Molecular targeting agents in renal cell carcinoma: present strategies and future perspectives

Treatment options for metastatic renal cell carcinoma (RCC) have been limited due to its resistance to chemotherapy and radiotherapy. Benefits from immunotherapeutic agents provide only a small subset of patients. During the past decade major advances have been made toward understanding the molecular basis of RCC development. Such acquired knowledge has offered unique opportunities for the development of molecular targeting agents. These agents are predominately small molecules or monoclonal antibodies that exert their action through modulation of protein activity or inhibition of amplified signals directly implicated in disease mechanism. To date, some of newly molecular targeted agents have entered advanced phases of clinical development, received marketing authorization by regulatory agencies and have opened a possibility of multiple treatment options. This article overviews current knowledge in RCC molecular pathology with recent clinical data, and discuss present strategies for future development of targeted therapies.     

Comparison of benzydamine hydrochloride and Salvia officinalis as an adjuvant local treatment to systemic nonsteroidal anti-inflammatory drug in controlling pain after tonsillectomy, adenoidectomy, or both: an open-label, single-blind, randomized clinical trial

Background

Benzydamine hydrochloride (BNZD) is a nonsteroidal anti-inflammatory drug (NSAID) used in an oral rinse formulation as an adjuvant to other NSAIDs in controlling postoperative pain after tonsillectomy, adenoidectomy, or both. Salvia officinalis (SO) is a topically applied herbal preparation frequently used for the same indication. Pain, bleeding, and infection are the most common postoperative complications of tonsillectomy.

Objective

The aim of this study was to compare the efficacy and tolerability of BNDZ with those of SO as adjuvant treatments in controlling postoperative pain.

Methods

This open-label, single-blind, randomized clinical trial was conducted at the Department of Otorhinolaryngology, Clinical Hospital Center “Dr. Dragiša Mišović—Dedinje” (Belgrade, Serbia and Montenegro). Pediatric and adult patients undergoing tonsillectomy, adenoidectomy, or both were enrolled. Patients were randomized to receive BNZD or SO, in addition to ibuprofen 20 mg/kg·d (children) or diclofenac 100 mg/d (adults). The primary end point was the proportion of patients with mild or no pain on postoperative days 1, 2, 4, and 7. Secondary end points were the incidences of infection, hemorrhage, and other adverse events.

Results

A total of 420 patients were enrolled (217 females, 203 males; 278 children, 142 adults; mean [SD] age, 6.2 [2.1] years [children] and 24.1 [9.8] years [adults] [range, 3–45 years]). One hundred thirty-eight children received BNZD; 140 received SO (both in addition to ibuprofen 20 mg/kg·d). Seventy-two adults received BNZD; 70 received SO (both in addition to diclofenac 100 mg/d). A significantly lower proportion of children treated with adjuvant BNZD experienced moderate or severe pain than those treated with SO at each time point (P < 0.01 at days 1 and 4; P < 0.001 at days 2 and 7). In children, the risk for postoperative infection was similar between BNZD and SO (absolute risk reduction [ARR], 6.9%; 95% CI, 6.4%–7.6%); however, the risk was reduced in adults (ARR, 19.0%; 95% CI, 16.5%–21.9%; P = 0.008).

Conclusions

In this clinical trial of children and adults who underwent tonsillectomy, adenoidectomy, or both, BNZD, as an adjuvant to an NSAID, was more effective than SO in controlling postoperative pain and infection. The pain-reducing effect of BNZD was of quick onset and persisted for 1 week after surgery. The safety profile of BNZD was comparable to that of SO, with the exception of postoperative infection in adults, for which BNZD was more efficacious. In particular, the use of BNZD was not associated with a high risk for early postoperative hemorrhage.     

Impact of concomitant tricuspid regurgitation on outcome after edge-to-edge mitral valve repair

Aims

To evaluate the impact of tricuspid regurgitation (TR) on echocardiographic and functional outcome after mitral valve transcatheter edge-to-edge-repair (M-TEER).

Methods and Results

A total of 740 patients underwent M-TEER at our center from 2010 to 2021. Patients were analyzed according to severity of concomitant TR at the time of M-TEER procedure: low-grade TR (grade ≤I [trace–mild], 279 patients [37.7%]), moderate TR (grade II, 170 patients [23.0%]) and high-grade TR (grade III-V [severe–torrential], 291 patients [39.3%]). Patients with moderate to high-grade TR had higher morbidity. Procedural success of M-TEER was achieved similarly in all groups (98.2% vs. 97.6% vs. 95.9%, p = 0.22). TR severity decreased rapidly and consistently after M-TEER to only 48.0% of high-grade TR patients after 3 months (p < 0.001) and to 46.8% after 12 months (p = 0.99). High-grade TR patients had significantly higher mortality (21.5% vs. 18.2% vs. 11.1%, p = 0.003) up to 12 months after M-TEER. However, high-grade TR did not independently predict mortality (HR 1.302, 95% CI 0.937–1.810; p = 0.116). Echocardiographic and functional outcome was similar in both secondary and primary MR patients.

