PD-L1 overexpression induces STAT signaling and promotes the secretion of pro-angiogenic cytokines in non-small cell lung cancer (NSCLC).

BACKGROUND: Monoclonal antibodies (ICI) targeting the immune checkpoint PD-1/PD-L1 alone or in combination with chemotherapy have demonstrated relevant benefits and established new standards of care in first-line treatment for advanced non-oncogene addicted non-small cell lung cancer (NSCLC). However, a relevant percentage of NSCLC patients, even with high PD-L1 expression, did not respond to ICI, highlighting the presence of intracellular resistance mechanisms that could be dependent on high PD-L1 levels. The intracellular signaling induced by PD-L1 in tumor cells and their correlation with angiogenic signaling pathways are not yet fully elucidated. METHODS: The intrinsic role of PD-L1 was initially checked in two PD-L1 overexpressing NSCLC cells by transcriptome profile and kinase array. The correlation of PD-L1 with VEGF, PECAM-1, and angiogenesis was evaluated in a cohort of advanced NSCLC patients. The secreted cytokines involved in tumor angiogenesis were assessed by Luminex assay and their effect on Huvec migration by a non-contact co-culture system. RESULTS: PD-L1 overexpressing cells modulated pathways involved in tumor inflammation and JAK-STAT signaling. In NSCLC patients, PD-L1 expression was correlated with high tumor intra-vasculature. When challenged with PBMC, PD-L1 overexpressing cells produced higher levels of pro-angiogenic factors compared to parental cells, as a consequence of STAT signaling activation. This increased production of cytokines involved in tumor angiogenesis largely stimulated Huvec migration. Finally, the addition of the anti-antiangiogenic agent nintedanib significantly reduced the spread of Huvec cells when exposed to high levels of pro-angiogenic factors. CONCLUSIONS: In this study, we reported that high PD-L1 modulates STAT signaling in the presence of PBMC and induces pro-angiogenic factor secretion. This could enforce the role of PD-L1 as a crucial regulator of the tumor microenvironment stimulating tumor progression, both as an inhibitor of T-cell activity and as a promoter of tumor angiogenesis.

Is implant placement performed at the same surgical time as orbital exenteration a viable procedure?

PURPOSE: To assess the efficacy and safety of bone-anchored dental implant placement at the same time as orbital exenteration compared with delayed implant placement. MATERIALS AND METHODS: A retrospective comparative study was conducted in a single tertiary care center between December 2003 and December 2017. Patients who underwent bone-anchored implant placement at the same time as orbital exenteration were included (group 1) and compared with patients who underwent delayed implant placement (group 2). The main outcome was the 1-year success rate of implant osseointegration. The secondary outcomes were the 5-year success rate of osseointegration, postoperative complications, and time between orbital exenteration and prosthesis placement. RESULTS: Ten and 11 patients (21 and 22 implants) with a mean follow-up of 50.2 and 48.5 months were included in groups 1 and 2, respectively. Patients in group 1 were significantly older (69.7 vs 61.2 years, P = .026). No significant differences were found between both groups regarding tumor type and location, prior treatments, smoking status, and postoperative radiation beam radiotherapy. The 1- and 5-year success rates of osseointegration were 95.5% and 93.3% in group 1, and 100% and 100% in group 2, respectively (P = .488 and P = .450 between both groups). One implant did not osseointegrate in group 1 due to osteitis. Ethmoidal fistula was the most common postoperative complication found in both groups (P = .670). The mean time between orbital exenteration and episthesis placement was 8 (3 to 14) vs 11 (3 to 15) months in groups 1 and 2, respectively (P = .467). CONCLUSION: Placing implants at the same time as orbital exenteration is a viable procedure. It reduces surgical morbidity and allows placement of implants in a nonirradiated area.

Orbital exenteration and conjunctival melanoma: a 14-year study at the Jules Gonin Eye Hospital.

