The predictive and prognostic significance of liquid biopsy in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: A prospective study.

OBJECTIVE: To determine the predictive and prognostic roles of three blood-based biomarkers: circulating tumour DNA (ctDNA), circulating tumour cells (CTC) and carcinoembryonic antigen (CEA), in patients with advanced epidermal growth factor receptor-mutated (EGFR+) lung cancer. MATERIALS AND METHODS: We recruited 28 patients with 103 serial blood samples. We performed mutational analyses for EGFR mutations using droplet digital PCR (ddPCR) on ctDNA. We evaluated the accuracy of EGFR mutation detection in ctDNA compared with tissue biopsy. We also quantified CTCs, ctDNA and CEA in serially collected blood samples, and evaluated the baseline and changes in these blood-based biomarkers with clinical outcomes. RESULTS: EGFR mutation detection in plasma was highly concordant as compared with tissue biopsy. Detectable baseline ctDNA was associated with higher disease burden (p < 0.01). Early disappearance of ctDNA at 4 weeks was associated with radiological response at 12 weeks of treatment (p = 0.01) and improved progression free survival (PFS) (HR 5.47, 95%CI 1.32-22.72, p = 0.02) and overall survival (OS) (HR 5.46, 95%CI 1.28-23.22, p = 0.02). A decrease in CTC count at 4 weeks was associated with improved PFS (HR 3.81, 95%CI 1.13-12.79, p = 0.03) but not OS. 85% of patients with radiological progression had a ctDNA rise compared with 22% of patients with stable disease (p=0.01). ctDNA rise was seen on average 170 days prior to radiological progression. There is a significant association between the rise of CEA level with radiological progression (p=0.001). CONCLUSION: Early change in ctDNA, CTC and CEA levels may be long-term predictors of treatment benefit and failure prior to availability of radiological response data.

AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC.

Inflammasomes are protein complexes assembled upon recognition of infection or cell damage signals, and serve as platforms for clustering and activation of procaspase-1. Oligomerisation of initiating proteins such as AIM2 (absent in melanoma-2) and NLRP3 (NOD-like receptor family, pyrin domain-containing-3) recruits procaspase-1 via the inflammasome adapter molecule ASC (apoptosis-associated speck-like protein containing a CARD). Active caspase-1 is responsible for rapid lytic cell death termed pyroptosis. Here we show that AIM2 and NLRP3 inflammasomes activate caspase-8 and -1, leading to both apoptotic and pyroptotic cell death. The AIM2 inflammasome is activated by cytosolic DNA. The balance between pyroptosis and apoptosis depended upon the amount of DNA, with apoptosis seen at lower transfected DNA concentrations. Pyroptosis had a higher threshold for activation, and dominated at high DNA concentrations because it happens more rapidly. Gene knockdown showed caspase-8 to be the apical caspase in the AIM2- and NLRP3-dependent apoptotic pathways, with little or no requirement for caspase-9. Procaspase-8 localised to ASC inflammasome 'specks' in cells, and bound directly to the pyrin domain of ASC. Thus caspase-8 is an integral part of the inflammasome, and this extends the relevance of the inflammasome to cell types that do not express caspase-1.

Augmentation of the buttocks by micro fat grafting.

BACKGROUND: Requests for buttock augmentation are increasing in the United States because of changes in lifestyle and fashion that emphasize the "gluteal aesthetic unit." OBJECTIVES: We review the use of micro fat grafting for enhancing the buttocks in a series of 566 patients. METHODS: Tumescent solution (1 mg epinephrine per 1000 mL saline solution) was infiltrated; for small cases the volume used was less than half the amount of expected fat to be harvested. Harvesting was accomplished either manually with a syringe or with a liposuction pump that allowed precise control of the vacuum. The fat was injected both intramuscularly and subcutaneously into all levels of the desired area for augmentation of the buttocks. The typical augmentation averaged 300 to 400 mL per side but ranged from 175 mL to about 800 mL, depending on the patient's desires and the amount of donor fat available. RESULTS: Patient and physician satisfaction with the results was high. Approximately 50% to 75% of the fat grafted remains in the long term. Complications included cellulitis (1.9% of cases), which responded promptly to treatment with cephalosporin, and infrequent seromas and hematomas (0.8% of cases). CONCLUSIONS: Buttock augmentation by micro fat grafting is a safe, simple procedure. Compared with implant placement, the advantages of micro fat grafting include greater flexibility in the size and placement of augmentations, less pain and faster recovery for the patient, and less risk of complications. The technique is limited only by the amount of donor fat available. (Aesthetic Surg J 2001;21:311-319.).

