Patterns of recurrence in HNSCC patients treated definitively with upfront surgery, chemoradiation.

PURPOSE: Locally-advanced oropharynx (LA-OPSCC) and hypopharynx/larynx (LA-HPLSCC) cancers may be treated with surgical or non-surgical modalities. While survival outcomes are comparable, patterns of disease recurrence are not well established. METHODS: Retrospective review of 98 consecutive patients with LA-OPSCC or LA-HPLSCC treated by either surgery plus adjuvant therapy (S-POAT, n = 48) or chemoradiation (CRT, n = 50). RESULTS: CRT-treated patients had higher recurrence risk (42% vs 14.6%, p = 0.003). This was significant only among LA-OPSCC (p = 0.002) but not LA-HPLSCC patients (p = 0.159). Median time to recurrence in LA-OPSCC was 16.8 vs 11.6 months, and 16.6 vs 15.1 months in LA-HPLSCC, comparing surgically treated and CRT cohorts. Surgically-treated p16-negative LA-OPSCC experienced improved locoregional control than CRT-treated patients (100% vs 12.5%, p = 0.045) and 3-year RFS (83.0% vs 33.3%, p < 0.001). CONCLUSION: Locoregional control and RFS benefit was observed in surgically treated p16 negative LA-OPSCC patients. Locoregional recurrence is the main reason of treatment failure in LA-HNSCC, occurring commonly within the first 2 years post-treatment, regardless of treatment option.

Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism.

Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution. Increased S70pBcl2 levels are inversely correlated with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma patient-derived primary cells as well as in reactive oxygen species (ROS)- or chemotherapeutic drug-treated cell lines. Bioinformatic analyses suggest that S70pBcl2 is associated with lower median overall survival in lymphoma patients. Empirically, sustained expression of the redox-sensitive S70pBcl2 prevents oxidative stress-induced DNA damage and cell death by suppressing mitochondrial ROS production. Using cell lines and lymphoma primary cells, we further demonstrate that S70pBcl2 reduces the interaction of Bcl-2 with the mitochondrial complex-IV subunit-5A, thereby reducing mitochondrial complex-IV activity, respiration and ROS production. Notably, targeting S70pBcl2 with the phosphatase activator, FTY720, is accompanied by an enhanced drug-induced DNA damage and cell death in CLL primary cells. Collectively, we provide a novel facet of the anti-apoptotic Bcl-2 by demonstrating that its phosphorylation at serine-70 functions as a redox sensor to prevent drug-induced oxidative stress-mediated DNA damage and execution with potential therapeutic implications.

Histopathologic prognostic indices in tongue squamous cell carcinoma.

PURPOSE: Consistent prognosticators are needed to guide adjuvant treatment in tongue squamous cell carcinoma (SCC). We validate the prognostic significance of histopathologic parameters in surgically treated tongue SCC. METHODS: Archival specimens of 88 consecutive patients who were treated surgically for tongue SCC from 2003 to 2016 were re-analyzed by one pathologist. Patient records were retrospectively reviewed. Prognosticators of recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were identified using multivariate analysis. RESULTS: Tumor depth of invasion (DOI) > 6 mm (OR 4.76; 95%CI 1.22-18.5; p = 0.024) and lymphovascular invasion (OR 5.61; 95%CI 1.00-31.5; p = 0.05) were independent predictors of nodal metastases. The overall 5-year RFS, OS and DSS were 70%, 82% and 84% respectively. Positive margins predicted poor RFS (HR 3.91; 95%CI 1.58-9.65; p = 0.003) and local recurrence-free survival (HR 4.96; 95%CI 1.36-18; p = 0.015). Presence of nodal metastases (HR 5.03; 95%CI 1.73-14.6; p = 0.003), tumor DOI > 6 mm (HR 9.91; 95%CI 1.26-78.0; p = 0.029) and positive margins (HR 8.26; 95%CI 2.75-24.8; p < 0.001) were independent predictors of poor OS. Presence of nodal metastases (HR 3.87; 95%CI 1.17-12.8; p = 0.027) and positive margins (HR 12.3; 95%CI 3.54-42.9; p < 0.001) also independently predicted poor DSS. CONCLUSION: Margins' status was the only independent predictor of local recurrence. Tumor DOI, nodal and margin status were key prognosticators of survival and may determine the necessity for adjuvant therapy.

