Patient-reported outcomes after oesophagectomy in the multicentre LASER study.

BACKGROUND: Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. METHODS: This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. RESULTS: Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. CONCLUSION: A long-term symptom burden is common after oesophageal cancer surgery.

Exaggerated postprandial GLP-1 secretion following esophagectomy is not associated with gastric emptying and intestinal transit.

Esophagectomy causes postprandial symptoms associated with an exaggerated postprandial gut hormone response. This study aimed to compare the gastrointestinal transit time of patients 1 year after esophagectomy with unoperated controls, including its relation to satiety gut hormone release. In this cross-sectional study, consecutive, disease-free patients after esophagectomy with pyloroplasty were compared with unoperated control subjects to assess gastric emptying (GE) and cecal arrival time (CAT). Serial plasma samples were collected before, and for 300 minutes after, a mixed-meal challenge. Body composition was assessed, and symptom scores were calculated. Eleven patients 1 year post-esophagectomy (age: 62.6 ± 9.8, male: 82%) did not show a significantly different GE pattern compared with 10 control subjects (P = 0.245). Rather, patients could be categorized bimodally as exhibiting either rapid or slow GE relative to controls. Those with rapid GE trended toward a higher postprandial symptom burden (P = 0.084) without higher postprandial glucagon-like peptide-1 (GLP-1) secretion (P = 0.931). CAT was significantly shorter after esophagectomy (P = 0.043) but was not significantly associated with GE, GLP-1 secretion, or symptom burden. Neither early nutrient delivery to the proximal small intestine nor to the colon explains the exaggerated postprandial GLP-1 response after esophagectomy. GE varies significantly in these patients despite consistent pyloric management.

Nosocomial SARS-CoV-2 transmission in postoperative infection and mortality: analysis of 14 798 procedures.

This study used a national administrative database to estimate perioperative SARS-CoV-2 infection risk, and associated mortality, relative to nosocomial transmission rates. The impact of nosocomial transmission was greatest after major emergency surgery, whereas laparoscopic surgery may be protective owing to reduced duration of hospital stay. Procedure-specific risk estimates are provided to facilitate surgical decision-making and informed consent. Estimated risks.

3D characterisation of dry powder inhaler formulations: Developing X-ray micro computed tomography approaches.

Carrier-based dry powder inhaler (DPI) formulations need to be accurately characterised for their particle size distributions, surface roughnesses, fines contents and flow properties. Understanding the micro-structure of the powder formulation is crucial, yet current characterisation methods give incomplete information. Commonly used techniques like laser diffraction (LD) and optical microscopy (OM) are limited due to the assumption of sphericity and can give variable results depending on particle orientation and dispersion. The aim of this work was to develop new three dimensional (3D) powder analytical techniques using X-ray computed tomography (XCT) that could be employed for non-destructive metrology of inhaled formulations. α-lactose monohydrate powders with different characteristics have been analysed, and their size and shape (sphericity/aspect ratio) distributions compared with results from LD and OM. The three techniques were shown to produce comparable size distributions, while the different shape distributions from XCT and OM highlight the difference between 2D and 3D imaging. The effect of micro-structure on flowability was also analysed through 3D measurements of void volume and tap density. This study has demonstrated for the first time that XCT provides an invaluable, non-destructive and analytical approach to obtain number- and volume-based particle size distributions of DPI formulations in 3D space, and for unique 3D characterisation of powder micro-structure.

Measuring the impact of oesophagectomy on physical functioning and physical activity participation: a prospective study.

