Prevalence of cranial involvement in a cohort of Italian patients with chronic non-bacterial osteomyelitis.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a non-infectious inflammatory disease characterised by uni- or multi-focal bone lytic lesions. CNO mainly affects metaphysis of long bones, pelvis and shoulder girdle. Neurocranium lesions are extremely rare. The objective of the study is to describe the prevalence and clinical manifestations of CNO patients with neurocranium involvement in an Italian cohort of CNO patients. METHODS: This is a retrospective study. Medical records of patients with CNO admitted to eight paediatric rheumatology centres were reviewed. RESULTS: Among 86 patients with CNO enrolled in the study, three of them were female and presented neurocranium involvement - multifocal lesions. Two out of the 3 patients were completely asymptomatic for cranial involvement, while one of the 3 complained of cranial bossing. Cranial involvement was detected with bone scintigraphy and then confirmed by magnetic resonance imaging and/or computed tomography. Two patients presented fever and two with skin manifestations. Laboratory inflammatory markers were increased in two of them. All patients underwent bone biopsy confirming the diagnosis. They all received NSAIDs. Two patients received corticosteroids and then methotrexate and achieved clinical remission, while one patient received pamidronate. CONCLUSIONS: This is the first report of neurocranium involvement in a cohort of patients affected by CNO. In our cohort no patient showed significant signs attributable to cranial involvement.

Preoperative Intra-Aortic Counterpulsation in Cardiac Surgery: Insights From a Retrospective Series of 588 Consecutive High-Risk Patients.

OBJECTIVE: To support a rational use of preoperative intra-aortic balloon pump (IABP) in cardiac surgery. DESIGN: Retrospective, observational study. SETTING: Single university hospital. PARTICIPANTS: The study included 588 (mean age 68.5 ± 9.6 yr) consecutive patients who received IABP before cardiac surgery from 1999 to 2016. INTERVENTIONS: Coronary surgery was performed in 573 (97.4%) cases. IABP indications were prophylaxis (n = 147), unstable angina (n = 239), and rapid worsening of hemodynamics (n = 202). Baseline characteristics of patients were analyzed with multivariable methods. Comparison of outcomes postsurgery between 74 patients undergoing IABP because of left main coronary artery disease (LMCAD) (stenosis ≥ 50%) and a new series of 1,360 patients experiencing LMCAD but who did not receive an IABP using propensity-score matching. MEASUREMENTS AND MAIN RESULTS: Throughout the study period, the rate of IABP use for prophylaxis and unstable angina increased (p = 0.0029) despite reduction in patient surgical risk (p = 0.0051). Early period of surgery (p = 0.032), rapid worsening of hemodynamics in the operating room (p = 0.0029), renal impairment (p < 0.0001), and ventilation before surgery (p = 0.0032) were predictors of in-hospital mortality. The cumulative rate of IABP-related complications was 6.8%. Current smoking (p = 0.025) and the use of a 9 Fr catheter (p = 0.0017) were predictors of IABP-related vascular complications. No difference was found regarding outcomes postsurgery for 43 pairs of IABP/non-IABP matched patients with LMCAD, even though preoperative IABP was associated with an increased use of bilateral internal thoracic artery grafting. CONCLUSIONS: Preoperative use of IABP in cardiac surgery was shown in this study to be safe, even for high-risk patients. LMCAD is not by itself a sufficient indication for prophylactic IABP.

A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents.

The complexity of the tumor microenvironment is difficult to mimic in vitro, particularly regarding tumor-host interactions. To enable better assessment of cancer immunotherapy agents in vitro, we developed a three-dimensional (3D) heterotypic spheroid model composed of tumor cells, fibroblasts, and immune cells. Drug targeting, efficient stimulation of immune cell infiltration, and specific elimination of tumor or fibroblast spheroid areas were demonstrated following treatment with a novel immunocytokine (interleukin-2 variant; IgG-IL2v) and tumor- or fibroblast-targeted T cell bispecific antibody (TCB). Following treatment with IgG-IL2v, activation of T cells, NK cells, and NKT cells was demonstrated by increased expression of the activation marker CD69 and enhanced cytokine secretion. The combination of TCBs with IgG-IL2v molecules was more effective than monotherapy, as shown by enhanced effects on immune cell infiltration; activation; increased cytokine secretion; and faster, more efficient elimination of targeted cells. This study demonstrates that the 3D heterotypic spheroid model provides a novel and versatile tool for in vitro evaluation of cancer immunotherapy agents and allows for assessment of additional aspects of the activity of cancer immunotherapy agents, including analysis of immune cell infiltration and drug targeting.

The protein tyrosine phosphatase receptor type J is regulated by the pVHL-HIF axis in clear cell renal cell carcinoma.

