Chong Hee Lim

G-CSF for stem cell therapy in acute myocardial infarction: friend or foe?

Stem cell-based therapy has emerged as a potential therapeutic option for patients with acute myocardial infarction. The ability of granulocyte colony-stimulating factor (G-CSF) to mobilize endogenous stem cells as well as to protect cardiomyocytes at risk via paracrine effects has attracted considerable attention. In the past decade, a number of clinical trials were carried out to study the efficacy of G-CSF in cardiac repair. These trials showed variable outcomes in terms of improved cardiac contractile function and suppressed left ventricular negative remodelling. Critical examinations of these results have raised doubts concerning the effectiveness of G-CSF in modulating functional recovery. However, these cumulative clinical experiences are helpful in the understanding of mechanisms and roles of signalling pathways in regulating homing and engraftment of bone marrow stem cells to the infarcted heart. In this review, we discuss some of the observations that may have influenced the clinical outcomes. Improving strategies that target the critical aspects of G-CSF-driven cardiac therapy may provide a better platform to augment clinical benefits in future trials.

iPSC-derived human mesenchymal stem cells improve myocardial strain of infarcted myocardium

We investigated global and regional effects of myocardial transplantation of human induced pluripotent stem cell (iPSC)‐derived mesenchymal stem cells (iMSCs) in infarcted myocardium. Acute myocardial infarction (MI) was induced by ligation of left coronary artery of severe combined immunodeficient mice before 2 × 105 iMSCs or cell‐free saline were injected into peri‐infarcted anterior free wall. Sham‐operated animals received no injection. Global and regional myocardial function was assessed serially at 1‐week and 8‐week by segmental strain analysis by using two dimensional (2D) speckle tracking echocardiography. Early myocardial remodelling was observed at 1‐week and persisted to 8‐week with global contractility of ejection fraction and fractional area change in saline‐ (32.96 ± 14.23%; 21.50 ± 10.07%) and iMSC‐injected (32.95 ± 10.31%; 21.00 ± 7.11%) groups significantly depressed as compared to sham control (51.17 ± 11.69%, P < 0.05; 34.86 ± 9.82%, P < 0.05). However, myocardial dilatation was observed in saline‐injected animals (4.40 ± 0.62 mm, P < 0.05), but not iMSCs (4.29 ± 0.57 mm), when compared to sham control (3.74 ± 0.32 mm). Furthermore, strain analysis showed significant improved basal anterior wall strain (28.86 ± 8.16%, P < 0.05) in the iMSC group, but not saline‐injected (15.81 ± 13.92%), when compared to sham control (22.18 ± 4.13%). This was corroborated by multi‐segments deterioration of radial strain only in saline‐injected (21.50 ± 5.31%, P < 0.05), but not iMSC (25.67 ± 12.53%), when compared to sham control (34.88 ± 5.77%). Improvements of the myocardial strain coincided with the presence of interconnecting telocytes in interstitial space of the infarcted anterior segment of the heart. Our results show that localized injection of iMSCs alleviates ventricular remodelling, sustains global and regional myocardial strain by paracrine‐driven effect on neoangiogenesis and myocardial deformation/compliance via parenchymal and interstitial cell interactions in the infarcted myocardium.

Factors influencing radial artery size.

Size matching of radial artery conduits to coronary arteries is important as it affects the long-term patency. However, factors affecting radial artery size have not been adequately investigated. We retrospectively reviewed 327 consecutive patients who had duplex ultrasonography of their radial arteries over a 2-year period. There were 225 men and 102 women. The mean radial artery size was 2.45 ± 0.54 mm. The factors found to positively affect the size of the radial artery were sex, hypertension, and hyperlipidemia. Diabetes mellitus and age were found to negatively affect radial artery size. Renal disease, race, and smoking did not significantly influence the size of the radial artery. However, as the R squared of this model was insignificant, further studies need to be undertaken to determine other factors that may influence radial artery size.

Outcome and survival analysis of surgical repair of post-infarction ventricular septal rupture

