Cardiovascular Risk Management in Patients Treated with JAK Inhibitors.

ABSTRACT: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in the pathogenesis of many immune-mediated inflammatory diseases (IMIDs). Although Janus kinase inhibitors (JAKi) are an effective treatment for several IMIDs, they have come under scrutiny as a class due to a potential risk of venous thromboembolism (VTE) and cardiovascular (CV) events, specifically noted with the oral JAKi, tofacitinib, as reported in the ORAL Surveillance Trial of a high CV risk rheumatoid arthritis population. This trial resulted in a black box warning from the Food and Drug Administration and European Medicines Agency regarding risk of VTE and CV events that was extended across several types of JAKi (including topical ruxolitinib) when treating IMIDs, leading to considerable controversy. Included is an up-to-date review of the current and rapidly evolving literature on CV risk in patients with IMIDs on JAKi therapy, including identification of potential risk factors for future VTE and CV events on JAKi therapy. We suggest a comprehensive, multimodal, and systematic approach for evaluation of CV risk in patients considering taking JAKi and emphasize that cardiologists play an important role in risk stratification and mitigation for patients with high CV risk factors or on long-term JAKi therapies.

The big squeeze: balancing the hemodynamics of cardiac tamponade and superior vena cava syndrome.

In this clinical vignette, we describe an unusual aetiology of shock that was precipitated by the drainage of malignant pericardial effusion. Therapeutic intervention of the patient's cardiac tamponade led to decreased venous pressures, increased external lung mass compression, worsening superior vena cava syndrome, and ultimately haemodynamic compromise leading to his expiration.

A Retrospective Study to Assess the Accuracy of Frozen Sections in Laser Laryngeal Surgery.

OBJECTIVE: The basis of good vocal outcomes following Transoral Laser Microlaryngeal Cordectomy (TLMC) is the narrow margin that is oncologically accepted for the glottis. Our objective is to evaluate the reliability of frozen section (FS) compared to paraffin section (PS) during TLMC and during laser laryngeal surgery when an incisonal or excisional biopsy is being performed. METHODS: Retrospectively, records of 159 sequential patients who underwent CO2 laser laryngeal surgery with intraoperative FS were reviewed along with the final PS. Group A patients were TLMC patients where FS was utilized for free margin confirmation (42 specimens) and Group B patients were those in whom FS was performed for primary diagnosis (122 specimens). RESULTS: A total of 164 samples were included where specimens submitted for FS were also processed for PS. Concordance was observed in 156 samples, discordance in 8, with 4 cases belonging to each group. FS was reported as false negative in 5 and false positive in 3 cases. In Group A where FS was utilized for free margin confirmation, the sensitivity was found to be 60%, specificity and positive predictive value (PPV) 100%, and negative predictive value (NPV) 88.9%. In Group B where FS was performed for primary diagnosis, the sensitivity was found to be 98.4%, specificity 95.1%, PPV 95.2%, and NPV 98.3%. CONCLUSION: A 100% PPV of FS in group A suggests that positive FS margins during TLMC may be safely relied upon in making decisions to upgrade the type of cordectomy being performed. A NPV of 88.9% in group A suggests that despite a clear frozen margin report during TLMC, 11.1% of patients would need further treatment. A PPV of 95.2% in group B suggests that although FS analysis is important for guiding further management, decisions regarding major laryngeal surgery should not be undertaken based solely on FS.

A Rare Case of Eosinophilic Gastroenteritis and Ampullitis Leading to Benign Papillary Stenosis.

Eosinophilic gastroenteritis is characterized by eosinophilic infiltration of the gastrointestinal wall. There have been limited studies of eosinophilic infiltration involving the ampulla. We present a 70-year-old woman with a history of asthma, eosinophilic esophagitis, and eosinophilic sinusitis, who underwent work up for postprandial abdominal pain and abnormal liver function tests. The patient had various imaging studies done, including computed tomography (CT) scan, magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP). Dilated extrahepatic bile duct with distal tapering towards the ampulla was noted on MRCP and afterwards on endoscopic ultrasound (EUS). Endoscopic retrograde cholangiopancreatography (ERCP) revealed an inflamed major ampulla with benign papillary stenosis. The patient was treated with sphincterotomy, sphincteroplasty/dilation of distal common bile duct, and placement of an 11.5 Fr × 7 cm plastic stent into the bile duct. Additionally, she was started on prednisone, which was gradually tapered down. The patient demonstrated significant improvement with systemic steroid therapy. Liver function tests (LFTs) completely normalized after ERCP. Ampullitis leading to papillary stenosis secondary to eosinophilic infiltration of the major papilla is a rare manifestation of eosinophilic gastrointestinal disorders (EGIDs). Early diagnosis would lead to appropriate medical and endoscopic management.

