Druggable targets meet oncogenic drivers: opportunities and limitations of target-based classification of tumors and the role of Molecular Tumor Boards.

The therapeutic landscape of cancer is changing rapidly due to the growing number of approved drugs capable of targeting specific genetic alterations. This aspect, together with the development of noninvasive methods for the assessment of somatic mutations in the peripheral blood of patients, generated a growing interest toward a new tumor-agnostic classification system based on 'predictive' biomarkers. The current review article discusses this emerging alternative approach to the classification of cancer and its implications for the selection of treatments. It is suggested that different types of cancers sharing the same molecular profiles could benefit from the same targeted drugs. Although recent clinical trials have demonstrated that this approach cannot be generalized, there are also specific examples that demonstrate the clinical utility of this alternative vision. In this rapidly evolving scenario, a multidisciplinary approach managed by institutional Molecular Tumor Boards is fundamental to interpret the biological and clinical relevance of genetic alterations and the complexity of their relationship with treatment response.

Qualitative Analysis of Effective Teamwork in the Operating Room (OR).

OBJECTIVE: To conduct focus group interviews with operating room (OR) personnel to determine components of effective teamwork to inform a revision of a teamwork assessment instrument. DESIGN: Qualitative research study targeting OR personnel using semi-structured focus group interviews of interprofessional OR personnel. Responses were digitally recorded and transcribed. Qualitative analysis was undertaken by 2 reviewers who identified major themes related to effective teamwork. Inter-coder agreement was employed to confirm findings and themes. SETTING: Major academic medical center and Level 1 Trauma Center in Southeastern United States. PARTICIPANTS: Fifteen OR staff members including surgeons, an anesthesiologist, nurse anesthetists, circulating nurses, and scrub technicians. RESULTS: Three focus groups involving 15 individuals (2 surgeons, 1 anesthesiologist, 8 nurse anesthetists, 2 circulating nurses, and 2 surgical technologists) were conducted over a 1-month period in 2017. Four major themes related to effective teamwork emerged from analysis: (1) Smooth flow, (2) United effort, (3) Communication, and (4) Positive attitude. CONCLUSIONS: Among the OR team members, agreement regarding effective teamwork centers around the concepts of smooth procedural flow, unified effort, clear communication, and positive attitude of the team. These findings have helped refine a teamwork instrument to increase its utility for formative use in the clinical environment.

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges.

Management of small cell lung cancer (SCLC) has not changed over the last decades. In more recent years, alterations of DNA repair machinery and other molecular pathways have been identified in SCLC and preclinical data suggest that dysregulation of these pathways might offer new therapeutic opportunities.While immune checkpoint inhibitors (ICIs) have had a major impact on the clinical outcome of several solid tumors, including non-small cell lung cancer, the potential role of ICIs is currently under investigation in SCLC and some promising data are available. However, several clinical and biological hurdles have to be overcome and predictive markers are still eagerly needed. Knowledge of molecular pathways specifically involved in SCLC growth and treatment resistance is essential for a more rational planning of new combinations including ICIs.The present manuscript summarizes the current clinical evidence on immunotherapy in SCLC, describes the molecular bases underlying treatment resistance and discusses the potentialities and the rationale of different therapeutic combinations.

Central nervous system involvement in late-onset Pompe disease: clues from neuroimaging and neuropsychological analysis.

BACKGROUND AND PURPOSE: Late-onset Pompe disease (LOPD) is a rare, multisystem disorder that is well established to mainly impair skeletal muscle function. Systematic studies exploring brain functions in LOPD are lacking. The aim of this study was to detect morphological and functional brain alterations as well as neuropsychological impairment in LOPD. METHODS: We studied 21 patients (10 male, mean age 49 ± 18.4 years) with defined diagnosis of LOPD, divided into two groups: one with pre-symptomatic hyperCKemia with no muscle weakness and the second with limb-girdle muscle weakness. All patients underwent 3T magnetic resonance imaging (MRI) to obtain morphological/angiographic evaluation as well as normalized cortical brain volume and resting-state functional MRI. Fazekas score was applied to quantify white matter lesions, whereas Smoker's criteria were used to examine dolichoectasia. A complete neuropsychological assessment was performed. RESULTS: The MRI data showed that 12/21 patients (57%) demonstrated signs of cerebral vasculopathy, with a Fazekas score >2 in 67%. According to Smoker's criteria, 11/21 patients (52%) had a dolichoectasia of the vertebrobasilar system; an intracranial aneurysm was detected in 3/21 patients (14%). Resting-state functional MRI demonstrated significantly decreased brain connectivity in the salience network with a more relevant reduction in the bilateral middle and superior frontal gyrus. Gray matter atrophy correlated with age and disease duration. A mild impairment in executive functions was also identified. CONCLUSIONS: In this LOPD cohort the results showed morphological and functional brain alterations with mild neuropsychological dysfunction, mainly in the limb-girdle muscle weakness group. Cerebrovascular alterations seemed to be not related to common risk factors, suggesting a major role of enzymatic deficiency in the pathogenesis of brain abnormalities.