Mass spectrometry analysis of renal cancer cell lines recently suggested that the protein-tyrosine phosphatase receptor type J (PTPRJ), an important regulator of tyrosine kinase receptors, is tightly linked to the von Hippel-Lindau protein (pVHL). Therefore, we aimed to characterize the biological relevance of PTPRJ for clear cell renal cell carcinoma (ccRCC). In pVHL-negative ccRCC cell lines, both RNA and protein expression levels of PTPRJ were lower than those in the corresponding pVHL reconstituted cells. Quantitative RT-PCR and western blot analysis of ccRCC with known VHL mutation status and normal matched tissues as well as RNA in situ hybridization on a tissue microarray (TMA) confirmed a decrease of PTPRJ expression in more than 80% of ccRCCs, but in only 12% of papillary RCCs. ccRCC patients with no or reduced PTPRJ mRNA expression had a less favourable outcome than those with a normal expression status (p = 0.05). Sequence analysis of 32 PTPRJ mRNA-negative ccRCC samples showed five known polymorphisms but no mutations, implying other mechanisms leading to PTPRJ's down-regulation. Selective silencing of HIF-α by siRNA and reporter gene assays demonstrated that pVHL inactivation reduces PTPRJ expression through a HIF-dependent mechanism, which is mainly driven by HIF-2α stabilization. Our results suggest PTPRJ as a member of a pVHL-controlled pathway whose suppression by HIF is critical for ccRCC development.

Relevance of periostin splice variants in renal cell carcinoma.

The extracellular matrix N-glycoprotein periostin is thought to enhance tumor invasion. In this study, the expression patterns of periostin and its splice isoforms were investigated in renal cell carcinoma (RCC). Periostin mRNA expression patterns were characterized in 30 fresh-frozen RCCs in normal fetal and adult renal tissues by both isoform-specific and nonspecific RT-PCR and by gene expression array analysis. Its protein expression was analyzed by immunohistochemistry, using tissue microarrays with tissue from 1007 RCC patients. Periostin mRNA in RCC was increased, as observed in both RT-PCR and gene microarray analyses, with significantly higher expression in the clear cell than in the papillary subtype. Four of eight periostin isoforms, identified in fetal kidney by direct sequencing, have not been described to date. Three isoforms could be detected in both RCC and matched non-neoplastic tissue, and one of them was expressed more frequently in RCC. Periostin protein was detected in both mesenchymal cells of the tumor stroma and epithelial tumor cells. Greater amounts of periostin in tumor epithelia correlated with the presence of sarcomatoid differentiation, higher tumor stage, lymph node metastases, and poor overall survival in the clear cell subtype. In conclusion, periostin expression in tumor epithelia may contribute to sarcomatoid differentiation and more aggressive behavior of RCC. The presence of a tumor-associated periostin isoform suggests splice-specific regulation in RCC tissue.

Neonatal presentation of Loeys-Dietz syndrome: two case reports and review of the literature.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by cardiovascular manifestations, especially aortic dilatations and arterial tortuosity, craniofacial and skeletal features, joint laxity or contractures, skin abnormalities, hypotonia and motor delay. Its diagnosis is established by the identification of a pathogenic variant in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 or TGFB3 genes. In newborns and toddlers, vascular complications such as aneurism rupture, aortic dissection, and intracerebral incidents, can occur already in the weeks of life. To avoid these events, it is crucial to precociously identify this condition and to start an apunderwent a surgical procedurepropriate treatment which, depending on the severity of the vascular involvement, might be medical or surgical. CASE PRESENTATION: We report two cases of Loeys-Dietz syndrome precociously diagnosed. The first describes a male, born at 38 + 1 weeks of gestation, with hypotonia, joint hypermobility, arachnodactyly, and fingers joint contractures, as well as senile appearance and facial dysmorphisms. In the suspect of a connective tissue disorder, an echocardiography was performed and revealed an aortic root dilatation of 13 mm (Z score + 3). A trio based Whole Exome Sequencing found a novel de novo variant in the TGFBR2 gene. Despite the onset of a low-dose angiotensin receptor blocker therapy, the aneurysm progressed. The second case describes a female, born at 41 + 3 weeks of gestation. During the neonatal examination a cleft palate was noticed, as well as minor dysmorphisms. Since the family history was suspicious for connective tissue disorders, a genetic panel was performed and identified a pathogenetic variant in TGFB3 gene. In this case, the echocardiography revealed no abnormalities. CONCLUSIONS: In addition to our cases, we identified 14 subjects with neonatal LDS in the medical literature. All of them had aortic involvement. Skeletal and face abnormalities, including eyes and palate malformations, were also highly frequent. Overall, 10 subjects required medical therapy to avoid aneurysm progression, and 8 patients underwent surgical procedures. Benefits of an early diagnosis of LDS are various and imply a potential modification of the natural history of the disease with early interventions on its complications.

Routine use of bilateral internal thoracic artery grafting in women does not increase in-hospital mortality and could improve long-term survival.

