Predictive risk factors for pneumothorax following fluoroscopic-guided transbronchial lung biopsy.

INTRODUCTION: Fluoroscopic-guided transbronchial lung biopsy (FG-TBLB) is routinely performed via bronchoscopy to diagnose focal peripheral lesions and diffuse lung disease. Identifying the risk factors of FG-TBLB-related pneumothorax can assist the operator in taking pre-emptive measures to prepare for this potential complication. MATERIALS AND METHODS: We retrospectively analysed data from 157 patients who underwent FG-TBLB, with the primary outcome being procedure-related pneumothorax. We assessed several risk factors for pneumothorax following FG-TBLB: patient characteristics, location of biopsy, number of biopsies and computed tomography pattern. Univariate and multivariate logistic regression analyses were performed. RESULTS: One-hundred fifty-seven patients were included [mean (SD) age 57.9 (16.2) years; 60.5% male]. The most common location for FG-TBLB was the right upper lobe (n=45, 28.7%). The mean (SD) number of biopsy samples was 6.7 (2.1). Radiographic evidence of pneumothorax was reported in 12 (7.6%) patients, with 11 of those requiring intercostal chest tube intervention (mean air leak time: 5.7 days and 1 had persistent air leak requiring autologous blood patch pleurodesis. None experienced pneumothorax recurrence. Female gender and upper lobe location of the biopsy were identified as predisposing factors for pneumothorax. In the multivariable analysis, upper lobe biopsies were associated with a higher risk of pneumothorax (OR 0.120; 95% CI 0.015-0.963; p = 0.046). CONCLUSION: The overall rate of pneumothorax is low. We recognise the increased risk of pneumothorax associated with upper lobe biopsy. These findings suggest that clinicians should exercise caution when performing FGTBLB in this region and consider alternative biopsy locations whenever feasible. We suggest adequate planning and preparation should be implemented to minimise the risk of pneumothorax following FG-TBLB.

Lung computed tomography patterns of a cluster of asymptomatic young males with COVID-19 admitted to a teaching hospital in Kuala Lumpur.

BACKGROUND AND OBJECTIVE: Coronavirus Disease 2019 (COVID- 19) was first reported in Malaysia in March 2020. We describe here the clinical characteristics and computed tomography (CT) patterns in asymptomatic young patients who had laboratory-confirmed COVID-19. METHODS: This is a retrospective observational study where 25 male in-patients with laboratory-confirmed COVID-19 in Hospital Canselor Tuanku Muhriz. Demographics, clinical data and CT images of these patients were reviewed by 2 senior radiologists. RESULTS: In total there were 25 patients (all males; mean age [±SD], 21.64±2.40 years; range, 18-27 years). Patients with abnormal chest CT showed a relatively low normal absolute lymphocytes count (median: 2.2 x 109/L) and absolute monocyte count (median: 0.5 x 109/L). Lactate dehydrogenase was elevated in 5 (20%) of the patients. The procalcitonin level was normal while elevated levels of alanine aminotransferase, total bilirubin, platelet and C-reactive protein were common. Baseline chest CT showed abnormalities in 6 patients. The distribution of the lesions were; upper lobe 3 (12%) lower lobe 3 (12%) with peripheral distribution 4 (16%). Of the 25 patients included, 4 (16%) had ground glass opacification (GGO), 1 (4%) had a small peripheral subpleural nodule, and 1 (4%) had a dense solitary granuloma. Four patients had typical CT features of COVID-19. CONCLUSION: We found that the CT imaging showed peripheral GGO in our patients. They remained clinically stable with no deterioration of their respiratory symptoms suggesting stability in lung involvement. We postulate that rapid changes in CT imaging may not be present in young, asymptomatic, non-smoking COVID-19 patients. Thus the use of CT thoraxfor early diagnosis may be reserved for patients in the older agegroups, and not in younger patients.

Triple negative breast cancer in Asia: An insider's view.