BACKGROUND: Oesophagectomy remains the only curative intervention for oesophageal cancer, with defined nutritional and health-related quality of life (HR-QOL) consequences. It follows therefore that there is a significant risk of decline in physical wellbeing with oesophagectomy however this has been inadequately quantified. This study prospectively examines change in physical functioning and habitual physical activity participation, from pre-surgery through 6-months post-oesophagectomy. METHODS: Patients scheduled for oesophagectomy with curative intent were recruited. Key domains of physical functioning including exercise tolerance (six-minute walk test (6MWT)) and muscle strength (hand-grip strength), and habitual physical activity participation, including sedentary behaviour (accelerometry) were measured pre-surgery (T0) and repeated at 1-month (T1) and 6-months (T2) post-surgery. HR-QOL was measured using the EORTC-QOL C30. RESULTS: Thirty-six participants were studied (mean age 62.4 (8.8) years, n = 26 male, n = 26 transthoracic oesophagectomy). Mean 6MWT distance decreased significantly from T0 to T1 (p = 0.006) and returned to T0 levels between T1 and T2 (p < 0.001). Percentage time spent sedentary increased throughout recovery (p < 0.001) and remained significantly higher at T2 in comparison to T0 (p = 0.003). In contrast, percentage time spent engaged in either light or moderate-to-vigorous intensity activity, all reduced significantly (p < 0.001 for both) and remained significantly lower at T2 in comparison to T0 (p = 0.009 and p = 0.01 respectively). Patients reported deficits in multiple domains of HR-QOL during recovery including global health status (p = 0.04), physical functioning (p < 0.001) and role functioning (p < 0.001). Role functioning remained a clinically important 33-points lower than pre-operative values at T2. CONCLUSION: Habitual physical activity participation remains significantly impaired at 6-months post-oesophagectomy. Physical activity is a measurable and modifiable target for physical rehabilitation, which is closely aligned with patient-reported deficits in role functioning. Rehabilitation aimed at optimising physical health in oesophageal cancer survivorship is warranted.

Effect of neoadjuvant chemoradiation on preoperative pulmonary physiology, postoperative respiratory complications and quality of life in patients with oesophageal cancer.

BACKGROUND: It remains controversial whether neoadjuvant chemoradiation (nCRT) for oesophageal cancer influences operative morbidity, in particular pulmonary, and quality of life. This study combined clinical outcome data with systematic evaluation of pulmonary physiology to determine the impact of nCRT on pulmonary physiology and clinical outcomes in locally advanced oesophageal cancer. METHODS: Consecutive patients treated between 2010 and 2016 were included. Three-dimensional conformal radiation was standard, with a lung dose-volume histogram of V20 less than 25 per cent, and total radiation between 40 and 41·4 Gy. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) were assessed at baseline and 1 month after nCRT. Radiation-induced lung injury (grade 2 or greater), comprehensive complications index (CCI) and pulmonary complications were monitored prospectively. Health-related quality of life was assessed among disease-free patients in survivorship. RESULTS: Some 228 patients were studied. Comparing pulmonary physiology values before with those after nCRT, FEV1 decreased from mean(s.d.) 96·8(17·7) to 91·5(20·4) per cent (-3·6(10·6) per cent; P < 0·001), FVC from 104·9(15·6) to 98·1(19·8) per cent (-3·2(11·9) per cent; P = 0·005) and DLCO from 97·6(20·7) to 82·2(20·4) per cent (-14·8(14·0) per cent; P < 0·001). Five patients (2·2 per cent) developed radiation-induced lung injury precluding surgical resection. Smoking (P = 0·005) and increased age (P < 0·001) independently predicted percentage change in DLCO. Carboplatin and paclitaxel with 41·4 Gy resulted in a greater DLCO decline than cisplatin and 5-fluorouracil with 40 Gy (P = 0·001). On multivariable analysis, post-treatment DLCO predicted CCI (P = 0·006), respiratory failure (P = 0·020) and reduced physical function in survivorship (P = 0·047). CONCLUSION: These data indicate that modern nCRT alters pulmonary physiology, in particular diffusion capacity, which is linked to short- and longer-term clinical consequences, highlighting a potentially modifiable index of risk.

