Outcome of brain metastases from adrenocortical carcinoma: a pooled analysis.

PURPOSE: Brain metastases rarely complicate the natural history of patients with adrenocortical carcinoma (ACC). No information is available regarding the life expectancy and efficacy of treatments in ACC patients with brain involvement. METHODS: A pooled analysis was performed by searching on PubMed and using the keywords: "brain metastases in adrenocortical carcinoma", and "leptomeningeal metastases in adrenocortical carcinoma". Four patients diagnosed at Spedali Civili Hospital in Brescia were added to the analysis. Data concerning demographic, disease characteristics, adopted treatments and patient prognosis were collected. RESULTS: A total of 27 patients (18 adults and 9 children) were included in this study, 22 of them had an adequate follow-up. Brain metastases occurred late in the natural history of adult patients but not in that of children. Surgery plus/minus radiation therapy was the treatment of choice. Adult patients with brain metastases had a poor prognosis with a median progression-free survival (PFS) and overall survival (OS) of 2 and 7 months, respectively. Median PFS and OS were not attained in children. CONCLUSION: Brain metastases in ACC patients are rare and are associated with poor prognosis, particularly in adults. Surgery plus/minus radiotherapy is the only therapeutic approach that can offer patients a chance to obtain durable local disease control.

CSF-1R inhibitor PLX3397 attenuates peripheral and brain chronic GVHD and improves functional outcomes in mice.

Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood-brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.

Patterning of perovskite-polymer films by wrinkling instabilities.

Organic-inorganic perovskites are semiconductors used for applications in optoelectronics and photovoltaics. Micron and submicron perovskite patterns have been explored in semitransparent photovoltaic and lasing applications. In this work, we show that a polymeric medium can be used to create a patterned perovskite, by using a novel and inexpensive approach.

An efficient perovskite solar cell with symmetrical Zn(ii) phthalocyanine infiltrated buffering porous Al2O3 as the hybrid interfacial hole-transporting layer.

A new Zn(ii) phthalocyanine (Pc) based low bandgap HTM is introduced for perovskite solar cells. Steady state and time-resolved photoluminescence (PL) measurements indicated an evenly matched hole extraction efficiency between sym-HTPcH and spiro-OMeTAD. On account of the low film quality and resulting high recombination, Zn(ii) Pc normally cannot work as an effective HTM. We adopted insulating Al2O3 for the infiltration of sym-HTPcH to form a hybrid interfacial buffer layer, affording perovskite solar cells (PSCs) with an average PCE value of up to 12.3%, which is a significant improvement with respect to the control cell without the meso-Al2O3 layer (4.21%) and is the highest value ever reported for Zn(ii) phthalocyanine based devices under AM1.5G standard conditions. A hysteresis test revealed that our device structure with the new HTM exhibited a balanced charge extraction behaviour.

Microwave ablation of hepatic tumors with a third generation system: loco­regional efficacy in a prospective cohort study with intermediate term follow-up.

PURPOSE: To evaluate the safety and intermediate-term efficacy of percutaneous microwave ablation (MWA) in primary and secondary liver tumors using a third generation MWA device, under ultrasound guidance. PATIENTS AND METHODS: Sixty-two patients (median age 74 years, 73 % males) with 69 liver tumors were enrolled in this prospective observational study. Forty-seven patients (76 %) had hepatocellular carcinoma (HCC) and 15 (24 %) metastases. Median follow-up was 3.6 years. RESULTS: Median tumor diameter at contrast enhanced computed tomography was 23 mm (I-III quartiles, 18 - 31 mm). All procedures were performed percutaneously using a 2.45 GHz generator. Median ablation time was 10 minutes (I-III quartiles, 10 - 14 minutes). A single percutaneous antenna insertion was performed for 56/69 (81 %) of the tumors. Technical success was obtained in all tumors. Primary efficacy at 24 hours was achieved in 68/69 (99 %) tumors. The overall one-year cumulative local tumor progression rate was 15.1 % (95 % CI, 7.7 - 24.8 %) with no significant difference between HCC and metastases (p = 0.26). There was one procedure-related mortality (1.6 %) and one major bleeding (1.6 %). CONCLUSION: Microwave ablation is a valid option for thermal ablation of HCC and liver metastases with comparable complication rate to other local ablative procedures.

