Role of bone marrow biopsy in staging of patients with classical Hodgkin's lymphoma undergoing positron emission tomography/computed tomography.

Several studies suggested that staging bone marrow biopsy (BMB) could be omitted in patients with classical Hodgkin's lymphoma (cHL) when a positron emission tomography/computed tomography (PET/CT) is performed at baseline.To address the concordance between BMB and PET/CT in the detection of bone marrow involvement (BMI) and the BMB role in determining the Ann Arbor stage, we retrospectively collected data on 1244 consecutive patients with cHL diagnosed from January 2007 to December 2013. One thousand eighty-five patients who had undergone both BMB and PET/CT were analyzed, comparing the Ann Arbor stage assessed with PET/CT only to that resulting from PET/CT combined with BMB.One hundred sixty-nine patients (16%) showed at least one focal skeletal lesion (FSL) at PET/CT evaluation. Only 55 patients had a positive BMB (5.1%); 34 of them presented at least one FSL at PET/CT. To the contrary, 895 out of 1030 patients with a negative BMB did not show any FSL (86.9%). Positive and negative predictive values of PET/CT for BMI were 20 and 98%, respectively; sensitivity and specificity were 62 and 87%, respectively. Fifty-four out of 55 patients with a positive BMB could have been evaluated as an advanced stage just after PET/CT; only one patient (0.1%) would have been differently treated without BMB.Our data showed a very high negative predictive value of PET/CT for BMI and a negligible influence of BMB on treatment planning, strengthening the recent indications that BMB could be safely omitted in cHL patients staged with PET/CT.

Attention modulation regulates both motor and non-motor performance: a high-density EEG study in Parkinson's disease.

We have previously shown that, in early stages of Parkinson's disease (PD), patients with higher reaction times are also more impaired in visual sequence learning, suggesting that movement preparation shares resources with the learning of visuospatial sequences. Here, we ascertained whether, in patients with PD, the pattern of the neural correlates of attentional processes of movement planning predict sequence learning and working memory abilities. High density Electroencephalography (EEG, 256 electrodes) was recorded in 19 patients with PD performing reaching movements in a choice reaction time paradigm. Patients were also tested with Digit Span and performed a visuomotor sequence learning task that has an important declarative learning component. We found that attenuation of alpha/beta oscillatory activity before the stimulus presentation in frontoparietal regions significantly correlated with reaction time in the choice reaction time task, similarly to what we had previously found in normal subjects. In addition, such activity significantly predicted the declarative indices of sequence learning and the scores in the Digit Span task. These findings suggest that some motor and non motor PD signs might have common neural bases, and thus, might have a similar response to the same behavioral therapy. In addition, these results might help in designing and testing the efficacy of novel rehabilitative approaches to improve specific aspects of motor performance in PD and other neurological disorders.

Comorbid Normal Pressure Hydrocephalus with Parkinsonism: A Clinical Challenge and Call for Awareness.

Idiopathic normal pressure hydrocephalus (iNPH) is the most common cause of hydrocephalus in adults. The diagnosis may be challenging, requiring collaborative efforts between different specialists. According to the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders, iNPH should be considered in the differential of any unexplained gait failure with insidious onset. Recognizing iNPH can be even more difficult in the presence of comorbid neurologic disorders. Among these, idiopathic Parkinson's disease (PD) is one of the major neurologic causes of gait dysfunction in the elderly. Both conditions have their peak prevalence between the 6th and the 7th decade. Importantly, postural instability and gait dysfunction are core clinical features in both iNPH and PD. Therefore, diagnosing iNPH where diagnostic criteria of PD have been met represents an additional clinical challenge. Here, we report a patient with parkinsonism initially consistent with PD who subsequently displayed rapidly progressive postural instability and gait dysfunction leading to the diagnosis of concomitant iNPH. In the following sections, we will review the clinical features of iNPH, as well as the overlapping and discriminating features when degenerative parkinsonism is in the differential diagnosis. Understanding and recognizing the potential for concomitant disease are critical when treating both conditions.

Visuospatial exploration and art therapy intervention in patients with Parkinson's disease: an exploratory therapeutic protocol.

