Tocilizumab in COVID-19 interstitial pneumonia.

BACKGROUND: Published reports on tocilizumab in COVID-19 pneumonitis show conflicting results due to weak designs or heterogeneity in critical methodological issues. METHODS: This open-label trial, structured according to Simon's optimal design, aims to identify factors predicting which patients could benefit from anti-IL6 strategies and to enhance the design of unequivocal and reliable future randomized trials. A total of 46 patients with COVID-19 pneumonia needing of oxygen therapy to maintain SO2 > 93% and with recent worsening of lung function received a single infusion of tocilizumab. Clinical and biological markers were measured to test their predictive values. Primary end point was early and sustained clinical response. RESULTS: Twenty-one patients fulfilled pre-defined response criteria. Lower levels of IL-6 at 24 h after tocilizumab infusion (P = 0.049) and higher baseline values of PaO2/FiO2 (P = 0.008) predicted a favourable response. CONCLUSIONS: Objective clinical response rate overcame the pre-defined threshold of 30%. Efficacy of tocilizumab to improve respiratory function in patients selected according to our inclusion criteria warrants investigations in randomized trials.

MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine.

We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5'-untranslated region (UTR) 3RG, TS 3'-UTR -6 bp/-6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P<0.001; P=0.026; P=0.058; P=0.024). MTHFR 677T/T, TS 3'-UTR -6 bp/-6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P<0.001; P=0.004; P=0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.

Evolution of Ventricular Energetics in the Different Stages of Palliation of Hypoplastic Left Heart Syndrome: A Retrospective Clinical Study.

Hyperplastic left heart syndrome (HLHS) patients are palliated by creating a Fontan-type circulation passing from different surgical stages. The aim of this work is to describe the evolution of ventricular energetics parameters in HLHS patients during the different stages of palliation including the hybrid, the Norwood, the bidirectional Glenn (BDG), and the Fontan procedures. We conducted a retrospective clinical study enrolling all HLHS patients surgically treated with hybrid procedure and/or Norwood and/or BDG and/or Fontan operation from 2011 to 2016 collecting echocardiographic and hemodynamic data. Measured data were used to calculate energetic variables such as ventricular elastances, external and internal work, ventriculo-arterial coupling and cardiac mechanical efficiency. From 2010 to 2016, a total of 29 HLHS patients undergoing cardiac catheterization after hybrid (n = 7) or Norwood (n = 6) or Glenn (n = 8) or Fontan (n = 8) procedure were retrospectively enrolled. Ventricular volumes were significantly higher in the Norwood circulation than in the hybrid circulation (p = 0.03) with a progressive decrement from the first stage to the Fontan completion. Ventricular elastances were lower in the Norwood circulation than in the hybrid circulation and progressively increased passing from the first stage to the Fontan completion. The arterial elastance and Rtot increased in the Fontan circulation. The ventricular work progressively increased. Finally, the ventricular efficiency improves passing from the first to the last stage of palliation. The use of ventricular energetic parameters could lead to a more complete evaluation of such complex patients to better understand their adaptation to different pathophysiological conditions.

Mason type III radial head fractures treated by anatomic radial head arthroplasty: Is this a safe treatment option?

BACKGROUND: Radial head fractures make up approximately 3% of all fractures and they are the most common elbow fracture in adults. Replacement through arthroplasty is the recommended treatment in the context of unstable elbow injury and comminuted radial head fracture. The midterm clinical, functional, and radiographic results in patients treated with anatomic radial head arthroplasty for a Mason type III radial head fracture are presented. MATERIAL AND METHODS: We performed a retrospective search of our facility's prospective trauma database to identify all skeletally mature patients who were treated by primary radial head replacement or open reduction and internal fixation following an acute radial head fracture. Inclusion criteria were Mason type III fractures and anatomic radial head arthroplasty (RHA). All the patients included were evaluated using a standard postoperative protocol including clinical and radiographic evaluation at 1, 3 and 12 months of follow-up. All the patients were reviewed clinically at an average of 30 months' follow-up. RESULTS: Forty-one subjects (32 Mason type III and 9 Mason IV fractures) were treated with anatomic RHA (Acumed, Hillsboro, OR, USA). Of these, two patients (1 Mason type III and 1 Mason type IV) were excluded from the analysis because severe cognitive impairment. Moreover, we decided to exclude the subjects with a Mason type IV fracture to obtain a more homogeneous sample. Therefore, 31 patients with a Mason type III fracture were included in this study. Based on the Mayo Elbow Performance Score, excellent results were obtained in 24 (77%) patients, good in 3 (10%) and fair in 4 (13%) patients. Heterotopic ossification was reported in 8 patients (26% of cases). The final elbow flexion-extension range of motion was of 112°, with a mean flexion of 125°. The final forearm rotational range of motion was 134° with a mean pronation of 68° and a mean supination of 66°. DISCUSSION: Anatomic radial head replacement leads to a good functional recovery, even in the presence of severe instability, such as coronoid fractures and LUCL injury. However, patients should be informed of the high number of adverse events (mainly heterotopic ossification) following this treatment. LEVEL OF EVIDENCE: Therapeutic IV.