VITAMIN D DEFICIENCY IN ADULTS: SEARCHING FOR THE PROPER LOADING DOSE.

Vitamin D is the main hormone regulating calcium phosphate homeostasis and mineral bone metabolism. Vitamin D deficiency is indeed extremely frequent in musculoskeletal diseases. Recent studies have shown that the treatment of osteoporosis needs to have an optimal vitamin D and calcium supplementation for its efficacy. Actually no agreement exists on the estabilished dose of vitamin D to administer in deficency states. We conducted a prospective study to develop a practical cholecalciferol loading dose regimen that would enable rapid correction of vitamin D deficiency. Sixty post-menopausal age woman were enrolled secondary to a fragility fracture (hip, vertebral, wrist) and screened for 25-hydroxyvitamin D (25(OH)D), calcium, and PTH at baseline (T0), after one month (T1), two months (T2), three months (T3) and six months (T4). Secondary to initial blood values of vitamin D patients were divided into 2 groups; the first group (group A, n=30) included patients with 25(OH)D values between 10-30 ng/ml and the second group (group B, n=30) with values under 10 ng/ml. Each group was then divided in 3 subgroups secondary to the randomized administered dose of 25(OH)D. By this, patients can alternatively receive 25000 UI two times monthly, 100000 UI monthly, 10000 UI (25 drops) weekly. The highest values of mean increase of 25(OH)D were observed in patients treated with 100000 UI. Patients treated with 10000 UI weekly did never achieve the target value. Additionally, as vitamin levels increased, pain intensity decreased. Vitamin D supplementation of 100000 UI monthly seems to be adequate to ensure that serum 25(OH)D values reach the threshold level; by this, it will confer the expected effects without risks of toxicity.

ASSESSING BONE MINERAL DENSITY IN ITALIAN ADULT CYSTIC FIBROSIS PATIENTS: A CROSS SECTIONAL STUDY.

The purpose of this study was to assess bone mineral density in a cystic fibrosis (CF) outpatient clinic population and to investigate the relationship between BMD and forced expiratory volume in one second (FEV1), DEXA T-scores and 25-hidroxivitamin D (25-OHD) serum levels. We examined a consecutive series of 44 CF patients. Bone mass density was measured by dual-photon X-ray absorptiometry of lumbar spine and femur (total and neck) and lung function was performed in all patients. Medication data were obtained from medical records. A correlation analysis was performed to determine the relationship between BMD and forced expiratory volume in one second (FEV1), DEXA T-scores and 25-hidroxivitamin D (25-OHD) serum levels. In the results, age showed a significant inverse correlation indicating that as the age increases, bone density decreases and we concluded that most CF patients have low BMD and that there is a positive correlation with lung function and an inverse correlation with age.

OPTIMAL IMPROVEMENT IN FUNCTION AFTER TOTAL HIP AND KNEE REPLACEMENT: HOW DEEP DO YOU KNOW YOUR PATIENT’S MIND?