BRAF mutation in papillary thyroid cancer-Prevalence and clinical correlation in a South-East Asian cohort.

OBJECTIVE: BRAF mutation is the commonest mutation seen in papillary thyroid cancer (PTC), but its prevalence and clinical significance vary across countries. We aim to evaluate the prevalence and clinico-pathological correlation of BRAF mutation in PTC patients at our centre. STUDY DESIGN: Retrospective cohort study of 75 consecutive archival thyroid specimens, whereby BRAF mutation was detected using a polymerase chain reaction (PCR) technique and correlated with clinical and pathological features and outcomes. SETTING: Tertiary university hospital in Singapore. PARTICIPANTS: A total of 75 consecutive histologically proven archival thyroid specimens from patients who underwent thyroidectomy for PTC were accrued for this study. MAIN OUTCOME MEASURES: Main outcome is to determine the prevalence of the BRAF mutation in our South-East Asian population. Secondary aim is to correlate the mutational status with adverse pathological features like histological variants, multi-focality, lymphovascular invasion and extra-thyroidal extension, clinical features like demographics, TNM stage, recurrence and survival, as well as treatment details like type of surgery performed and radioiodine doses. RESULTS: BRAF mutation was detected in 56% (42/75) of PTC. All but one BRAF-mutated PTC had the BRAFV600E mutation. BRAF-mutated tumours were associated with an advanced T-stage (P = 0.049) and were more likely to have a central neck dissection (P = 0.036). There was no significant correlation between BRAF mutation status and clinical outcomes. CONCLUSION: The prevalence of BRAF mutation is 56%. BRAF mutation-positive tumours were associated with locally advanced disease, but not poorer survival.

Single-center retrospective review of ultrasound-accelerated versus traditional catheter-directed thrombolysis for acute lower extremity deep venous thrombosis.

Objective Systemic anticoagulation remains the standard for acute lower extremity (LE) deep venous thrombosis (DVT), but growing interest in catheter-directed thrombolysis (CDT) and its potential to reduce the incidence of post-thrombotic syndrome (PTS) has led to advent of ultrasound-accelerated CDT (US-CDT). Few studies to date have examined the outcomes of US-CDT against traditional CDT (T-CDT). Methods This is a retrospective, single-center review of all patients treated for acute LE DVT over a five-year period with either US- and T-CDT. Patients were stratified based on demographics, presentation, co-morbidities, risk factors, and peri-procedural data. Results Seventy-six limbs in 67 patients were treated; 51 limbs in 42 patients were treated with US-CDT, and 25 limbs in 25 patients were treated with T-CDT. Adjuncts include: pharmacomechanical thrombolysis ( n = 28 vs. 20, p = 0.04), angioplasty ( n = 22 vs. 18, p = 0.11), stenting ( n = 30 vs. 6, p ≤ 0.001), and IVC filter insertion ( n = 5 vs. 0, p = 0.07). Mean lysis times were 21 ± 1.7 and 24 ± 1.8 h for US- and T-CDT, respectively ( p = 0.26). Thirty (25 ultrasound, 5 traditional) limbs had complete lysis. Thirty-one (22 ultrasound, 9 traditional) limbs had incomplete lysis. Fifteen (4 ultrasound, 11 traditional) limbs had ineffective lysis ( p = 0.002 in favor of ultrasound). Four patients (3 US-CDT, 1 T-CDT) had recurrent ipsilateral thrombosis within 30 days ( p = 0.60). By Kaplan-Meier analysis, there were no significant difference between primary patency, primary-assisted patency, secondary patency, re-thrombosis, and recurrent symptoms at 6, 12, and 24 months. Conclusion US-CDT does not significantly improve mid-term patencies but results in greater acute clot burden reduction in patients with acute LE DVTs compared to T-CDT, which may be beneficial in reducing the long-term incidence of PTS.

Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity.