PURPOSE: To report our 14-year experience with orbital exenteration and assess risk factors for poor prognosis by focusing on conjunctival melanoma. PATIENTS AND METHOD: A retrospective study was conducted in our tertiary care centre (Jules Gonin Eye Hospital, Lausanne, Switzerland) between 2003 and 2017. Inclusion criteria were patients aged ≥18 years with a follow-up >12 months, without metastatic spread at the time of surgery. Data recorded were age, gender, tumour histology, surgical technique, postoperative complications, surgical margin status, local recurrence, postoperative radiation beam therapy and metastatic status. RESULTS: Twenty-five patients with a mean age of 63.2 years (38-92) were included. Conjunctival melanoma was the most frequently identified tumour (n = 14, 56%) followed by conjunctival squamous cell carcinoma (n = 4, 16%), sebaceous carcinoma (n = 3, 12%), choroidal melanoma (n = 2, 8%) and basal cell carcinoma (n = 2, 8%). Eighteen tumours (72%) originated from the conjunctival tissue. Clear surgical margins were achieved in 21 (84%) patients. Fourteen (56%) patients experienced distant metastases and died from metastatic spread after a mean follow-up of 52.3 months (6-120). The 1-, 3- and 5-year overall survival (OS) was 96%, 72% and 60%, respectively. In the univariate analysis, positive surgical margins, local recurrence and metachronous metastases were associated with a decreased OS (p = 0.002, p = 0.005 and p = 0.007, respectively). In the multivariate analysis, positive surgical margins and metachronous metastases were also associated with a decreased OS (p = 0.02 and p = 0.042, respectively). Conjunctival melanoma was not associated with a poorer prognosis (p = 0.280). CONCLUSION: Free surgical margins are needed to increase OS. To achieve clearer surgical margins, neoadjuvant targeted therapies/immunotherapies may be considered.

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers.

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.

Bovine xenograft application for treatment of a metatarsal nonunion fracture in an alpaca (Vicugna pacos).

CASE HISTORY: A 15-year-old female huacaya alpaca (Vicugna pacos) was referred because of a non-weight-bearing lameness (4/4) in the left pelvic limb caused by a grade three open metatarsal fracture. The referring veterinarian treated the fracture with conservative management using bandages, but it progressively evolved to a non-union. CLINICAL FINDINGS AND DIAGNOSIS: Clinical examination revealed external wounds on the medial and lateral surfaces of the metatarsus. Radiographs confirmed an open, nonarticular, displaced, diaphyseal fracture of the left metatarsus. TREATMENT AND OUTCOME: Cancellous bone was sourced from bovine proximal and distal femur epiphyses, followed by a thermal shock procedure to achieve decellularisation, to produce a xenograft. Open reduction and internal fixation of the fracture using locking plates was performed. Alignment of the fracture fragments was corrected and the xenograft was placed at the debrided fracture site to stimulate and harness osteogenesis in situ. Clinical and radiographic follow-up was performed up to 40 weeks postoperatively. Clinical evaluations revealed that the alpaca gradually increased weight bearing following bandage removal 10 days after surgery. Serial radiographs showed correct alignment of the left metatarsus, progressive bone modelling and, complete bone union at 12 weeks. Ten months postoperatively the alpaca showed no signs of lameness and resumed normal activity. CLINICAL RELEVANCE: For management of a metatarsal non-union, a combination of bovine xenograft application and angular stable internal fixation progressed toward an excellent long-term recovery.

Abdominal ultrasound features and reference values in 21 healthy rabbits.

This study aimed to determine the ultrasonographic features and reference values of the abdominal anatomy in mixed-breed dwarf rabbits. Complete abdominal ultrasonographic examination was performed in 21 mixed-breed rabbits (12 males and 9 females) referred for examination to the Department of Animal Medicine, Production and Health, University of Padua, Italy. All animals were sedated during the procedure. The ultrasonographic anatomy of the abdomen was determined, including measurement (mean±SD) of the right kidney (length 2.87±0.34 mm; width 1.62±0.17 mm; height 1.66±0.14 mm) and left kidney (length 2.86±0.33 mm; width 1.72±0.19; height 1.58±0.15 mm), left adrenal gland (width 0.38±0.11 mm; length 0.71±0.14), right adrenal gland (width 0.34±0.08 mm; length 0.73±0.15 mm) and thickness of the walls of the stomach (0.10±0.01 mm), pylorus (0.28±0.04 mm), duodenum (0.19±0.04 mm), sacculus rotundus (0.22±0.06 mm), caecum (0.08±0.01 mm), appendix (0.19±0.04 mm), spiral loop of the ascending colon (0.14±0.04 mm) and distal colon (0.10±0.02 mm). A significant positive correlation between bodyweight and kidney size, adrenal gland length, stomach wall and sacculus rotundus wall was detected.

