With complements: C3 inhibition in the clinic

C3 is a key complement protein, located at the nexus of all complement activation pathways. Extracellular, tissue, cell-derived, and intracellular C3 plays critical roles in the immune response that is dysregulated in many diseases, making it an attractive therapeutic target. However, challenges such as very high concentration in blood, increased acute expression, and the elevated risk of infections have historically posed significant challenges in the development of C3-targeted therapeutics. This is further complicated because C3 activation fragments and their receptors trigger a complex network of downstream effects; therefore, a clear understanding of these is needed to provide context for a better understanding of the mechanism of action (MoA) of C3 inhibitors, such as pegcetacoplan. Because of C3's differential upstream position to C5 in the complement cascade, there are mechanistic differences between pegcetacoplan and eculizumab that determine their efficacy in patients with paroxysmal nocturnal hemoglobinuria. In this review, we compare the MoA of pegcetacoplan and eculizumab in paroxysmal nocturnal hemoglobinuria and discuss the complement-mediated disease that might be amenable to C3 inhibition. We further discuss the current state and outlook for C3-targeted therapeutics and provide our perspective on which diseases might be the next success stories in the C3 therapeutics journey.     

Eye Coordination and Vestibular Testing in Electroconvulsive Therapy

Nine depressive patients were examined before bilateral electroconvulsive therapy (ECT), immediately after ECT, and 2 days later with saccadic, pursuit tracking, and Hallpike caloric vestibular tests. Before ECT, all tests showed normal results. Immediately after ECT, the saccadic test displayed dysmetria of the fast eye movements in six of nine patients. The pursuit tracking test showed decreased gain of the slow eye movements with compensatory saccades in seven of nine patients. These findings were for both directions in the horizontal plane. In the caloric vestibular test, the changes were not significant. Two days after ECT, the eye coordination and vestibular testing showed normal function. We conclude that the eye coordination and vestibular function disturbances induced by ECT are transient.     

Omega-3 Poly-Unsaturated Fatty Acids for the Prevention of Severe Neutropenic Enterocolitis in Patients with Acute Myeloid Leukemia

Neutropenic enterocolitis is a potentially fatal complication of myeloablative chemotherapy in patients with acute myeloid leukemia. Omega-3 polyunsaturated fatty acids (PUFA) are precursors of potent anti-inflammatory prostaglandins. Our aim was to explore the safety and effectiveness of omega-3 PUFA added to parenteral nutrition in protecting leukemia patients from severe enterocolitis. Fourteen patients with acute myeloid leukemia who received omega-3 PUFA in a Phase II trial were compared with 66 consecutive control patients not getting this intervention. We performed crude and adjusted comparisons, using inverse probability of treatment weighting for adjusted analysis, and blind outcome assessment to minimize assessor bias. Primary outcome was severe enterocolitis (≥Grade 3). The crude odds ratio of Grade 3 colitis or higher was 1.36 (95% CI 0.37 to 4.96, P = 0.64), and the adjusted odds ratio was 0.79 (95% CI 0.35 to 1.78, P = 0.57). There was little evidence to suggest differences between groups in serious adverse events and overall mortality. Our results provide little evidence that addition of omega-3 PUFA is beneficial in this condition. Routine treatment with omega-3 PUFA is currently not warranted.     

A polymer inclusion membrane composed of the binary carrier PC-88A and Versatic 10 for the selective separation and recovery of Sc

This study reports on the selective separation of scandium (Sc) from other rare earth metals (REMs) using a polymer inclusion membrane (PIM). The PIM prepared with PC-88A (2-ethylhexyl hydrogen-2-ethylhexylphosphonate) alone as the carrier showed high extractability but the poor back-extraction of the extracted Sc³⁺ ions did not allow the transport of these ions to the receiving solution of a membrane transport system. To overcome this problem, a novel approach was introduced using a mixture of carriers that allowed Sc³⁺ transport into the receiving solution. A cellulose triacetate (CTA) based PIM containing both PC-88A and Versatic 10 (decanoic acid) as carriers and dioctyl phthalate (DOP) as a plasticizer was prepared for the selective separation of Sc³⁺ from other REM ions in nitrate media. The membrane composition was optimized and the effect of operational parameters such as pH of the feed solution and composition of the receiving solution was explored. The flux at the membrane/feed solution interface was found to depend significantly on the carrier concentration in the PIM, pH of the feed solution and the receiving solution acidity. The newly developed PIM allowed quantitative and selective transport of Sc³⁺ thus demonstrating its suitability for the selective recovery of this metal.

