The role of laboratory medicine in a value-based healthcare system: the example of heart failure patient management in the Italian context.

OBJECTIVE: As of today, healthcare systems worldwide face severe challenges that undermine their sustainability. The value-based healthcare (VBHC) approach has been proposed as a strategic and methodological framework to ensure the delivery of the best patient outcomes with economic efficiency. Through the illustrative example of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) for heart failure (HF) patient management in the context of the Italian National Healthcare system, this article explores the role that in vitro diagnostics (IVDs) can play in enabling value-based care models. SUBJECTS AND METHODS: 14 healthcare professionals representing the relevant professional figures involved in HF patient management met to revise the current HF patient journey and design a new care pathway that, leveraging on BNP/NT-proBNP, reflects the VBHC principles. RESULTS: The literature recognizes the dosage of BNP/NT-proBNP as the gold stan-dard for diagnosing HF. However, as of today, these IVDs are not employed at their full potential regarding HF patient management. A new patient journey is proposed so that patients are diagnosed early and properly monitored in the aftermath of hospitalization, improving outcomes at contained costs. CONCLUSIONS: As testified by the example of HF patient management in Italy, laboratory medicine can represent a lever for adopting value-based care models. Still, large-scale adoption of VBHC will call for structural reforms that revise how healthcare delivery is organized, measured, and reimbursed.

Safety and efficacy of autologous hematopoietic stem-cell transplantation following natalizumab discontinuation in aggressive multiple sclerosis.

BACKGROUND AND PURPOSE: Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem-cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs. METHODS: Patients with relapsing-remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6 months of follow-up were included. Patients underwent aHSCT after a minimum of 6 months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash-out period. Both hematological and neurological follow-up were assessed according to standard policies. RESULTS: A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3 years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group (P = 0.0212). Disease reactivation in the patients with aHSCT was observed only during wash-out/bridging therapy and 100% of the cases were free from disease activity after aHSCT. CONCLUSIONS: These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. aHSCT after 6 months from NTZ withdrawal appears to be safe.

Papillary glioneuronal tumor: case report and review of literature.

Papillary glioneuronal tumor (PGNT) is a recently described central nervous system neoplasm that mostly occurs in the supratentorial system, adjacent to the lateral ventricles. In 2007, WHO classified PGNT as grade I neuronal-glial tumor because of the characteristic papillary architecture and bipartite (astrocytic and neuronal/neurocytic) cell population. As a newly established entity of mixed glioneuronal tumor family, PGNT attracted extensive attention recently. In our report we discuss the clinical, neuroradiological and surgical features. The final result is compared with literature data.

A rare localization of cerebral venous sinus thrombosis. Case report.

In this work the Authors report their experience on the treatment of a case of cavernous venous sinus thrombosis. The diagnosis is clinical and neuroradiological, CT, MRN, cerebral angiography and orbital venography have aided in establishing the diagnosis during life. Very interesting is the therapeutic approach.

NADPH oxidase activation and 4-hydroxy-2-nonenal/aquaporin-4 adducts as possible new players in oxidative neuronal damage presents in drug-resistant epilepsy.

A correlation between epilepsy and cellular redox imbalance has been suggested, although the mechanism by which oxidative stress (OS) can be implicated in this disorder is not clear. In the present study several oxidative stress markers and enzymes involved in OS have been determined. In particular, we examined the levels of 4-hydroxy-2-nonenal protein adducts (HNE-PA), a by-product of lipid peroxidation, and the activation of NADPH oxidase 2 (NOX2), as cellular source of superoxide (O(2)(-)), in surgically resected epileptic tissue from drug-resistant patients (N=50). In addition, we investigated whether oxidative-mediated protein damage can affect aquaporin-4 (AQP4), a water channel implicated in brain excitability and epilepsy. Results showed high levels of HNE-PA in epileptic hippocampus, in both neurons and glial cells and cytoplasmic positivity for p47(phox) and p67(phox) suggesting NOX2 activation. Interestingly, in epileptic tissue immunohistochemical localization of AQP4 was identified not only in perivascular astrocytic endfeet, but also in neurons. Nevertheless, negativity for AQP4 was observed in neurons in degeneration. Of note, HNE-mediated post-translational modifications of AQP4 were increased in epileptic tissues and double immunofluorescence clearly demonstrated co-localization of AQP4 and HNE-PA in epileptic hippocampal structures. The idea is that sudden, disorderly, and excessive neuronal discharges activates NOX2 with O(2)(-) production, leading to lipid peroxidation. The resulting generation of HNE targets AQP4, affecting water and ion balance. Therefore, we suggest that seizure induces oxidative damage as well as neuronal loss, thereby promoting neuronal hyperexcitability, also affecting water and ion balance by AQP4 modulation, and thus generating a vicious cycle.