While tremendous improvement has been made for the treatment of breast cancers, the treatment of triple negative breast cancer (TNBC) still remains a challenge due to its aggressive characteristics and limited treatment options. Most of the studies on TNBC were conducted in Western population and TNBC is reported to be more frequent in the African women. This review encapsulates the studies conducted on TNBC patients in Asian population and elucidates the similarities and differences between these two regions. The current treatment of TNBC includes surgery, radiotherapy and chemotherapy. In addition to the current chemotherapies, which mainly include cytotoxic agents, such as taxanes and anthracyclines, many clinical trials are investigating the potential use of other chemotherapy drugs, targeted therapeutics and combinational therapies to treat TNBC. Moreover, this review also integrates the studies involving novel markers, which will help us to dissect the pathologic process of TNBC and in turn facilitate the development of better treatment strategies to combat TNBC.

Short communication: Diagnosis of lung cancer increases during the annual southeast Asian haze periods.

There have been few but timely studies examining the role of air pollution in lung cancer and survival. The Southeast Asia haze is a geopolitical problem that has occurred annually since 1997 in countries such as Malaysia, Singapore and Indonesia. To date, there has been no study examining the impact of the annual haze in the presentation of lung cancer. Data on all lung cancers and respiratory admissions to Universiti Kebangsaan Malaysia Medical Centre (UKMMC) from 1st January 2010 to 31th October 2015 were retrospectively collected and categorized as presentation during the haze and non-haze periods defined by the Department of Environment Malaysia. We report a lung cancer incidence rate per week of 4.5 cases during the haze compared to 1.8 cases during the non-haze period (p<0.01). The median survival for subjects presenting during the haze was 5.2 months compared to 8.1 months for the non-haze period (p<0.05). The majority of subjects diagnosed during the haze period initially presented with acute symptoms. Although this study could not suggest a cause and effect relationship of the annual haze with the incidence of lung cancer, this is the first study reporting a local air pollution-related modifiable determinant contributing to the increase in presentation of lung cancer in Southeast Asia.

Belinostat exerts antitumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma.

There have been advances in personalized therapy directed by molecular profiles in lung adenocarcinoma, but not in lung squamous cell carcinoma (SCC). The lack of actionable driver oncogenes in SCC has restricted the use of small-molecule inhibitors. Here, we show that SCC cell lines displayed differential sensitivities to belinostat, a pan-histone deacetylase inhibitor. Phosphoproteomic analysis of belinostat-treated SCC cells revealed significant downregulation of the MAPK pathway, along with the induction of apoptosis. In cisplatin-resistant cells that demonstrated aberrant MAPK activation, combined treatment with belinostat significantly inhibited cisplatin-induced ERK phosphorylation and exhibited strong synergistic cytotoxicity. Furthermore, belinostat transcriptionally upregulated the F-box proteins FBXO3 and FBXW10, which directly targeted son of sevenless (SOS), an upstream regulator of the MAPK pathway, for proteasome-mediated degradation. Supporting this, suppression of SOS/ERK pathway by belinostat could be abrogated by inhibiting proteasomal activity either with bortezomib or with siRNA knockdown of FBXO3/FBXW10. Taken together, these preclinical data offer a novel understanding of the epigenetic mechanism by which belinostat exerts its cytotoxicity and supports the combination with cisplatin in clinical settings for chemorefractory SCC tumors.

Vascular surgery-related organ injury and protective strategies: update and future prospects.

Whilst there has been a reduction in the prevalence of peripheral vascular disease worldwide, a significant proportion of the world's growing population is still affected by disease of the aorta, carotid, iliac and lower limb arteries. These if left untreated can result in severe morbidity and mortality. However vascular surgery, the main definitive treatment for such conditions, is associated with subsequent injury to vital organs including the kidneys, heart, brain, intestines and lungs, with a consequent increase in both morbidity and mortality. The current thinking is that the underlying mechanism of injury is direct organ ischaemia and ischaemia induced formation of free radicals, cytokine release and mitochondrial failure. Various methods to alleviate such injuries have been investigated including pre- and postconditioning strategies, pharmacological therapies including volatile anaesthetic and alpha2 adrenoceptor agonist drugs and more recently remote conditioning strategies. Although these interventions have demonstrated some reduction in the biomarkers for organ injury, attempts to translate these benefits into clinical practice have not been successful in terms of morbidity, mortality or length of hospital stay. For this reason, further research is needed in this area to facilitate the translation of the potential interventional benefits from bench to bedside.

Recurrent spontaneous pneumothorax during pregnancy managed conservatively: a case report.

