Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian Registry Investigative Neuro AIDS (IRINA)

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.     

The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms.

OBJECTIVE: To evaluate the prevalence and clinico/prognostic significance of the presence of pre-invasive lesions in patients resected for primary lung neoplasm. METHODS: From 1993 to 2002, 1090 patients received resection for primary lung carcinomas. Of these, 73 presented an associated pre-invasive lesion in the surgical specimen distant from the primary tumour. Classification of pre-invasive lesions included Atypical Adenomatous Hyperplasia (AAH); Carcinoma In Situ (CIS) either diffuse or at the bronchial resection margin; Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH). Correlation between the presence of pre-invasive lesion and the following variables were calculated by logistic regression analysis: sex, age, median tumour size, histology, histologic differentiation, histologic evidence of invasiveness (vascular and perineural invasion), peritumoural lymphocytic infiltrate, pTNM, lobe location, history of previous malignancy. Survival rates were computed using Kaplan-Meier method and survival differences with the total patient population of resected lung carcinomas were tested using the log-rank method. RESULTS: There were 28 AAH, 42 CIS (5 at the bronchial resection margin) and 3 DIPNECH. Histology of the primary tumor included bronchioloalveolar carcinoma (9 patients), adenocarcinoma (19), squamous cell carcinoma (39), typical carcinoid tumour (3) and adenosquamous carcinoma (3). Overall prevalence of pre-invasive lesion was 6.7%. A strong correlation was found between the presence of AAH and the co-existence of either adenocarcinoma, bronchioloalveolar carcinoma or mixed adenocarcinoma-containing tumours (P = 0.00002) between CIS and squamous cell carcinoma (P = 0.009) and between DIPNECH and carcinoid tumours (P = 0.001). No significant correlation was found between the presence of any type of pre-invasive lesion and sex, age, median tumour size, histologic differentiation, histologic evidence of invasiveness, pTNM, lobe location and history of previous malignancy or the probability to develop a second primary lung carcinoma in the remaining lobe(s) after resection. Survival rates in the patients with AAH and CIS were not significantly different from those of patients without pre-invasive lesion (P = 0.3 and P = 0.1). CONCLUSIONS: Associated pre-invasive lesions in patients resected for primary lung neoplasms are not infrequent. AAH is associated with adenocarcinoma, CIS with squamous cell carcinoma, DIPNECH with typical carcinoid tumours. Our experience indicates that in these patients histology, stage distribution and survival do not differ from the total population of resected patients with lung tumors.     

Granulocyte-macrophage colony-stimulating factor regulates cytokine production in cultured macrophages through CD14-dependent and -independent mechanisms

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has multiple effects on the antigen phenotype and function of macrophages. In this study we investigated the effect of GM-CSF on cytokine production by macrophages. We found that GM-CSF may modify the tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) response to lipopolysaccharide (LPS) through two different mechanisms. Relatively early in culture, GM-CSF increases the amount of cytokines synthesized by responding cells; this effect appears to be unrelated to modulation of CD14 expression and LPS-binding capacity. After prolonged incubation, GM-CSF up-regulates both CD14 expression and LPS-binding capacity, and the frequency of cytokine-producing cells. Release of CD14 in the culture supernatant was decreased in the presence of GM-CSF, suggesting that a reduced shedding was responsible for the effect of GM-CSF on CD14 expression. Enhancement of cytokine production was also observed in GM-CSF-treated macrophages after stimulation by phorbol 12-myristate 13-acetate (PMA), thus indicating that GM-CSF affects both CD14-dependent and -independent cytokine production. Finally, GM-CSF did not modulate the LPS- and PMA-induced production of IL-10 and IL-12. We conclude that GM-CSF may play a role in manipulating the activation-induced expression of pro-inflammatory cytokines by macrophages. Enhanced production of these cytokines could play an important role in the pathogenesis of Gram-negative septic shock syndrome and in defence against infectious agents.     

