Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers.

INTRODUCTION: Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker. METHODS: Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded. RESULTS: MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy. CONCLUSION: This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.

Botulinum toxin for benign essential blepharospasm: A systematic review and an algorithmic approach.

BACKGROUND: Currently, there is no standardised approach for benign essential blepharospasm treatment with botulinum toxin, and controversies still exist regarding this subject. OBJECTIVE: The objective of this systematic review is to summarise and compare all the published data regarding benign essential blepharospasm treatment with botulinum toxin. METHODS: On October 3, 2018, an online search of the Medline database was conducted. All articles with a detailed description of their botulinum toxin injection technique for benign essential blepharospasm were included in this review. RESULTS: Five studies were selected for inclusion with a total of 854 patients. Four of the included studies used onabotulinumtoxin A and one study used abobotulinumtoxin A. All studies injected the pretarsal orbicularis occuli muscle. The preseptal orbicularis occuli was injected in four studies, and the preorbital muscle in three studies. The most commonly used method of evaluation was the Jankovic Rating Scale. Adverse events were transient, and dose related. Ptosis was more frequently encountered with the preseptal orbicularis injections. CONCLUSION: Botulinum toxin injection for benign essential blepharospasm is a non-invasive and safe procedure. The pretarsal muscle should be considered as the key component when treating benign essential blepharospasm with botulinum toxin. We developed an algorithmic approach to the treatment of benign essential blepharospasm with botulinum toxin. However, further randomised controlled trials are warranted.

Should we consider the hemi-tip as a proper aesthetic subunit in a nasal reconstruction?

BACKGROUND: Defects involving several aesthetic subunits (ASUs) or lying at the junction of an ASU are challenging and require a complex reconstruction. This study aimed to describe the hemi-tip as a new ASU. MATERIAL AND METHODS: We conducted a retrospective study including patients who underwent a nasal reconstruction for lower nasal pyramid defects according to our modified ASU principle. Patients who suffered from a subtotal alar defect, which also involved <50% of the tip, were reconstructed after excising the remaining tissue of the hemi-tip subunit. An aesthetic evaluation was performed using a patient satisfaction scale and by independent raters. RESULTS: From 2010 to 2014, 21 patients underwent a lower hemi-nose reconstruction. All patients had a full-thickness defect and underwent a reconstruction of the three layers of the nose. Sixty-four percent of our patients were very satisfied, 26% were satisfied, and only 10% were unsatisfied with their nasal tip appearance, with a mean score of 4.4/5. The nasal tip was also rated by independent raters with a mean score of 4.1/5. DISCUSSION: Our results and experience showed that a midline scar between the two hemi-tips is inconspicuous. The majority of the defects involving only one side of the tip would benefit from the hemi-tip ASU reconstruction. CONCLUSION: We have modified the number of ASUs by considering the hemi-tip as a proper subunit.

SGLT2 inhibitors.

Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM.

Dapagliflozin in type 2 diabetes: effectiveness across the spectrum of disease and over time.

BACKGROUND: Despite many available therapies, patients with type 2 diabetes mellitus (T2DM) frequently do not achieve/maintain glycaemic control. Furthermore, side effects such as hypoglycaemia and weight gain may limit therapy choices. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces hyperglycaemia by increasing glucosuria independently of insulin, representing a novel approach in T2DM. Dapagliflozin efficacy, safety and tolerability were evaluated across a wide range of clinical trials. METHODS: Dapagliflozin 10-mg efficacy data from (i) two short-term, active-comparator studies (vs. metformin-XR over 24 weeks and vs. glipizide over 52 weeks), (ii) pooled 24-week analyses of five placebo-controlled trials (as monotherapy or add-on therapy), and (iii) long-term studies over 2 years; dapagliflozin 5- and 10-mg pooled safety data from 12 placebo-controlled trials; and cardiovascular safety and malignancy data from 19 dapagliflozin studies were evaluated. RESULTS: In treatment-naïve patients (baseline HbA1c 9%), dapagliflozin reduced HbA1c (-1.45%) similarly to metformin-XR (-1.44%). In metformin-treated patients (baseline HbA1c 7.7%), dapagliflozin achieved a clinically significant reduction (-0.52%) similar to glipizide (-0.52%). In pooled 24-week analyses, dapagliflozin vs. placebo differences in HbA1c, weight and systolic blood pressure (SBP) were -0.60%, -1.61 kg and -3.6 mmHg, respectively. At 2 years, dapagliflozin vs. placebo differences in HbA1c and weight were -0.44 to -0.80% and -2.41 to -3.19 kg, respectively, and vs. glipizide, differences in HbA1c, weight, and SBP were -0.18%, -5.06 kg, and -3.89 mmHg, respectively. Major hypoglycaemia with dapagliflozin was rare (< 0.1%). Urinary tract and genital infections were more common with dapagliflozin, but responded to standard care and rarely led to study discontinuation. Events of renal failure/impairment and malignancies were rare and balanced across treatment groups. Pooled analyses did not indicate that dapagliflozin increased cardiovascular event risk. CONCLUSIONS: Dapagliflozin improved glycaemic control, decreased body weight, and lowered blood pressure across the spectrum of T2DM disease, with maintenance of these benefits over time.