BackgroundTo review the experience of surgical repair of post-infarction ventricular septal rupture (VSR) and analyze the associated outcomes and prognostic factors.MethodsFollowing approval from the Singhealth Centralised Institutional Review Board (reference: 2011/881/C), a retrospective review was performed on 38 consecutive patients who had undergone surgical repair of post-infarction VSR between 1999 and 2011. Continuous variables were expressed as either mean ± standard deviation or median with 25th and 75th percentiles. These were compared using two-tailed t-test or Mann–Whitney U test respectively. Categorical variables were compared using chi-square or Fisher’s exact test. To identify predictors of operative mortality, univariate analysis of perioperative variables followed by multivariate analysis of significant univariate risk factors was performed. A two-tailed p-value < 0.05 was used to indicate statistical significance.ResultsMean age was 65.7 ± 9.4 years with 52.6% males. The VSR was anterior in 28 (73.7%) and posterior in 10 patients. Median interval from myocardial infarction to VSR was 1 day (1, 4). Pre-operative intra-aortic balloon pump was inserted in 37 patients (97.8%). Thirty-six patients (94.7%) underwent coronary angiography.Thirty-five patients (92.1%) underwent patch repair. Mean aortic cross clamp time was 82 ± 40 minutes and mean cardiopulmonary bypass time was 152 ± 52 minutes. Coronary artery bypass grafting (CABG) was performed in 19 patients (50%), with a mean of 1.5 ± 0.7 distal anastomoses. Operative mortality within 30 days was 39.5%.Univariate analysis identified emergency surgery, New York Heart Association (NYHA) class, inotropic support, right ventricular dysfunction, EuroSCORE II, intra-operative red cell transfusion, post-operative renal failure and renal replacement therapy (RRT) as predictors of operative mortality. Multivariate analysis identified NYHA class and post-operative RRT as predictors of operative mortality.Ten year overall survival was 44.4 ± 8.4%. Right ventricular dysfunction, LVEF and NYHA class at presentation were independent factors affecting long-term survival. Concomitant CABG did not influence early or late survival.ConclusionsSurgical repair of post-infarction VSR carries a high operative mortality. NYHA class at presentation and post-operative RRT are predictors of early mortality. Right ventricular dysfunction, LVEF and NYHA class at presentation affect long-term survival. Concomitant CABG does not improve survival.

Surgical management of infective endocarditis: an analysis of early and late outcomes

OBJECTIVES To review our experience of surgical management of infective endocarditis (IE) over a 13-year period and analyse the outcomes and associated prognostic factors. METHODS A retrospective review was conducted for 191 consecutive patients who underwent surgery for native and prosthetic valve endocarditis (PVE) between January 2000 and December 2012. Surgical outcomes were reviewed to include survival and postoperative complications. Follow-up was complete for 172 of 179 patients (96.1%) surviving to hospital discharge, with a mean follow-up of 6.6 ± 3.7 years. RESULTS Mean age was 47.4 ± 14.9 years with 113 (63.9%) males. Native valve endocarditis was present in 177 patients (92.7%). Sixty-three patients (33.0%) presented with embolic complications. The brain was the most common site of embolism, involving 25 patients (13.1%). Streptococcus viridans was the most common infective organism, isolated in 68 patients (35.7%), followed by Staphylococcus aureus in 30 patients (15.7%). Eighty-seven patients (45.5%) had active endocarditis at the time of surgery. The mitral valve was infected in 136 patients (71.2%), the aortic valve in 66 (34.6%), the tricuspid valve in 29 (15.2%) and multiple valves in 38 (19.9%). Nineteen patients (9.9%) were intravenous drug users (IVDU). Twelve IVDUs (63.2%) suffered from tricuspid valve IE, compared with 7 of 162 patients (4.3%) in the non-IVDU population (P < 0.001). The most common indication for early surgery was intractable cardiac failure. Twelve patients (6.3%) died during the hospital stay for surgical treatment of IE. Logistic multivariate analysis identified preoperative creatinine clearance and stroke as independent predictors of in-hospital mortality. Overall 10-year survival and freedom from valve-related reoperation were 74.8 and 90.3%, respectively. Age, PVE, S. aureus endocarditis and postoperative left ventricular ejection fraction (LVEF) ≤45% were factors influencing long-term survival. CONCLUSIONS Surgical management of endocarditis continues to be challenging and is associated with significant morbidity and mortality. This report of 191 patients who underwent valve surgery for IE shows that in-hospital mortality is influenced by preoperative renal function and stroke at the time of presentation. The optimal timing for surgery in patients with stroke remains controversial. Long-term survival was negatively influenced by increasing age, moderate to severely impaired LVEF, prosthetic valve IE and S. aureus infection.

Impact of Smoking and Brain Metastasis on Outcomes of Advanced EGFR Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Objectives This purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in EGFR mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI. Methods A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival. Results 444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M+. Amongst never-smokers (n=468), EGFR M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival. Conclusions The high prevalence of EGFR M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.

Sternoclavicular Joint Infection: Classification of Resection Defects and Reconstructive Algorithm

Background Aggressive treatment of sternoclavicular joint (SCJ) infection involves systemic antibiotics, surgical drainage and resection if indicated. The purpose of this paper is to describe a classification of post resectional SCJ defects and highlight our reconstructive algorithm. Defects were classified into A, where closure was possible often with the aid of topical negative pressure dressing; B, where parts of the manubrium, calvicular head, and first rib were excised; and C, where both clavicular, first ribs and most of the manubrium were resected. Methods Twelve patients (age range, 42 to 72 years) over the last 8 years underwent reconstruction after SCJ infection. There was 1 case of a type A defect, 10 type B defects, and 1 type C defect. Reconstruction was performed using the pectoralis major flap in 6 cases (50%), the latissimus dorsi flap in 4 cases (33%), secondary closure in 1 case and; the latissimus and the rectus flap in 1 case. Results All wounds healed uneventfully with no flap failure. Nine patients had good shoulder motion. Three patients with extensive clavicular resection had restricted shoulder abduction and were unable to abduct their arm past 90°. Internal and external rotation were not affected. Conclusions We highlight our reconstructive algorithm which is summarised as follows: for an isolated type B SCJ defect we recommend the ipsilateral pectoralis major muscle for closure. For a type C bilateral defect, we suggest the latissimum dorsi flap. In cases of extensive infection where the thoracoacromial and internal mammary vessels are thrombosed, the pectoralis major and rectus abdominus cannot be used; and the latissimus dorsi flap is chosen.