The RSVP facelift: a highly vascular flap permitting safe, simultaneous, comprehensive facial rejuvenation in one operative setting.

This study describes our effort to develop a reliably safe method for combining currently available treatment modalities in an effort to obtain comprehensive facial rejuvenation in one operative setting. Detailed evaluation of 101 available consecutive patients, their per- and postoperative photos and charts was undertaken. Five groups of patients were studied: (1) traditional facelift with wide subcutaneous undermining and SMAS plication. (2) Similar traditional facelift with regional laser resurfacing. (3) RSVP (rejuvenation with sparing of vascular perforators) facelift. Subcutaneous undermining stops 3 cm lateral to the nasolabial fold to preserve the rich angular/facial arterial supply and venous drainage, still permitting lateral SMASectomy or SMAS plication. Subcutaneous neck undermining is discontinuous, the posterior dissection being limited to that which is necessary for identification of the posterior edge of the platysma and its plication to the mastoid and SCM muscle. The anterior dissection is limited to that necessary for anterior platysmal repair leaving intact a vertical subcutaneous non-undermined zone 4-6 cm in width, preserving the submental perforating artery. If indicated, gentle liposuction with a fine cannula is performed through this area. (4) RSVP facelift and regional laser resurfacing. (5) RSVP facelift with total facial laser resurfacing. Mean follow-up was 13.6 months, minimum 6 months. There were no additional major complications associated with the addition of laser resurfacing or fat grafting to the RSVP group. The patients with laser resurfacing were pleased with their result, and estimated that their apparent age had been reduced by a mean of 10.4 years, compared with 6.6 years for the non-lased group. We conclude that the RSVP flap is a hardy, vascular flap permitting simultaneous laser resurfacing, fat grafting, and other adjunctive procedures without significant fear of flap loss.

A national Survey of Acute Myocardial Infarction and Ischaemia (SAMII) in the U.K.: characteristics, management and in-hospital outcome in women compared to men in patients under 70 years.

AIMS: To assess the clinical characteristics, management and outcome of women compared to men with acute myocardial infarction or ischaemia. DESIGN: A prospective clinical survey was made in a random sample of 94 District General Hospitals in the U.K. 1064 patients, <70 years of age, comprising six consecutive females and six consecutive males from each hospital, diagnosed on admission as acute coronary syndromes (myocardial infarction or myocardial ischaemia) were studied. Outcome measures included: admission and final diagnosis, time to delivery of care, inpatient management, complications and clinical outcome. RESULTS: Five hundred and three women and 561 men were admitted with a diagnosis of acute myocardial infarction or myocardial ischaemia. Women were older, waited longer between seeking and receiving advice, and much less likely to have infarction than men. After adjustment for age, diagnosis and past medical history there were no gender differences in initial and subsequent hospital management, in complications (recurrent ischaemia, arrhythmias, temporary pacing, heart failure), any routine procedure or outcome. Of all patients, 3.4% died in a District General Hospital, 12.2% were transferred to Specialist Cardiac Centres and 84.4% discharged home. Prophylactic medication on discharge was similar for men and women. CONCLUSION: After adjustment for age, diagnosis and past medical history, although women waited longer between seeking and receiving medical advice, in hospital their assessment, management, complications, outcome and follow-up arrangements were the same as for men. In hospital, management and outcomes were mainly influenced by age, diagnosis (infarction or ischaemia), a past history of coronary disease, but not by gender. This large, nationally representative, survey has found no evidence of important gender difference in the hospital management of acute ischaemic syndromes.