Osteoarthritis (OA) of the hip and knee causes pain and loss of joint mobility, leading to limitations in physical function. When conservative treatment fails total hip and knee replacement is a cost-effective surgical option. Patients have high expectations regarding functional outcome after these procedures. If such expectations are not met, they may still be dissatisfied with the outcome of a technically successful procedure. Recently, numerous studies reported that psychological factors can influence the outcome of total knee replacement (tkr) and total hip artrhoplasty with total hip replacement (thr). We conducted a prospective study on a consecutive sample of 280 patients affected by hip or knee OA who underwent total joint replacement. At patients’ admission, Harris Hip Score (HHS) and Knee Society Score (KSS) were used to assess pain and function. Furthermore, SF-36, Mini-Mental Status Examination (MMSE), Symptom Checklist-90-R (SCL-90-R), Coping Orientation to Problems Experienced (BRIEF-COPE) and the Amsterdam Preoperative Anxiety and Information Scale (APAIS) were administered. Patients had clinical and radio graphical follow up at 1, 3 and 6 months post-operatively. The HHS and KSS values before surgery showed a linear correlation with both SCL-90-R and MMSE. None of the investigated variables influenced post-operative HHS and KSS scores; however, the improvement of functional scores resulted conditioned by SCL-90-R values, VAS score, schooling and MMSE. Psychological factors and mental status in primary total hip and knee replacement can affect outcome and patient satisfaction. Strategies focused on identification and facing of these conditions must be considered to improve outcome of total replacement.

Effects On Palatal Surface Area In Mixed Dentition Patients Treated With Leaf Expander And Rapid Palatal Expander, Compared To Untreated Subjects: A Randomised Clinical Trial.

AIM: To evaluate palatal surface effects induced by LE and RPE, alongside spontaneous changes in an untreated group, and to compare differences in canine and molar inclination among the three groups. MATERIALS: This randomised clinical trial aimed to compare digital models pre- and post-treatment over 12 months in patients receiving tooth-borne Leaf Expander® (LE) and tooth-borne Hyrax-type maxillary expander (RPE) treatments, alongside untreated patients. Analysis included 24 LE patients (13 males, 11 females, mean age 8.5±1.5), 22 RPE patients (10 males, 12 females, mean age 7.9±1.6), and 17 untreated subjects (7 males, 10 females, mean age 8.1±1.2). Inclusion criteria comprised indications for maxillary expansion treatment, mixed dentition, CVMS ≤ 3, erupted first molars, and good oral hygiene. Digital models were obtained using an intraoral scanner pre- and post-treatment. Palatal surface, segmented into anterior, median, and posterior zones, and canine/molar inclination were measured at T0-T1 using VAM software as the primary and secondary endpoint. Statistical analyses involved paired-sample T-tests for intra-group comparisons and ANOVA tests with Bonferroni correction for inter-group comparisons. CONCLUSION: No significant difference in palatal surface increment was found between the two experimental groups (LE and RPE); both demonstrated a significant increase in palatal surface. The greatest increment occurred in the median palate zone for both experimental groups. The increment in the untreated control group was not significant. Furthermore, the RPE group showed a greater inclination of permanent molars compared to those treated with LE, indicating that expansion with lighter and continuous forces may lead to fewer dental side effects.

Pericyte phenotype switching alleviates immunosuppression and sensitizes vascularized tumors to immunotherapy in preclinical models.

T cell-based immunotherapies are a promising therapeutic approach for multiple malignancies, but their efficacy is limited by tumor hypoxia arising from dysfunctional blood vessels. Here, we report that cell-intrinsic properties of a single vascular component, namely the pericyte, contribute to the control of tumor oxygenation, macrophage polarization, vessel inflammation, and T cell infiltration. Switching pericyte phenotype from a synthetic to a differentiated state reverses immune suppression and sensitizes tumors to adoptive T cell therapy, leading to regression of melanoma in mice. In melanoma patients, improved survival is correlated with enhanced pericyte maturity. Importantly, pericyte plasticity is regulated by signaling pathways converging on Rho kinase activity, with pericyte maturity being inducible by selective low-dose therapeutics that suppress pericyte MEK, AKT, or notch signaling. We also show that low-dose targeted anticancer therapy can durably change the tumor microenvironment without inducing adaptive resistance, creating a highly translatable pathway for redosing anticancer targeted therapies in combination with immunotherapy to improve outcome.

Buccal Alveolar Bone changes and upper first molar displacement after maxillary expansion with RME, Ni-Ti leaf springs expander and Tooth- Bone-borne Expander. A CBCT based analysis.