Bcl-2 is frequently overexpressed in hematopoietic malignancies, and selective phosphorylation at ser70 enhances its antiapoptotic activity. Phospho-ser70 is dephosphorylated by specific heterotrimers of protein phosphatase 2A (PP2A). We report here that a mild pro-oxidant intracellular milieu induced by either pharmacological inhibition or genetic knockdown of superoxide dismutase 1 (SOD1) inhibits the functional holoenzyme assembly of PP2A and prevents Bcl-2 ser70 dephosphorylation. This redox-dependent regulation of Bcl-2 phosphorylation is due to nitrosative modification of B56δ, which we identify as the regulatory subunit mediating PP2A-dependent Bcl-2 dephosphorylation. Redox inhibition of PP2A results from peroxynitrite-mediated nitration of a conserved tyrosine residue within B56δ (B56δ(Y289)). Although nitrated B56δ(Y289) binds efficiently to ser70-phosphorylated Bcl-2, this specific modification inhibits the recruitment of the PP2A catalytic core (A and C subunits). Furthermore, inhibition of B56δ(Y289) nitration restores PP2A holoenzyme assembly, thereby permitting S70 dephosphorylation of Bcl-2 and inhibiting its antiapoptotic activity. More important, in primary cells derived from clinical lymphomas, Bcl-2 phosphorylation at S70 directly correlates with B56δ nitration and repression of SOD1, but inversely correlates with B56δ interaction with the PP2A-C catalytic subunit. These data underscore the role of a pro-oxidant milieu in chemoresistance of hematopoietic and other cancers via selective targeting of tumor suppressors such as PP2A.

Revision using distal inflow is a safe and effective treatment for ischemic steal syndrome and pathologic high flow after access creation.

OBJECTIVE: Ischemic steal syndrome (ISS) and pathologic high flow (HF) are a complications after hemodialysis access creation. Their management is complex and varied with most requiring surgical revision for correction of symptoms. Revision using distal inflow (RUDI) has been described in small series for the treatment of ISS. We present our experience with RUDI for the treatment of ISS and pathologic HF. METHODS: We retrospectively reviewed consecutive patients who underwent RUDI for ISS from April, 2010 to March, 2014. Data collection included demographic characteristics, medical histories, subsequent procedures, volume flows, access usage, limb salvage, and patient survival. RESULTS: We performed 29 RUDI procedures in 28 patients (16 women, 12 men). Indications for surgery were pathologic HF in 13 and ISS in 19. Ten percent had previous banding for ISS or HF. Sixty-nine percent of patients had a history of diabetes. Fifty-two percent had a history of atherosclerotic disease. Mean time to intervention from creation was 40 months (range, 6-88 months). Accesses included 1 upper arm graft and 27 brachial artery-based fistulas. Outflow included 25 cephalic veins and 3 basilic veins. Distalization targets were 19 radial arteries and 10 ulnar arteries. Mean flow reduction was 1191 mL/min. Primary assisted patency at 1 year was 74%. Secondary patency at 1 year was 87%. A single access was ligated for continued heart failure after RUDI. ISS symptom resolution was reported as complete in 69% and partial in 31%. CONCLUSIONS: RUDI is an effective and durable treatment of ISS and HF comparable with reported experiences with distal revascularization-interval ligation, proximalization of the arterial inflow, and banding. Patient selection is key for optimizing relief of symptoms and maintaining use of the access.

Retrograde Pedal Access and Endovascular Revascularization: A Safe and Effective Technique for High-Risk Patients with Complex Tibial Vessel Disease.

BACKGROUND: Endovascular revascularization is an established approach for limb salvage in the setting of critical limb ischemia. However, failure rate of antegrade recanalization in complex femoropopliteal to infrapopliteal occlusions is as high as 20%. We report a series of 21 patients who underwent retrograde pedal access and recanalization of below-the-knee chronic total occlusions after failed antegrade attempts. METHODS: This is a retrospective review of prospectively maintained data for all patients who underwent ultrasound-guided percutaneous pedal access for retrograde endovascular treatment of advanced tibial vessel disease between 2011 and 2014. All patients had undergone prior unsuccessful attempts at antegrade revascularization. Pedal vessel access was followed by angioplasty with selective stenting and completion angiogram. Patients were followed up with duplex ultrasound to evaluate for patency. Time-dependent outcomes were determined by Kaplan-Meier survival analyses. Median follow-up was 9 months. RESULTS: A total of 21 patients (17 men, 4 women, mean age 68) underwent retrograde tibial recanalization. Eighty-one percent of the patients presented with Rutherford category 4, 5, or 6 critical limb ischemia. The average Prevent III amputation risk score was 7.0 ± 2.9. Eighteen patients (86%) were medium or high risk (Prevent III amputation risk score ≥ 4). Retrograde pedal access was successful in 95% of the patients (dorsalis pedis = 11, posterior tibial = 5, anterior tibial = 4). Retrograde revascularization was achieved in 14 patients (67%) using balloon angioplasty (n = 14) and additional stent placement (n = 2). Revascularization failed in 7 patients (33%). There were no pedal access site complications. Forty-eight percent of the patients experienced improvement or resolution of their symptoms. The 30-day major adverse cardiac events (MACE), major adverse limb events (MALE), and amputations were all 5%. At 1 year, limb salvage was 88 ± 8% with amputation-free survival of 61 ± 12% and freedom from MALE of 81 ± 10%. Primary assisted and secondary patencies were both 84 ± 10% at 1 year. CONCLUSIONS: Early outcomes for ultrasound-guided retrograde pedal access show that it is safe, with low 30-day mortality, and a low rate of MACE. Freedom from MALE and limb salvage are both high at 1-year follow-up. This technique expands revascularization options after failed conventional endovascular antegrade approaches.