Variable-pulse width ER:YAG laser resurfacing.

New resurfacing laser systems have been introduced that offer the ablative capacity of Er:YAG lasers with the ability to add controlled degrees of thermal effect to provide collagen tightening and hemostasis. This article discusses the current systems available and offers comparisons to short-pulse Er:YAG and carbon dioxide lasers. A histologic study and initial clinical results are presented and discussed.

In pursuit of optimal rejuvenation of the forehead: endoscopic brow lift with simultaneous carbon dioxide laser resurfacing.

Coronal foreheadplasty has long been the traditional method of improving the aesthetic appearance of the forehead, permitting not only repositioning of ptotic tissues but also direct access for modification of the "frown" muscles. However, it was only moderately successful in eliminating vertical corrugator lines or deeply etched transverse wrinkles. The recent advent of the endoscopic brow lift has permitted us to minimize the dysesthesias associated with the coronal approach by making the incisions shorter and radially oriented and by being more precise in the muscle resection. Nonetheless, endoscopic brow lift gives no further improvement in persistent deep vertical and transverse wrinkles. Carbon dioxide laser resurfacing can improve the existing wrinkles but does not eliminate the muscular cause of forehead wrinkles. It seemed reasonable that combining these techniques might yield better results than either procedure alone. To evaluate this possibility, 30 patients with simultaneous endoscopic brow lift and carbon dioxide resurfacing were compared with 24 patients having laser resurfacing only and with 26 patients who had traditional coronal foreheadplasty. Both foreheadplasty groups had corrugator resection. All patients were evaluated at least 4 to 6 months postoperatively. Ratings were based on the percent of wrinkles removed, both vertical and transverse. The ratings were performed with predetermined criteria by a surgeon not involved with the operative procedures nor after care. A rating of "excellent" (> or = 95 percent reduction in wrinkles) was obtained in 50 percent of coronal foreheadplasties; 41.7 percent of carbon dioxide resurfacing alone and 80 percent of endobrow lifts with carbon dioxide laser resurfacing. There was no vascular compromise from this latter combination of procedures, no hypertrophic scars, and no impairment of healing. We conclude that endoscopic brow lift with carbon dioxide laser resurfacing is a safe and perhaps more effective means of aesthetic rejuvenation of the forehead.

The emerging role of laser resurfacing in combination with traditional aesthetic facial plastic surgery.

Traditional aesthetic plastic surgery procedures (facelift, browlift, blepharoplasty, etc.) can make dramatic improvement in the facial appearance by removing excess skin and fat and tightening and repositioning the soft tissues of the face, but make no improvement in the quality of the skin. Laser resurfacing is the safest, most predictable method for improving facial wrinkles and actinic damage. This paper discusses the combination of these techniques in pursuit of optimal rejuvenation of the face.

Laser blepharoplasty and laser resurfacing of the periorbital area.

Although blepharoplasty has long been the traditional method of improving the aesthetic appearance of the eyelid area, it yields little improvement in several of the major signs of periorbital aging including (1) wrinkling of the infrabrow and lower lid skin, (2) crow's foot wrinkles, (3) malar bags and wrinkles, (4) crepey changes in the periorbital skin texture, (5) pigment spots and other actinic damage, (6) elongation of the apparent vertical height of the lower lid, and (7) loss of the gentle, indistinct transition between the lower lid and cheek skin. All of these indications can be improved by the combination of laser blepharoplasty and laser resurfacing of the periorbital region. In addition to resurfacing, the author prefers to use the laser for the incisional aspects of the blepharoplasty, as it is quick, causes less sensory nerve stimulation, is less likely to damage the inferior oblique muscle, and has essentially no bleeding--and therefore, less ecchymosis--postoperatively. This technique is described and illustrated photographically. Its outcomes include a high-quality result that maintains itself well over time, improvement in the signs of periorbital aging not treated by traditional blepharoplasty, a low rate of complication, and high patient satisfaction.

In pursuit of optimal periorbital rejuvenation: laser resurfacing with or without blepharoplasty and brow lift.