Fluvoxamine alone in the treatment of delusional depression.

OBJECTIVE: The aim of this study was to evaluate the efficacy of fluvoxamine in the treatment of delusional depression. METHOD: Fifty-nine inpatients who met the DSM-III-R criteria for major depression with psychotic features were treated with fluvoxamine for 6 weeks. Patients were assessed at baseline and weekly thereafter with the Hamilton Depression Rating Scale and the Dimensions of Delusional Experience rating scale. RESULTS: Of the 57 subjects completed the trial, 84.2% (N=48) recovered. The index episodes of the patients who did not respond to fluvoxamine were of significantly longer duration than those of the responders. CONCLUSIONS: Fluvoxamine has a response rate similar to that of the currently most efficacious treatments for delusional depression, including antidepressants plus antipsychotics and ECT.

Nephrotic edema.

This article starts with a concise synopsis of the history of edema. The role of underfilling, overflow, antidiuretic hormone, and acquaporins is subsequently discussed. Emphasis is given to the use of diuretics in edematous patients. The role and risks of albumin infusion are illustrated. The new hypothesis of pulse reverse osmosis is discussed. The final section deals with the measurement of colloid osmotic pressure in the clinical setting.

Value of cerebrospinal fluid cytochemical examination for the diagnosis of congenital toxoplasmosis at birth in France.

BACKGROUND: Because of routine screening and treatment of pregnant women for Toxoplasma infection in France, most neonates born to mothers who seroconverted during pregnancy are either not infected or asymptomatic. Early diagnosis relies mainly on radiologic, ophthalmologic and biologic tests. Cerebrospinal fluid (CSF) cytochemical evaluation is one of several tests performed in parallel to increase the overall sensitivity of the diagnostic evaluation. Our goal was to assess the value of cytochemical examination and to confirm whether using a portion of available CSF for this analysis is legitimate. METHODS: The individual performance of each of the two cytochemical tests and their combined value when used in parallel were assessed. These findings were then compared with the anti-Toxoplasma IgM and IgA serum titers and the clinical, ophthalmologic and radiologic findings at birth. RESULTS: CSF cytochemical analysis was possible in only 52% of the 233 children in the study. Our results in 112 children indicated poor sensitivity estimates. There was no significant change in the posttest probability of infection compared with the pretest estimation of risk in cases of a negative finding. After a mean follow-up of 80 months there was no evidence that CSF cytochemistry helped predict the risk of sequelae. CONCLUSION: In our setting cytochemical examination did not significantly contribute to the diagnosis of congenital infection at birth. Because of the limited quantity of CSF available, we suggest the use of other methods with higher yield.

Frontal and callosal neuropsychological performances in schizophrenia. Further evidence of possible attention and mnesic dysfunctions.

Some level of frontal and callosal dysfunction has been reported in patients with schizophrenia. In the present study 68 normal controls and 117 schizophrenic patients were administered the Wisconsin Card Sorting Test (WCST), which involves the function of the frontal areas, and the Auditory Comprehension Test (ACT) which involves the corpus callosum and to a lesser degree attention and mnesic mechanisms. WCST correctly discriminated 69.8% of schizophrenics and 74.2% of controls, ACT 86.7% of schizophrenics and 90.2% of controls. Moreover, schizophrenics correctly classified by the WCST performed more poorly than schizophrenics incorrectly classified by the WCST on the related ACT indices for the attention and mnesic mechanisms. There were no differences in present age, age at onset, duration of the illness, diagnostic subtype and course of the disease between correctly and incorrectly classified schizophrenics by the WCST and the ACT. These data indicate a prevalent malfunctioning of attention and mnesic mechanisms in schizophrenia. Finally there seems to be no relationship between these neurofunctional abnormalities and demographic and clinical characteristics of the disease.

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Feedback is an essential component of medical education and adult learning; however, there are several challenges inherent in measuring the feedback directed at medical students. The authors describe the use of a daily e-mail questionnaire to gather information from medical students about the feedback they receive.

Neurofunctional assessment of lateralized hemispheric asymmetries in affective illness.