A 36-year-old lady presented with four episodes of right sided pneumothorax during pregnancy requiring multiple chest drain insertion. It was complicated with persistent air leak despite low pressure high volume suction applied to the chest drainage. She delivered safely through spontaneous vaginal delivery with chest drainage. Further imaging by high resolution computed tomography (HRCT) scan of thorax done revealed bilateral scattered pulmonary cysts and sub pleural bullae and was later followed up with respiratory unit. She had no further episodes of pneumothorax postpartum. This case highlights the vital importance of prompt recognition and management of pneumothorax in pregnancy as the patient involved is at higher risk for acute respiratory failure leading to maternal and/or foetal mortality. It is essential for early involvement of obstetric team and to expedite the delivery for a better perinatal and maternal outcome.

Prospective purification of perivascular presumptive mesenchymal stem cells from human adipose tissue: process optimization and cell population metrics across a large cohort of diverse demographics.

BACKGROUND: Adipose tissue is an attractive source of mesenchymal stem cells (MSC) as it is largely dispensable and readily accessible through minimally invasive procedures such as liposuction. Until recently MSC could only be isolated in a process involving ex-vivo culture and their in-vivo identity, location and frequency remained elusive. We have documented that pericytes (CD45-, CD146+, and CD34-) and adventitial cells (CD45-, CD146-, CD34+) (collectively termed perivascular stem cells or PSC) represent native ancestors of the MSC, and can be prospectively purified using fluorescence activated cell sorting (FACS). In this study we describe an optimized protocol that aims to deliver pure, viable and consistent yields of PSC from adipose tissue. We analysed the frequency of PSC within adipose tissue, and the effect of patient and procedure based variables on this yield. METHODS: Within this twin centre study we analysed the adipose tissue of n = 131 donors using flow cytometry to determine the frequency of PSC and correlate this with demographic and processing data such as age, sex, BMI and cold storage time of the tissue. RESULTS: The mean number of stromal vascular fraction (SVF) cells from 100 ml of lipoaspirate was 34.4 million. Within the SVF, mean cell viability was 83 %, with 31.6 % of cells being haematopoietic (CD45+). Adventitial cells and pericytes represented 33.0 % and 8 % of SVF cells respectively. Therefore, a 200 ml lipoaspirate would theoretically yield 23.2 million viable prospectively purified PSC - sufficient for many reconstructive and regenerative applications. Minimal changes were observed in respect to age, sex and BMI suggesting universal potential application. CONCLUSIONS: Adipose tissue contains two anatomically and phenotypically discreet populations of MSC precursors - adventitial cells and pericytes - together referred to as perivascular stem cells (PSC). More than 9 million PSC per 100 ml of lipoaspirate can be rapidly purified to homogeneity using flow cytometry in clinically relevant numbers potentially circumventing the need for purification and expansion by culture prior to clinical use. The number and viability of PSC are minimally affected by patient age, sex, BMI or the storage time of the tissue, but the quality and consistency of yield can be significantly influenced by procedure based variables.

Adipose derived pericytes rescue fractures from a failure of healing--non-union.

Atrophic non-union is attributed to biological failure of the fracture repair process. It occurs in up to 10% of fractures, results in significant morbidity to patients, and treatment often requires complex reconstructive procedures. We tested the ability of human bone derived marrow mesenchymal stem cells (MSC), and human adipose derived pericytes (the native ancestor of the MSC) delivered percutaneously to the fracture gap to prevent the formation of atrophic non-union in a rat model. At eight weeks, 80% of animals in the cell treatment groups showed evidence of bone healing compared to only 14% of those in the control group. Radiographic parameters showed significant improvement over the eight-week period in the cell treatment groups, and histology confirmed bone bridges at the fracture gap in the both treatment groups. The quality of bone produced and its biomechanical properties were significantly enhanced in both treatment groups. The results from this study demonstrate that MSC and pericytes have significant bone regeneration potential in an atrophic non-union model. These cells may have a role in the prevention of atrophic non-union and could enable a paradigm shift in the treatment of fractures at high risk of failing to heal and developing non-union.

Ischaemic conditioning strategies reduce ischaemia/reperfusion-induced organ injury.