Butterfly tragal cartilage for repair of focal canal wall defects / Cartílago tragal en mariposa para reparar los defectos focales de la pared del conducto auditivo externo

BACKGROUND: Meato-mastoid fistula is a connection between the external auditory canal and the mastoid cavity. It may be iatrogenic or pathological. The repair of these focal canal wall defects is necessary to prevent retraction pockets or sequential cholesteatoma and attain relief from otorrhoea. AIM/OBJECTIVE: To study the effectiveness of an innovative technique for repair of meato-mastoid fistula (less than or equal to 10 mm in size) in the bony external auditory canal. MATERIAL AND METHODS: We performed a retrospective review of 5 surgeries performed in our hospital between January 2017 and December 2017 for the repair of posterior bony canal wall defects. Active ear disease was ruled out before the repair. We used full-thickness butterfly tragal cartilage graft for the repair of these fistulae. All our surgeries were endoscopic and sutureless. RESULTS: The butterfly tragal cartilage graft was in situ at the repair site and viable on examination at 2 years follow-up, in all our cases. CONCLUSION AND SIGNIFICANCE: Small posterior canal wall defects can be successfully repaired using this technique. The method is minimally invasive and cosmetic, with good patient compliance. The curling property of the cartilage graft is exploited effectively in this method of repair

INTRODUCCIÓN: La fístula meato-mastoidea es una conexión entre el canal auditivo externo y la cavidad mastoidea. Puede ser iatrogénica o patológica. La reparación de estos defectos focales de la pared del canal es necesaria para evitar las bolsas de retracción o el colesteatoma secuencial, y aliviar la otorrea. OBJETIVO: Estudiar la eficacia de una técnica innovadora para reparación de fístula meato-mastoidea (inferior o igual a 10 mm de tamaño) en el hueso del canal auditivo externo. MATERIAL Y MÉTODOS: se realizó una revisión retrospectiva de 5 cirugías en nuestro hospital de atención terciaria entre enero y diciembre de 2017 para la reparación de defectos de la pared ósea del canal posterior. Se descartó la enfermedad activa del oído antes de la reparación. Utilizamos injerto de cartílago tragal en mariposa de espesor completo para la reparación de estas fístulas. Todas las cirugías fueron endoscópicas y sin sutura. RESULTADOS: El injerto de cartílago tragal en mariposa se realizó in situ en el sitio de reparación, siendo viable durante el examen de seguimiento a los 6 meses, en todos nuestros casos. CONCLUSIÓN: Los defectos de la pared del canal posterior pequeños pueden repararse exitosamente con esta técnica. El método es mínimamente invasivo y cosmético, con buena aceptación del paciente. La propiedad ondulada del injerto de cartílago se aprovecha eficazmente en este método de reparación

Butterfly tragal cartilage for repair of focal canal wall defects.

BACKGROUND: Meato-mastoid fistula is a connection between the external auditory canal and the mastoid cavity. It may be iatrogenic or pathological. The repair of these focal canal wall defects is necessary to prevent retraction pockets or sequential cholesteatoma and attain relief from otorrhoea. AIM/OBJECTIVE: To study the effectiveness of an innovative technique for repair of meato-mastoid fistula (less than or equal to 10mm in size) in the bony external auditory canal. MATERIAL AND METHODS: We performed a retrospective review of 5 surgeries performed in our hospital between January 2017 and December 2017 for the repair of posterior bony canal wall defects. Active ear disease was ruled out before the repair. We used full-thickness butterfly tragal cartilage graft for the repair of these fistulae. All our surgeries were endoscopic and sutureless. RESULTS: The butterfly tragal cartilage graft was in situ at the repair site and viable on examination at 2 years follow-up, in all our cases. CONCLUSION AND SIGNIFICANCE: Small posterior canal wall defects can be successfully repaired using this technique. The method is minimally invasive and cosmetic, with good patient compliance. The curling property of the cartilage graft is exploited effectively in this method of repair.

