Machine learning to predict early recurrence after oesophageal cancer surgery.

BACKGROUND: Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20-30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches. METHODS: Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model. RESULTS: A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal-external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent). CONCLUSION: The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.

ANTECEDENTES: la recidiva precoz del cáncer tras esofaguectomía es un problema frecuente con una incidencia del 20-30% a pesar del uso generalizado del tratamiento neoadyuvante. La cuantificación de este riesgo es difícil y los modelos actuales funcionan mal. Este estudio se propuso desarrollar un modelo predictivo para la recidiva precoz después de la cirugía para el adenocarcinoma de esófago utilizando una gran cohorte multinacional y enfoques con aprendizaje automático. MÉTODOS: Se analizaron pacientes consecutivos sometidos a esofaguectomía por adenocarcinoma y que recibieron tratamiento neoadyuvante en 6 unidades de cirugía esofagogástrica del Reino Unido y 1 de los Países Bajos. Con la utilización de características clínicas y la histopatología postoperatoria se generaron modelos mediante regresión de red elástica (elastic net regression, ELR) y métodos de aprendizaje automático Random Forest (RF) y XG boost (XGB). Finalmente, se generó un modelo combinado (Ensemble) de dichos métodos. La importancia relativa de los factores respecto al resultado se calculó como porcentaje de contribución al modelo. RESULTADOS: En total se incluyeron 812 pacientes. La tasa de recidiva a menos de 1 año fue del 29,1%. Todos los modelos demostraron una buena discriminación. Las áreas bajo la curva ROC (AUC) validadas internamente fueron similares, con el modelo Ensemble funcionando mejor (ELR = 0,791, RF = 0,801, XGB = 0,804, Ensemble = 0,805). El rendimiento fue similar cuando se utilizaba validación interna-externa (validación entre centros, Ensemble AUC = 0,804). En el modelo final, las variables más importantes fueron el número de ganglios linfáticos positivos (25,7%) y la invasión linfovascular (16,9%). CONCLUSIÓN: El modelo derivado con la utilización de aproximaciones con aprendizaje automático y un conjunto de datos internacional proporcionó un rendimiento excelente para cuantificar el riesgo de recidiva precoz tras la cirugía y será útil para clínicos y pacientes a la hora de establecer un pronóstico.

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma.

BACKGROUND: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. METHODS: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging. RESULTS: TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1-2; median overall survival (OS) not reached) and non-responders (TRG 3-5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001). CONCLUSION: A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1-2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders.

Effect of nitrogen flushing and storage temperature on flavor and shelf-life of whole milk powder.

The US industry standard for shelf-life of whole milk powder (WMP) is 6 to 9 mo, although previous research has demonstrated flavor changes by 3 mo at ambient storage. This study evaluated the influence of packaging atmosphere, storage temperature, and storage time on WMP shelf-life using sensory and instrumental techniques. Two commercial batches of WMP were repackaged in plastic laminate pouches with air or nitrogen and stored at 2 degrees C or 23 degrees C for 1 yr. Descriptive analysis was conducted using a 10-member trained panel; volatile analysis was performed using solid-phase microextraction with gas chromatography-mass spectrometry. Consumer acceptance (n = 75) was conducted every 3 mo with reconstituted WMP and white and milk chocolate made from each treatment. Data were analyzed using ANOVA with Fisher's LSD, Pearson correlation analysis, and principal component analysis. Air-stored WMP had higher peroxide values, lipid oxidation volatiles, and grassy and painty flavors than nitrogen-flushed WMP. Storage temperature did not affect levels of straight chain lipid oxidation volatiles; 23 degrees C storage resulted in higher cooked and milkfat flavors and lower levels of grassy flavor compared with 2 degrees C storage. Consumer acceptance was negatively correlated with lipid oxidation volatiles and painty flavor. Nitrogen flushing prevented the development of painty flavor in WMP stored up to 1 yr at either temperature, resulting in chocolate with high consumer acceptance. Nitrogen flushing can be applied to extend the shelf life of WMP for use in chocolate; storage temperature also plays a role, but to a lesser extent.

The synergistic effects of cyclosporine and endothelin--demonstration of an important cardiodepressor action.