ANTECEDENTES: El tema de si en el cáncer de esófago la quimiorradioterapia neoadyuvante (neoadjuvant chemoradiation, nCRT) repercute sobre la morbilidad postoperatoria, especialmente sobre la morbilidad pulmonar y la calidad de vida de los pacientes que sobreviven sigue siendo controvertido. Este estudio combina datos sobre resultados clínicos con una evaluación sistemática de la fisiología pulmonar para determinar el impacto de la nCRT sobre la fisiología pulmonar y los resultados clínicos en el cáncer de esófago localmente avanzado. MÉTODOS: Se incluyeron pacientes consecutivos tratados entre 2010-2016. La radioterapia conformal 3D fue la estándar, con un histograma dosis-volumen del pulmón V20 < 25% y radiación entre 40-41,4 Gy. Se evaluaron el volumen espiratorio forzado (forced expiratory volume, FEV1), la capacidad vital forzada (forced vital capacity, FVC) y la capacidad de difusión del monóxido de carbono (diffusion capacity for carbon monoxide, DLCO) al inicio y un mes tras la nCRT. La lesión pulmonar inducida por la radioterapia (EORTC grado ≥ 2), el índice de complicaciones integral (comprehensive complications index, CCI), grado de Clavien-Dindo, y complicaciones pulmonares fueron analizadas de manera prospectiva. Se evaluó la calidad de vida relacionada con la salud entre los pacientes supervivientes libres de enfermedad (EORTC QLQ-C30, OG25, OES18). RESULTADOS: Se estudiaron un total de 228 pacientes. Al comparar los valores de la fisiología pulmonar antes y después de la nCRT respectivamente, la FEV1 disminuyó de 96,8 ± 17,7% a 91,5 ± 20,4% (-3,6 ± 10,6%, P = 0,0002), la FVC de 104,9 ± 15,6 a 98,1 ± 19,8% (-3,2 ± 11,9%, P = 0,005) y la DLCO de 97,6 ± 20,7 a 82,2 ± 20,4% (-14,8 ± 14,0%, P < 0,0001). Cinco pacientes (2,2%) desarrollaron lesión pulmonar relacionada con la radioterapia impidiendo la resección quirúrgica. Los factores predictores independientes de %ΔDLCO fueron el hábito tabáquico (P = 0,005) y la edad avanzada (P < 0,001). El tratamiento con carboplatino/paclitaxel/41,4Gy determinó un mayor descenso de la DLCO en comparación con cisplatino/5-fluorouracilo/40Gy (P = 0,001). En el análisis multivariable, la DLCO tras el tratamiento fue una variable predictora de CCI (P = 0,006), fracaso respiratorio/intubación prolongada (P = 0,020) y reducción de la función física en los supervivientes (P = 0,047). CONCLUSIÓN: Estos datos indican que la moderna nCRT altera la fisiología pulmonar, especialmente la difusión pulmonar, con consecuencias clínicas a corto y largo plazo. La DLCO podría constituir un factor de riesgo potencialmente modificable.

Cardiorespiratory Comorbidity and Postoperative Complications following Esophagectomy: a European Multicenter Cohort Study.

BACKGROUND: The impact of cardiorespiratory comorbidity on operative outcomes after esophagectomy remains controversial. This study investigated the effect of cardiorespiratory comorbidity on postoperative complications for patients treated for esophageal or gastroesophageal junction cancer. PATIENTS AND METHODS: A European multicenter cohort study from five high-volume esophageal cancer centers including patients treated between 2010 and 2017 was conducted. The effect of cardiorespiratory comorbidity and respiratory function upon postoperative outcomes was assessed. RESULTS: In total 1590 patients from five centers were included; 274 (17.2%) had respiratory comorbidity, and 468 (29.4%) had cardiac comorbidity. Respiratory comorbidity was associated with increased risk of overall postoperative complications, anastomotic leak, pulmonary complications, pneumonia, increased Clavien-Dindo score, and critical care and hospital length of stay. After neoadjuvant chemoradiotherapy, respiratory comorbidity was associated with increased risk of anastomotic leak [odds ratio (OR) 1.83, 95% confidence interval (CI) 1.11-3.04], pneumonia (OR 1.65, 95% CI 1.10-2.47), and any pulmonary complication (OR 1.52, 95% CI 1.04-2.22), an effect which was not observed following neoadjuvant chemotherapy or surgery alone. Cardiac comorbidity was associated with increased risk of cardiovascular and pulmonary complications, respiratory failure, and Clavien-Dindo score ≥ IIIa. Among all patients, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio > 70% was associated with reduced risk of overall postoperative complications, cardiovascular complications, atrial fibrillation, pulmonary complications, and pneumonia. CONCLUSIONS: The results of this study suggest that cardiorespiratory comorbidity and impaired pulmonary function are associated with increased risk of postoperative complications after esophagectomy performed in high-volume European centers. Given the observed interaction with neoadjuvant approach, these data indicate a potentially modifiable index of perioperative risk.

