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.

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.

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.

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.

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.

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.

Alemanno's brachial plexus block ten years later: topographic study of the anesthetized areas.

AIM: The study analyzes the extension of anesthesia induced by Alemanno's brachial plexus block technique on the various areas of competence of the different nerves. METHODS: The study was conducted on 58 patients in ASA classes 1 and 2 scheduled to receive shoulder arthroscopy. At the end of the operation, about 2 hours after induction of anesthesia, extension of anesthesia was evaluated by the pin-prick test. RESULTS: Anesthesia was achieved in 100% of cases for the circumflexus, musculocutaneous and radial nerves; the median nerve escaped in 7% of cases, the medial cutaneous nerve of forearm in 20%, the ulnar nerve in 27.5%, the medial cutaneous nerve of arm and intercostobrachial nerves in 46%; no major complications were associated with the technique. CONCLUSION: Alemanno's technique is recommended for operations on the shoulder and humerus, whereas more peripheral techniques may be preferable for interventions on the forearm and hand.

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.

Have you had your feedback today?

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.

Health and health care among housestaff in four U.S. internal medicine residency programs.

BACKGROUND: Although there have been many studies of the health care services that resident physicians provide, little is known about the health care services they receive. OBJECTIVE: To describe residents' perceptions of the health care they receive. DESIGN: Anonymous mailed survey. SUBJECTS: All 389 residents in four U.S. categorical internal medicine training programs. MAIN RESULTS: Three hundred sixteen residents responded (83%). In aggregate, 116 (37%) reported having no primary care physician, and 36 (12%) reported that they are their own primary care physician. These figures varied substantially across the four programs. Most residents reported receiving basic screening and preventive services; however, their attitudes toward their health and health care differed across postgraduate level, gender, and program. Many residents reported that their long and unpredictable hours interfered with their ability to schedule clinician visits, that their health had declined because of residency, that programs and other residents were unsupportive of residents' health care needs, and that residency raised special issues of privacy that limited access to health care. CONCLUSIONS: Despite high rates of receipt of preventive services, these internal medicine residents identified several barriers that limited their access to health care. Program directors should explore these barriers and, at the same time, reevaluate the messages being sent to resident physicians about maintaining their health and health care.