Cyclosporine represents the foundation for current immunosuppressive therapy following solid organ transplantation. CsA use is associated with renal insufficiency and systemic hypertension. We hypothesized that CsA would enhance the vascular actions of endothelin (ET). Three groups of anesthesized dogs (n = 15) were studied. Group 1 received CsA alone (1 mg/kg), group 2 received ET alone (1 ng/kg/min), and group 3 received combined CsA (1 mg/kg) and ET (1 ng/kg/min). The hemodynamic and renal effects were evaluated after 30 min. Combined treatment resulted in a profound reduction in mean arterial pressure (-62 +/- 14 mmHg (P < .05) and cardiac output (-2.2 +/- 0.4.1/min (P < .05). The reduction in mean arterial pressure and cardiac output were significantly greater than that observed with CsA or ET alone. Systemic vascular resistance was not significantly changed. Combined CsA and ET resulted in a significant reduction in renal blood flow (195 +/- 18 to 101 +/- 11 ml/mm P < .05) but without evidence of active renal vasoconstriction. The decline in GFR (31.8 +/- 5.6 ml/min to being unmeasurable) was of greater magnitude than the change in renal blood flow, suggesting enhanced afferent anteriolar vasoconstriction or an alteration in the ultrafiltration coefficient. These studies demonstrate an important and synergistic cardiodepressor effect when CsA and ET are combined.

Snare removal of a telectronics accufix atrial J retention wire.

A voluntary recall of the Telectronics Accufix models 330-801 and 329-701 "J"-shaped atrial pacemaker leads has been issued because of fracture and extrusion of the J-shaped retention wire. Such extrusion can result in laceration of the atrium or surrounding vascular structures. Herein we describe a patient with a fractured and extruded retention wire that was snared and removed percutaneously; the atrial lead was left intact, and pacing function was satisfactory. This unique procedure can be used to avoid the morbidity associated with percutaneous lead extraction or thoracotomy and to prevent potential dislodgment and embolization of the retention wire during lead extraction.

Dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy: a clinical perspective in 2000.

In some patients with hypertrophic cardiomyopathy, the dynamic left ventricular outflow tract obstructive gradient results in exercise-limiting symptoms of dyspnea, angina, and syncope. Dual chamber pacing has been proposed as a widely available alternative treatment for a subset of patients with symptomatic hypertrophic obstructive cardiomyopathy. Initial studies showed a reduction in gradient and an improvement in symptoms in almost 90% of patients with severe symptoms. We report the Mayo Clinic experience with dual chamber pacing in 38 patients with hypertrophic obstructive cardiomyopathy who had permanent pacemakers implanted for limiting symptoms intractable to medical therapy. After a mean +/- SD follow-up of 24 +/- 14 months, subjective improvement was reported in 47% of patients. However, there was no statistical difference between the maximal oxygen consumption at last follow-up and AAI pacing (atrial sensing and atrial pacing) (18.6 +/- 1.1 mL.kg-1.min-1) (i.e., when the pacemaker was implanted but not pacing continuously). This article discusses the clinical perspective on the utility of dual chamber pacing for patients with hypertrophic obstructive cardiomyopathy.

Extraction of the Telectronics Accufix 330-801 atrial lead: the Mayo Clinic experience.

OBJECTIVE: To document a cumulative experience with removal of the Telectronics 330-801 Accufix atrial lead after it was withdrawn from the market. DESIGN: We reviewed our results with 96 attempted lead extraction procedures through Dec. 1, 1995. MATERIAL AND METHODS: All patients underwent preoperative assessment, including fluoroscopic screening of the lead. Patients had blood typing and screening done before the extraction procedure, and extractions were performed with cardiac surgical intervention available. Pacing dependence was assessed to determine the need for temporary pacing. RESULTS: The mean patient age was 65.7 +/- 1.6 years and the mean duration of lead implantation was 31.0 +/- 1.4 months. Of the 96 lead extractions attempted, 94 were successful. Of the 96 cases, the retention wires were normal in 29, fractured without protrusion in 34, and fractured with protrusion in 33. Fifty-three leads were removed with use of simple traction only, and seven leads were removed by using a locking stylet and telescoping sheaths. The Cook workstation was used in the removal of 32 leads through the femoral vein; in 1 of these 32 patients, the retention wire was removed before lead extraction. The retention wire was removed but the lead was left intact in one patient. One lead was removed during an opertive maze procedure. Associated complications were minimal. CONCLUSION: Although lead extraction is a potentially fatal procedure, the Telectronics 330-801 Accufix atrial lead can be extracted safely with minimal morbidity when performed by experienced personnel.