Changes in gut hormones, glycaemic response and symptoms after oesophagectomy.

BACKGROUND: Oesophagectomy is associated with reduced appetite, weight loss and postprandial hypoglycaemia, the pathophysiological basis of which remains largely unexplored. This study aimed to investigate changes in enteroendocrine function after oesophagectomy. METHODS: In this prospective study, 12 consecutive patients undergoing oesophagectomy were studied before and 10 days, 6, 12 and 52 weeks after surgery. Serial plasma total fasting ghrelin, and glucagon-like peptide 1 (GLP-1), insulin and glucose release following a standard 400-kcal mixed-meal stimulus were determined. CT body composition and anthropometry were assessed, and symptom scores calculated using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires. RESULTS: At 1 year, two of the 12 patients exhibited postprandial hypoglycaemia, with reductions in bodyweight (mean(s.e.m.) 17·1(3·2) per cent, P < 0·001), fat mass (21.5(2.5) kg versus 25.5(2.4) kg before surgery; P = 0·014), lean body mass (51.5(2.2) versus 54.0(1.8) kg respectively; P = 0·003) and insulin resistance (HOMA-IR: 0.84(0.17) versus 1.16(0.20); P = 0·022). Mean(s.e.m.) fasting ghrelin levels decreased from postoperative day 10, but had recovered by 1 year (preoperative: 621·5(71·7) pg/ml; 10 days: 415·1(59·80) pg/ml; 6 weeks: 309·0(42·0) pg/ml; 12 weeks: 415·8(52·1) pg/ml; 52 weeks: 547·4(83·2) pg/ml; P < 0·001) and did not predict weight loss (P = 0·198). Postprandial insulin increased progressively at 10 days, 6, 12 and 52 weeks (mean(s.e.m.) insulin AUC0-30 min : fold change 1·7(0·4), 2·0(0·4), 3·5(0·7) and 4·0(0·8) respectively; P = 0·001). Postprandial GLP-1 concentration increased from day 10 after surgery (P < 0·001), with a 3·3(1·8)-fold increase at 1 year (P < 0·001). Peak GLP-1 level was inversely associated with the postprandial glucose nadir (P = 0·041) and symptomatic neuroglycopenia (Sigstad score, P = 0·017, R2 = 0·45). GLP-1 AUC predicted loss of weight (P = 0·008, R2 = 0·52) and fat mass (P = 0·010, R2 = 0·64) at 1 year. CONCLUSION: Altered enteroendocrine physiology is associated with early satiety, weight loss and postprandial hypoglycaemia after oesophagectomy.

Sarcopenia during neoadjuvant therapy for oesophageal cancer: characterising the impact on muscle strength and physical performance.

PURPOSE: Preoperative chemo(radio)therapy for oesophageal cancer (OC) may have an attritional impact on body composition and functional status, impacting postoperative outcome. Physical decline with skeletal muscle loss has not been previously characterised in OC and may be amenable to physical rehabilitation. This study characterises skeletal muscle mass and physical performance from diagnosis to post-neoadjuvant therapy in patients undergoing preoperative chemo(radio)therapy for OC. METHODS: Measures of body composition (axial computerised tomography), muscle strength (handgrip), functional capacity (walking distance), anthropometry (weight, height and waist circumference), physical activity, quality-of-life and nutritional status were captured prospectively. Sarcopenia status was defined as pre-sarcopenic (low muscle mass only), sarcopenic (low muscle mass and low muscle strength or function) or severely sarcopenic (low muscle mass and low muscle strength and low muscle function). RESULTS: Twenty-eight participants were studied at both time points (mean age 62.86 ± 8.18 years, n = 23 male). Lean body mass reduced by 4.9 (95% confidence interval 3.2 to 6.7) kg and mean grip strength reduced by 4.3 (2.5 to 6.1) kg from pre- to post-neoadjuvant therapy. Quality-of-life scores capturing gastrointestinal symptoms improved. Measures of anthropometry, walking distance, physical activity and nutritional status did not change. There was an increase in sarcopenic status from diagnosis (pre-sarcopenic n = 2) to post-treatment (pre-sarcopenic n = 5, severely sarcopenic n = 1). CONCLUSIONS: Despite maintenance of body weight, functional capacity and activity habits, participants experience declines in muscle mass and strength. Interventions involving exercise and/or nutritional support to build muscle mass and strength during preoperative therapy, even in patients who are functioning normally, are warranted.

