toxicity. CONCLUSION: The maximum tolerated doses suggested by this trial are lower than those in other similar phase I trials, but they are consistent with those reported by most of the trials investigating gemcitabine either in combination with cisplatin or in heavily pretreated patients. Carboplatin 4.5 mg/ml per min on day 1 plus gemcitabine 800 mg/m2 on days 1, 8, and 15 every 28 days may represent a promising schedule for further phase II trials.
Adolescent↗
Extended transsphenoidal approach.
The authors have developed an extended transsphenoidal approach with submucosal posterior ethmoidectomy for resection of tumors located in the cavernous sinus or the suprasellar region that are difficult to remove via the conventional transsphenoidal approach. Surgery was performed using this approach in 14 patients with large pituitary adenomas, three patients with craniopharyngiomas, and one patient with a meningioma of the tuberculum sellae. The submucosal dissection of the nasal septum used in the conventional transsphenoidal approach was extended to the superior lateral wall of the nasal cavity to expose the bony surface of the superior turbinate lying under the nasal mucosa. Submucosal posterior ethmoidectomy widened the area visualized through the conventional transsphenoidal approach both superiorly and laterally. This provided a safer and less invasive access to lesions in the cavernous sinus or the suprasellar region through the sphenoid sinus. Using this approach the authors encountered no postoperative complications, such as olfactory disturbance, cranial nerve palsy, or arterial injury. In this article the authors present the surgical methods used in this approach.
Brain Neoplasms↗