Left ventricular and biventricular pacing in congestive heart failure.

Dual-chamber pacing improved hemodynamics acutely in a subset of patients with left ventricular (LV) dysfunction but conveyed no long-term symptomatic benefit in most. More recently, LV pacing and biventricular (multisite) pacing have been used to improve systolic contractility by altering the electrical and mechanical ventricular activation sequence in patients with severe congestive heart failure (CHF) and intraventricular conduction delay or left bundle branch block (LBBB). Intraventricular conduction delay and LBBB cause dyssynchronous right ventricular and LV contraction and worsen LV dysfunction in cardiomyopathies. Both LV and biventricular cardiac pacing are thought to improve cardiac function in this situation by effecting a more coordinated and efficient ventricular contraction. Short-term hemodynamic studies have shown improvement in LV systolic function, which seems more pronounced with monoventricular LV pacing than with biventricular pacing. Recent clinical studies in limited numbers of patients suggest long-term clinical benefit of biventricular pacing in patients with severe CHF symptoms. Continuing and future studies will demonstrate whether and in which patients LV and biventricular pacing are permanently effective and equivalent and which pacing site within the LV produces the most beneficial hemodynamic results.

Ring chromosome 2 in a child with growth failure and few congenital abnormalities.

A ring chromosome 2 mosaic [46,XX/46,XX,r(2)(p25q37)] was found in a newborn female with severe intrauterine growth retardation (IUGR), postnatal growth failure, and a few minor abnormalities. Psychomotor development has been normal to 19 months old. A ring chromosome 2 is present in 77.8% of the nuclei examined and is not found in the parents or a sibling. G- and R-banding reveal the break points to be p25q37. The presence of a normal cell line indicates that the chromosome abnormality arose after conception.

Effects of morphine and chlorpromazine on the detection of shock.

A discrete-trial, two-choice, 'yes-no' procedure was used to determine the extent to which the perceptual effects of compounds such as morphine and chlorpromazine (CPZ) can be attributed to drug-induced changes in ability to detect shock stimuli (sensitivity). Both morphine (4.0, 5.0, and 6.0 mg/kg) and CPZ (0.25, 0.50, and 1.0 mg/kg) significantly reduced accuracy and increased the times (i.e., lowered the speeds) to initiate trials and to make choice responses. The effects of morphine appeared to be somewhat greater than those of CPZ, particularly at the lowest shock intensity (0.05 mA). When compared to appropriate saline control days, morphine, but not CPZ, significantly reduced accuracy of discrimination on trials when shocks were presented, whereas CPZ, but not morphine, reduced accuracy on no-shock trials. The effects of morphine, but not of CPZ, on accuracy (both overall and on shock trials) decreased as shock intensity increased. The effects of shock intensity were generally inversely related to the effects of morphine and directly related to the effects of CPZ.

Trabeculectomy for traumatic hyphema with increased intraocular pressure.

We reviewed the medical records of 11 consecutive patients who underwent trabeculectomy with anterior chamber washout and peripheral iridectomy as the primary surgical treatment for traumatic hyphema that was unresponsive to medical management. The mean intraocular pressure before surgery was 48 mm Hg. In ten of the patients the intraocular pressure was lowered to 21 mm Hg or lower after surgery and remained below that level up to the most recent follow-up visit, which ranged from eight to 97 months. One patient required a topical beta-blocker and oral acetazolamide to lower pressure to this level after surgery. Eight patients had visual acuity of 20/60 or better at last follow-up. Corneal blood staining occurred in eight patients. Compared with other techniques for surgical management of traumatic hyphema, trabeculectomy provides a means to keep intraocular pressure lowered while the remaining blood is clearing from the anterior chamber. Trabeculectomy with anterior chamber washout and peripheral iridectomy appears to be a safe and reliable procedure in the management of traumatic hyphemas in which medical management fails to control intraocular pressure.

Is there an adverse outcome from abandoned pacing leads?