Though abnormalities of visuospatial function occur in Parkinson's disease, the impact of such deficits on functional independence and psychological wellbeing has been historically under- recognized, and effective treatments for this impairment are unknown. These symptoms can be encountered at any stage of the disease, affecting many activities of daily living, and negatively influencing mood, self-efficacy, independence, and overall quality of life. Furthermore, visuospatial dysfunction has been recently linked to gait impairment and falls, symptoms that are known to be poor prognostic factors. Here, we aim to present an original modality of neurorehabilitation designed to address visuospatial dysfunction and related symptoms in Parkinson's disease, known as "Art Therapy". Art creation relies on sophisticated neurologic mechanisms including shape recognition, motion perception, sensory-motor integration, abstraction, and eye-hand coordination. Furthermore, art therapy may enable subjects with disability to understand their emotions and express them through artistic creation and creative thinking, thus promoting self-awareness, relaxation, confidence and self-efficacy. The potential impact of this intervention on visuospatial dysfunction will be assessed by means of combined clinical, behavioral, gait kinematic, neuroimaging and eye tracking analyses. Potential favorable outcomes may drive further trials validating this novel paradigm of neurorehabilitation.

c-Myc Sustains Transformed Phenotype and Promotes Radioresistance of Embryonal Rhabdomyosarcoma Cell Lines.

We have previously reported that the MEK/ERK pathway sustains in vitro and in vivo transformed phenotype and radioresistance of embryonal rhabdomyosarcoma (ERMS) cell lines. Furthermore, we found that aberrant MEK/ERK signaling activation promotes c-Myc oncoprotein accumulation. In this study, the role of c-Myc in sustaining the ERMS transformed and radioresistant phenotype is characterized. RD and TE671 cell lines conditionally expressing MadMyc chimera protein, c-Myc-dominant negative and shRNA directed to c-Myc were used. Targeting c-Myc counteracted in vitro ERMS adherence and in suspension, growth motility and the expression of pro-angiogenic factors. c-Myc depletion decreased MMP-9, MMP-2, u-PA gelatinolytic activity, neural cell adhesion molecule sialylation status, HIF-1α, VEGF and increased TSP-1 protein expression levels. Rapid but not sustained targeting c-Myc radiosensitized ERMS cells by radiation-induced apoptosis, DNA damage and impairing the expression of DNA repair proteins RAD51 and DNA-PKcs, thereby silencing affected ERMS radioresistance. c-Myc sustains ERMS transformed phenotype and radioresistance by protecting cancer cells from radiation-induced apoptosis and DNA damage, while promoting radiation-induced DNA repair. This data suggest that c-Myc targeting can be tested as a promising treatment in cancer therapy.

Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson's disease on L-dopa monotherapy.

The aim of the study was to investigate the relationship between dyskinesias and motor fluctuations in patients with Parkinson's disease on l-dopa monotherapy. We identified 116 patients on l-dopa monotherapy treated between 1965 and 1992 and followed until death. Dyskinesias occurred in 102 patients. Of these, 48 only developed dyskinesias while 54 had both dyskinesias and motor fluctuations. Among patients with both complications, 49 developed dyskinesias before fluctuations, and only five had dyskinesias after the onset of fluctuations. Our findings suggest that dyskinesias predict the onset of motor fluctuations, and may share a common pathophysiological mechanism.

[Therapeutic advances in neoplastic hematology: target therapy anti-CD33]. / Approcci terapeutici innovativi in oncoematologia: terapia mirata anti-CD33.