Open Removal of Penetrating Inferior Vena Cava Filter with Repair of Secondary Aortic Dissection: Case Report.

Inferior vena cava (IVC) filters are indicated for the management of venous thromboembolism in patients who are not candidates for anticoagulation, have a contraindication to anticoagulation or who have recurrent thromboembolism despite anticoagulation. As IVC filter usage has increased, there has been a corresponding increase in presentation of filter-related complications. Filter leg penetration is commonly seen although is infrequently associated with complications. But in a small percentage of patients, penetration can result in damage to adjacent structures: duodenum, lumbar spine, and rarely the aorta. We report the case of a 77-year-old man with a chronic aortoiliac dissection secondary to aortic IVC filter penetration who underwent open filter retrieval and aortic repair.

Intervention Versus Medical Management of Pulmonary Embolism.

With a multitude of options for pulmonary embolism management, we review the most common diagnostic tools available for assessing risk as well as how each broad risk category is typically treated. Right heart dysfunction is the cornerstone for triage of these patients and should be the focus for decision-making, especially in challenging patients. We aim to provide a modern, clinical perspective for PE management in light of the multitude of intervention options.

Pulmonary Embolism and Cardiovascular Care: Revolutionary Advances for the Decade Ahead.

Introductory overview for Methodist DeBakey Cardiovascular Journal Issue 20.3 on Pulmonary Embolism, written by the issues' guest editors.

Performance of a multigene genomic classifier and clinical parameters in predicting malignancy in a Southeast Asian cohort of patients with cytologically indeterminate thyroid nodules.

BACKGROUND: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy. METHODS: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed. RESULTS: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria. CONCLUSIONS: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters.

The small GTPase Rac1 is a novel binding partner of Bcl-2 and stabilizes its antiapoptotic activity.

The small GTPase Rac1 is involved in the activation of the reduced NAD phosphate oxidase complex resulting in superoxide production. We recently showed that Bcl-2 overexpression inhibited apoptosis in leukemia cells by creating a pro-oxidant intracellular milieu, and that inhibiting intracellular superoxide production sensitized Bcl-2-overexpressing cells to apoptotic stimuli. We report here that silencing and functional inhibition of Rac1 block Bcl-2-mediated increase in intracellular superoxide levels in tumor cells. Using confocal, electron microscopy and coimmunoprecipitation, as well as glutathione S-transferase-fusion proteins, we provide evidence for a colocalization and physical interaction between the 2 proteins. This interaction is blocked in vitro and in vivo by the BH3 mimetics as well as by synthetic Bcl-2 BH3 domain peptides. That this interaction is functionally relevant is supported by the ability of the Bcl-2 BH3 peptide as well as the silencing and functional inhibition of Rac1 to inhibit intracellular superoxide production as well as overcome Bcl-2-mediated drug resistance in human leukemia cells and cervical cancer cells. Notably, the interaction was observed in primary cells derived from patients with B-cell lymphoma overexpressing Bcl-2 but not in noncancerous tissue. These data provide a novel facet in the biology of Bcl-2 with potential implications for targeted anticancer drug design.

Telerobotic Endovascular Interventions and Their Potential for Cerebrovascular Treatment.