LEARNING OBJECTIVES: The reader is presumed to have a broad understanding of plastic surgical procedures and concepts. After studying this article, the participant should be able to: Physicians may earn 1 hour of Category 1 CME credit by successfully completing the examination based on material covered in this article. The examination begins on page 333. Although blepharoplasty and coronal foreheadplasty have been the traditional methods for improving the periorbital region, in our opinion these techniques together can address only three of the 11 major signs of periorbital aging. We found no improvement with skin-muscle flap type blepharoplasty and coronal lift in the wrinkling and pigmentation changes in the infrabrow, crow's-foot, lower lid, and malar regions, and no improvement in malar bags, "dark circles" under the eyes, or the apparent lengthening of the vertical height of the lower lid and its associated sharp transition between cheek and lid skin. CO(2) laser resurfacing can improve these signs of periorbital aging and permits the laser transconjunctival approach if blepharoplasty is necessary, thus eliminating a visible lower lid incision. When brow ptosis is present, we prefer endoscopic brow lift to minimize dysesthesia and incision size. We evaluated 174 patients and contrasted the results of the traditional approach versus laser resurfacing with or without laser blepharoplasty and endoscopic brow lift. The mean time to evaluation was 9 months, ranging up to 2 (1/2) years. We found that the laser approach can address almost all of the 11 major signs of periorbital aging at one procedure. It is minimally invasive, technically simple and fast, offers lasting improvements, and yields high patient satisfaction and better results with fewer persistent problems than the traditional surgical approach.

Aesthetic skin resurfacing with the high-energy ultrapulsed CO2 laser.

CO2 laser resurfacing, using the new generation high-energy output pulsed lasers, provides a highly accurate method of resurfacing and rejuvenating facial skin. Its applications are widespread and well accepted by the general population (Color Figs. 3 to 8). Complications may occur, which may be minimized through adequate laser training and appreciation of the mechanisms of skin healing.

Women married to men with myocardial infarction are at increased risk of coronary heart disease.

AIM: To measure the prevalence of coronary heart disease (CHD) risk factors in the female partners of men with acute myocardial infarction (AMI). METHOD: Consecutive incident cases of men under 65 years of age with AMI surviving to 3 months, their female partners and female healthy controls matched for age and marital status drawn from the general population were investigated. RESULTS: One-hundred and seventeen cases of AMI in men under 65 years of age and 89 female partners were identified; 133 age- and sex-matched controls were examined for CHD risk factors. Cigarette smoking was more common among the younger partners (25-44 years of age) compared with controls. A body mass index > 28 kg/m2, systolic blood pressure > 150 mmHg, diastolic blood pressure > 90 mmHg and cholesterol > 6.5 mmol/l were all significantly more common in partners compared with controls. In a logistic regression of age, smoking habit, blood pressure, cholesterol and body mass index, based on 89 female partners and 132 controls with complete data, body mass index > 28 kg/m2 (odds ratio 2, 17, 95% CI 1.11-4.23) and cholesterol > 6.5 mmol/l (odds ratio 2.21, 95% CI 1.08-4.49) were both significantly more common in the female partners compared with controls. CONCLUSIONS: Women married to men with AMI have a higher frequency of CHD risk factors compared with married women in the general population, consistent with a shared family lifestyle putting both adults at higher risk of CHD. Screening blood relatives in families prematurely affected by CHD is widely advocated; such screening should include partners.

Aesthetic CO(2) laser surgery: evaluation of 907 patients.