Conclusions

High-grade concomitant TR did not independently predict adverse outcome following M-TEER. A wait-and-observe approach for these patients is reasonable.     

Natural killer T cells in pulmonary disorders

Natural killer T (NKT) cells, a unique subgroup of lymphocytes with features of both T and natural killer (NK) cells, represent a bridge between innate and adaptive immunity. They have the ability to either promote or suppress immune responses. With these immunoregulatory functions, NKT cells have emerged as an important subset of lymphocytes with a protective role in some disorders, such as infections, cancer, and possibly sarcoidosis, and a pathogenic role in others, such as asthma, chronic obstructive pulmonary disease and hypersensitivity pneumonitis. Immunotherapeutic interventions to modulate the immune response by targeting iNKT cell functions has become a challenging field and has shown promising results for the development of new therapies.     

Rib fracture following stereotactic body radiotherapy: a potential pitfall

Although the incidence of rib fractures after conventional radiotherapy is generally low (<2%), rib fractures are a relatively common complication of stereotactic body radiotherapy. For malignancy adjacent to the chest wall, the incidence of rib fractures after stereotactic body radiotherapy is as high as 10%. Unrecognized bone fractures can mimic bone metastases on bone scintigraphy, can lead to extensive workup, and can even lead to consideration of unnecessary systemic chemotherapy, as treatment decisions can be based on imaging findings alone. Nuclear medicine physicians and diagnostic radiologists should always consider rib fracture in the differential diagnosis.     

Exploring Raman spectroscopy for the evaluation of glaucomatous retinal changes

Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cells and subsequent loss of visual function. Early detection of glaucoma is critical for the prevention of permanent structural damage and irreversible vision loss. Raman spectroscopy is a technique that provides rapid biochemical characterization of tissues in a nondestructive and noninvasive fashion. In this study, we explored the potential of using Raman spectroscopy for detection of glaucomatous changes in vitro. Raman spectroscopic imaging was conducted on retinal tissues of dogs with hereditary glaucoma and healthy control dogs. The Raman spectra were subjected to multivariate discriminant analysis with a support vector machine algorithm, and a classification model was developed to differentiate disease tissues versus healthy tissues. Spectroscopic analysis of 105 retinal ganglion cells (RGCs) from glaucomatous dogs and 267 RGCs from healthy dogs revealed spectroscopic markers that differentiated glaucomatous specimens from healthy controls. Furthermore, the multivariate discriminant model differentiated healthy samples and glaucomatous samples with good accuracy [healthy 89.5% and glaucomatous 97.6% for the same breed (Basset Hounds); and healthy 85.0% and glaucomatous 85.5% for different breeds (Beagles versus Basset Hounds)]. Raman spectroscopic screening can be used for in vitro detection of glaucomatous changes in retinal tissue with a high specificity.     

Hemodynamic changes in the posterior cerebral circulation triggered by insufficient sympathetic innervation – Cause of primary intracerebral hemorrhage?

Primary intracerebral hemorrhage (ICH) is caused by hypertensive disease of small penetrating blood vessels in the basal ganglia, brain stem and cerebellum. Those regions are supplied by arteries of the so-called posterior brain circulation with insufficient sympathetic innervation. We propose the following hypothesis: due to insufficient sympathetic innervation hemodynamic changes occur in the vascular bed of the posterior brain circulation serving as a key factor for arterial rupture. If autoregulation is insufficient to maintain normal cerebral blood flow, in abrupt rise in the blood pressure, the amount of blood is rising causing higher static pressure, and according to Laplace's law higher pressure and larger radius leads to higher wall tension and subsequent rupture of arterial wall previously weakened by prolonged hypertension.     

Effect of beta blockade on natriuretic peptides and copeptin in elderly patients with heart failure and preserved or reduced ejection fraction: results from the CIBIS-ELD trial

BackgroundWe sought to investigate the effect of beta-blocker (BB) up-titration on serum levels of NT-proBNP and copeptin in patients with heart failure (HF) with reduced (HFREF) or preserved ejection fraction (HFPEF).MethodsSerial measurements of NT-proBNP and copeptin were obtained after initiation of BB up-titration in 219 elderly patients with HFREF or HFPEF.ResultsAfter initial increasing trend of NT-proBNP at 6 weeks in HFREF patients, there was a subsequent decrease at 12 weeks of BB treatment up-titration (p = 0.003), while no difference was found compared to baseline levels. In contrast to NT-proBNP, there was a continuous decreasing trend of copeptin in HFREF patients (at 12 weeks: p = 0.026). In HFPEF patients, NT-proBNP significantly decreased (p = 0.043) compared to copeptin after 12 weeks of BB up-titration.ConclusionsAfter 12 weeks of BB optimization copeptin might reflect successful up-titration faster than NT-proBNP in HFREF, while the opposite was found in patients with HFPEF.