BACKGROUND: Indications for extraction of an abandoned pacemaker lead (APL) are controversial. The purpose of this study was to determine whether or not APLs should be extracted in the absence of pacemaker-related problems. METHODS AND RESULTS: We retrospectively reviewed, from 1977 through 1998, all patients with retained, non-functional leads and identified 433-266 males and 167 females. Mean age at initial pacemaker implantation was 68[emsp4 ]years. These patients received a total of 259 atrial and 948 ventricular leads. Of the total of 1,207 leads, 611 became non-functional. A total of 531 non-functional leads were abandoned, of which 18 were later extracted: one APL in 345 patients, two in 78, and three in 10. Indications for new lead placement when non-functional leads were abandoned included capture and/or sensing failure (243), lead recall (177), lead fracture (86), pacing system replacement to the contralateral side (11), accommodating patient growth (5), pacemaker function upgrade (5), replacement with implantable cardioverter defibrillator (ICD, 2), interference with ICD (1), and unknown (1). Complications that were associated with pacemakers were found in 24 patients (5.5%)-pacemaker system infection (8 patients) and venous occlusion at the time of a subsequent procedure of new lead placement when APLs had already been in place (16) which resulted in APL extraction (7) or transfer of the pacemaker system to the contralateral side (9). Neither venous thrombosis nor other complications were found in the remaining 409 patients (94.5%). The incidence of complications was higher in patients with three APLs than in patients with two or fewer APLs (40% vs. 4.7%, P=1x10(-6)), in patients with four or more total lead implantations than in patients with three or fewer total lead implantations (26.2% vs. 0. 6%, P<1x10(-10)), and in patients with three or more procedures of new lead placements than in patients with two or fewer procedures of new lead placements (36.4% vs. 3.9%, P=1x10(-10)). Patients with complications were younger than those without complications both at the time of initial pacemaker implantation (59+/-16 vs. 68+/-17 y, P=0.01) and when non-functional leads were abandoned (63+/-15 vs. 71+/-16 y, P=0.04). Mean numbers of APLs, total leads implanted, and procedures of new lead placement were significantly larger in patients with complications than in those without complications (1.58+/-0.78 vs. 1.2+/-0.44, 4.96+/-1.23 vs. 2.66+/-0.8, and 2.13+/-0.85 vs. 1.25+/-0.53, P=0.03, 4x10(-9) and 4x10(-5), respectively). CONCLUSIONS: 1. With only 5.5% of patients having had pacemaker-related complications, the adverse outcome of APL is small. 2. Clinical clues to the possible occasion for pacemaker-related complications include three or more APLs, four or more total leads, three or more procedures of new lead placement, and a younger age at initial pacemaker implantation. 3. Patients with a large number of APLs, total lead implantations, and procedures of new lead placement should be carefully observed to detect possible pacemaker-associated complications.

Long-term histologic studies of the Baerveldt implant in a rabbit model.

PURPOSE: The Baerveldt glaucoma implant is an aqueous shunting device with large surface area that is installed through a single-quadrant conjunctival incision. A rabbit model of the Baerveldt implant was created to obtain serial histology and clinical information over 1 year. METHODS: Modified versions of the Baerveldt implant (110 or 160 mm2) were implanted in 18 normal New Zealand white rabbit eyes. The rabbits were examined periodically and their intraocular pressures (IOPs) recorded. They were killed at monthly intervals to obtain histology of the bleb capsules. RESULTS: Thin capsules were present at 1 month, which consisted of lamellar collagen deposition surrounded by a granulomatous reaction with multinucleate giant cells. Inflammatory cells (probably macrophages) were scattered on the inner bleb surface. The granulomatous reaction resolved after 4 months. Subsequently, capsule thickness and cellularity remained relatively stable, although the collagen stroma became less compact over time. Sixteen rabbit eyes had initial IOP reductions of > or = 3 mm Hg compared with fellow eyes, which persisted up to 4 weeks postoperatively. Seven eyes (39%) exhibited a hypertensive phase (IOP exceeded that of fellow eye by > or = 3 mm Hg) from 2 weeks to 3 months postoperatively. CONCLUSION: The Baerveldt explant is surrounded by a fibrous capsule that matures over time. The bleb histology in the rabbit model is similar to that described with the Molteno implant in primates and humans, except for the eventual development of a fibroblastic inner lining in the rabbit model. This contrasts with primate and human models, in which the inner lining remains an open mesh.

Suprachoroidal hemorrhage after Molteno implantation.