Humerus shaft fracture complicated by radial nerve palsy: Is surgical exploration necessary?

Fractures of the humerus shaft often are complicated by radial nerve palsy. Controversy still exists in the treatment that includes clinical observation and eventually late surgical exploration or early surgical exploration. Algorithms have been proposed to provide recommendations with regard to management of the injuries. However, advantages and disadvantages are associated with each of these algorithms. The aim of this study was to analyze the indications of each treatment options and facilitate the surgeon in choosing the conduct for each lesion, proposing our own algorithm.

Double-locking precontoured plating system for malunited fractures of the distal end of humerus.

BACKGROUND: Distal humeral malunions are uncommon injuries, often associated with limited elbow motion, pain, instability, weakness, and sometimes ulnar neuritis. The complex anatomy of the elbow joint makes this condition one of the most complex elbow injuries to treat. MATERIALS AND METHODS: Four patients were treated by the same surgeon between 2011 and 2013 using a double-locking precontoured plating system for malunited intra-articular or extra-articular fractures of the distal end of the humerus. RESULTS: At a mean 3 years of follow-up, a significant improvement in the elbow motion and functional outcome, evaluated with the Mayo Elbow Performance Index and the Disability of the Arm, Shoulder, and Hand, were observed. Articular reduction obtained after the surgery was maintained in all patients without evidence of avascular necrosis. No other complications (i.e., infection, nervous iatrogenic lesions) were reported. CONCLUSIONS: Corrective osteotomy using double-locking precontoured plating system preceded by preoperative planning using a CT scan allowed an improvement in the functional outcome and elbow motion, without complications.

Environmental nanoparticles are significantly over-expressed in acute myeloid leukemia.

The increase in the incidence of acute myeloid leukemia (AML) may suggest a possible environmental etiology. PM2.5 was declared by IARC a Class I carcinogen. No report has focused on particulate environmental pollution together with AML. The study investigated the presence and composition of particulate matter in blood with a Scanning Electron Microscope coupled with an Energy Dispersive Spectroscope, a sensor capable of identifying the composition of foreign bodies. 38 peripheral blood samples, 19 AML cases and 19 healthy controls, were analyzed. A significant overload of particulate matter-derived nanoparticles linked or aggregated to blood components was found in AML patients, while almost absent in matched healthy controls. Two-tailed Student's t-test, MANOVA and Principal Component Analysis indicated that the total numbers of aggregates and particles were statistically different between cases and controls (MANOVA, P<0.001 and P=0.009 respectively). The particles detected showed to contain highly-reactive, non-biocompatible and non-biodegradable metals; in particular, micro- and nano-sized particles grouped in organic/inorganic clusters, with statistically higher frequency of a subgroup of elements in AML samples. The demonstration, for the first time, of an overload of nanoparticles linked to blood components in AML patients could be the basis for a possible, novel pathogenetic mechanism for AML development.

Narrow band imaging with magnification endoscopy for celiac disease: results from a prospective, single-center study.

In celiac disease (CD), the intestinal lesions can be patchy and partial villous atrophy may elude detection at standard endoscopy (SE). Narrow Band Imaging (NBI) system in combination with a magnifying endoscope (ME) is a simple tool able to obtain targeted biopsy specimens. The aim of the study was to assess the correlation between NBI-ME and histology in CD diagnosis and to compare diagnostic accuracy between NBI-ME and SE in detecting villous abnormalities in CD. Forty-four consecutive patients with suspected CD undergoing upper gastrointestinal endoscopy have been prospectively evaluated. Utilizing both SE and NBI-ME, observed surface patterns were compared with histological results obtained from biopsy specimens using the k-Cohen agreement coefficient. NBI-ME identified partial villous atrophy in 12 patients in whom SE was normal, with sensitivity, specificity, and accuracy of 100%, 92.6%, and 95%, respectively. The overall agreement between NBI-ME and histology was significantly higher when compared with SE and histology (kappa score: 0.90 versus 0.46; P = 0.001) in diagnosing CD. NBI-ME could help identify partial mucosal atrophy in the routine endoscopic practice, potentially reducing the need for blind biopsies. NBI-ME was superior to SE and can reliably predict in vivo the villous changes of CD.