Case study: cochlear implantation in cochlear otospongiosis.

Objective and importance: Cochlear implantation can be performed successfully in patients with otospongiosis of the temporal bone with the potential for excellent audiological outcomes and high patient satisfaction. The purpose of this case report is to highlight the clinical considerations for implantation in cochlear otospongiosis including the need for careful pre-operative implant device selection, intra-operative surgical challenges such as the presence of hypervascularity and possible cochlear ossification resulting in difficulty in placing the electrode array and the possibility of postoperative facial nerve stimulation.Clinical presentation: A 14-year-old girl with cochlear otospongiosis likely due to osteogenesis imperfecta presented with progressive bilateral profound sensorineural hearing loss underwent successful cochlear implantation despite several challenges.Conclusion: Cochlear implantation in patients with cochlear otospongiosis with profound sensorineural hearing loss potentially may be very successful. Thorough pre-operative radiological evaluation is necessary. Possible intra-operative and post-operative challenges unique to these patients must be kept in mind. Adequate precautions should be taken to optimize the likelihood of complete electrode insertion such as using a depth gauge prior to inserting the electrode array and performing an intra-operative x-ray and / or neural response telemetry to confirm correct electrode placement.

Neoadjuvant treatments for locally advanced, resectable esophageal cancer: A network meta-analysis.

The relative survival benefits and postoperative mortality among the different types of neoadjuvant treatments (such as chemotherapy only, radiotherapy only or chemoradiotherapy) for esophageal cancer patients are not well established. To evaluate the relative efficacy and safety of neoadjuvant therapies in resectable esophageal cancer, a Bayesian network meta-analysis was performed. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for publications up to May 2016. ASCO and ASTRO annual meeting abstracts were also searched up to the 2015 conferences. Randomized controlled trials that compared at least two of the following treatments for resectable esophageal cancer were included: surgery alone, surgery preceded by neoadjuvant chemotherapy, neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy. The primary outcome assessed from the trials was overall survival. Thirty-one randomized controlled trials involving 5496 patients were included in the quantitative analysis. The network meta-analysis showed that neoadjuvant chemoradiotherapy improved overall survival when compared to all other treatments including surgery alone (HR 0.75, 95% CR 0.67-0.85), neoadjuvant chemotherapy (HR 0.83. 95% CR 0.70-0.96) and neoadjuvant radiotherapy (HR 0.82, 95% CR 0.67-0.99). However, the risk of postoperative mortality increased when comparing neoadjuvant chemoradiotherapy to either surgery alone (RR 1.46, 95% CR 1.00-2.14) or to neoadjuvant chemotherapy (RR 1.58, 95% CR 1.00-2.49). In conclusion, neoadjuvant chemoradiotherapy improves overall survival but may also increase the risk of postoperative mortality in patients locally advanced resectable esophageal carcinoma.

Baha Attract: Our Experience.

In this study, we have highlighted our experience with a new transcutaneous bone conduction hearing device, the Baha Attract System along with finer details on its surgical technique, some challenges faced intraoperatively and the surgical outcome. This study was carried out in our tertiary care hospital over the last 1 year. Our study included the first 4 patients, all of which were males; with a mean age of 13.25 years in whom the new Baha Attract System was used. The mean air-bone gap was 48 dB. Bone smoothening around the implant was needed in 2 patients. We did the switch-on after 6-12 weeks for all the patients where the programmed processor was applied with the help of a magnet at the implanted site. Our study results suggest that the Baha Attract System is promising for the patients with microtia-anotia having conductive or mixed hearing loss. These patients cannot be offered conventional air conduction hearing aids. Their hearing outcomes were comparable to percutaneous Baha systems.

Paediatric endonasal dacryocystorhinostomy using an otology set: How I do it.