AIM: To evaluate the buccal alveolar bone changes and the upper first molar displacement in subjects treated with conventional rapid maxillary expansion (RME), Ni-Ti leaf springs expander (Leaf Expander) and Tooth-Bone-borne Expander (Hybrid Expander) using CBCT scans. METHODS: The sample consisted of 52 children treated with RME (n=18), Leaf Expander (n= 17) and Hybrid Expander (n= 17). CBCTs were taken before and after maxillary expansion and the Horos software was used for the analysis. Descriptive statistics and paired t-test were used to assess changes between the pre-treatment and post-treatment measurements. ANOVA test and Tukey's post hoc test with Bonferroni correction was used for between groups comparison. CONCLUSION: The Hybrid Expander during preadolescence showed few advantages over the use of tooth-anchored expanders. An expansion approach with mini-screws is not preferable during early mixed dentition to a conventional approach. The differences in dental tipping values were clinically insignificant and the reduction in cortical bone thickness remained less than 1 mm. When possible, the use of second primary molars as anchorage should be preferred.

Skeletal and dento-alveolar changes obtained with customised and preformed eruption guidance appliances after 1-year treatment in early mixed dentition.

AIM: The aim of this study was to assess the skeletal and dento-alveolar changes produced by a customised eruption guidance appliance (EGA) and a preformed EGA in subjects presenting a skeletal class II pattern during early mixed dentition and to evaluate the differences between the two devices. METHODS: All subjects included in the study were randomly selected from the record's archive according to the following inclusion criteria: (1) patients presenting upper central incisor and first permanent molars fully erupted; (2) early mixed dentition with age between 7 to 9 years old; (3) Angle class I or class II malocclusion; (4) increased overjet > 4 mm;(5) deep bite with at least 2/3 overlapping of the incisors; (6) no previous orthodontic treatment apart from maxillary expansion treatment. All children belonging to the case group received treatment with a 3D printed EGA whereas the other patients belonging to the control group were treated with preformed EGA. Records consisted in digital dental models and lateral cephalogram at the beginning (T0) and after 1 year of treatment (T1). Data collected on the digital models included the dentoalveolar changes in overbite, overjet, sagittal molar relationship, and dental crowding. Cephalometric tracings were computed by a single blinded observer using Dolphin Imaging software. Statistical analysis was performed with SPSS (version 25.00; IBM Corp, Armonk, NY). Comparison regarding the cephalometric changes between T1-T2 was carried out with paired t-test. Difference in distribution regarding sagittal molar and canine relationship and anterior crowding between groups at T1 and T2 has been computed with chi-square test. The independent sample t-test was used to perform the between group comparison. CONCLUSION: In the short time, both the appliances showed to be effective in correcting class II malocclusion, anterior crowding, overjet and overbite. Custom-made appliance demonstrated to be significantly more effective in correcting anterior crowding, the dento-skeletal vertical relation and position of permanent incisor compared to the preformed appliance. Adopting a customised device, effects due to an average prescription appliance used to a specific patient can be reduced, resulting in more predictable results.

Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis. No efficacious treatment options are currently available for patients with advanced metastatic disease with disease progression to standard etoposide, doxorubicin, cisplatin and mitotane (EDP-M) therapy. We assessed the activity and tolerability of cabazitaxel as a second/third-line approach in metastatic ACC. PATIENTS AND METHODS: Patients included in this single-center, phase II study (ClinicalTrials.gov identifier NCT03257891) had disease progression to a cisplatin-containing regimen (such as EDP) plus mitotane, plus/minus a further chemotherapy line. Cabazitaxel was administered intravenously at 25 mg/m2 on day 1 of a 21-day cycle, for a maximum of six cycles. The primary endpoint was a disease control rate after 4 months. RESULTS: From March 2018 to September 2019, 25 eligible patients were enrolled. A disease control rate after 4 months was obtained in six patients (24%). No patients attained a disease response according to RECIST 1.1, 9 patients (36%) had stable disease and 16 patients (64%) progressive disease. Median progression-free survival and overall survival were 1.5 months (range 0.3-7 months) and 6 months (range 1-22.2 months), respectively. Cabazitaxel therapy was well tolerated and only three (12%) patients developed grade 3 toxicity which were nausea in one patient (4%) and anemia in two patients (8%). CONCLUSIONS: Cabazitaxel has a manageable toxicity profile but is poorly active as second/third-line treatment in advanced ACC patients. These results do not support further evaluation of cabazitaxel in this setting.