Arthroscopic Latarjet procedure: analysis of the learning curve.

BACKGROUND: The arthroscopic Latarjet procedure is an innovative technique that aims to combine the optimal results of the original open approach with those of arthroscopic stabilization. METHODS: We evaluated the learning curve and the preliminary results of the first 30 patients (29 males, 1 female; mean age 32 years, range 21-52) subjected to an arthroscopic Latarjet procedure at a mean follow-up of 13 months (range 6-22). RESULTS: Operative time fell significantly from 132 to 99 min (p < 0.001, t test) in the last 15 patients compared with the first 15 without significant differences in terms of Rowe score, patient satisfaction, complications, or graft placement. There were 21 (70 %) excellent and 9 (30 %) good outcomes according to the Rowe score. All complications (10 %) correlated with age >40 years (p = 0.002, Fisher's exact test). CONCLUSIONS: The arthroscopic Latarjet procedure is a standardized, hence reproducible technique whose complexity makes it suitable only for surgeons with solid experience in arthroscopy and shoulder surgery.

Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.

BACKGROUND: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. PATIENTS AND METHODS: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. RESULTS: MCs accounted for 17.4% (n=178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. CONCLUSIONS: For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.

Characterization of a new trabectedin-resistant myxoid liposarcoma cell line that shows collateral sensitivity to methylating agents.

Myxoid Liposarcomas (MLS), characterized by the expression of FUS-CHOP fusion gene are clinically very sensitive to the DNA binding antitumor agent, trabectedin. However, resistance eventually occurs, preventing disease eradication. To investigate the mechanisms of resistance, a trabectedin resistant cell line, 402-91/ET, was developed. The resistance to trabectedin was not related to the expression of MDR related proteins, uptake/efflux of trabectedin or GSH levels that were similar in parental and resistant cells. The 402-91/ET cells were hypersensitive to UV light because of a nucleotide excision repair defect: XPG complementation decreased sensitivity to UV rays, but only partially to trabectedin. 402-91/ET cells showed collateral sensitivity to temozolomide due to the lack of O(6) -methylguanine-DNA-methyltransferase (MGMT) activity, related to the hypermethylation of MGMT promoter. In 402-91 cells chromatin immunoprecipitation (ChIP) assays showed that FUS-CHOP was bound to the PTX3 and FN1 gene promoters, as previously described, and trabectedin caused FUS-CHOP detachment from DNA. Here we report that, in contrast, in 402-91/ET cells, FUS-CHOP was not bound to these promoters. Differences in the modulation of transcription of genes involved in different pathways including signal transduction, apoptosis and stress response between the two cell lines were found. Trabectedin activates the transcription of genes involved in the adipogenic-program such as c/EBPα and ß, in 402-91 but not in 402-91/ET cell lines. The collateral sensitivity of 402-91/ET to temozolomide provides the rationale to investigate the potential use of methylating agents in MLS patients resistant to trabectedin.

Production and characterization of two monoclonal antibodies to bovine tumour necrosis factor alpha (TNF-alpha) and their cross-reactivity with ovine TNF-alpha.

Tumour necrosis factor alpha (TNF-alpha) is an innate pro-inflammatory cytokine involved in protection against intracellular pathogens. Existing methods for measuring TNF-alpha production and function in ruminants are limited to ELISA and many rely on polyclonal antisera. With a view to developing improved detection methods for bovine (bov) TNF-alpha, monoclonal antibodies (mAb) were produced by immunising mice with a plasmid encoding bov TNF-alpha. Two of the resulting mAb, termed CC327 and CC328, were used to develop a sandwich ELISA capable of detecting both native and recombinant bov TNF-alpha. This ELISA did not detect recombinant ovine (ov) TNF-alpha. A luminometric method was applied to the ELISA to improve sensitivity for detection of native bov TNF-alpha in culture supernatants derived from bovine monocyte-derived dendritic cells (DC) infected with Mycobacterium bovis. Both CC327 and CC328 detected intracytoplasmic expression of TNF-alpha in mitogen-activated bovine T lymphocytes. However, only CC328 detected intracytoplasmic ovine TNF-alpha in transfected cells, explaining the failure of the sandwich ELISA to detect recombinant ov TNF-alpha. These mAbs have generated the capability to study the role of TNF-alpha in host immune protection and disease pathogenesis in ruminants.

Genetic modulation of the Let-7 microRNA binding to KRAS 3'-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan.

