Alterations in intervertebral disc composition,matrix homeostasis and biomechanical behavior in the UCD‐T2DM rat model of type 2 diabetes

Type 2 diabetes (T2D) adversely affects many tissues, and the greater incidence of discogenic low back pain among diabetic patients suggests that the intervertebral disc is affected too. Using a rat model of polygenic obese T2D, we demonstrate that diabetes compromises several aspects of disc composition, matrix homeostasis, and biomechanical behavior. Coccygeal motion segments were harvested from 6‐month‐old lean Sprague‐Dawley rats, obese Sprague‐Dawley rats, and diabetic obese UCD‐T2DM rats (diabetic for 69 ± 7 days). Findings indicated that diabetes but not obesity reduced disc glycosaminoglycan and water contents, and these degenerative changes correlated with increased vertebral endplate thickness and decreased endplate porosity, and with higher levels of the advanced glycation end‐product (AGE) pentosidine. Consistent with their diminished glycosaminoglycan and water contents and their higher AGE levels, discs from diabetic rats were stiffer and exhibited less creep when compressed. At the matrix level, elevated expression of hypoxia‐inducible genes and catabolic markers in the discs from diabetic rats coincided with increased oxidative stress and greater interactions between AGEs and one of their receptors (RAGE). Taken together, these findings indicate that endplate sclerosis, increased oxidative stress, and AGE/RAGE‐mediated interactions could be important factors for explaining the greater incidence of disc pathology in T2D. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:738–746, 2015.     

Preoperative Carcinoembryonic Antigen and Prognosis of Colorectal Cancer. An Independent Prognostic Factor Still Reliable

To evaluate whether, in a sample of patients radically treated for colorectal carcinoma, the preoperative determination of the carcinoembryonic antigen (p-CEA) may have a prognostic value and constitute an independent risk factor in relation to disease-free survival. The preoperative CEA seems to be related both to the staging of colorectal neoplasia and to the patient''s prognosis, although this—to date—has not been conclusively demonstrated and is still a matter of intense debate in the scientific community. This is a retrospective analysis of prospectively collected data. A total of 395 patients were radically treated for colorectal carcinoma. The preoperative CEA was statistically compared with the 2010 American Joint Committee on Cancer (AJCC) staging, the T and N parameters, and grading. All parameters recorded in our database were tested for an association with disease-free survival (DFS). Only factors significantly associated (P < 0.05) with the DFS were used to build multivariate stepwise forward logistic regression models to establish their independent predictors. A statistically significant relationship was found between p-CEA and tumor staging (P < 0.001), T (P < 0.001) and N parameters (P = 0.006). In a multivariate analysis, the independent prognostic factors found were: p-CEA, stages N1 and N2 according to AJCC, and G3 grading (grade). A statistically significant difference (P < 0.001) was evident between the DFS of patients with normal and high p-CEA levels. Preoperative CEA makes a pre-operative selection possible of those patients for whom it is likely to be able to predict a more advanced staging.Key words: Colorectal carcinoma, Preoperative carcinoembryonic antigen, Disease-free survival, Independent prognostic factorIn the world today, more than 1 million cases of patients with colorectal neoplasia are identified each year. Forty percent of these will have a poor prognosis for which targeted therapeutic strategies could most likely be more effective.^1–3 For this reason, finding prognostic factors that are early, reliable, and related to the extent of the tumor is of the utmost importance. Among these, the most that are considered even to this day are T and N parameters.^1,2,4,5 Less relied upon, however, is the M parameter, which is often understaged due to inadequate pretreatment diagnostic methods.⁶ However, these parameters, which are available to us only after surgery, do not represent the gold standard. In fact, the prognosis of patients with the same staging is often various and that the need to continually implement ever-changing variables in an already excessively fragmented staging is still present.^2,4,7–9Recently, in light of these needs, great attention has been paid to the study of molecular and genetic markers. At present, these markers still have not found a regular application due to the complexity of their determination, the difficulty of standardization and, last but not least, the low cost-benefit ratio.^1,3,4,9,10With this in mind, in our opinion, the carcinoembryonic antigen (CEA) maintains its position, as for over 30 years it has continued to be the most widely used marker¹¹ and whose validity, with regard to colorectal follow-up, has been sanctioned by leading organizations such as the American Society of Clinical Oncology (ASCO)¹² and the European Group on Tumor Markers.¹³ Moreover, as Herrera¹⁴ and Wanebo¹⁵ had already reported by the end of the ‘70s, the preoperative determination of the CEA (p-CEA) seems to be related both to the staging of colorectal neoplasia and to the patient''s prognosis. However, to date, none of this has been conclusively demonstrated and is still a matter of intense debate both in prestigious scientific journals^{4,7,11,16–21} as well as in different guidelines.²²The American Society of Clinical Oncology itself, if on the one hand suggests using the determination of the CEA in the preoperative staging thus justifying a worse prognosis when increased,¹² on the other, does not validate using the p-CEA in the determination of an adjuvant or neo-adjuvant therapeutic strategy.²³Regarding this issue, we believe it still pertinent to evaluate whether in a sample of patients radically treated for colorectal carcinoma, the determination of the p-CEA may have a prognostic value and constitute an independent risk factor in relation to disease-free survival (DFS).     