Reperfusion of tissues subjected to prolonged ischaemia results in ischaemic/reperfusion injury. Fortunately, there are strategies that can be applied to attenuate this injury. These include ischaemic pre- and post-conditioning; both have been shown experimentally to reduce ischaemic/reperfusion injury by up to 75%. The molecular mechanisms of ischaemic conditioning involve the activation of surface G-protein-coupled receptors for adenosine, bradykinin, opioids, and cannabinoids. These in turn stimulate growth receptors which then trigger the activation of cytoprotective pathways resulting in a reduction in apoptosis via the mitogen-activated protein kinase/extracellular-signal regulated kinase 1/2 kinase route and a reduction in opening of mitochondrial permeability transition pores (mPTPs) via the phosphatidylinositol 3-kinase pathway. Opening of mPTPs can cause cell death. Recently, activated surface tumour necrosis factor-α receptors have been shown to also contribute to cytoprotection by activating the Janus kinase and the signal transducer and activating factor of transcription-3 pathway. Research into the mechanisms of ischaemic conditioning is still ongoing and hopefully, with the better understanding of this phenomenon, new therapeutic strategies, with possible translation into meaningful clinical trials, will be developed to reduce ischaemic/reperfusion injury.

Recent insights into the identity of mesenchymal stem cells: Implications for orthopaedic applications.

The ability of mesenchymal stem cells (MSCs) to differentiate in vitro into chondrocytes, osteocytes and myocytes holds great promise for tissue engineering. Skeletal defects are emerging as key targets for treatment using MSCs due to the high responsiveness of bone to interventions in animal models. Interest in MSCs has further expanded in recognition of their ability to release growth factors and to adjust immune responses. Despite their increasing application in clinical trials, the origin and role of MSCs in the development, repair and regeneration of organs have remained unclear. Until recently, MSCs could only be isolated in a process that requires culture in a laboratory; these cells were being used for tissue engineering without understanding their native location and function. MSCs isolated in this indirect way have been used in clinical trials and remain the reference standard cellular substrate for musculoskeletal engineering. The therapeutic use of autologous MSCs is currently limited by the need for ex vivo expansion and by heterogeneity within MSC preparations. The recent discovery that the walls of blood vessels harbour native precursors of MSCs has led to their prospective identification and isolation. MSCs may therefore now be purified from dispensable tissues such as lipo-aspirate and returned for clinical use in sufficient quantity, negating the requirement for ex vivo expansion and a second surgical procedure. In this annotation we provide an update on the recent developments in the understanding of the identity of MSCs within tissues and outline how this may affect their use in orthopaedic surgery in the future.

Perioperative antibiotic use of dermatologic surgeons in 2012.

BACKGROUND: Recommendations for antibiotic prophylaxis in dermatologic surgery have been established, but there is variability in perioperative antibiotic use of dermatologists. Authoritative guidelines have shifted away from routine use of antibiotic prophylaxis because there is no conclusive evidence that antibiotic use reduces risk of infective endocarditis or prosthetic joint infection. OBJECTIVE: To determine current practices of perioperative antibiotic use of Mohs-trained surgeons and to compare patterns of use with updated administration guidelines. METHODS AND MATERIALS: A survey was sent to American College of Mohs Surgery members in 2012. The main outcome measures were survey responses relating to demographic characteristics, experience with postoperative infection, familiarity with antibiotic guidelines, perioperative antibiotic practices, attitudes regarding antibiotic use, and antibiotic selection. RESULTS: Most survey respondents are familiar with the Antibiotic Prophylaxis in Dermatologic Surgery Advisory Statement 2008, but respondents give antibiotics for more indications than are recommended. Although not recommended, a high percentage reported giving antibiotics to patients at high risk of infective endocarditis or joint infection even when surgery does not breach oral mucosa or involve infected skin. CONCLUSION: Dermatologic surgeons overuse perioperative antibiotics for prevention of surgical site infection, infective endocarditis, and prosthetic joint infection based on current recommendations.

Herpes folliculitis masquerading as cutaneous lymphoma.