There is increasing evidence that the Let-7 microRNA (miRNA) exerts an effect as a tumor suppressor by targeting the KRAS mRNA. The Let-7 complementary site (LCS6) T>G variant in the KRAS 3'-untranslated region weakens Let-7 binding. We analyzed whether the LCS6 variant may be clinically relevant to patients with metastatic colorectal cancer (MCRC) treated with anti-epidermal growth factor receptor (EGFR) therapy. LCS6 genotypes and KRAS/BRAF mutations were determined in the tumor DNA of 134 patients with MCRC who underwent salvage cetuximab-irinotecan therapy. There were 34 G-allele (T/G+G/G) carriers (25%) and 100 T/T genotype carriers (75%). G-allele carriers were significantly more frequent in the KRAS mutation group than in patients with KRAS wild type (P=0.004). In the 121 patients without BRAF V600E mutation, overall survival (OS) and progression-free survival (PFS) times were compared between carriers of the LCS6 G-allele genotypes and carriers of the wild-type T/T genotype. LCS6 G-allele carriers showed worse OS (P=0.001) and PFS (P=0.004) than T/T genotype carriers (confirmed in the multivariate model including the KRAS status). In the exploratory analysis of the 55 unresponsive patients with KRAS mutation, LCS6 G-allele carriers showed adverse OS and PFS times. These findings deserve additional investigations as they may open novel perspectives for the treatment of patients with MCRC.

Genomic segmental duplications on the basis of the t(9;22) rearrangement in chronic myeloid leukemia.

A crucial role of segmental duplications (SDs) of the human genome has been shown in chromosomal rearrangements associated with several genomic disorders. Limited knowledge is yet available on the molecular processes resulting in chromosomal rearrangements in tumors. The t(9;22)(q34;q11) rearrangement causing the 5'BCR/3'ABL gene formation has been detected in more than 90% of cases with chronic myeloid leukemia (CML). In 10-18% of patients with CML, genomic deletions were detected on der(9) chromosome next to translocation breakpoints. The molecular mechanism triggering the t(9;22) and deletions on der(9) is still speculative. Here we report a molecular cytogenetic analysis of a large series of patients with CML with der(9) deletions, revealing an evident breakpoint clustering in two regions located proximally to ABL and distally to BCR, containing an interchromosomal duplication block (SD_9/22). The deletions breakpoints distribution appeared to be strictly related to the distance from the SD_9/22. Moreover, bioinformatic analyses of the regions surrounding the SD_9/22 revealed a high Alu frequency and a poor gene density, reflecting genomic instability and susceptibility to rearrangements. On the basis of our results, we propose a three-step model for t(9;22) formation consisting of alignment of chromosomes 9 and 22 mediated by SD_9/22, spontaneous chromosome breakages and misjoining of DNA broken ends.

210Po Log-normal distribution in human urines: survey from central Italy people.

The death in London of the former secret service agent Alexander Livtinenko on 23 November 2006 generally attracted the attention of the public to the rather unknown radionuclide (210)Po. This paper presents the results of a monitoring programme of (210)Po background levels in the urines of noncontaminated people living in Central Italy (near the Republic of S. Marino). The relationship between age, sex, years of smoking, number of cigarettes per day, and (210)Po concentration was also studied. The results indicated that the urinary (210)Po concentration follows a surprisingly perfect Log-normal distribution. Log (210)Po concentrations were positively correlated to age (p < 0.0001), number of daily smoked cigarettes (p = 0.006), and years of smoking (p = 0.021), and associated to sex (p = 0.019). Consequently, this study provides upper reference limits for each sub-group identified by significantly predictive variables.

A novel fusion 5'AFF3/3'BCL2 originated from a t(2;18)(q11.2;q21.33) translocation in follicular lymphoma.

Follicular lymphoma is the second most frequent type of non-Hodgkin's lymphoma in adults. The basic molecular defect consists of the t(14;18)(q32;q21) translocation, juxtaposing the B-cell lymphoma protein 2 gene BCL2 to the immunoglobulin heavy chain locus IGH@, and leading to the antiapoptotic BCL2 protein overproduction. Variations in the t(14;18) are rare and can be classified into two categories: (i) simple variants, involving chromosomes 18 and 2, or 22, in which the fusion partner of BCL2 is the light-chain IGK@ or IGL@; (ii) complex variant translocations occurring among chromosomes 14, 18 and other chromosomes. We report a follicular lymphoma case showing BCL2 overexpression, detected by immunohistochemistry and real-time quantitative PCR, consequently to the formation of a novel fusion gene between the 5' of the lymphoid nuclear transcriptional activator gene AFF3 at 2q11.2, and the 3' of BCL2. This case shows evidence, for the first time, of BCL2 overexpression consequently to the fusion of BCL2 to a non-IG partner locus.