Outcome and survival analysis of intestinal ischaemia following cardiac surgery

OBJECTIVES Intestinal ischaemia is an uncommon (<1%) but serious complication of cardiac surgery with a mortality rate exceeding 50%. Diagnosis of this potentially lethal condition can be difficult and requires a high index of suspicion. The purpose of this study was to analyse the outcomes and prognostic factors in patients who develop intestinal ischaemia following cardiac surgery. METHODS In a retrospective review from August 1999 to December 2010, we identified 31 out of 9925 (0.31%) consecutive patients who developed acute intestinal ischaemia following cardiac surgery at our tertiary centre. RESULTS The overall mortality was 71.0%. The operative mortality was 65.4% in patients who underwent a laparotomy. Survivors of this complication had surgical intervention earlier (7.4 ± 4.9 h) compared with the non-survivors (13.9 ± 11.1 h). A total of 35 perioperative variables were analysed. A univariate analysis identified 12 variables associated with an increased risk of mortality. Logistic multivariate analysis identified the preoperative logistic EuroSCORE and the base excess at the point of diagnosis of intestinal ischaemia as significant predictors of mortality. These factors may aid prognostication in this group of patients. CONCLUSIONS Despite the high mortality rates associated with intestinal ischaemia following cardiac surgery, early diagnosis and surgical intervention remain the only effective means to reduce mortality.

Ciliated muconodular papillary tumor: a solitary peripheral lung nodule in a teenage girl ☆

Papillary tumors of the peripheral lung containing ciliated cells and extracellular mucin include solitary peripheral ciliated glandular papilloma, ciliated muconodular papillary tumor, and well-differentiated papillary adenocarcinoma with cilia formation. We report the case of a 19-year-old woman who was a nonsmoker and presented with an incidental small peripheral lung nodule. The resection specimen showed a soft grayish nodule. Histologic examination further revealed a relatively circumscribed mucinous nodule featuring a tubulopapillary tumor composed of ciliated columnar cells and goblet cells, accompanied with abundant extracellular mucin. No lepidic growth pattern was evident. The tumor cells were immunoreactive for cytokeratin 7, thyroid transcription factor-1, and carcinoembryonic antigen, whereas p63 and cytokeratin 5/6 highlighted the presence of basal cells. Next-generation sequencing did not identify any genetic alterations in targeted regions and mutational hotspots of a panel of 22 genes commonly implicated in lung and colon cancers. Taken together, our case was most likely a ciliated muconodular papillary tumor.

Iliofemoral anatomy among Asians: Implications for transcatheter aortic valve implantation

BACKGROUND/OBJECTIVES This study aims to examine iliofemoral anatomy and predictors of vessel size and tortuosity in Asian patients as transfemoral transcatheter aortic valve implantation (TAVI) may be limited by the smaller Asian physique. METHODS Characteristics and vessel dimensions of 549 patients undergoing ultrasonography were reviewed. The minimal luminal diameter (MLD) along the iliofemoral vasculature of each side was identified and the larger of the two sides was used to determine suitability for transfemoral TAVI. RESULTS The mean age was 66 ± 11 years (68% males). Mean iliac MLD was 7.6 ± 1.7 mm, females smaller than males (7.2 ± 1.7 vs 7.8 ± 1.7, p<0.001). Mean iliac MLD decreased with age: 7.9 ± 1.7 mm, 7.4 ± 1.9 mm and 7.3 ± 1.6mm for ages <70 years, 70-79 years and ≥ 80 years respectively (p=0.038). Mean femoral MLD was 7.0 ± 1.7 mm, females smaller than males (6.3 ± 1.5mm vs 7.3 ± 1.8mm, p<0.001). Females were more likely than males to have iliac and femoral MLD <6mm (20% vs 12%, p=0.019 and 34% vs 21%, p=0.001). Independent predictors of smaller iliofemoral dimensions were female gender, lower body surface area, diabetes mellitus, dyslipidemia and smoking history. Significant iliac tortuosity was present in 11.8%, more frequent in males than females (15% vs 6%, p=0.005), and in those with logistic EuroSCORE ≥ 15 than <15 (27% vs 10%, p=0.001). CONCLUSIONS This study establishes the mean iliac and femoral artery diameters in a cohort of relatively young Asian patients. Age and female gender were associated with smaller vessel dimension and several independent predictors of smaller vasculature and tortuosity were identified. These results have implications for TF TAVI in Asia.