This study reports on the selective separation of scandium (Sc) from other rare earth metals (REMs) using a polymer inclusion membrane (PIM).     

Feasibility and diagnostic performance of hybrid PET/MRI compared with PET/CT for gynecological malignancies: a prospective pilot study

Purpose

The purpose of the study was to assess the feasibility and diagnostic performance of FDG-PET/MR imaging compared to PET/CT for staging of patients with a gynecological malignancy.

Methods

25 patients with a gynecological malignancy were prospectively enrolled into this pilot study. Patients underwent sequential full-body PET/CT and PET/MR of the abdomen and pelvis after administration of a single dose of F-18 FDG. PET/MRI and PET/CT images were independently reviewed by two expert radiologists. Readers were blinded to the results of the other imaging procedures. Clinical and pathologic information was abstracted from medical charts.

Results

18 patients were included in the final analysis with a median age of 62 years (range 31–88). 61% of patients (11/18) had cervical cancer, while the remaining patients had endometrial cancer. PET/MRI as compared to PET/CT detected all primary tumors, 7/7 patients with regional lymph nodes, and 1/1 patient with an abdominal metastasis. Two patients had additional lymph nodes outside of the abdominopelvic cavity detected on PET/CT that were not seen on PET/MRI, whereas 6 patients had parametrial invasion and one patient had invasion of the bladder seen on PET/MRI not detected on PET/CT. Five cervical cancer patients had discordant clinical vs. radiographic staging based on PET/MRI detection of soft tissue involvement. Management changed for two patients who had clinical stage IB1 and radiographic stage IIB cervical cancer.

Conclusions

PET/MRI is feasible and has at least comparable diagnostic ability to PET/CT for identification of primary cervical and endometrial tumors and regional metastases. PET/MRI may be superior to PET/CT for initial radiographic assessment of cervical cancers.

     

Ambivalent roles of carboxypeptidase B in the lytic susceptibility of fibrin

Background

Removal of C-terminal lysine residues that are continuously exposed in lysing fibrin is an established anti-fibrinolytic mechanism dependent on the plasma carboxypeptidase TAFIa, which also removes arginines that are exposed at the time of fibrinogen clotting by thrombin.

Objective

To evaluate the impact of alterations in fibrin structure mediated by constitutive carboxypeptidase activity on the function of fibrin as a template for tissue plasminogen activator-(tPA) induced plasminogen activation and its susceptibility to digestion by plasmin.

Methods and results

We used the stable carboxypeptidase B (CPB), which shows the same substrate specificity as TAFIa. If 1.5 – 6 μM fibrinogen was clotted in the presence of 8 U/mL CPB, a denser fibrin network was formed with thinner fibers (the median fiber diameter decreased from 138 – 144 nm to 89 – 109 nm as established with scanning electron microscopy). If clotting was initiated in the presence of 5 – 10 μM arginine, a similar decrease in fiber diameter (82 -95 nm) was measured. The fine structure of arginine-treated fibrin enhanced plasminogen activation by tPA, but slowed down lysis monitored using fluorescent tPA and confocal laser microscopy. However, if lysis was initiated with plasmin in CPB-treated fibrin, the rate of dissolution increased to a degree corresponding to doubling of the plasmin concentration.

Conclusion

The present data evidence that CPB activity generates fine-mesh fibrin which is more difficult to lyse by tPA, but conversely, CPB and plasmin together can stimulate fibrinolysis, possibly by enhancing plasmin diffusion.     