INTRODUCTION: Endonasal DCR is safely performed in children presenting with persistent epiphora, not responding to conservative management. The surgical technique of endoscopic DCR in the paediatric age group essentially remains the same as that performed in adults, but children have narrower nasal passages and relatively larger inferior turbinates which limit the surgeon's working space. The standard 2.7 mm paediatric nasal endoscope gives a smaller surgical work field as compared to the 4 mm adult endoscope. Hence, we have used the otology set of instruments for performing endoscopic DCR in children to allow the negotiation of a wider 4 mm scope which gives a larger field of surgery and better illumination. MATERIALS AND METHODS: It is a prospective study of 23 children done over the last 5 years at our tertiary care hospital. We have successfully used this less invasive technique of endoscopic dacryocystorhinostomy who didn't respond to conservative management. RESULTS: The overall success rate was 95.65% without any major complications. CONCLUSION: Using the fine delicate otology set for endonasal DCR is advantageous as it not only allows the use of a 4 mm endoscope but also allows the surgeon to perform a more meticulous surgery by preventing unnecessary mucosal abrasions and creation of raw areas thereby improving surgical outcome. It thus combines a high success rate with a lesser invasive technique. At the same time, it is important to have an experienced surgeon due to the variable anatomy and technical accuracy required in children.

Endonasal dacryocystorhinostomy in children: Our experience.

INTRODUCTION: Epiphora affects approximately 20% neonates, but most resolve spontaneously. Dacryocystorhinostomy (DCR) is indicated only when conservative management fails. OBJECTIVE: To observe clinical presentation, treatment modalities and effectiveness of endoscopic DCR in paediatric population. METHODS: It is a prospective study of 21 children done at our tertiary care hospital from 2011 to 2016. All were initially subjected to a trial of conservative management. Those that responded and didn't require surgery were excluded. RESULTS: The age group ranged from 40 days to 11.5 years. 19 underwent unilateral & 2 underwent bilateral endoscopic DCR. After a 6 month follow-up, 20 children were benefitted by surgery, 2 had an incomplete resolution and 1 required revision surgery. The overall success rate was 95.23% and failed cases were mainly due to post-traumatic distortion of the anatomy. No major complications were noted. CONCLUSION: Endoscopic DCR is safe and effective in children presenting with persistent epiphora.

A Misdiagnosed Laryngeal Web: Treated with an Innovative Self-Made Keel.

Laryngeal web is a rare congenital anomaly. Late presentation at the age of 10 years as in our case, with misleading diagnosis of asthma in a Cohen's type III glottic web is even rarer. In cases of congenital laryngeal web the aim is to provide a patent airway and to achieve a good voice quality. Regardless of the technique used; the primary concern is recurrence. Traditionally, the treatment of choice for laryngeal web was laryngofissure with placement of a keel however; endoscopic laser excision of the web with keel placement is now the preferred technique for thin anterior glottic webs. This endoscopic technique not only requires a Lichtenberger needle carrier but also the ready-made keel, which many of the government set-ups in our country cannot provide. For an alternative to this problem, we have described an innovative, minimally invasive technique for placement of a self-made silicone keel without any sophisticated instruments.

Cost-Effectiveness Analysis of Systemic Therapies in Advanced Pancreatic Cancer in the Canadian Health Care System.

OBJECTIVES: To assess the cost-effectiveness of gemcitabine (G), G + 5-fluorouracil, G + capecitabine, G + cisplatin, G + oxaliplatin, G + erlotinib, G + nab-paclitaxel (GnP), and FOLFIRINOX in the treatment of advanced pancreatic cancer from a Canadian public health payer's perspective, using data from a recently published Bayesian network meta-analysis. METHODS: Analysis was conducted through a three-state Markov model and used data on the progression of disease with treatment from the gemcitabine arms of randomized controlled trials combined with estimates from the network meta-analysis for the newer regimens. Estimates of health care costs were obtained from local providers, and utilities were derived from the literature. The model estimates the effect of treatment regimens on costs and quality-adjusted life-years (QALYs) discounted at 5% per annum. RESULTS: At a willingness-to-pay (WTP) threshold of greater than $30,666 per QALY, FOLFIRINOX would be the most optimal regimen. For a WTP threshold of $50,000 per QALY, the probability that FOLFIRINOX would be optimal was 57.8%. There was no price reduction for nab-paclitaxel when GnP was optimal. CONCLUSIONS: From a Canadian public health payer's perspective at the present time and drug prices, FOLFIRINOX is the optimal regimen on the basis of the cost-effectiveness criterion. GnP is not cost-effective regardless of the WTP threshold.