Painless fractures and thermoregulation disturbances in sensory-autonomic neuropathy: electrophysiological abnormalities and sural nerve biopsy

We describe the case of a young girl suffering from thermoregulation disturbances, painless fractures and arthropathy since early childhood. The patient was diagnosed as having a hereditary sensory autonomic neuropathy. Although needle EMG, conventional nerve conduction studies and somatosensory evoked potentials gave normal results, sympathetic skin responses (SSRs) were absent. Sural nerve biopsy showed a substantial reduction in the number of small myelinated and unmyelinated fibers. We emphasize the importance of SSR testing in revealing a condition which is otherwise difficult to identify by electrophysiological techniques. The combined evidence of functional and morphological findings is strongly suggestive of selective peripheral nerve involvement.     

Visible Light Curable Restorative Composites for Dental Applications Based on Epoxy Monomer

A cationic photo-curable cycloaliphatic epoxy resin has been investigated as reactive monomer in blue light crosslinking process. We have demonstrated that camphorquinone is able to abstract labile hydrogen from the epoxy monomer, giving rise to the formation of carbon-centered radicals that are oxidized by the onium salt; a complete epoxy group conversion was reached after 50 s of irradiation. The presence of water up to 1 wt% was tolerated without any important detrimental effect on the kinetics of light-curing. The presence of the inorganic filler up to 65 wt% did not significantly influence the curing process.     

ALK-negative lung inflammatory myofibroblastic tumor in a young adult: A case report and literature review of molecular alterations

Rationale:Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that is prevalent among children and adolescents. Surgery is the most important therapeutic approach for IMT and complete resection is recommended. Although 50% of IMTs show anaplastic lymphoma kinase (ALK) rearrangements, crizotinib has proven an effective therapeutic approach. However, the genetic landscape of this tumor is still not fully understood and treatment options are limited, especially in the majority of ALK-negative tumors.Patient concerns:We describe the clinical case of a healthy 18-year-old female in whom a pulmonary nodule was incidentally detectedDiagnoses:Following a small increase in the size of the nodule, the patient underwent both ¹⁸FDG-PET/CT and ⁶⁸Ga-PET/CT, resulting in a suspicion of bronchial hamartoma.Interventions:The patient underwent surgery and a salivary gland-like lung tumor was diagnosed.Outcomes:After surgery, the patient was referred to our cancer center, where a review of the histology slides gave a final diagnosis of ALK-negative lung IMT. Given the histology, it was decided not to administer adjuvant therapy and the patient was placed in a 3-monthly follow-up program. The patient is still disease-free 2 years post-surgery.Lessons:Although there is no standard of care for the treatment of IMT, identifying genomic alterations could help to redefine the management of patients with negative-ALK disease. Our review of the literature on IMT and other kinase fusions revealed, in addition to ALK rearrangements, the potential association of ROS1, NTRK, RET, or PDGFR beta alterations with the tumor.     

Effects of prefrontal repetitive transcranial magnetic stimulation on the autonomic regulation of cardiovascular function

Several protocols based on repetitive transcranial magnetic stimulation (rTMS) have been proposed for treatment of a variety of neurological disorders. Despite the widespread use, little is known about the effects of rTMS on the autonomic nervous control of the cardiovascular system. Twelve volunteers underwent rTMS sessions consisted in 8-min baseline recording, 8-min 0.7-Hz rTMS stimulation at 100 % of the motor cortex excitability threshold on the prefrontal cortex of one randomly assigned hemisphere. After 8-min recovery, the same procedure was performed on the contra-lateral hemisphere. Non-invasive (Portapres device) beat-by-beat blood pressure and heart period time series were recorded and analyzed by spectral and cross-spectral analysis in the low-frequency (LF ≈ 0.1 Hz) and in the high-frequency (HF = respiratory frequency) range. Repetitive TMS, particularly after stimulation of the right hemisphere, induced a slight increase in the parasympathetic drive and no effects on the sympathetic activity. There was a significant bradycardia after stimulation on the right hemisphere, not significant bradycardia after left stimulation. LF/HF ratio was 3.8 ± 2.1 during baseline and changed to 1.9 ± 0.6 during rTMS on the left and to 1.6 ± 0.6 during rTMS on the right. No significant changes were observed in blood pressure. Low-frequency rTMS of the prefrontal cortex induces a slight parasympathetic activation and no changes in the sympathetic function.