The Role of 3-D Endorectal Ultrasound in Rectal Cancer: Our Experience

In the last 20 years, endorectal ultrasound (ERUS) has been one of the main diagnostic methods for locoregional staging of rectal cancer. ERUS is accurate modality for evaluating local invasion of rectal carcinoma into the rectal wall layers (T category). Adding the three-dimensional modality (3-D) increases the capabilities of this diagnostic tool in rectal cancer patients. We review the literature and report our experience in preoperative 3-D ERUS in rectal cancer staging. In the group of 71 patients, the staging of preoperative 3-D endorectal ultrasonography was compared with the postoperative morphologic examination. Three-dimensional ERUS preoperative staging was confirmed with morphologic evaluation in 66 out of 71 cases (92.9%). The detection sensitivities of rectal cancer with 3-D ERUS were as follows: T1, 92.8%; T2, 93.1%; T3, 91.6%; and T4, 100.0%; with specificity values of T1, 98.2%; T2, 95.4%; T3, 97.8%; and T4, 98.5%. Three-dimensional ERUS correctly categorized patients with T1, 97.1%; T2, 94.3%; T3, 95.7%; and T4, 98.5%. The percentage of total overstaged cases was 2.75% and that of understaged cases was 6.87%. The metastatic status of the lymph nodes was determined with a sensitivity of 79.1% (19 of 24), specificity of 91.4% (43 of 47), and diagnostic accuracy of 87.3% (62 of 71). In our experience, 3-D ERUS has the potential to become the diagnostic modality of choice for the preoperative staging of rectal cancer.Key words: Three-dimensional endorectal ultrasound, Rectal cancerEndorectal ultrasound (ERUS) has been used as a diagnostic tool for evaluation and staging of rectal cancer since the 1980s.¹ According to the literature, in studies with more than 50 patients included, an overall accuracy of approximately 81.8% was reported.² Most of the studies present data between 85% and 95%, but in the studies with more than 200 patients, the accuracy rates are relatively lower—63.3% and 69%, respectively.^3,4 A common disadvantage of ERUS and magnetic resonance imaging (MRI) is the overstaging of T2 tumors owing to an irregular outer rectal wall resulting from transmural tumor extension or inflammation around the tumor. Another challenge for the ERUS, and especially the rigid probes, are the locally advanced, stenotic tumors, where the probe may not be able to pass above the lesion.⁵ The nodal staging accuracy of ERUS ranges from 70% to 75%.^1,5,6 The metastatic lymph nodes are distinguished by hypoechoic appearance, round shape, peritumoral location, and size >5 mm.^7,8 Lymph nodes >5 mm have a 50% to 70% chance of being malignant, while those <4 mm have only a 20% chance.^9,10 A new modality of endorectal ultrasound represents a three-dimensional (3-D) ERUS that provides better visual images of the tumor volume and spatial relations to the adjacent organs and structures, even better than those of MRI, which leads to better diagnostic accuracy than MRI and standard ERUS.^11–15 The unique 3-D–ERUS longitudinal scan can precisely assess the tumor size and location.¹⁶ The most important feature of this upgraded modality is the ability to reduce interpreter errors and offer potential predictive value. Three-dimensional ERUS provides the possibility to distinguish blood vessels from lymph nodes and allow precise fine needle aspiration (FNA) biopsies.^13,17 The infiltration of circumferential margin has been proven to correlate with T category, lymph node metastasis histologic tumor differentiation, and lymphovascular invasion.^13,17 Three-dimensional ERUS gives the possibility of multiplane evaluation of the tumor, allowing visualization of more subtle changes in the tumor characteristics and therefore better T and N categorizing.¹⁸ A review of 86 patients who underwent standard 3-D ERUS, ERUS and 4-channel detector computed tomography (CT) demonstrated T-category accuracy of 78%, 69%, and 57%, respectively.¹⁹ After analysis of the examiner''s error, the accuracy of 3-D ERUS for T category has reached 91% for 3-D ERUS and 88% for standard ERUS, and the N category accuracy improved to 90% and 76%, respectively. Also, ERUS can be used for diagnosis of premalignant lesions such as adenomas and polyps.²⁰ The main goal is to properly identify any chance of tumor invasion in the primary lesion and involvement of the surrounding lymph nodes in case the absence of those alarming characteristics allows for endoscopic resection of the lesion. Using higher-resolution probes, ERUS can distinguish T0 from T1 lesions. According to a meta-analysis of 258 biopsy-negative tumors, ERUS identified tumor mass in 81% of the 24 lesions, which were found to be invasive tumors on morphologic examination.²⁰ Another series of 60 patients with pT0/pT1 lesions demonstrated sensitivity and specificity of ERUS 89% and 88%, respectively.²¹ As with MRI, 3-D ERUS could provide an evaluation of the mesorectal fascia.^14,22The reported data lead to the position that 3-D ERUS combines the high-resolution images of the rectal wall and cost-effectiveness of standard ERUS with the multiplanar and stereoscopic imaging capabilities of MRI. Three-dimensional ERUS may be the future premier imaging modality used in rectal cancer management.     