Resurfacing the skin to improve skin quality is an important concept in aesthetic plasticsurgery. Although time-honored methods (e.g., dermabrasion and chemical peel) are available for this purpose, they have several disadvantages. A newer method with a highenergy pulsed carbon dioxide laser provides a more controllable and more predictable method of resurfacing facial skin. In our study of 907 patients, monitored up to 2 years 868 laser resurfacing procedures were done for facial wrinkles. Eight hundred two of 868 (92.4%) achieved very good to excellent results (>75% removal of wrinkles in 92.4% of cases). Forty-six of 61 (75.4%) patients with acne scars also obtained very good to excellent results. Most patients with selected skin lesions (rhinophyma, actinic cheilitis, epidermal nevi, seborrheic keratoses, syringomas, xanthelasmas, and postsurgical scars) achieved good to excellent results, although these are admittedly more difficult to quantify. Major complications were uncommon. One hundred one of 907 (11.1%) patients had development of temporary hyperpigmentation, which resolved in an average of 2.6 weeks. Thirty-four of 907 (3.8%) patients had development of mild permanent hypopigmentation. Eight of 908 (0.9%) patients had development of some induration that resolved with use of intralesional steroids. Most of these (5 of 8) were in the perioral area. Three of 907 (0.3%) patients had development of a small persistent scar. Seven of 316 (2%) patients undergoing periorbital resurfacing had development of some mild scleral show. Early in our experience one patient developed ectropion that required surgical correction. We conclude that the new generation high-energy pulsed carbon dioxide laser is safe andeffective for resurfacing facial skin. However, this procedure is very technique dependent and requires a combination of didactic and hands-on training, conservative surgical judgment, and diligent patient follow-up to obtain optimal results with minimal complications.

Maintenance of adequate hemodialysis access. Prevention of neointimal hyperplasia.

The maintenance of adequate hemodialysis vascular access is frequently complicated in the patient with polytetrafluoroethylene (PTFE) A-V hemodialysis grafts by venous anastomotic stenosis. This stenosis is caused by neointimal hyperplasia (NIH), a response to vascular injury. In this study, the authors prospectively analyzed the effect of a short-term regimen consisting of administration of two medications, heparin and low molecular weight dextran, on the development of NIH at the venous anastomosis in 79 patients with PTFE A-V hemodialysis grafts. In addition, they evaluated other parameters' effects on the development of NIH. In comparison with control subjects, heparin had some effect in minimizing the development of NIH in the PTFE grafts when evaluated radiologically at 3 months, although this effect was not statistically significant. Low molecular weight dextran, however, had no trend or statistically significant effect on this venous anastomotic narrowing. Interestingly, patient age, use of calcium channel blockers, and presence of diabetes mellitus (DM) all appeared to affect the development of NIH. Increasing age and use of calcium channel blockers was associated with decreased development of NIH; conversely, DM was associated with worsened NIH. In evaluation of access survival (time to first access failure), degree of venous anastomosis stenosis at 3 months was not predictive. Patient time on dialysis pre graft placement was the only measured parameter related to access failure. The method of dialysis pre graft placement (hemodialysis versus peritoneal dialysis) was not a significant factor in early access failure. Pharmacologic treatment of venous anastomotic narrowing in PTFE hemodialysis grafts due to NIH continues to be difficult. Short-term treatment with the tested medication failed to statistically affect NIH. Patient age, use of calcium channel blockers, and presence of DM were all factors in the development of NIH. Of measured parameters, time on dialysis pre graft placement was the only factor correlated with early access failure. In future treatment regimens, one should consider more prolonged treatment. In addition, noted risk factors should be considered when determining type of renal replacement therapy.

trans isomers of oleic and linoleic acids in adipose tissue and sudden cardiac death.