A model of impaired Langerhans cell maturation associated with HPV induced epithelial hyperplasia.

Langerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers.

In situ Near-Ambient Pressure X-ray Photoelectron Spectroscopy Reveals the Influence of Photon Flux and Water on the Stability of Halide Perovskite.

For several years, scientists have been trying to understand the mechanisms that reduce the long-term stability of perovskite solar cells. In this work, we examined the effect of water and photon flux on the stability of CH3 NH3 PbI3 perovskite films and solar cells using in situ near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS), field emission scanning electron microscopy (FESEM), and current density-voltage (J-V) characterization. The used amount of water vapor (up to 1 mbar) had a negligible impact on the perovskite film. The higher the photon flux, the more prominent were the changes in the NAP-XPS and FESEM data; also, a faster decline in power conversion efficiency (PCE) and a more substantial hysteresis in the J-V characteristics were observed. Based on our results, it can be concluded that the PCE decrease originates from the creation of Frenkel pair defects in the perovskite film under illumination. The stronger the illumination, the higher the number of Frenkel defects, leading to a faster PCE decline and more substantial hysteresis in the J-V sweeps.

Impact of inlet channel geometry on microfluidic drop formation.

We study the impact of inlet channel geometry on microfluidic drop formation. We show that drop makers with T-junction style inlets form monodisperse emulsions at low and moderate capillary numbers and those with Flow-Focus style inlets do so at moderate and high capillary numbers. At low and moderate capillary number, drop formation is dominated by interfacial forces and mediated by the confinement of the microchannels; drop size as a function of flow-rate ratio follows a simple functional form based on a blocking-squeezing mechanism. We summarize the stability of the drop makers with different inlet channel geometry in the form of a phase diagram as a function of capillary number and flow-rate ratio.

A heterogeneous dose distribution in simultaneous integrated boost: the role of the clonogenic cell density on the tumor control probability.

IMRT with inverse planning allows simultaneous integrated boost strategies that exploit the heterogeneous dose distribution within the planning target volumes (PTVs). In this scenario, the location of cold spots within the target becomes a crucial issue and has to be related to the distribution of the clonogenic cell density (CCD). The main aim of this work is to provide the means to calculate the optimal prescription dose in a relative inhomogeneous dose distribution. To achieve this, the prescription dose has to be assigned to obtain the same tumor control probability (TCP) as the ideal homogeneous distribution, taking into account different CCDs in different PTVs (i.e. visible and subclinical regions). An adapted formulation of the linear-quadratic model, within the F-factor formalism, has been derived to preserve a chosen TCP value for the whole target volume. The F-factor has been investigated to show its potential applications in clinical practice.

A lifelong story: Case report of a humeral shaft nonunion successfully treated after 30 years.

Nonunion of the humeral shaft occurs in 2%-10% of nonsurgically treated fractures and in up to 15% of fractures treated by primary open reduction and internal fixation. Gunshot humerus shaft fractures are a frequent type of injury; the degree of comminution and bone loss, as well as soft tissue disruption may influence the healing process, causing major sequelae with loss of function. Here we describe a 30 years old midshaft nonunion of the humerus, that occurred in a young woman after a gunshot. She was initially treated with hanging cast with definitive nonunion and secondary loss of limb function. After 30 years, careful management of the non union fracture ends, locked intramedullary nailing and bone grafting harvested from the femoral canal using the Reamer Irrigator Aspirator (RIA) system led to union with recovery of limb function.