Indicators of a Reduced Intercarotid Artery Distance in Patients Undergoing Endoscopic Transsphenoidal Surgery

Objective To identify clinicopathologic factors associated with a reduced intercarotid distance (ICD) and subgroups at risk for internal carotid artery injury during transsphenoidal surgery. Design A retrospective case-control study. Setting This study was conducted at the McGill University Health Centre, a university-affiliated tertiary care center. Participants Patients with a sellar or parasellar tumor and nontumor controls were included in the study. Main Outcome Measures The smallest distance between the internal carotid arteries at the clival, cavernous, and paraclinoid segments on coronal magnetic resonance imaging was measured. Demographic profiles, cephalometric measurements, tumor dimensions, and sphenoid configuration were assessed as potential determinants of the ICD. Results A total of 212 cases and 34 controls were analyzed. Widening of the ICD at the three segments of the internal carotid arteries was found in patients with pituitary macroadenomas (p < 0.01). Patients with a growth hormone–secreting adenoma had a markedly reduced ICD at the clivus compared with controls (1.59 cm versus 1.77 cm; p = 0.02; 95% confidence interval [CI], 0.03–0.32). The paraclinoid ICD was reduced in patients with an anterior fossa meningioma (1.24 cm versus 1.33 cm; p = 0.04; 95% CI, 0.01–0.45). Conclusion Identifying clinicopathologic factors affecting the ICD can help surgeons recognize constraints to endoscopic access of the skull base and avoid inadvertent arterial injury.     

AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs

Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cell–promoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.     

Randomised trial comparing Lichtenstein vs Trabucco vs Valenti techniques in inguinal hernia repair

Purpose

Following Lichtenstein’s technique, over the last 15 years several variation have been proposed, such as Trabucco’s sutureless technique and the use of two self-regulating prostheses, proposed by Valenti that have given excellent results. The aim of this prospective and randomised study was to determine whether there are differences in the results obtained with these three techniques.

Methods

Of 812 patients submitted to inguinal hernia repair, we selected and randomised 162 patients into three groups of 54 patients each: Lichtenstein (Group L), Trabucco (Group T) and Valenti (Group V). Surgical procedures were performed in all cases by residents in surgery using local anaesthesia. Primary endpoint was intensity of postoperative pain. Median follow-up was 8 years.

Results

The primary analysis of postoperative pain at 48 h did not report any significant difference between the three groups as for secondary analyses except that the Trabucco procedure took less operative time than the Lichtenstein, and the Valenti group was more painful than the Lichtenstein group at the third postoperative day. In our series median operation time was 60 min. Recurrence rate was 1.85 %.

Conclusions

Surgical repair of inguinal hernia according to the Lichtenstein, Trabucco and Valenti techniques is safe and easy to perform regardless of the surgical experience of the operator, with excellent results and no differences due to technique used as regards almost all of the parameters studied.     

Perforation during TUR of bladder tumours influences the natural history of superficial bladder cancer

Objectives

Bladder perforation is the second most common complication during transurethral resection of bladder tumours. It is unknown whether perforation affects the natural history of the tumour through cell seeding. The aim of this study was to study the impact of perforation on the oncologic outcomes of bladder carcinoma.