Internal haemorrhagic pachymeningiosis: specific disease or complication of chronic subdural hematoma? Report of five cases surgically treated and literature review.

BACKGROUND: Internal haemorrhagic pachymeningiosis (IHP) is a rare disease characterized by a fibrous thickening and inflammatory infiltration in dural space mimicking chronic subdural hematoma. The pathogenesis of IHP is not entirely clear yet and treatment is still controversial. OBJECTIVE: We want to emphasize the importance of differentiating pachymeningiosis from chronic subdural hematoma as distinct pathological entities. PATIENTS AND METHODS: The records of five selected cases of IHP histologically confirmed were reviewed, focusing onset, neuroimaging, surgery and outcomes. CONCLUSIONS: IHP is most likely underestimated. Only through multidisciplinary approach it is possible to plane the proper therapeutic strategy. The diagnosis of IHP is confirmed by definitive histology but in some cases is possible with intraoperative frozen section.

Operative case of Langerhans'cell histiocytosis of the skull with dural invasion. An immunohystochemical study of ki-67 expression of eosinophilic granuloma: case report and review of the literature.

Eosinophilic granuloma (EG), Letterer-Siwe disease and Hand-Schuller-Christian disease are collectively called Langherans-cell histiocytosis (LCH). While the latter two are systemic diseases, the former is a localized form of histiocytosis. Solitary EG of the skull are rare lesions characterized by a natural history not well defined yet. In this context, we report a case of a 23-year-old male suffering for a recurrent and progressive right parietal headache. On computed tomography (CT) it was observed an ostelytic lesion which on magnetic resonance imaging (MRI) appeared as an hyperintense soft mass on both T1 and T2 weighted images. The lesion showed a marked and heterogeneous enhancement after gadolinium administration. The surgical excision was complete and the severe headache disappeared. Immunohistochemical analysis of the specimen indicated an eosinophilic granuloma characterized by Ki-67 nuclear antigen expression with a labeling index of 20%. In the pertinent literature we have found two aggressive cases of EG showing the Ki-67 expression with a respectively 6.2% (occipital bone granuloma) and 10% (parietal bone granuloma) labeling index. That high proliferative activity suggests a local Langherans' cell proliferation along with an exuberant inflammatory response and also explains the aggressive clinical course and the rapid expansion of the lesion observed in some rare cases of solitary EG. This is the third case-report of calvarial EG characterized by Ki-67 nuclear antigen expression.

Schwannoma of median nerve at the elbow. Case report and short review of the literature.

The Authors present a case of rare elbow localization of schwannoma of the median nerve, in 42 year old woman. The surgical treatment and the short follow-up are presented.

Therapeutic strategy of late cerebral radionecrosis. A retrospective study of 21 cases.

AIM: Late cerebral radiation necrosis (LCR) is a serious complication of radiation treatment for brain tumors. This study investigates the diagnosis and management of patients with late clinical and neuroradiological cerebral radionecrosis after primary removal of brain neoplasm. The authors discuss the clinical features and long-term outcome of 21 patients with late cerebral radionecrosis and emphasize the importance of surgical and medical therapy. METHODS: Twenty-one patients with brain tumor treated by surgical resection or brain biopsy alone after radiotherapy during follow-up developed radionecrosis. The magnetic resonance imaging (MRI), surgical and clinical findings of these patients with radionecrosis are reviewed. RESULTS: MRI showed radionecrosis in 21 patients, 9 of which had undergone craniotomy for lesion removal. CONCLUSION: Late radionecrosis is infrequent following radiation therapy and may simulate tumor recurrence on MRI scans. From the authors' experience it is evident that, once begun, radiation treatment of neoplastic lesions can lead to complications such as late cerebral radionecrosis which often require surgical treatment. As correct diagnosis is necessary for appropriate treatment, a fair balance needs to be struck when considering ionizing radiation, medical therapy, surgery and diagnostic imaging.

Infection due to a novel mycobacterium, mimicking multidrug-resistant Mycobacterium tuberculosis.