Translation,cross-cultural adaptation and validation of the Bulgarian version of the Dizziness Handicap Inventory

Purpose

The aim of the present study was the translation, cross-cultural adaptation and validation of the Dizziness Handicap Inventory in Bulgarian language (DHI-BG).

Methods

Ninety-seven vestibular patients (19 men and 78 women, mean age 45.08 ± 13.85 years) took part in the investigation. All participants were asked to fill in the DHI-BG. Internal consistency was estimated using Cronbach’s alpha and item-total correlation, reproducibility by calculating Bland–Altman’s limits of agreement and intraclass correlation coefficients (ICCs). Associations were estimated by Spearman’s correlation coefficients.

Results

The Cronbach’s alpha for the total score, functional, physical and emotional subscales of DHI-BG were 0.88, 0.75, 0.72 and 0.81. The floor and ceiling effects of the DHI-BG total scale were evaluated with respect to the limits of agreement which were ±9.4–14.53 points. Intraclass correlation coefficients (ICCs) for all scale and subscales were higher than the recommended value of 0.75 and determined good test–retest reliability. The range of items correlation for DHI-BG was from 0.27 (item 12) to 0.72 (item 3). No significant differences were observed in the Cronbach’s alpha coefficients between the DHI-BG and the original version, the German and Italian versions of the questionnaire. The most significant difference was observed in comparison with the German version of DHI. Construct validity presented a moderate correlation between Romberg coefficients and DHI-BG scores and strong correlation between all scores of DHI and the self-perceived disability. The results suggest that DHI-BG scores show a good discriminative validity between groups with different levels of self-assessed disability.

Conclusion

The Bulgarian version of the DHI is a reliable and valid tool in assessing the impact of dizziness on the quality of life in Bulgarian vestibular patients.     

Prognostic Significance of VEGF Expression in Correlation With COX-2, Microvessel Density,and Clinicopathological Characteristics in Human Gastric Carcinoma

Background Many studies have shown that angiogenesis plays an important role in the process of cancer development and progression. Vascular endothelial growth factor (VEGF) has a potent angiogenic activity, and cyclooxygenase-2 (COX-2) supports angiogenesis by regulated production of angiogenic factors, including VEGF. The purpose of this study was to examine the expression of VEGF in combination with COX-2 and CD34, their correlation with various clinicopathological factors, and their prognostic significance in human gastric carcinoma. Methods Specimens from 169 patients with different grade and stage gastric carcinoma were investigated by immunohistochemistry for COX-2 and VEGF expression. Tumor microvessel density was assessed with CD34 immunostaining. Correlations between the expression of VEGF, COX-2, CD34, and various clinicopathological factors were studied. The effect of these proteins on patient survival was determined. Results COX-2 and VEGF were positively expressed in 36.7% and 50.3% of the patients, respectively. Positive correlation was found between VEGF and COX-2 and between VEGF and CD34. VEGF expression was correlated with depth of invasion; metastatic lymph nodes; lymphatic and venous invasion; and tumor, node, metastasis system stage. Patients with positive staining for VEGF showed far lower disease-free (64.9% vs. 81.3%) and overall (58.3% vs. 76.9%) survival rates than VEGF-negative patients. In multivariate analysis, only tumor location, depth of invasion, and lymph node metastasis were shown to be independent prognostic factors. Conclusions VEGF expression correlates with angiogenesis and tumor progression and is a valuable prognostic factor in patients with gastric carcinoma.