After the introduction of the first robotic-assisted surgical procedures, the technology soon reached the world of endovascular specialists, giving rise to several publications about robotic-assisted endovascular therapy. Compared with conventional procedures, robotic-assisted procedures can be more accurate and reduce radiation exposure. The latest commercially available endovascular robotic system is the CorPath GRX, which can be operated remotely. Robotic-assisted approaches have proved applicable in the fields of coronary and peripheral vascular intervention and neurointervention. Remote intervention has already proved feasible in the coronary and peripheral vascular systems and, according to expert opinion, could revolutionize acute stroke management as well. We review current knowledge about robotic-assisted therapies and remote interventions, and the future prospects and pitfalls.

The genome of Cyanothece 51142, a unicellular diazotrophic cyanobacterium important in the marine nitrogen cycle.

Unicellular cyanobacteria have recently been recognized for their contributions to nitrogen fixation in marine environments, a function previously thought to be filled mainly by filamentous cyanobacteria such as Trichodesmium. To begin a systems level analysis of the physiology of the unicellular N(2)-fixing microbes, we have sequenced to completion the genome of Cyanothece sp. ATCC 51142, the first such organism. Cyanothece 51142 performs oxygenic photosynthesis and nitrogen fixation, separating these two incompatible processes temporally within the same cell, while concomitantly accumulating metabolic products in inclusion bodies that are later mobilized as part of a robust diurnal cycle. The 5,460,377-bp Cyanothece 51142 genome has a unique arrangement of one large circular chromosome, four small plasmids, and one linear chromosome, the first report of a linear element in the genome of a photosynthetic bacterium. On the 429,701-bp linear chromosome is a cluster of genes for enzymes involved in pyruvate metabolism, suggesting an important role for the linear chromosome in fermentative processes. The annotation of the genome was significantly aided by simultaneous global proteomic studies of this organism. Compared with other nitrogen-fixing cyanobacteria, Cyanothece 51142 contains the largest intact contiguous cluster of nitrogen fixation-related genes. We discuss the implications of such an organization on the regulation of nitrogen fixation. The genome sequence provides important information regarding the ability of Cyanothece 51142 to accomplish metabolic compartmentalization and energy storage, as well as how a unicellular bacterium balances multiple, often incompatible, processes in a single cell.

Preclinical study testing feasibility and technical requirements for successful telerobotic long distance peripheral vascular intervention.

BACKGROUND: Robotic-assisted endovascular surgery enables us to perform interventions from long distances. This study evaluates the workflow and telecommunication requirements of telerobotic peripheral vascular interventions. METHODS: Ten superficial femoral artery cases were performed by the operator being 44 miles away from the interventional suite, with an endovascular robotic system, on a high-fidelity endovascular simulator. Procedural success, technical success, fluoroscopy time, residual stenosis, contrast dose and network delay were registered. Communication success was assessed after each procedure on a scale from 1 (unacceptable) to 5 (ideal). RESULTS: Procedural success and technical success were 100% and 80%, respectively. The mean residual stenosis, fluoroscopy time and contrast dose were 1.7 ± 5.25%, 6.5 ± 1.8 min and 58.8 ± 14.8 ml. The mean network latency was 38.9 ± 3.5 ms. Median communication success scores were 4.5 (min: 4, max: 5) reported by both the operator and the bedside technician on a scale of 1 (unacceptable) to 5 (ideal). CONCLUSION: With a stable network connection and good communication protocol, a high success rate was achieved for remote robotic-assisted peripheral vascular intervention in an ex vivo model.

A Multiplex Thyroid-Specific Assay for Quantification of Circulating Thyroid Cell-Free RNA in Plasma of Thyroid Cancer Patients.