The treatment of multidrug-resistant tuberculosis (TB) requires the use, for long periods, of drugs liable to cause significant side effects. In the case of misdiagnosis of multidrug-resistant TB, the patient is exposed to toxic substances without any benefit. In low-income countries, where the microbiological diagnosis of TB relies on microscopy only, the misdiagnosis of multidrug-resistant TB is very frequent in patients persistently smear-positive despite anti-TB treatment, with the possibility of an infection due to non-tuberculous mycobacteria (NTM) being neglected. The isolation of a mycobacterium from the sputum of a Somali patient apparently confirmed the previous diagnosis of cavitary pulmonary disease. Preliminary investigations led, at first, to the strain being identified as multidrug-resistant Mycobacterium tuberculosis, with findings fully in agreement with the patient's history, which was characterized by repeated interruptions of anti-TB treatment. Thorough phenotypic and genotypic analyses led subsequently to the recognition that the strain was a previously unreported non-tuberculous mycobacterium. The patient, who was unresponsive to the anti-TB treatment, dramatically improved once a drug combination active against NTM was used. A major objective of this article is to alert the medical community to the risk, present also in settings in which sophisticated diagnostic techniques are used, that a cavitary infection due to NTM, and consequently not responding to the anti-TB standard regimen, will be mistaken for multidrug-resistant TB.

Novel mutations in of the ABCR gene in Italian patients with Stargardt disease.

PURPOSE: Stargardt disease (STGD) is the most prevalent juvenile macular dystrophy, and it has been associated with mutations in the ABCR gene, encoding a photoreceptor-specific transport protein. In this study, we determined the mutation spectrum in the ABCR gene in a group of Italian STGD patients. METHODS: The DNA samples of 71 Italian patients (from 62 independent pedigrees), affected with autosomal recessive STGD, were analysed for mutations in all 50 exons of the ABCR gene by the DHPLC approach (with optimization of the DHPLC conditions for mutation analysis) and direct sequencing techniques. RESULTS: In our group of STGD patients, 71 mutations were identified in 68 patients with a detection rate of 95.7%. Forty-three mutations had been already reported in the literature, whereas 28 mutations had not been previously described and were not detected in 150 unaffected control individuals of Italian origin. Missense mutations represented the most frequent finding (59.2%); G1961E was the most common mutation and it was associated with phenotypes in various degrees of severity. CONCLUSIONS: Some novel mutations in the ABCR gene were reported in a group of Italian STGD patients confirming the extensive allelic heterogeneity of this gene-probably related to the vast number of exons that favours rearrangements in the DNA sequence.

Passage of mannitol into the brain around gliomas: a potential cause of rebound phenomenon. A study on 21 patients.

AIM: Widespread use of mannitol to reduce brain edema and lower elevated ICP in brain tumor patients continues to be afflicted by the so-called rebound phenomenon. Leakage of mannitol into the brain parenchyma through an altered BBB and secondary reversal of osmotic gradient is considered the major cause of rebound . This has only been demonstrated experimentally in animals. As a contribution to this issue we decided to research the possible passage of mannitol into the brain after administration to 21 brain tumor patients. METHODS: Mannitol (18% solution; 1 g/kg) was administered as a bolus to patients (ten had malignant glioma, seven brain metastases and four meningioma) about 30 minutes before craniotomy. During resection, a sample of the surrounding edematous white matter was taken at the same time as a 10 ml venous blood sample. Mannitol concentrations were measured in plasma and white matter by a modified version of the enzyme assay of Blonquist et al. RESULTS: In most glioma patients, mannitol concentrations in white matter were 2 to 6 times higher than in plasma (mean 3.5 times). In meningioma and metastases patients plasma concentrations of mannitol were higher than white matter concentrations except in three cases with infiltration by neoplastic cells. CONCLUSIONS: The results of our study show that even after a single bolus, mannitol may leak through the altered BBB near gliomas, reversing the initial plasma-to-blood osmotic gradient, aggravating peritumoral edema and promoting rebound of ICP.

Chronic subdural hematoma: comparison of two surgical techniques. Preliminary results of a prospective randomized study.