Antibodies capable to recognize antigen expressed on cancer cells represents the ideal approach for targeted anti neoplastic therapies. The CD33 antigen is present on 90% of acute myeloid leukemia blasts and is shared on normal hemopoietic cells only on the non stem dillerentiating fraction. Gemtuzumab Ozogamicin (GO) is an engineered humanized antibody anti-CD33 conjugated with a potent intercalating agent, named calicheamicin, which is release only at intracellular level (lower pH), following a selective binding to CD33-positive cells, thus representing a promising approach for target anti-leukemia therapy. GO was approved conditionally by the Federal Drug Administration in May 2000 as a single therapy for first recurrence of Acute Myeloid Leukemia (AML) in a subset of older patients. Since 2000, treatment trials and pilot studies have revealed potential expanded applications along with potential limitations. Phase II trials have confirmed the activity and the efficacy of GO as single agent in the treatment of relapsed AML. More recently, clinical trials on induction and post-remission treatment of adult AML have shown efficacy of GO in combination chemotherapy. The strong and homogeneous CD33 expression in Acute Promyelocytic Leukemia (APL), have resulted in an effective treatment of this disease with GO used as salvage treatment, as well as innovative approach for molecular relapsed patients. However, the incidence of veno-occlusive disease, better defined as sinusoidal occlusive syndrome (SOS), must be taken into account as potential complication associated with the GO administration, especially in patients treated with ablative regimens. In conclusion, the extension of the approval in Italy to AML CD33+ in relapsed, regardless age limitation, along with the ongoing evaluation by the European EMEA, represent the basis for a large clinical application of GO in myeloid malignancies potentially extended to paediatric patients with AML and to ALL CD33+.

The role of somatosensory evoked potentials in the diagnosis of AIDS-associated myelopathy.

BACKGROUND: Although AIDS-associated vacuolar myelopathy is detected in >50% of autopsy cases, it is often unrecognized during life. The clinical assessment is often difficult because of concurrent peripheral neuropathy and lack of specific diagnostic markers. Somatosensory evoked potentials (SEPs) have been successfully used to evaluate central conduction in a number of diseases involving the spinal cord. OBJECTIVES: To assess the diagnostic yield of SEPs in AIDS-associated myelopathy. METHODS: We recorded tibial and median nerve SEPs in 69 HIV-infected subjects referred for evaluation of lower extremity neurologic abnormalities. Stimulation of the peroneal nerve at the popliteal fossa was performed in patients with absent response to ankle stimulation. RESULTS: HIV-infected subjects had significantly delayed latencies of both peripheral and central potentials, suggesting a combination of peripheral and CNS abnormalities. Analysis of peripheral and central latencies allowed us to discriminate between neuropathy and myelopathy in individual patients. Abnormalities of tibial central conduction time (CCT) correlated with clinical diagnosis of myelopathy. There was no significant difference in median CCTs between patients and controls, suggesting that conduction abnormalities were restricted to the thoracolumbar spinal cord. A derived spinal conduction time was a sensitive indicator of central conduction abnormalities in AIDS patients with myelopathy. CONCLUSIONS: The combination of median, posterior tibial, and peroneal SEPs is a valuable tool in the diagnosis of AIDS-associated myelopathy, particularly when myelopathy and peripheral neuropathy coexist. The use of a derived spinal conduction time improves the diagnostic yield of SEPs in AIDS-associated myelopathy.

A pilot study of L-methionine for the treatment of AIDS-associated myelopathy.

The pathogenesis of AIDS-associated vacuolar myelopathy (VM) may be related to abnormality of transmethylation mechanisms in the nervous system. To evaluate the safety and potential efficacy of the methyl-group donor L-methionine in AIDS-associated VM, we conducted a pilot clinical trial in 12 patients with VM. Seven of the nine patients who completed the study had clinical and electrophysiologic improvement. Controlled studies may be indicated to assess the efficacy and safety of L-methionine in AIDS-associated VM.

Abnormal cobalamin-dependent transmethylation in AIDS-associated myelopathy.

BACKGROUND: White matter vacuolization of the spinal cord is common in patients with AIDS and may lead to clinical manifestations of myelopathy. The pathogenesis of AIDS-associated myelopathy (AM) is unknown and may be related to metabolic abnormalities rather than to direct HIV infection. The striking pathologic similarity between AM and the vacuolar myelopathy associated with vitamin B(12) deficiency suggests that abnormal metabolism of the B(12)-dependent transmethylation pathway may be important in the pathogenesis of AM. METHODS: The authors compared S-adenosyl-methionine (SAM), methionine, homocysteine, and glutathione in serum and CSF of 15 patients with AM vs. 13 HIV-infected controls without myelopathy (HWM). They also compared the results with a non-HIV--infected reference population (NC). All patients had normal B(12), folate, and methylmalonic acid levels. RESULTS: There was a decrease in CSF SAM in the AM group compared with the HWM group (p < 0.0001) and the NC group (p < 0.0001). CSF SAM in the HWM group was also lower than that in the NC group (p = 0.015). Serum methionine was also reduced in serum of the myelopathic group compared with the NC group (p = 0.006). CONCLUSIONS: AM is associated with an abnormality of the vitamin B(12)-dependent transmethylation pathway.

AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid.

The pathogenesis of AIDS-associated myelopathy is unknown. Elevated HIV-1 viral load in CSF has been associated with cognitive impairment. The authors investigated if a similar association exists in patients with myelopathy. The authors evaluated levels of HIV-1 RNA in the CSF of 16 individuals with AIDS myelopathy and in 16 nonmyelopathic HIV-infected control subjects. There was no correlation between levels of HIV-1 RNA and the presence or severity of myelopathy.

COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against L-dopa toxicity in vitro.

L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.

Methionine in the treatment of nitrous-oxide-induced neuropathy and myeloneuropathy.

Two cases of severe myeloneuropathy and macrocytic anemia associated with a low serum level of vitamin B12 after prolonged exposure to nitrous oxide are reported. In both cases, the neurological manifestations worsened initially despite B12 supplementation, although in one case the use of methionine seemed to arrest the progression of the disease and accelerate recovery. This offers further support for the biochemical hypothesis of methionine synthetase inhibition by nitrous oxide and reproduces in man previously reported animal studies with methionine. Methionine may be an important first-line therapy in the initial treatment of neuropathy and myeloneuropathy induced by nitrous oxide, and has a hypothetical role in the treatment of subacute combined degeneration of the cord.

MR findings in AIDS-associated myelopathy.

BACKGROUND AND PURPOSE: The most common cause of spinal cord disease among patients with AIDS or those infected with HIV-1 is AIDS-associated myelopathy. The purpose of this study was to determine the MR characteristics of the spinal cord in this patient population and to correlate these findings with the clinical severity of myelopathy. METHODS: MR images of the spinal cord in 21 patients with documented HIV-1 infection or AIDS and a clinical diagnosis of AIDS-associated myelopathy were assessed retrospectively for atrophy, intrinsic signal abnormality, and abnormal enhancement. The clinical severity of myelopathy was graded by a neurologist on the basis of physical examination, and a qualitative correlation was made with the MR findings. RESULTS: MR findings were abnormal in 18 of the 21 patients. The most common feature was spinal cord atrophy (n = 15), typically involving the thoracic cord with or without cervical cord involvement, followed by intrinsic cord signal abnormality (n = 6), and normal-appearing cord (n = 3). Three patients had both cord atrophy and intrinsic cord signal abnormality. The cord signal abnormality was diffuse, without predilection for any specific distribution pattern. Enhancement was not seen in any of the 10 patients who received intravenous contrast material. Only one of 16 patients with moderate to severe myelopathy had normal MR findings, as compared with two of five patients with mild myelopathy. CONCLUSION: MR findings in the spinal cord are abnormal in the majority of patients with AIDS-associated myelopathy, typically showing spinal cord atrophy, with or without intrinsic cord signal abnormality. Patients with moderate to severe myelopathy have an increased frequency of spinal cord abnormalities, but a definite correlation between clinical severity of myelopathy and extent of MR abnormalities remains to be established.

Decreased homovanilic acid in cerebrospinal fluid correlates with impaired neuropsychologic function in HIV-1-infected patients.

To determine whether dopamine metabolism is abnormal in HIV infected patients and whether dopamine metabolism abnormalities are related to specific neuropsychologic characteristics in HIV-infected patients, we measured cerebrospinal fluid (CSF) levels of homovanilic acid (HVA), the primary dopamine metabolite, in 10 HIV-infected patients and compared it to HVA levels in CSF in a group of 13 healthy control subjects. HIV-infected patients were also assessed with a battery of neuropsychologic tests and HVA levels were then correlated with performance on specific neuropsychologic tests. The mean (+/-SD) HVA level in CSF was 100.9 +/- 29.3 nmol/L in the HIV-infected study group and 230.5 +/- 50.0 nmol/L in the non-HIV-infected control group (p < 0.0001). The decrease in concentrations of HVA in CSF correlated with impairment on performance on neuropsychologic testing (Spearman r = 0.67; p = 0.03). When the relationship between HVA levels and specific cognitive domains was evaluated, we observed trends for positive correlation between HVA levels and tests that measure motor speed (r = 0.59; p = 0.074) and those testing attention, concentration, and executive control (r = 0.54; p = 0.108). There was no relationship between performance on memory tests and CSF HVA levels (r = -0.0061; p = 0.987). These results further support the hypothesis that dopaminergic dysfunction plays an important role in the pathogenesis of AIDS dementia complex (ADC) and suggest that specific motor and cognitive abnormalities may be related to depressed dopaminergic activity. This may have important implications for the development of treatments or preventive strategies for ADC.