Performances of 59 affective patients, 59 schizophrenics and 59 normal controls on the Quality Extinction Test (QET), which has been proven to be valuable for detecting abnormal hemisphere functioning in neurological and psychiatric patients, are presented. Frequencies of the left and right extinctions of the affective patients did not exceed those of normal controls. Compared to schizophrenics, fewer affective patients had left and right extinctions and the number of these extinctions was significantly lower in affective patients. These results would indicate that affective patients do not differ from controls relative to lateralized cerebral malfunctioning as measured by the QET. The differences between affective and schizophrenic patients' QET performances may be explained by differences in the course and chronicity of the disease.

A comparison between delusional and non-delusional depressives.

Delusional depressive episodes may represent more sever degrees of depressive manifestations or a distinct subtype of depressive illness. To test these two alternative hypotheses, characteristics on demographic, clinical and symptomatic variables, presence of personality disorders and familial loading were compared in 57 delusional and 57 non-delusional depressive patients. The delusional group did not differ on symptomatological intensity degree, clinical and familial loading characteristics. They did differ on higher distribution of Cluster 1 personality disorders. In the delusional sample the presence of mood incongruent psychotic features and hallucinations were evaluated as possible indicators of different subtypes of delusional depression.

Renal hemodynamics, plasma amino acids and hormones after a meat meal in progressive nephron loss.

Ten patients with chronic renal failure (GFR 29-97 ml/min), on free diets providing 1 g/kg B.W. of proteins, ingested an oral protein load (meat meal, 2 g/kg B.W.). GFR and RPF increased significantly over baseline with no change in filtration fraction. Within 30 min of the meal and for the next 3 h a statistically significant increase was observed in the plasma concentrations of the following amino acid groups: essential, non-essential, total, branched-chain, ketogenic, glycogenic, glycogenic and ketogenic, basic, acid, polar and non-polar. At 30 min the smallest increase was seen in acid and polar amino acids (6.7% and 7.6%, respectively). At 180 min the largest increase (78.8%) was seen for glycogenic and ketogenic amino acids and total plasma amino acids were 1.58 times baseline. After the meat meal plasma glucagon and insulin rose significantly, while growth hormone, plasma renin activity and aldosterone did not vary.

Evaluation of sedation and clinical effects of midazolam with ketamine or dexmedetomidine in pet rabbits.

The effects of two sedation protocols combining midazolam with ketamine (ketamine group) or dexmedetomidine (dexmedetomidine group) were studied in dwarf companion rabbits undergoing abdominal ultrasound scan. The onset of sedation was faster in the ketamine group; a few rabbits in the dexmedetomidine group required additional doses to lose the righting reflex, although sedation time was not different between groups. A semi-quantitative scale was used to score sedation quality, which was higher in rabbits that received dexmedetomidine rather than ketamine. Pulse rate was lower in the dexmedetomidine group (206 vs 240 bpm), although Doppler blood pressure was higher than in the ketamine group (109 vs 89 mm Hg). Respiratory rate decreased in relation to the baseline values with both protocols but arterial haemoglobin saturation with oxygen was maintained similar to the pre-sedation values throughout the entire procedure, regardless of protocol used and without oxygen supplementation. Both protocols allowed performance of ultrasound scanning, although dexmedetomidine may be preferred if a deep sedation level is required.

Two-dimensional and Doppler echocardiographic findings in healthy non-sedated red-eared slider terrapins (Trachemys scripta elegans).

Echocardiographic evaluation was performed in six healthy young adult non-sedated terrapins (Trachemys scripta elegans). The best imaging quality was obtained through the right cervical window. Base-apex inflow and outflow views were recorded, ventricular size, ventricular wall thickness and ventricular outflow tract were measured, and fractional shortening was calculated. Pulsed-wave Doppler interrogation enabled the diastolic biphasic atrio-ventricular flow and the systolic ventricular outflow patterns to be recorded. The following Doppler-derived functional parameters were calculated: early diastolic (E) and late diastolic (A) wave peak velocities, E/A ratio, ventricular outflow systolic peak and mean velocities and gradients, Velocity-Time Integral, acceleration and deceleration times, and Ejection Time. For each parameter the mean, standard deviation and 95% confidence interval were calculated. Echocardiography resulted as a useful and easy-to-perform diagnostic tool in this poorly known species that presents difficulties during evaluation.