PURPOSE: The objective of this study is to identify the rate and the associated risk factors for suprachoroidal hemorrhage (SCH) after Molteno drain implantation. METHODS: Data from the Molteno pilot study and single versus double-plate Molteno study were reviewed retrospectively for the occurrence of SCH. Follow-up intervals, demographic variables, ocular data, and medical history were collected. RESULTS: SCH occurred in 6% of the patients enrolled in the Molteno studies; all cases were delayed and none were intraoperative. Significantly associated factors in a multiple logistic regression for SCH were the extent of intraocular pressure (IOP) drop after surgery, the post-operative IOP, a diagnosis of angleclosure glaucoma, and possibly the number of prior surgeries as well. Eyes with SCH did significantly less well in terms of visual acuity outcomes and were more likely to have inadequately controlled IOP. CONCLUSIONS: This study suggests that SCH occurs at the same frequency after Molteno implantation as after filtering surgery with antimetabolite use and that eyes with SCH do less well.

Flavor variability and flavor stability of U.S.-produced whole milk powder.

Flavor variability and stability of U.S.-produced whole milk powder (WMP) are important parameters for maximizing quality and global competitiveness of this commodity. This study characterized flavor and flavor stability of domestic WMP. Freshly produced (<1 mo) WMP was collected from 4 U.S. production facilities 5 times over a 1 y period. Each sample was analyzed initially and every 2 mo for sensory profile, volatiles, color, water activity, and moisture through 12 mo storage. Selected volatiles were quantified using solid phase microextraction (SPME) with gas chromatography/mass-spectrometry: dimethyl sulfide, 2-methylbutanal, 3-methylbutanal, hexanal, 2-heptanone, heptanal, 1-octen-3-ol, octanal, 3-octen-2-one, and nonanal. Multiple linear regression with backwards elimination was applied to generate equations to predict grassy and painty flavors based on selected volatiles. All WMP were between 2% and 3% moisture and 0.11 and 0.25 water activity initially. WMP varied in initial flavor profiles with varying levels of cooked, milk fat, and sweet aromatic flavors. During storage, grassy and painty flavors developed while sweet aromatic flavor intensities decreased (P < 0.05). Painty and grassy flavors were confirmed by increased levels (P < 0.05) of lipid oxidation products such as hexanal, heptanal, and octanal. Hexanal, 2-heptanone, 1-octen-3-ol, and nonanal concentrations were best predictors of grassy flavor (R(2)= 0.38, P < 0.0001) while hexanal, 2-methylbutanal, 3-methylbutanal, octanal, and 3-octen-2-one concentrations were best predictors of painty flavor (R(2)= 0.61, P < 0.0001). These results provide baseline information to determine specific factors that can be controlled to optimize U.S. WMP flavor and flavor stability.

Signal detection theory and the psychophysics of pain: an introduction and review.

A brief explanation of signal detection theory is presented, followed by a review of the literature in which differences in pain report were analyzed to determine if changes were in sensitivity (physiological processes) or in response bias (a subject's willingness to report that a signal occurred). Three kinds of studies are reviewed: modification, procedural, and comparative and normative. The advantages of using a signal detection approach in pain research are emphasized. It is concluded that experimenters applying signal detection analysis to pain research should give greater consideration to methodological procedures and be cognizant of all possibilities for shifts in sensitivity (d)'.

Acupuncture analgesia and radiant-heat pain: a signal-detection analysis.

Responses to radiant-heat stimulation to the back of the hand were obtained during baseline conditions and during acupuncture sessions. Signal-detection methodology and analysis were used to determine whether acupuncture affects d' (changes physiologic processes) relative to pain report. A binary rather than a rating-scale procedure was used to obtain more accurate measures of sensitivity. Results indicated that acupuncture decreased sensitivity only at intensity levels that were never described as painful.

BKm minisatellite sequences are not sex associated but reveal DNA fingerprint polymorphisms in rainbow trout.

GATA-GACA repetitive sequences first isolated from a female snake (termed BKm sequences) and associated with sex chromosomes in some species were hybridized to DNA from rainbow trout (Salmo gairdneri). Genomic DNA was studied from three groups of rainbow trout: (i) randomly selected males and females from an outbred group, (ii) androgenetic individuals from an inbred strain, and (iii) parents and offspring of an outbred strain. Three restriction enzymes (EcoRI, HaeIII, or HinfI) were used to digest the genomic DNA. The DNA was electrophoresed in agarose gels, transferred to nylon membranes, and the GATA-GACA repetitive sequence probe was hybridized to this DNA. There was no evidence of sex-associated patterns of hybridization with the enzymes used. However, the sequences reveal DNA fingerprint polymorphisms which appear to be inherited in a stable manner.