SU-E-J-41: Fluoroscopy Based Adaptive Setup Approach for Thoracic Cancer IGRT.

PURPOSE: To develop a fluoroscopy imaging based approach that can determine the magnitude and phase variation in respiratory motion against the treatment planning images in order to quantify the online patient setup deviation in thoracic cancer IGRT for the real time adaptive patient positionadjustment. METHODS: A numerical phantom was generated to test the strength of the approach. The 2D phantom consist a static outside wall and an inner target moving in temporal pattern similar to the respiratory motion. Four motion parameters: frequency (0.5Hz∼2Hz), amplitude (40∼60mm), position offset (5∼10mm), and phase shift (starting phase 0, 45, and 90 degrees) vary to generate phantom image sets with different motions. White noise of level SNR=5 was added to all phantom images to simulate the impact of clinical image quality. A manifold based machine learning technique was used to construct the respiratory motion model under thestandard condition (frequency 1 Hz, amplitude 50mm, and no position offset and/or phase shift). Then the phase and position shift in other phantom image series were quantified by finding the MAP solution to fit theembedded motion to the standard motion model. RESULTS: The proposed approach can detect the variation in motion patterns between two image sets. The method is insensitive to frequency changes and image noise up to SNR=5, but is very effective at capturing and quantifying the change in motion amplitude, position shift, and also the phase shift. CONCLUSIONS: This work proposed an effective mathematical approach to quantify the difference in motion between the pre-treatment images and the treatment planning images by extraction of the motion model in fluoroscopy images using the machine learning technique. By applying the approach during online patient setup, the positioning deviation can be separated from the respiratory motion and adjusted to minimize the normal tissue toxicity in gated IGRT.

Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes.

BACKGROUND: The kidney plays a central role in the regulation of plasma glucose levels, although until recently this has not been widely appreciated or considered a target for therapeutic intervention. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke the renal excretion of glucose have been discovered, thereby providing a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. OBJECTIVE: To explore the physiology of SGLT2 action and discuss several SGLT2 inhibitors that have entered early clinical development. METHODS: All publicly available data were identified by searching the internet for 'SGLT2' and 'SGLT2 inhibitor' through 1 November 2007. Published articles, press releases and abstracts presented at national and international meetings were considered. RESULTS/CONCLUSION: Sodium glucose co-transporter type 2 inhibition is a novel treatment option for diabetes, which has been studied in preclinical models and a few potent and selective SGLT2 inhibitors have been reported and are currently in clinical development. These agents appear to be safe and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral antihyperglycaemic agents.

Endocrine incidentalomas.

OBJECTIVES: Endocrine incidentalomas are very common in the practice of every physician, mostly primary care and family physicians. Incidentalomas are discovered in the thyroid, pituitary and adrenal glands during imaging studies performed for non-endocrine reasons. The aim of this review article is to familiarise health professionals with all three endocrine incidentalomas, and give some guidance on how to initiate the right endocrine workup. METHODS: We reviewed the most pertinent literature published on this topic through PubMed and Medline. We also discussed our own approach to incidentalomas in the endocrine clinic at Thomas Jefferson Hospital in Philadelphia. RESULTS/CONCLUSIONS: Thyroid incidentalomas are very common, with a prevalence close to 50% on imaging studies. Thyroid-stimulating hormone (TSH) is the first test to obtain; if not suppressed, next step is fine-needle aspiration biopsy of any nodule above 1 cm and/or with suspicious ultrasound characteristics. Adrenal incidentalomas have a prevalence of almost 5%. All adrenal nodules above 4 cm should be resected. Regardless of the size, a workup for pheochromocytoma should always be done. Only hypertensive patients should be screened for primary hyperaldosteronism. Pituitary incidentalomas are also common, with a prevalence of 10-20%. All patients with pituitary masses should have a workup for hormonal hypersecretion. Only patients with macroadenomas will have additional screening for hypopituitarism and visual field defects. All hyperfunctioning adenomas are resected except prolactinomas which are treated medically. Similarly, if a macroadenoma is causing hypopituitarism or visual deficit, surgery should also be considered.