Materials and methods

Between 2003 and 2007, 926 consecutive patients underwent transurethral resection of bladder tumours at our institution; 327 cases were staged ≥pT2 and were treated immediately with cystectomy and/or multimodal therapy and therefore excluded from the study. An additional 34 cases without urothelial carcinoma were excluded. Of the remaining 565 patients with non-muscle invasive bladder cancer, 457 (80.8 %) were male and 108 (19.2 %) were female with a mean age of 69.5 years in men and 67.3 years in women. Thirty-seven patients (6.5 %) experienced bladder perforation at the time of tumour resection. This group of patients (Group 1) was compared to the remaining 528 patients (Group 2) who did not experience a bladder perforation.

Results

Patients with bladder wall perforation experienced a shorter disease-free survival in both univariate (p = 0.003) and multivariate analyses (p = 0.006). In addition, subsequent recurrences revealed stage progression of recurrent disease (p = 0.05) and trended to a higher number of cystectomies in the perforated group of patients (p = 0.06). Nevertheless, perforation did not appear to influence overall survival (p = 0.127) or cancer-specific survival (p = 0.141).

Conclusion

The results indicate that bladder perforation during resection of superficial bladder tumours is burdened by a shortened disease-free survival and T-stage progression.     

Complication rate in adult deformity surgical treatment: safety of the posterior osteotomies

Purpose

The treatment of adult scoliosis is a challenge especially in patients over 50 years old with severe, rigid curves in whom the use of vertebral osteotomies may be necessary to correct the deformity. The aim the study was to analyse the perioperative complications related to vertebral osteotomies in elderly treated for spinal deformity.

Methods

We analysed 72 consecutive cases of kyphoscoliosis, we classify them according to Berjano–Lamartina classification. We divided patients into two groups: we only practised SPO and/or PO in patients that composed group A; we practised also PSO in patients that composed group B. We retrospectively analysed the perioperative complications and radiographical results. Average follow-up was 30 months.

Results

We had 50 cases of degenerative segment diseases (DSD) Type III, 13 Type IVa DSD and 9 Type IVb DSD. Mean age was 60.7 years old. Overall complication rate was 22.2 %. In group A, the complication rate was 16.9 % while in group B it was 46.2 %. Mean Cobb primary curve angle was 41.75° with average C7 plumb line (C7PL) of 4.49 cm, residual scoliosis after surgery was 15.41° and average C7PL of 2.08 cm, with statistically significant differences.

Conclusions

Previous studies have shown increased complication rates with vertebral osteotomies in elderly patients, our experience support this evidence. Our study demonstrates a high incidence of intraoperative complication rate in elderly patients underwent a PSO. PSO is a demanding technique to be considered in very selected and motivated patients who must be carefully informed about the risks of the procedure.

     

Kidney‐Induced Cardiac Allograft Tolerance in Miniature Swine is Dependent on MHC‐Matching of Donor Cardiac and Renal Parenchyma

Kidney allografts possess the ability to enable a short course of immunosuppression to induce tolerance of themselves and of cardiac allografts across a full‐MHC barrier in miniature swine. However, the renal element(s) responsible for kidney‐induced cardiac allograft tolerance (KICAT) are unknown. Here we investigated whether MHC disparities between parenchyma versus hematopoietic‐derived “passenger” cells of the heart and kidney allografts affected KICAT. Heart and kidney allografts were co‐transplanted into MHC‐mismatched recipients treated with high‐dose tacrolimus for 12 days. Group 1 animals (n = 3) received kidney and heart allografts fully MHC‐mismatched to each other and to the recipient. Group 2 animals (n = 3) received kidney and heart allografts MHC‐matched to each other but MHC‐mismatched to the recipient. Group 3 animals (n = 3) received chimeric kidney allografts whose parenchyma was MHC‐mismatched to the donor heart. Group 4 animals (n = 3) received chimeric kidney allografts whose passenger leukocytes were MHC‐mismatched to the donor heart. Five of six heart allografts in Groups 1 and 3 rejected <40 days. In contrast, heart allografts in Groups 2 and 4 survived >150 days without rejection (p < 0.05). These data demonstrate that KICAT requires MHC‐matching between kidney allograft parenchyma and heart allografts, suggesting that cells intrinsic to the kidney enable cardiac allograft tolerance.