BACKGROUND: The standard of care for thyroid cancer management is thyroidectomy and adjuvant radioactive iodine (RAI). There is a paucity of clinical tool that quantifies residual thyroid volume reliably for precise adjuvant RAI dosing. Serum thyroglobulin (TG), tumour marker for thyroid cancer, takes 4 weeks for complete clearance due to its long half-life, and might be undetectable in 12% of structural disease patients. It detects recurrence with a sensitivity of 19-40%, mainly attributed to issue of TG antibody interference with TG immunometric assay. We hypothesise that the quantity of thyroid-specific cell-free RNA (cfRNA) is indicative of amount of thyroid tissues, and that during thyroid surgery, cfRNA levels decrease accordingly. METHODS: We identified 11 biologically significant and highly expressed thyroid-specific targets from Human Protein Atlas and literature. To assess for a fall in thyroid-specific cfRNA level, we recruited 16 patients undergoing thyroid surgery or RAI for malignant or benign thyroid disease, and tracked longitudinal trend of cfRNA. To assess the utility of cfRNA in detecting metastatic thyroid cancer, cfRNA of 11 patients at intermediate to high risk of recurrence was measured during surveillance and at time of clinical recurrence. RESULTS: The multiplex assay was capable of amplifying and quantifying multiple thyroid-specific genes in a single reaction. The selected targets were amplified successfully from RNA extracted directly from the thyroid (positive control), indicating that they were highly expressed within thyroid tissue. These cfRNAs were present in plasma, in amounts quantifiable using qRT-PCR. Four cfRNA transcripts (TPO, GFRA2, IVD, TG) fell post-treatment in more than 50% of cohort. The thyroid peroxidase (TPO) cfRNA fell post-therapy in 63% of cohort by 80%, as early as 1 day post-treatment, supporting the potential role as early indicator of remnant thyroid tissue volume. We demonstrated the clinical relevance of circulating TPO cfRNA by tracking temporal changes in setting of peri-treatment, recurrence, and TG Ab positive state. CONCLUSION: Using a multiplex pre-amplification approach, the TPO cfRNA was a potential biomarker that can track residual thyroid mass. It can be further optimised for quantification of thyroid volume to guide RAI doses and for detection of thyroid cancer recurrence.

SARS-CoV-2 in migrant worker dormitories: Geospatial epidemiology supporting outbreak management.

BACKGROUND: Migrant worker dormitories-residential complexes where 10-24 workers share living spaces-account for the majority of cases of SARS-CoV-2 infection in Singapore. To prevent overspill of transmission to the wider population, starting in early April 2020, residents were confined to their dormitories while measures were put in place to arrest the spread of infection. This descriptive study presents epidemiological data for a population of more than 60 000 migrant workers living in two barracks-style and four apartment-style dormitories located in western Singapore from April 3 to June 10, 2020. METHODS: Our report draws from data obtained over the first 50 days of outbreak management in order to describe SARS-CoV-2 transmission in high-density housing environments. Cumulative counts of SARS-CoV-2 cases and numbers of housing units affected were analyzed to report the harmonic means of harmonic means of doubling times and their 95% confidence intervals (CI). RESULTS: Multiple transmission peaks were identified involving at least 5467 cases of SARS-CoV-2 infection across six dormitories. Our geospatial heat maps gave an early indication of outbreak severity in affected buildings. We found that the number of cases of SARS-CoV-2 infection doubled every 1.56 days (95% CI 1.29-1.96) in barracks-style buildings. The corresponding doubling time for apartment-style buildings was 2.65 days (95% CI 2.01-3.87). CONCLUSIONS: Geospatial epidemiology was useful in shaping outbreak management strategies in dormitories. Our results indicate that building design plays an integral role in transmission and should be considered in the prevention of future outbreaks.

Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer.

PURPOSE: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. EXPERIMENTAL DESIGN: Patients with treatment-naïve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. RESULTS: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T. CONCLUSIONS: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.

Current utilization and future directions of robotic-assisted endovascular surgery.

INTRODUCTION: Endovascular surgery has become the standard of care to treat most vascular diseases using a minimally invasive approach. The CorPath system further enhances the potential and enables surgeons to perform robotic-assisted endovascular procedures in interventional cardiology, peripheral vascular surgery, and neurovascular surgery. With the introduction of this technique, the operator can perform multiple steps of endovascular interventions outside of the radiation field with high precision movements even from long-geographical distances. AREAS COVERED: The first and second-generation CorPath systems are currently the only commercially available robotic devices for endovascular surgery. This review article discusses the clinical experiences and outcomes with the robot, the advanced navigational features, and the results with recent hardware and software modifications, which enables the use of the system for neurovascular interventions, and long-distance interventional procedures. EXPERT OPINION: A high procedural success was achieved with the CorPath robotic systems in coronary and peripheral interventions, and the device seems promising in neurovascular procedures. More experience is needed with robotic neurovascular interventions and with complex peripheral arterial cases. In the future, long-distance endovascular surgery can potentially transform the management and treatment of acute myocardial infarction and stroke, with making endovascular care more accessible for patients in remote areas.