The role of immune microenvironment in small-cell lung cancer: Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.

INTRODUCTION: The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data on immune microenvironment are very limited. METHODS: We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated. RESULTS: The analysis included 66 stage I-III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I-III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval [CI]: 0.16-0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17-0.81, p: 0.013) for multivariate analysis. CONCLUSIONS: Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I-III SCLCs and warrants further investigation.

Neural correlates of fatigue in multiple sclerosis: a combined neurophysiological and neuroimaging approach (R1).

The present study is aimed at further exploring structural and functional correlates of fatigue in Relapsing- Remitting Multiple Sclerosis (RRMS) patients by using a combined approach by means of transcranial magnetic stimulation (TMS) and a Diffusion Tensor Imaging (DTI). The physiopathology of fatigue in MS is still poorly understood, although a variety of pathogenic mechanisms has been proposed. Our working hypothesis is that diffuse microstructural white matter damage may subtend the cortico-subcortical functional disconnection described in patients with MS and fatigue. We enrolled 30 RRMS patients (mean age 39±13; age range 24-63 years) with mild neurological impairment Expanded Disability Status Scale <3.5, divided into two groups on the basis of their fatigue severity scale (FSS) scoring (cutoff ≥ 4). All the patients underwent a neurological evaluation, a brain MRI acquisition (including DTI study) and a neurophysiological assessment by means of TMS in a pre-movement facilitation paradigm. Our data showed a significant mean diffusivity (MD) increase (p=0.036) in left thalamo-frontal reconstructions in the MS patients with fatigue compared to those classified as non-fatigued. Moreover, significant correlations were observed between FSS scale and MD as well as planar coefficient (CP) values extracted from frontal-thalamic connections bilaterally. Instead, the pre-movement facilitation showed a significant difference between the groups with particular regard to the Reaction Time- MEP50ms amplitude (p=0.03). Our work confirms that fatigue is associated with a disruption of brain networks involved in motor preparation processes, depending on several frontal-thalamic pathways. Such findings can have an important role when dealing with fatigue management in MS patients and could be eventually used as prognostic marker of MS course.

Quantitative, functional MRI and neurophysiological markers in a case of Gerstmann-Sträussler-Scheinker syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is an inherited autosomal dominant prion disease, caused by a codon 102 proline to leucine substitution (P102L) in the prion protein gene (PRNP). We describe the case of a 40-year-old male, affected by a slowly progressive gait disturbance, leg weakness and cognitive impairment. Genomic DNA revealed a point mutation of PRNP at codon 102, resulting in P102L, and the diagnosis of GSS was confirmed. Somatosensory evoked potentials showed alterations of principal parameters, particularly in the right upper and lower limbs. Laser-evoked potentials were indicative of nociceptive system impairment, especially in the right upper and lower limbs. Conventional magnetic resonance imaging (MRI) revealed marked atrophy of the vermis and cerebellar hemispheres and mild atrophy of the middle cerebellar peduncles and brainstem, as confirmed by a brain volume automatic analysis. Resting-state functional MRI showed increased functional connectivity in the bilateral visual cortex, and decreased functional connectivity in the bilateral frontal pole and supramarginal and precentral gyrus. Albeit limited to a single case, this is the first study to assess structural and functional connectivity in GSS using a multimodal approach.

Olfactory event-related potentials: a new approach for the evaluation of olfaction in nasopharyngeal carcinoma patients treated with chemo-radiotherapy.

OBJECTIVE: Olfactory dysfunction is a possible side effect of chemo-radiotherapy performed in patients affected by nasopharyngeal carcinoma. Self-rating measurements and olfactory event-related potentials were used and compared in order to evaluate the impact of this treatment on the olfactory system. METHODS: Nine patients underwent subjective evaluation of olfactory function (using visual analogue scales for olfactory symptoms and quality of life, and a six-item Hyposmia Rating Scale), and a quantitative and objective measurement (olfactory event-related potentials). RESULTS: Spearman's rank correlation analyses highlighted significant relationships between the clinical scales and olfactory event-related potentials. Inter-group analyses showed significant differences in the latency and in the amplitude of olfactory event-related potentials between patients and controls. CONCLUSION: Taking into account the small sample size and the lack of pre-treatment assessment, olfactory event-related potentials seemed to allow a more objective diagnosis of unilateral and bilateral olfactory loss. Moreover, olfactory event-related potentials and subjective scales results were concordant.