A comparison of glycaemic variability in CSII vs. MDI treated type 1 diabetic patients using CGMS.

OBJECTIVE: To evaluate and compare glucose variability, hypoglycaemic events and daily glycaemic control in well-controlled (HbA1c or= 180 mg/dl] and hypoglycaemic (BG

Knowledge, attitudes, and practices of argileh (water pipe or hubble-bubble) and cigarette smoking among pregnant women in Lebanon.

BACKGROUND: Currently, little is known about argileh (water pipe or hubble-bubble) and cigarette smoking among pregnant women in the Arab world, despite emerging evidence on the adverse health effects of argileh smoking and well-established knowledge about the health risks of cigarette smoking during pregnancy. OBJECTIVES: The present study assesses pregnant Arab women's knowledge of chemical contents and related harmful effects of argileh and cigarettes, their attitudes towards smoking argileh and cigarettes, and their actual smoking of argileh and cigarettes, both before and during pregnancy. METHODS: A stratified sample of 864 women from 23 health care centers in Lebanon completed a structured, interviewer-administered questionnaire. Information was collected on basic demographic variables, women's knowledge, attitudes, and cigarette and argileh smoking. RESULTS: Women were partially knowledgeable about the health risks of cigarette smoking, knew little about the harmful ingredients of argileh smoking, and had many misconceptions regarding how argileh worked or how it can produce harm. Attitudes were permissive towards all forms of smoking. Almost one quarter (23%) of participants reported smoking during pregnancy, with 17% smoking only cigarettes, 4% smoking only argileh, and 1.5% smoking both cigarette and argileh. CONCLUSION: A significant and growing percentage of pregnant Arab women are smoking in Lebanon, with four cigarette smokers for every argileh smoker. Smoking behaviors are empirically linked with important gaps in knowledge and with permissive attitudes. These data may be used to design more effective prevention programs targeting this vulnerable population.

Steroids and the surgical patient.

In patients undergoing surgery, a thorough history is important to obtain, including use of any steroid therapy within the previous year. If there is a history of steroid use, and if time permits, testing of the HPA axis should be performed. If adrenal unresponsiveness is documented or if clinical suspicion of [table: see text] adrenal insufficiency is high (without testing), a stress dose of steroids should be administered during the perioperative period to prevent an adrenal crisis.

Scintigraphic features of autoimmune thyroiditis.

The term autoimmune thyroiditis encompasses multiple inflammatory conditions of the thyroid gland, each with variable clinical manifestations. The more acute forms, silent (painless) thyroiditis and postpartum thyroiditis, are associated with transient hyperthyroidism and are sometimes mistaken for Graves disease. The chronic form, Hashimoto thyroiditis (chronic autoimmune thyroiditis), results in goiter and eventual hypothyroidism unless it is recognized and treated promptly. Thyroid uptake measurements and scintigraphic findings (usually obtained with technetium-99m or iodine-123) play a complementary role along with thyroid function testing in differentiating autoimmune thyroiditis from other thyroid diseases, thereby influencing treatment. In some cases, histologic evaluation of biopsy specimens is required to yield the definitive diagnosis. Knowledge of the entire spectrum of these disorders is essential for appropriate case management.

Uncontrolled diabetes mellitus.

The conditions of DKA and NKH are life-threatening complications of poorly controlled diabetes mellitus. They have characteristic clinical and laboratory features. If not treated appropriately, they can result in a high mortality rate of 15% to 28% in DKA and 17% to 50% in NKH.

Exercise performance-based outcomes of medically treated patients with coronary artery disease and profound ST segment depression.