trans isomers of unsaturated fatty acids are formed by biological or industrial hydrogenation. A population case-control study of sudden cardiac death in mean was done to test the hypothesis that trans isomers of oleic acid and linoleic acid increase the risk of sudden cardiac death due to coronary artery disease. In adipose tissue obtained at necropsy from 66 cases of sudden cardiac death and taken from 286 healthy age and sex matched controls, the proportions of trans isomers of oleic and linoleic acid were measured by gas-liquid chromatography. In cases, the mean (SE) percentage of total trans fatty acids (C18:1 plus C18:2), expressed as a proportion of all fatty acids, was significantly lower (2.68 [0.08]%) than in healthy controls (2.86 [0.04]%; p < 0.05). trans C18:1 was 2.1 (0.7)% in cases compared with 2.27 (0.04)% (p < 0.05) in controls. The proportion of all trans isomers of linoleic acid was 0.58 (0.02)% in cases compared with 0.59 (0.01)% in controls (p = 0.98). The estimated relative risk for sudden cardiac death of trans C18:1 and C18:2 fatty acids combined did not differ significantly from 1.0 in relation to the distribution of these trans isomers by quintile in the control population. The relative risk (95% CI) of sudden cardiac death in the top quintile was 0.40 (0.15-1.02) for C18:1 and 1.08 (0.48-2.74) for C18:2 compared with the bottom quintiles of their respective control distributions. When these univariate relations for trans fatty acids were adjusted for coronary risk factors, smoking was the only factor that remained independently associated with risk of sudden cardiac death (2.27 [1.23-4.17]). Overall, there was no evidence of a relation between trans isomers of oleic and linoleic acids combined and sudden cardiac death. However, trans oleic acid was negatively associated with risk of sudden cardiac death, whereas no association with trans forms of linoleic acid was seen. This study does not support the hypothesis that trans isomers increase the risk of sudden cardiac death.

Linoleic acid and risk of sudden cardiac death.

OBJECTIVE: To test the hypothesis that the essential fatty acid, linoleic acid, measured in adipose tissue as an indicator of long term dietary intake, is inversely related to the risk of sudden cardiac death. DESIGN: A population case-control study. SETTING: A regional health district. SUBJECTS: 84 men (age 25-64 years) who died instantaneously or within 24 hours of the onset of symptoms with no history of coronary heart disease or medically treated hyperlipidaemia, and in whom coronary artery disease was diagnosed at postmortem examination as the primary cause of death, were compared with 292 age (to within two years) and sex matched healthy controls and their partners drawn from the general practitioners' records with whom the cases were registered. MAIN OUTCOME MEASURES: Fatty acid composition of adipose tissue and the risk of sudden cardiac death. RESULTS: Linoleic acid in adipose tissue was inversely related to the risk of sudden cardiac death. The estimated relative risk (95% CI) of sudden cardiac death was 5.7 (1.8 to 17.9) for the lowest quintile and 4.0 (1.2 to 12.9) for the next quintile of adipose linoleic acid in the control population when compared with the highest quintile. This inverse relation was independent of age, reported smoking habits, history of hypertension, and diabetes, although there was a close association with cigarette smoking. The estimated adjusted proportionate increase in risk (95% CI) of sudden cardiac death was 1.14 (1.03 to 1.23) for every 1% reduction of linoleic acid in adipose tissue. CONCLUSIONS: The percentage content of linoleic acid in adipose tissue was inversely related to the risk of sudden cardiac death. Populations with a high risk of sudden cardiac death may benefit from increasing their dietary intake of polyunsaturated fatty acid oils, principally from cereals and vegetables.

Lack of adverse effect of silicone implant on sarcoidosis of the breast.

Involvement of the breast by sarcoidosis is extremely rare, with only 11 case reports in the literature. The potential adverse interaction between silicone prostheses and this disease process poses an unusual clinical dilemma. However, two patients with sarcoidosis of the breast had silicone breast implants placed without exacerbation of their disease nor unusual periprosthetic complications. We conclude that sarcoidosis of the breast does not appear to be a contraindication to placement of silicone implants.

Antibiotic penetration into normal and inflamed tissues as reflected by peripheral lymph.

The concentration of antibiotic in peripheral lymph reflects the tissue levels. Following microsurgical cannulation of the right lymphatic duct in 28 healthy rabbits, either penicillin-G, nafcillin, erythromycin, or cefazolin was given intramuscularly, and lymph and serum samples obtained at frequent intervals. Penicillin or nafcillin was administered to 14 additional rabbits with cellulitis of the right upper extremity. A serum sample drawn between one and two hours after an intramuscular injection, in general, reflects the peak lymph antibiotic concentration and hence the peak tissue concentration of the drug. After two hours the lymph level remains equal to or greater than the simultaneous serum level. The presence of inflammation did not alter the peak antibiotic levels. However, nafcillin required longer for equilibration in the inflamed state than in the uninflamed state, whereas penicillin-G equilibrated more rapidly in the presence of inflammation.