Herpes virus infections presenting as folliculitis are uncommon. We describe a 48-year-old white man with a distant history of a childhood gastric lymphoma and renal cell carcinoma presenting with an itchy eruption. He was concerned about recurrence. A punch biopsy revealed interface dermatitis with a dense atypical superficial and deep perivascular and periadnexal lymphohistiocytic infiltrate with occasional eosinophils extending to the subcutis, with destruction of vessel walls. It was composed of predominantly CD3-positive lymphocytes with scattered CD56-positive cells and CD20-positive cells, concerning for lymphoma. A T-cell gene rearrangement study was negative. Deeper sections uncovered multinucleated giant keratinocytes in the follicular epithelium of 1 hair follicle, consistent with herpes folliculitis. Cutaneous herpes infections can exhibit several variable clinical and histopathological features. Knowledge of alternative presentations of herpes infections, histological clues to the presence of herpes infections, and careful clinicopathological correlation are necessary to differentiate herpes infections from cutaneous lymphomas and other inflammatory dermatoses.

Impedance changes according to the degree of atopi dermatitis in mice.

Variations in electrical impedance over frequency might be used to distinguish the degree of atopic dermatitis (AD), even if the mechanisms of the skin barrier impairment due to AD are still unknown. We observed the skin bioimpedance of normal mice and of abnormal mice having atopic with instrument measuring electrical impedance. Electrical impedance was measured from 20 Hz to 1 MHz at many frequencies and normalized with several indices such as IMP, PIX, IMIX, RIX, and et al. to reduce variation in subjects. The results showed the high relationship between subjective score and indices, especially, the capacitance change and impedance ratio, abs(Z(1 kHz))/abs(Z(10 kHz)). These results indicate electrical impedance may be a promising clinical diagnostic tool to monitor prognosis of skin care for atopic dermatitis. Using developed software application we easily acquired complex impedance data from the instrument and got the analysis results for very kinds of frequency. This may be useful in various bioimpedance studies such as skin cancer assessment or body composition analysis, or etc.

The role of NELL-1, a growth factor associated with craniosynostosis, in promoting bone regeneration.

Efforts to enhance bone regeneration in orthopedic and dental cases have grown steadily for the past decade, in line with increasingly sophisticated regenerative medicine. To meet the unprecedented demand for novel osteospecific growth factors with fewer adverse effects compared with those of existing adjuncts such as BMPs, our group has identified a craniosynostosis-associated secreted molecule, NELL-1, which is a potent growth factor that is highly specific to the osteochondral lineage, and has demonstrated robust induction of bone in multiple in vivo models from rodents to pre-clinical large animals. NELL-1 is preferentially expressed in osteoblasts under direct transcriptional control of Runx2, and is well-regulated during skeletal development. NELL-1/Nell-1 can promote orthotopic bone regeneration via either intramembranous or endochondral ossification, both within and outside of the craniofacial complex. Unlike BMP-2, Nell-1 cannot initiate ectopic bone formation in muscle, but can induce bone marrow stromal cells (BMSCs) to form bone in a mouse muscle pouch model, exhibiting specificity that BMPs lack. In addition, synergistic osteogenic effects of Nell-1 and BMP combotherapy have been observed, and are likely due to distinct differences in their signaling pathways. NELL-1's unique role as a novel osteoinductive growth factor makes it an attractive alternative with promise for future clinical applications. [Note: NELL-1 and NELL-1 indicate the human gene and protein, respectively; Nell-1 and Nell-1 indicate the mouse gene and protein, respectively.]

[Comparative study on two different methods of lumbar interbody fusion with pedicle screw fixation for the treatment of spondylolisthesis].

OBJECTIVE: To compare the clinical outcome of transforaminal lumbar interbody fusion (TLIF) and posterior lumbar interbody fusion (PLIF) with pedicle screw fixation on the treatment of spondylolisthesis. METHODS: One hundred and twenty patients with spondylolisthesis who were managed in our department were retrospectively evaluated. They were categorized into TLIF group and PLIF group according to the surgical methods, with 60 cases in each group. The slippage rate, the height of intervertebral space and intervertebral foramen were measured in each patient before and after operation and were compared between the two groups correspondingly. The interbody fusion rate, JOA score and complications after operation were also determined. RESULTS: All the 120 patients were followed up for an average of 23 months (range, 16 to 35 months). Interbody bony fusion was achieved in every case and cage excursion or subsidence occurred in not any case. JOA score was rated as good or excellent in 83.3% of the TLIF cases and in 81.7% of the PLIF cases. There were no difference between the two groups (P > 0.05). Postoperative slippage rate was significantly less than preoperative ones in both groups (P < 0.01). No difference in lost of reduction at the final follow-up was found between TLIF and PLIF groups (P > 0.05). Significant increases in the height of intervertebral space and intervertebral foramen after operation were approved in both groups (P < 0.01), but no difference in these increases was confirmed between the two groups (P > 0.05). The lost of the height of intervertebral space and intervertebral foramen at the final follow-up were also similar between the two groups (P > 0.05). CONCLUSIONS: TLIF and PLIF are good methods for the treatment of spondylolisthesis, both leading to satisfactory clinical outcomes. However, TLIF is relatively safer owing to its unilateral approach for interbody fusion.