OBJECTIVES: We sought to determine the relationship between exercise duration and cardiovascular outcomes in patients with profound (> or =2 mm) ST segment depression during exercise treadmill testing (ETT). BACKGROUND: Patients with stable symptoms but profound ST segment depression during ETT are often referred for a coronary intervention on the basis that presumed severe coronary artery disease (CAD) will lead to unfavorable cardiovascular outcomes, irrespective of symptomatic and functional status. We hypothesized that good exercise tolerance in such patients treated medically is associated with favorable long-term outcomes. METHODS: We prospectively followed 203 consecutive patients (181 men; mean age 73 years) with known stable CAD and > or =2 mm ST segment depression who are performing ETT according to the Bruce protocol for an average of 41 months. The primary end point was occurrence of myocardial infarction (MI) or death. RESULTS: Eight (20%) of 40 patients with an initial ETT exercise duration < or =6 min developed MI or died, as compared with five (6%) of 84 patients who exercised between 6 and 9 min and three (3.8%) of 79 patients who exercised > or =9 min (p = 0.01). Compared with patients who exercised < or =6 min, increased ETT duration was significantly associated with a reduced risk of MI/death (6 to 9 min: relative risk [RR] = 0.25, 95% confidence interval [CI] 0.08 to 0.76; >9 min: RR = 0.14, 95% CI 0.04 to 0.53). This protective effect persisted after adjustment for potentially confounding variables. We observed a 23% reduction in MI/death for each additional minute of exercise the patient was able to complete during the index ETT. CONCLUSIONS: Optimal medical management in stable patients with CAD with profound exercise-induced ST segment depression but good ETT duration is an appropriate alternative to coronary revascularization and is associated with low rates of MI and death.

Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction.

The administration of therapeutic doses of recombinant cytokines to patients with malignant disease can be complicated by systemic toxicities, which in their most severe form may present as a systemic inflammatory response. The combination of interleukin (IL)-18 and IL-12 has synergistic antitumor activity in vivo yet has been associated with significant toxicity. The effects of IL-18 plus IL-12 were examined in a murine model, and it was found that the daily, simultaneous administration of IL-18 and IL-12 resulted in systemic inflammation and 100% mortality within 4 to 8 days depending on the strain employed. Mice treated with IL-18 plus IL-12 exhibited unique pathologic findings as well as elevated serum levels of proinflammatory cytokines and acute-phase reactants. The actions of tumor necrosis factor-alpha did not contribute to the observed toxicity, nor did T or B cells. However, toxicity and death from treatment with IL-18 plus IL-12 could be completely abrogated by elimination of natural killer (NK) cells or macrophages. Subsequent studies in genetically altered mice revealed that NK-cell interferon-gamma mediated the fatal toxicity via the signal transducer and activator of transcription pathway of signal transduction. These data may provide insights into methods of ameliorating cytokine-induced shock in humans. (Blood. 2000;96:1465-1473)

Discrepancies in the use of medications: their extent and predictors in an outpatient practice.

BACKGROUND: Misuse of medications is a major cause of morbidity and mortality. Few studies have examined the frequency of, and factors associated with, discrepancies between what doctors prescribe and what patients take in actual practice. PATIENTS AND METHODS: Patients' medication bottles and their reported use of medications were compared with physicians' records of outpatients seen between November 1997 and February 1998 in a private practice affiliated with an academic medical center in Boston, Mass. Three hundred twelve patients from the practices of 5 cardiologists and 2 internists who were returning for their routine follow-up visits were included. MAIN OUTCOME MEASURE: The presence of discrepancies based on comparing medication bottles with medical records. RESULTS: Discrepancies were present in 239 patients (76%). The 545 discrepancies in these patients were the result of patients taking medications that were not recorded (n = 278 [51%]); patients not taking a recorded medication (n = 158 [29%]); and differences in dosage (n = 109 [20%]). Overall, discrepancies were randomly distributed among different drugs and discrepancy types with no discernible pattern. On multivariate analysis, patient age and number of recorded medications were the 2 most significant predictors of medication discrepancy. CONCLUSIONS: Discrepancies among recorded and reported medications were common and involved all classes of medications, including cardiac and prescription drugs. Older age and polypharmacy were the most significant correlates of discrepancy. The pervasiveness of discrepancies can have significant health care implications, and action is urgently needed to address their causes. Such action would likely have a positive impact on patient care.