AIM: The optimal treatment for chronic subdural hematoma (CSDH) is not yet well defined and research for efficient surgical solutions continues. Burr hole craniotomy (BHC) is a common treatment and twist drill craniostomy (TDC) is a less invasive alternative. A closed-system drainage with subdural expansion catheter and suction reservoir can be used to enhance the TDC procedure. METHODS: We report preliminary results of a prospective study comparing BHC and TDC with suction drainage, in a series of 47 patients randomized into two treatment groups. One group of 22 patients underwent TDC with closed-system drainage and suction reservoir (14 men, 8 women, mean age 78.7 years). Another group of 24 patients underwent BHC with subdural irrigation and closed drainage (16 men, 8 women, mean age 76.3 years). Neurological status was assessed by Markwalder's Grading Scale on admission and at follow-up. All patients underwent computed tomography (CT) before surgery, within 4 days after it, and 1 and 2 months later. RESULTS: Preoperative clinical and radiological data were similar in the two groups. Operating times were shorter in the TDC group, while drainage time was shorter in the BHC group (P<0.0001). Length of hospitalization was similar. Recurrence rate, mortality, and neurological recovery were similar, with non significant differences in favor of the TDC group. After 2 months, CT showed complete regression of subdural effusion in 66.6% of cases in the TDC group and in 31.8% in the BHC group (P<0.05). CONCLUSIONS: Preliminary results indicate TDC and BHC as at least equally effective, however TDC favors faster regression of residual subdural effusion, is a faster procedure, and seems to be associated with fewer recurrences. If confirmed at the end of the study, these results could indicate TDC with suction as the elective surgical treatment for CSDH.

Wrist median nerve motor conduction after end range repeated flexion and extension passive movements in Carpal Tunnel Syndrome. Pilot study.

Carpal Tunnel Syndrome (CTS) can be due to a variety of different pathological conditions. These etiological and epidemiological differences may explain the non-homogeneous response to ordinary conservative therapeutical options observed in this syndrome. The aim of our study was to investigate on the possibility of identifying different sub-groups of patients among conservatively treatable CTS with different susceptibility to physiotherapeutic treatments. We decided to utilize an objective approach measuring some median motor nerve function parameters. Short term variations of Compound Motor Action Potential (CMAP) from the thenar eminence were compared in two groups of 55 hands (CTS patients and normal controls) after performance of two different types of end range passive movement. We found a different distribution of CMAP amplitude modifications within a sub-group of patients that suddenly improved more than the controls after two series of 10 end range passive flexions or after two series of ten end range passive extensions. Amplitude changes proved to be much more useful than latency variation studies in the provocative test neurophysiological approach. The method we propose appears to be useful for better surgical indication and/or for improvement of conservative therapeutic choice.

Preliminary results of a soft novel lumbar intervertebral prothesis (DIAM) in the degenerative spinal pathology.

The authors report a series of 43 patients suffering from lower limb pain, almost constantly associated with chronic or acute backpain, treated by microsurgical nerve root decompression and by implantation of a soft intervertebral prothesis (DIAM). Satisfying results were obtained in 97% of cases, inducing the authors to consider the device a reliable tool for curing low-back pain and sciatica. Selection criteria are exposed and discussed.

Long-term follow-up of childhood cerebellar astrocytomas after incomplete resection with particular reference to arrested growth or spontaneous tumour regression.

BACKGROUND: The long-term prognosis for incompletely excised benign cerebellar astrocytomas in children remains largely unpredictable as the incidence of symptomatic recurrence ranges from 18 to 100%. Arrested growth and spontaneous tumour regression are a recognized but neglected phenomenon, the incidence and objective demonstration of which have received relatively little attention in the literature. With the aim of providing more information on this question, we reviewed our experience with incompletely resected benign cerebellar astrocytomas in children. CLINICAL MATERIAL AND METHODS: Our series consisted of 31 children with long-term follow-up. None had signs of type 1 neurofibromatosis (NF1). Histology included 22 classic pilocytic and nine diffuse astrocytomas. Seventeen children had symptomatic recurrence after 25 to 450 months and fourteen children remained in good health for 84 to 516 months. In looking for evident clinical differences that could help elucidate the different courses, we also examined recent radiographic images to assess tumour status. The literature was reviewed to obtain further information on nonrecurring and on regressing cerebellar astrocytomas after partial resection in the setting of modern surveillance imaging resources. FINDINGS: No differences in factors that could elucidate the different clinical courses were found between the two groups of children. Recent negative CT scans or NMR images were reported in seven cases. In two cases arrested growth or regression of a previously visible neoplastic remnant was noted. Review of the literature showed that radiographic follow-up has revealed arrested growth or spontaneous regression of benign cerebellar astrocytoma remnants in 32.5% and 14% of cases, respectively. CONCLUSIONS: As hypothesized by Cushing, our study shows that a large proportion of cerebellar astrocytomas do not progress or even regress after partial excision. This phenomenon is not understood and unfortunately cannot be anticipated. However, it suggests that a policy of "wait and see" with serial MR imaging can reasonably be recommended in children with cerebellar astrocytoma after partial resection, if the remnant is too risky to be removed by second-look surgery.

Operative results without invasive monitoring in patients with frontal lobe epileptogenic lesions.

PURPOSE: To further explore the still controversial issues regarding whether all or most candidates for epilepsy surgery should be investigated preoperatively with invasive long-term video-EEG monitoring techniques (ILTVE). METHODS: We studied five patients with intractable seizures since early childhood using the same protocol: clinical evaluation, magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery (FLAIR) sequences, long-term video-EEG (LTVE) monitoring with scalp electroencephalogram (EEG), interictal single photon emission computed tomography (SPECT), positron emission tomography (PET), and neuropsychological testing. The patients' seizures had clinical features suggesting a frontal lobe (FL) origin. MRI scans revealed focal cortical dysplasia (CD) in four patients and a probable gliotic lesion in the fifth. The findings in both PET and SPECT images were congruent with those of the MRI. Scalp LTVE failed to localize the ictal onset, although the data exhibited features suggestive of both CDs and FL seizures. On the basis of these results, surgery was performed with intraoperative corticography, and the cortical area exhibiting the greatest degree of spiking was ablated. RESULTS: Histopathologic study of four of the resected specimens confirmed the presence of CD, whereas in the fifth, there were features consistent with a remote encephaloclastic lesion. There were no postoperative deficits. Seizures in three of the patients were completely controlled at 2-3.5 years of follow-up; a fourth patient is still having a few seizures, which have required reinstitution of pharmacotherapy, and the fifth has obtained > or =70% control. All patients have had significant improvement in psychosocial measures. For comparison, five patients with generally similar clinical and neuroradiologic features to the previous group underwent preoperative ILTVE monitoring. The surgical outcomes between the two groups have not differed significantly. CONCLUSIONS: We conclude that patients with FL epilepsies may be able to undergo successful surgery without preoperative ILTVE monitoring, provided there is high concordance between neuroimaging tests (MRI, SPECT, PET) and the seizure phenotypes, even when routine EEGs and scalp LVTE fail to localize ictal onset unambiguously. The surgical outcomes of these patients generally paralleled those of the other subjects who also had FL epilepsy but who were operated on only after standard ILTVE monitoring.

Recruitment curve of the soleus H-reflex in chronic back pain and lumbosacral radiculopathy.

BACKGROUND: Needle EMG may be negative in mild or predominantly sensory lumbosacral radiculopathies. In such cases, an increase in the latency of the soleus H-reflex is a useful diagnostic criterion for establishing sensory fiber compromise at the S1 root level. However, if clinical signs of radicular involvement are lacking, the latency of the H-reflex is normal. We therefore studied the recruitment curve of the soleus H-reflex to investigate whether a change in the electrical threshold for eliciting the H-reflex might be a more sensitive criterion for detecting subclinical S1 root dysfunction. METHODS: Clinical and electrophysiological findings from 26 patients with chronic back pain and radiculopathy were compared with data obtained from 40 healthy subjects. RESULTS: An increase in the mean H-reflex threshold was the only abnormal electrophysiological finding in patients with no clinical sign of root injury (58%). A decrease in the mean H-reflex amplitude and a prolongation of H-reflex latency was observed in patients with radicular signs (42%). In both patients groups, F-wave and needle EMG studies were normal. No radiological evidence of S1 root compression was found. CONCLUSIONS: The study of the recruitment curve of the soleus H-reflex may be usefully associated to F-wave and needle EMG studies to detect possible S1 root dysfunction in mild lumbosacral radiculopathies. An increase in H-threshold may be the earliest abnormality in the absence of focal neurological signs.

Homocystinuria with transverse sinus thrombosis.

A case of cerebral venous thrombosis caused by undiagnosed homocystinuria is reported. The pitfalls regarding the diagnosis of a potentially medically treatable condition are discussed. Cerebral venous thrombosis in children has a variable type of onset and a multiplicity of causes. This type of pathology, although not frequent, is more common than previously thought. Among the different etiologies, undiagnosed homocystinuria is not routinely considered. We report a case of venous thrombosis of the left transverse cerebral sinus in a girl with drug-resistant partial epilepsy and homocystinuria. This diagnosis was considered and confirmed after the appearance of acute cerebral symptoms caused by venous thrombosis.