BACKGROUND: Bilateral internal thoracic artery (BITA) grafting is underused in women. METHODS: Outcomes of 798 consecutive women with multivessel coronary disease who underwent isolated coronary surgery (1999-2016) using BITA (n=530, 66.4%) or single internal thoracic artery (SITA) grafting (n=268, 33.6%) were reviewed retrospectively. Differences between BITA and SITA cohort were adjusted by propensity score matching. For both series, late survival was estimated with the Kaplan-Meier method. RESULTS: One-to-one propensity score matching resulted in 247 BITA/SITA pairs with similar baseline characteristics and risk profile. According to the propensity matching, BITA grafting was associated with a trend towards reduced in-hospital mortality (3.2% vs. 5.7%, p=0.19). However, BITA women had an increased chest tube output (p=0.0076) as well as higher rates of any (13% vs. 5.3%, p=0.003) and deep sternal wound infections (9.3% vs. 4.9%, p=0.054), this translating in a longer in-hospital stay (10 vs. 9days, p=0.029). Test for interaction showed that body mass index >30kg/m2 and extracardiac arteriopathy were associated with a higher risk of deep sternal wound infection in BITA than in SITA women (23.4% vs. 13.7%, p<0.001 and 23.9% vs. 3.4%, p=0.001, respectively). Freedom from all-cause death and cardiac or cerebrovascular death were improved in BITA cohort, even though the differences were not quite significant (p=0.16 and 0.076, respectively). CONCLUSIONS: When routinely performed, BITA grafting does not increase in-hospital mortality in women and could improve long-term survival. However, its use should be avoided in obese women with extracardiac arteriopathy because of increased risk of deep sternal wound infection.

Helicobacter pylori detected in pharyngeal and laryngeal pathologies in patients with proven gastric colonization.

BACKGROUND: Helicobacter pylori is known to cause gastric cancer. Presence and carcinogenicity in the upper aerodigestive system is doubtful. This study examined the prevalence of Helicobacter pylori and related factors in biopsies from the upper aerodigestive tract (UADT) in patients with gastric colonization by Helicobacter pylori. METHODS: In a case series study, 26 patients with histopathologically confirmed gastric colonization were identified. A polymerase chain reaction (PCR) was performed on matched formalin-fixed and paraffin-embedded tissues of the stomach and the oral cavity, pharynx, or larynx. RESULTS: Helicobacter pylori was found in 38% of the samples from the oral cavity, pharynx, and larynx. An association with malignancies in these regions or possible risk factors, such as age, smoking, or alcohol, was not found. CONCLUSION: The upper aerodigestive system seems to be an additional reservoir in a significant percentage of patients presenting with Helicobacter pylori gastritis.

Characterization of periostin isoform pattern in non-small cell lung cancer.

INTRODUCTION: The extracellular matrix N-glycoprotein periostin (OSF-2, POSTN) is a major constituent of the desmoplastic stroma around solid tumors. It promotes tumor invasion and metastasis via epithelial-mesenchymal transition (EMT). In this study we investigated periostin expression at both RNA and protein level as well as the expression pattern of its splice isoforms in non-small cell lung cancer (NSCLC). METHODS: Thirty fresh frozen and corresponding formalin-fixed NSCLC tissues (adeno- and squamous cell carcinoma subtype, each n=15) and their matched non-neoplastic tissues were investigated. Periostin mRNA levels were analyzed by quantitative RT-PCR. The EMT-markers periostin and vimentin were analyzed by immunohistochemistry. Laser capture microdissection allowed for analysis of periostin expression in tumor epithelia and stroma, separately. Isoform patterns were investigated by isoform-specific PCR following sequencing in NSCLC, fetal and adult normal lung tissue. RESULTS: The qRT-PCR analysis showed periostin mRNA up-regulation in NSCLC tissue in relation to normal lung, with significantly higher levels in the adeno-compared to the squamous cell subtype (p<0.05). However, protein levels in both tumor epithelia and stroma correlated with squamous cell carcinoma (p<0.001) and larger tumor size (p<0.05). Further, periostin tumor epithelia expression, correlated with higher tumor grade (p<0.05). Sequence analysis detected eight periostin isoforms in fetal lung, but only five in both NSCLC and matched normal lung tissue. Among the eight isoforms, four are new and were labelled 5, 7, 8 and 9. The exclusive presence of isoforms 1 and 9 in fetal tissue suggests splice-specific regulation during lung embryogenesis. Finally, laser capture microdissection demonstrated that both tumor epithelia and stromal cells can be a source of periostin production in NSCLC. CONCLUSIONS: This study represents the first analysis of periostin isoform expression patterns in NSCLC and a characterization of periostin expression in cancer versus stromal cells at both RNA and protein level.

Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update.

Periostin, also called osteoblast-specific factor 2, is a secreted cell adhesion protein, which shares a homology with the insect cell adhesion molecule fasciclin I. It has been shown to be an important regulator of bone and tooth formation and maintenance, and of cardiac development and healing. Recent studies revealed that periostin plays an important role in tumor development and is upregulated in a wide variety of cancers such as colon, pancreatic, ovarian, breast, head and neck, thyroid, and gastric cancer as well as in neuroblastoma. Periostin binding to the integrins activates the Akt/PKB- and FAK-mediated signaling pathways which lead to increased cell survival, angiogenesis, invasion, metastasis, and importantly, epithelial-mesenchymal transition of carcinoma cells. In this review we summarize recent clinicopathological studies that have investigated periostin expression in lung, kidney, prostate, liver cancer, and malignant pleural mesothelioma and discuss the role of periostin isoforms in tumorigenesis and their potential as targets for stroma-targeted anticancer therapy.