Assessment of nociceptive system in vegetative and minimally conscious state by using laser evoked potentials.

PRIMARY OBJECTIVE: The aim of this study is to assess if laser evoked potentials (LEPs) examination should be considered as an objective evidence of potential or residual pain perception capacity in vegetative (VS) and minimally conscious state (MCS) patients and if it could be a feasible methodology in order to differentiate these two clinical entities. RESEARCH DESIGN: This is a cross-sectional observational study focusing on the role of LEP examination, which is an easy and objective neurophysiological approach of the nociceptive system. METHODS AND PROCEDURES: Thirteen VS and 10 MCS patients were enrolled. All subjects were evaluated clinically by using validated behavioural scales and underwent to upper and lower limbs LEP recording. MAIN OUTCOMES AND RESULTS: Intra-group LEPs analysis in VS patients highlighted significant differences for N2P2 latency (p = 0.036) and amplitude (p = 0.018). Inter-group LEPs analysis showed significant differences in post-anoxic condition for N2P2 latency (p = 0.034), amplitude (p = 0.034) and a trend in N2P2 latency in brain trauma (p = 0.07). Interestingly, correlation analysis showed a significant relationship between N2P2 amplitude and Coma Recovery Scale-Revised scoring in the post-traumatic VS (r = 0.823, p = 0.044). CONCLUSIONS: The findings lead to detection of potential markers of conscious pain perception in patients with DOC, with important impact on therapeutic and rehabilitative management, and provide new information that may allow a better differential diagnosis.

GIS and spatial analysis for costs and services optimization in neurological telemedicine.

Telemedicine is an integrated, biomedical and psychosocial, secondary prevention intervention, where a specialized team guides the patient and his family in the course of the disease by reducing the stress of caregivers and allowing patients to stay longer at home, reducing, consequently, costs related to go to the specialist clinic. Teleneurology is a part of Telemedicine which uses modern communication technologies to allow neurology to be practiced when the doctor and patient are not present in the same place, and possibly not at the same time. This study focuses on identifying regional spots as potential territorial stations for the telemedicine service through the GIS (Geographical Information System), a computerized systems that allows placement of data of different types and sources into one system to manage and form spatial relationships that allow the display and analysis of relationships of geographic, environmental, and population factors (Scholten & de Lepper, 1991). We analyzed the optimal location of territorial telemedicine spots in correspondence of general practitioner clinics. It could be intended as a way to involve general practitioners in the management of those patients. The aim of this study is to improve the quality of life of patients and their caregivers providing a continuity of care through this system that reduces the inconvenience of travel and related costs. We estimated, then, the reduction of costs for patients and care-givers joining the telemedicine service in terms of hours out of work.

[Recanalizing entero-rectal fistula post-colostomy for inoperable rectal cancer]. / Fistola entero-rettale ricanalizzante dopo colostomia sinistra definitiva per tumore del retto inoperabile.

The Authors report a case of a spontaneous intestinal 'recanalization' after 1 year since the palliative surgery (definitive colostomy) for rectal cancer in a 79 years-old patient.

Amyand's hernia: case report and review of the literature.

The authors report a case of gangrenous acute appendicitis in the sac of an inguinal hernia (Amyand's hernia). After a review of the literature, they emphasise the extreme rarity of the case reported, they underline how the clinical picture is highly similar to that of a strangulated inguinal hernia. They affirm that appendicectomy and hernioplasty may be performed at the same time, since the repair of the hernia should be performed without prosthesis implantation due to the contamination of the operating field.

[Surgery of inguinal hernia in the elderly]. / La chirurgia dell'ernia inguinale nel paziente geriatrico.

The authors report their 14 years experiences with inguinal hernia repair in elderly. The result were compared with young (< 75 years old), and confirmed that there were no significant differences between the 2 groups. The study confirmed the safety and effectiveness of the "tension-free" technique under local anaesthesia, which is proposed as the treatment of choice in elderly.

[Fournier syndrome: report of a clinical case]. / La sindrome di Fournier: descrizione di un caso clinico.

The case of a Fournier's syndrome in a 58 years old patient is reported from the Authors that describe the ethiopathogenetic and therapeutic aspects. They analyse the importance of an early surgical treatment associated with antibiotic therapy and later a riparation of the lesions with a myocutaneous skin flap of TLF.

[Indications for preventive tracheostomy in the surgical treatment of non-neoplastic thyroid disease]. / Indicazioni alla tracheostomia precauzionale nella chirurgia delle tireopatie non neoplastiche.