A Bayesian network meta-analysis on second-line systemic therapy in advanced gastric cancer.

BACKGROUND: It is unclear which regimen is the most efficacious among the available therapies for advanced gastric cancer in the second-line setting. We performed a network meta-analysis to determine their relative benefits. METHODS: We conducted a systematic review of randomized controlled trials (RCTs) through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and American Society of Clinical Oncology abstracts up to June 2014 to identify phase III RCTs on advanced gastric cancer in the second-line setting. Overall survival (OS) data were the primary outcome of interest. Hazard ratios (HRs) were extracted from the publications on the basis of reported values or were extracted from survival curves by established methods. A Bayesian network meta-analysis was performed with WinBUGS to compare all regimens simultaneously. RESULTS: Eight RCTs (2439 patients) were identified and contained extractable data for quantitative analysis. Network meta-analysis showed that paclitaxel plus ramucirumab was superior to single-agent ramucirumab [OS HR 0.51, 95 % credible region (CR) 0.30-0.86], paclitaxel (OS HR 0.81, 95 % CR 0.68-0.96), docetaxel (OS HR 0.56, 95 % CR 0.33-0.94), and irinotecan (OS HR 0.71, 95 % CR 0.52-0.99). Paclitaxel plus ramucirumab also had an 89 % probability of being the best regimen among all these regimens. Single-agent ramucirumab, paclitaxel, docetaxel, and irinotecan were comparable to each other with respect to OS and were superior to best supportive care. CONCLUSIONS: This is the first network meta-analysis to compare all second-line regimens reported in phase III gastric cancer trials. The results suggest the paclitaxel plus ramucirumab combination is the most effective therapy and should be the reference regimen for future comparative trials.

A Systematic Review and Network Meta-Analysis of Biologic Agents in the First Line Setting for Advanced Colorectal Cancer.

BACKGROUND: Epithelial growth factor receptor inhibitors (EGFRis) and bevacizumab (BEV) are used in combination with chemotherapy for the treatment of metastatic colorectal cancer (mCRC). However, few randomized controlled trials (RCTs) have directly compared their relative efficacy on progression-free survival (PFS) and overall survival (OS). METHODS: We conducted a systematic review of first-line RCTs comparing (1) EGFRis vs. BEV, with chemotherapy in both arms (2) EGFRis + chemotherapy vs. chemotherapy alone, or (3) BEV + chemotherapy vs. chemotherapy alone, using Cochrane methodology. Data on and PFS and OS were extracted using the Parmar method. Pairwise meta-analyses and Bayesian network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios (HRs) comparing EGFRis to BEV. RESULTS: Seventeen RCTs contained extractable data for quantitative analysis. Combining direct and indirect data using an NMA did not show a statistical difference between EGFRis versus BEV (PFS HR = 1.11 (95% CR: 0.92-1.36) and OS HR = 0.91 (95% CR: 0.75-1.09)). Direct meta-analysis (3 RCTs), indirect (14 RCTs) and combined (17 RCTs) NMA of PFS HRs were concordant and did not show a difference between EGFRis and BEV. Meta-analysis of OS using direct evidence, largely influenced by one trial, showed an improvement with EGFRis therapy (HR = 0.79 (95% CR: 0.65-0.98)), while indirect and combined NMA of OS did not show a difference between EGFRis and BEV Successive inclusions of trials over time in the combined NMA did not show superiority of EGFRis over BEV. CONCLUSIONS: Our findings did not support OS or PFS benefits of EGFRis over BEV in first-line mCRC.

A Bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer.

BACKGROUND: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear. METHODS: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously. RESULTS: Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50-1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results. CONCLUSIONS: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons.