INAUGURAL ARTICLE by a Recently Elected Academy Member:Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors

The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.     

Cortical Tibial Bone Graft for Nasal Augmentation

Background

This study sought to determine the efficacy of cortical tibial bone graft for nasal augmentation. Nine cases of augmentation rhinoplasty with cortical tibial bone graft are presented.

Methods

This prospective study evaluated the postoperative results of nine patients who underwent augmentation rhinoplasty using cortical tibial bone graft. There were six males and three females aged between 21 and 36 years (mean age 29). All the nine cases were treated through closed rhinoplasty incisions.

Results

Nine patients were operated on and the average follow up was 18 months. The results were favorable. The aesthetic results were gratifying; with good nasal projection in every case without any significant postoperative effects or complications requiring surgery were noted during the follow up.

Conclusion

The findings of this study support the use of cortical tibial bone graft for nasal augmentation although further studies with more sample size are required.     

Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism

Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities. Recent evidence suggests that mitochondrial dysfunction and oxidative stress may contribute to the etiology of autism. This is the first study to compare the activities of mitochondrial electron transport chain (ETC) complexes (I–V) and pyruvate dehydrogenase (PDH), as well as mitochondrial DNA (mtDNA) copy number in the frontal cortex tissues from autistic and age-matched control subjects. The activities of complexes I, V and PDH were most affected in autism (n=14) being significantly reduced by 31%, 36% and 35%, respectively. When 99% confidence interval (CI) of control group was taken as a reference range, impaired activities of complexes I, III and V were observed in 43%, 29% and 43% of autistic subjects, respectively. Reduced activities of all five ETC complexes were observed in 14% of autistic cases, and the activities of multiple complexes were decreased in 29% of autistic subjects. These results suggest that defects in complexes I and III (sites of mitochondrial free radical generation) and complex V (adenosine triphosphate synthase) are more prevalent in autism. PDH activity was also reduced in 57% of autistic subjects. The ratios of mtDNA of three mitochondrial genes ND1, ND4 and Cyt B (that encode for subunits of complexes I and III) to nuclear DNA were significantly increased in autism, suggesting a higher mtDNA copy number in autism. Compared with the 95% CI of the control group, 44% of autistic children showed higher copy numbers of all three mitochondrial genes examined. Furthermore, ND4 and Cyt B deletions were observed in 44% and 33% of autistic children, respectively. This study indicates that autism is associated with mitochondrial dysfunction in the brain.     

Proposed guidelines for the management of nodding syndrome

Nodding Syndrome is a poorly understood neurologic disorder of unknown aetiology that affects children and adolescents in Africa. Recent studies have suggested that the head nods are due to atonic seizures and Nodding Syndrome may be classified as probably symptomatic generalised epilepsy. As part of the Ugandan Ministry of Health clinical management response, a multidisciplinary team developed a manual to guide the training of health workers with knowledge and skills to manage the patients. In the absence of a known cause, it was decided to offer symptomatic care. The objective is to relieve symptoms, offer primary and secondary prevention for disability and rehabilitation to improve function. Initial management focuses on the most urgent needs of the patient and the immediate family until ‘stability’ is achieved. The most important needs were considered as seizure control, management of behavioural and psychiatric difficulties, nursing care, nutritional and subsequently, physical and cognitive rehabilitation. This paper summarises the processes by which the proposed guidelines were developed and provides an outline of the specific treatments currently being provided for the patients.     

Comparison of periodontal open flap debridement versus closed debridement with Er,Cr:YSGG laser

Background

Traditional periodontal open flap debridement (OFD) results in reduced pocket depth (PD), clinical attachment loss (CAL), gingival recession (GR) and postoperative pain and discomfort. The quest to overcome these shortcomings has led to research into Er,Cr:YSGG laser assisted pocket therapy (ELAPT). This study was designed to compare the clinical outcomes of ELAPT versus OFD.

Methods

Fifteen patients with a PD of ≥5 mm and ≤8 mm at two sites were selected. Test sites (Group 1) were treated by ELAPT and the control (Group 2) by OFD. Clinical parameters were recorded at baseline, 3 and 6 months and included Plaque Index (PI), Gingival Index (GI), modified Sulcular Bleeding Index (mSBI), PD, CAL and GR.

Results

Both treatments produced a reduction in PI, GI, mSBI and PD, an increase in GR, and a gain in CAL at 3 and 6 months. The mean gain of CAL in Group 1 at 3 and 6 months (1.60 ± 0.78 and 1.80 ± 0.63) was similar (p > 0.05) to the value of Group 2 (1.93 ± 0.88 and 2.00 ± 0.54). GR increased significantly (p < 0.05) only in Group 2 at 3 and 6 months (1.80 ± 0.56 and 1.87 ± 0.64) compared to Group 1 (0.50 ± 0.68 and 0.60 ± 0.74).

Conclusions

ELAPT compared with OFD results in similar CAL gains with less GR and significant reductions in PD, GI and mSBI, and may be considered as an alternative to surgical therapy.     

Thoracic surgical management of colorectal lung metastases: a questionnaire survey of members of the Society for Cardiothoracic Surgery in great Britain and Ireland

Introduction

Distant metastases to liver and lung are not uncommon in colorectal cancer. Resection of metastases is accepted widely as the standard of care. However, there is no firm evidence base for this. This questionnaire survey was carried out to assess the current practice preferences of cardiothoracic surgeons in Great Britain and Ireland.

Methods

An online questionnaire survey was emailed to cardiothoracic surgeons in Great Britain and Ireland. The survey was live for 12 weeks. Responses were collated with SurveyMonkey^®.

Results

Overall, there were 75 respondents. The majority (83%) indicated thoracic surgery as a specialist interest. Almost all (99%) used thoracic computed tomography (CT) for staging; 70% added liver CT and 51% added pelvic CT. Fluorodeoxyglucose positron emission tomography was used by 86%. The most frequent indication for pulmonary resection (97%) was solitary lung metastasis without extrathoracic disease. Video assisted thoracoscopic surgery (VATS) was used by 85%. In addition, thoracotomy was used by 96%. A third (33%) used radiofrequency ablation. Synchronous liver and lung resection was contraindicated for 83% of respondents. Over three-quarters (77%) thought that scientific equipoise exists presently for lung resection for colorectal lung metastases but only 21% supported a moratorium on this type of surgery until further evidence becomes available.

Conclusions

The results confirm that the majority of respondents use conventional cross-sectional imaging and either VATS or formal thoracotomy for resection. The results emphasise the continuing need for formal randomised trials to provide evidence of any survival benefit from pulmonary metastasectomy for colorectal lung metastases.     

Extracorporeal membrane oxygenation--an anaesthesiologist's perspective--Part II: clinical and technical consideration

Although the concept of extracorporeal membrane oxygenation (ECMO) has remained unchanged, component technology has evolved considerably over the past three decades. Presently the clinical conditions requiring ECMO support have been updated with input from the outcome data of patient registries. Modern circuit configuration has become less cumbersome, safer, and more efficient. Technological advances now allow prolonged support with fewer complications compared to the past eras and facilitate transition to a single bedside caregiver model, similar to hemofiltration or ventricular-assist devices. The clinical considerations and indicators for placing the patient on ECMO, the various circuit configurations, clinical and technical issues, and management aspects are considered in this article.     

Evolving electroanatomic substrate and intra-atrial reentrant tachycardia late after Fontan surgery

Atrial Remodeling After the Fontan Operation. Introduction: The prevalence of intra‐atrial reentrant tachycardia (IART) increases with age in Fontan patients. This study aimed to characterize the atrial electroanatomic substrate for IART late after Fontan surgery. Methods and Results: Detailed electroanatomic mapping of the right atrium (RA) was performed in 11 consecutive patients (33 ± 9 years) with older style Fontan circulation (atriopulmonary and atrioventricular connection) who underwent their first radiofrequency catheter ablation (RFCA) for IART. A comparative group of 30 non‐Fontan congenital heart disease (CHD) patients were also studied. Fontan patients had larger RA (P = 0.004), larger low‐voltage area ≤0.5 mV (P = 0.01), and more fractionated potentials (P < 0.001) than non‐Fontan CHD patients. RA enlargement correlated significantly with both low‐voltage zones (Spearman ρ= 0.68, P < 0.001) and fractionated potentials (Spearman ρ= 0.48, P = 0.001). Among Fontan patients, both age and time since Fontan surgery were significantly correlated to the amount of low‐voltage areas (Spearman ρ= 0.87, P < 0.001; Spearman ρ= 0.63, P = 0.04, respectively). Successful RFCA was accomplished in 30 (73%) patients and was less likely in Fontan patients (54% vs 83%, P = 0.04). Larger RA was significantly associated with a lower success rate (P = 0.04). During a follow‐up duration of 2.3 ± 1.6 years, IART recurred in 47% of patients. Larger RA size and larger low‐voltage areas predicted IART recurrence after RFCA. Conclusion: Fontan patients demonstrate progressive adverse atrial electrical remodeling with increasing age and time since surgery. Newer strategies beyond surgical incisions, such as pharmacotherapies that retard the progression of atrial fibrosis, may be required to reduce the long‐term risk of atrial arrhythmias.