In thyroid surgery, an emergency tracheostomy is mandatory, as is well known, in acute pre- and postoperative asphyxia due to obstruction of the upper airways, especially in cases of malignant tumours. In particular conditions, in the presence of benign thyroid disease and when there is no reduction in the laryngo-tracheal lumen, tracheostomy has an important precautionary function following total thyroidectomy. The authors describe their experience with 6 patients treated by precautionary tracheostomy after total thyroidectomy for benign thyroid disease, analysing the indications and the advantages of this method.

[Incidental diagnosis of seminoma in male infertility: report of a clinical case]. / Diagnosi incidentale di seminoma nell'infertilità maschile: descrizione di un caso clinico.

The aims of the study were to evaluate the association between male infertility and risk of developing testis cancer and to establish guidelines for the early diagnosis of testis neoplasia in subfertile men. 32-year-old infertile man. The patient underwent random testicular biopsy to establish the exact cause of infertility. An incidental diagnosis of seminoma was made and the patient then underwent right testis excision. Anatomopathologic macroscopic examination revealed two nodules, the sizes of which were 0.8 x 0.4 and 0.3 x 0.2 cm, respectively. Histologic examination confirmed the diagnosis of typical seminoma, pT1, with copious lymphocytic struma infiltration. There appears to be a correlation between male infertility and occurrence of seminoma. Diagnosis of testis cancer is often incidental and sometimes occurs in men undergoing testicular biopsy to investigate infertility. Since the biopsy was not specifically targeted in our case, the diagnosis of seminoma was casual. This suggests the need for a careful follow-up, including testicular ultrasonography as a screening test to achieve an early diagnosis of testis cancer in all infertile men, because of their higher risk of developing testis cancer than the normal population.

Hypocalcemia and hypoparathyroidism after total thyroidectomy: a clinical biological study and surgical considerations.

BACKGROUND: Post-operative hypocalcemia is a common and most often transient event afterextensive thyroid surgery. It may be due to iatrogenic injury to the parathyroid glands. AIMS: We carried out a study aimed to evaluate the incidence of hypocalcemia and hypoparathyroidism following extracapsular total thyroidectomy. METHODS: The study was carried out in 312 patients (273 females and 39 males, whose age was between 23 and 76 years, median age 48.61 +/- 14.1) who had undergone total thyroidectomy (TT) in our department from 1995 to 1998 and in 100 patients (72 females and 28 males, whose age was between 24 and 75 years, median age 51.66 +/- 13.4) who had undergone other (non-thyroid) surgery. RESULTS: Post-operative hypocalcemia was observed in 62 patients of the control group (62%) and the decrease of the serum calcium level lasted about 3 days, and went back to normal within the 5th day. In 2 patients undergoing total thyroidectomy, hypocalcemia was considered severe (confirmed for more than 7 days, symptomatic), these had been operated for large multinodular goitre with mediastinal extension. In these patients the symptoms arose acutely about 5 h after the operation. In both cases the clinical and biological aspects went back to normal within 10 days, after a treatment with calcium and vitamin D. Transient asymptomatic hypocalcemia was observed in 234 thyroidectomized patients (75%) and thus did not need any treatment for it. CONCLUSION: The results obtained confirm that transient hypocalcemia can be observed after any operation; and particularly responsible is the decrease of the calcium concerning the proteins. We found that post-operative hypoparathyroidism is due to injury to the parathyroid glands (parathyroid ischaemia or surgical ablation of one or more glands). Here we see the delayed serum calcium level < or = 7.5 mg/dl or the delayed serum phosphorous level > 7.4 mg/dl. The results of our study, with 2 patients presenting transient post-operative hypoparathyroidism, contribute in confirming that the extracapsular total thyroidectomy aimed to reduce any injury to the parathyroid and to the recurrent nerves, represent the better operation also for the extended benignant thyroidopathies.

Activation of group III metabotropic glutamate receptors is neuroprotective in cortical cultures.

(RS)-alpha-Methyl-4-phosphonophenylglycine (MPPG) and (S)-alpha-methyl-3-carboxyphenylalanine (M3CPA), two novel preferential antagonists of group III metabotropic glutamate (mGlu) receptors, antagonized the neuroprotective activity of L-2-amino-4-phosphono-butanoate (L-AP4) or L-serine-O-phosphate in mice cultured cortical cells exposed to a toxic pulse of N-methyl-D-aspartate. In contrast, MPPG did not influence the neuroprotective activity of the selective group II mGlu receptor agonist, (2S,1'R,2'R,3'R)-2-(2,3-dicarboxy-cyclopropyl) glycine (DCG-IV). These results indicate that activation of group III mGu receptors exerts neuroprotective activity against excitotoxic neuronal death. At least one of the two major group III mGlu receptor subtypes, i.e. mGlu4 receptor, is expressed by cultured cortical neurons, as shown by immunocytochemical analysis with specific polyclonal antibodies.