Phase I trial of fixed dose-rate gemcitabine in combination with carboplatin in chemonaive advanced non-small-cell lung cancer: a Cancer Therapeutics Research Group study.

PURPOSE: To determine the maximally tolerated dose (MTD) of gemcitabine administered at a fixed dose-rate of 10 mg/m(2) per min in combination with fixed dose carboplatin, to evaluate the toxicity of this regimen and to determine the pharmacokinetics of plasma gemcitabine. METHODS: Patients with advanced stage non-small-cell lung cancer (NSCLC) received carboplatin (AUC 5) on day 1 followed by gemcitabine at a fixed dose rate of 10 mg/m(2) per min in escalating durations of infusion on days 1 and 8 every 21 days. Pharmacokinetic sampling was obtained on day 1, cycle 1 of treatment. RESULTS: A total of 15 patients received carboplatin and gemcitabine in cohorts of three to six patients at three dose levels. The doses of gemcitabine studied were 600, 750, and 900 mg/m(2). The MTD was reached at 900 mg/m(2). Dose-limiting toxicities were thrombocytopenia and liver failure, and with repeated dosing neutropenia was commonly observed. The recommended phase II dose of gemcitabine was 750 mg/m(2). Partial responses were observed at 600 and 750 mg/m(2) of gemcitabine. Plasma gemcitabine did not reach steady state except in one patient with the durations of infusion studied. Plasma concentrations, however, were above 10 micro mol/l between 20 and 90 min in all patients. CONCLUSIONS: Gemcitabine administered as a 75-min infusion at a fixed dose rate of 10 mg/m(2)/min on days 1 and 8 in combination with carboplatin on day 1 every 21 days is tolerable and active in NSCLC. Pharmacokinetic studies demonstrated that the target plasma gemcitabine concentration above 10 micro mol/l was achieved. Further studies are warranted to compare this regimen against standard regimens of carboplatin and gemcitabine.

Scheuermann kyphosis: long-term follow-up.

BACKGROUND CONTEXT: There is considerable controversy as to the optimal treatment of Scheuermann kyphosis. Proposed modalities have included exercise, bracing and surgery. PURPOSE: The purpose of this study was to document the functional capacity and radiographic findings in adults who have been previously treated for Scheuermann kyphosis. STUDY DESIGN: A cohort study of all patients with Scheuermann kyphosis treated in a single institution using three different treatment modalities: exercise and observation, Milwaukee bracing and surgical fusion using the Harrington Compression System. PATIENT SAMPLE: Sixty-three patients were evaluated at a mean of 14 years after treatment (10 to 28 years). OUTCOME MEASURES: Two different functional evaluation instruments were used. Radiographic evaluation was carried out in 38 patients (60%). METHODS: Patient interviews were conducted using a specially designed questionnaire. Patients were then asked to undergo standing radiographs. Patients were divided into groups depending on the location of their kyphosis and the manner in which they had been treated. Standard statistical analysis was then carried out. RESULTS: At time of follow-up evaluation there were no differences in marital status, general health, education level, work status, degree of pain and functional capacity between the various curve types, treatment modality and degree of curve. Patients treated by bracing or surgery did have improved self-image, which they attributed to their treatment. Patients with kyphotic curves exceeding 70 degrees at follow-up had an inferior functional result. At time of final follow-up there were no statistical differences in degree of kyphosis and mode of treatment. CONCLUSIONS: By carefully selecting the appropriate treatment for patients with Scheuermann kyphosis on the basis of the patient's age, spinal deformity and the severity of back pain, it is possible to achieve a similar functional result at long-term follow-up. Despite different treatment protocols, patients with Scheuermann kyphosis tend to achieve a similar functional result at long-term follow-up.