AIDS-associated vacuolar myelopathy.

AIDS-associated vacuolar myelopathy (VM) is a common neurologic complication of AIDS. Pathologically, VM is characterized by vacuolization in the lateral and posterior columns of the thoracic spinal cord and has a striking similarity with the myelopathy of vitamin B12 deficiency. In autopsy series, 20% to 55% of patients with AIDS have evidence of spinal cord disease consistent with VM. The myelopathy usually manifests late in the course of HIV infection, with slowly progressive weakness of the lower extremities, gait disorder, sensory abnormalities in the legs, impotence in men, and urinary frequency and urgency. Its course is invariably progressive and leads to severe paralysis of the lower limbs, with loss of the ability to walk and of sphincter control. The differential diagnosis is extensive and includes metabolic, infective, and neoplastic spinal cord diseases. The diagnosis is based on the clinical observation and the exclusion of other causes of myelopathy via serologic, radiographic, and cerebrospinal fluid studies. The pathogenesis of VM is unknown. Attempts to detect HIV in the spinal cord have not yielded significant results, and there is no evidence of a relationship between the presence of HIV and the development of myelopathy. A metabolic disorder of the vitamin B12-dependent transmethylation pathway, induced by HIV or cytokine activation, is considered the possible cause of VM associated with AIDS. There is no known treatment for AIDS myelopathy and there is no evidence that antiretroviral drugs can improve the symptoms or slow the progression of VM. The symptomatic treatment includes antispasticity agents, management of sphincter dysfunction, and physical therapy. Experimental treatments are being tested in clinical trials.

[Cholestatic jaundice secondary to distention of the gallbladder caused by cystic duct syndrome]. / Ittero colestatico da ectasia della colecisti per sindrome del dotto cistico.

The Authors describe a rare case of cholestatic jaundice which persisted due to compression of the biliary tract by a hugely swollen gallbladder due to cystic duct syndrome.

[Endoscopic sphincterotomy in the treatment of biliary lithiasis. Our experience]. / La sfinterotomia endoscopica nel trattamento della litiasi biliare. Nostra esperienza.

Endoscopic Sphincterotomy (E.S.) is a simple and efficacious method for the management of bile duct stones and papillary stenosis. In this series, the E.S. was attempted in 25 patients and performed in 23 (92%). Nine patients had common bile duct stones. Eleven patients (48%) had common bile duct and gallbladder stones. Two patients (8.7%) had intrahepatic lithiasis and one patient (4.3%) had papillary stenosis without gallstones. After E.S. all patients underwent instrument removal of bile duct stones, using "Dormia" basket and "Fogarty" balloon catheter. Transnasal bile duct drainage was performed in 20 patients (86.9%). Early complications were observed in three patients (13%); one sphincterotomy side bleeding and two acute pancreatitis, which were treated successfully conservatively. Mean follow-up was 10.7 months (range 3-27 months). Late complications did not occur for the method and/or for gallbladder stones. Four patients over 80 years of age, died for unrelated causes during follow-up.

[Intrahepatic biliary lithiasis: endoscopic transpapillary treatment]. / Litiasi biliare intraepatica: trattamento endoscopico trans-papillare.

Six cases of intrahepatic biliary lithiasis, condition rarely observed in western countries, are reported. Following a review of the literature and on the basis of personal experience, stress is laid on problems of classification, clinical and instrumental diagnosis and, in particular, the therapeutic approach to intrahepatic biliary lithiasis by the endoscopic transpapillary way.