Value of CT-PET after neoadjuvant chemoradiation in the prediction of histological tumour regression, nodal status and survival in oesophageal adenocarcinoma.

BACKGROUND: The role of CT-PET after neoadjuvant chemoradiation (nCRT) for prediction of pathological response and oncological outcome in oesophageal and junctional adenocarcinoma (OAC) is unclear. The relationship between complete metabolic response (cMR), pathological complete response (pCR) and nodal status has not been clarified. METHODS: Patients with locally advanced OAC selected to receive nCRT and surgery with curative intent, on the basis of staging that included CT-PET positivity, were included. Repeat scanning (PET2) with an identical protocol was performed 2-4 weeks after completion of nCRT (cisplatin and 5-fluorouracil plus 44 Gy radiation). Changes in [(18) F]fluorodeoxyglucose uptake, considered as either a maximum standardized uptake value (SUVmax) or a relative reduction (%ΔSUVmax), and PET-predicted nodal status following nCRT were compared with histopathological response, histological node positivity and survival. RESULTS: One hundred consecutive patients with PET-positive OAC were studied. Following nCRT, PET2 identified M1 disease in 2·0 per cent of patients. There were no significant associations between PET2 SUVmax or %ΔSUVmax with respect to primary tumour stage (ypT) (P = 0.216 and P = 0·975 respectively), tumour regression grade (P = 0·109 and P = 0·232), pCR (P = 0·633 and P = 0·870) or complete resection (R0) (P = 0·440 and P = 0·235). The sensitivity of PET2 for ypN was 10 per cent. %ΔSUVmax was not associated with disease-free or overall survival (P = 0·162 and P = 0·154 respectively). Of 46 patients with a cMR on PET2, 37 (80 per cent) had histological evidence of residual tumour in the resected specimen, and cMR was not associated with overall survival benefit (P = 0·478). CONCLUSION: CT-PET following nCRT for OAC has poor prognostic and discriminatory value for clinical application.

Increased photic sensitivity for phase resetting but not melatonin suppression in Siberian hamsters under short photoperiods.

Light regulates a variety of behavioral and physiological processes, including activity rhythms and hormone secretory patterns. Seasonal changes in the proportion of light in a day (photoperiod) further modulate those functions. Recently, short (SP) versus long days (LP) were found to markedly increase light sensitivity for phase shifting in Syrian hamsters. To our knowledge, photoperiod effects on light sensitivity have not been studied in other rodents, nor is it known if they generalize to other circadian responses. We tested whether photic phase shifting and melatonin suppression vary in Siberian hamsters maintained under LP or SP. Select irradiances of light were administered, and shifts in activity were determined. Photic sensitivity for melatonin suppression was examined in a separate group of animals via pulses of light across a 4 log-unit photon density range, with post-pulse plasma melatonin levels determined via RIA. Phase shifting and melatonin suppression were greater at higher irradiances for both LP and SP. The lower irradiance condition was below threshold for phase shifts in LP but not SP. Melatonin suppression did not vary by photoperiod, and the half saturation constant for fitted sigmoid curves was similar under LP and SP. Thus, the photoperiodic modulation of light sensitivity for phase shifting is conserved across two hamster genera. The dissociation of photoperiod effects on photic phase shifting and melatonin suppression suggests that the modulation of sensitivity occurs downstream of the common retinal input pathway. Understanding the mechanistic basis for this plasticity may yield therapeutic targets for optimizing light therapy practices.

Dose-injury relationships for cryoprotective agent injury to human chondrocytes.

Vitrification of articular cartilage (AC) could enhance tissue availability but requires high concentrations of cyroprotective agents (CPAs). This study investigated relative injuries caused by commonly used CPAs. We hypothesized that the in situ chondrocyte dose-injury relationships of five commonly used CPAs are nonlinear and that relative injuries could be determined by comparing cell death after exposure at increasing concentrations. Human AC samples were used from four patients undergoing total knee arthroplasty surgery. Seventy µm slices were exposed in a stepwise protocol to increasing concentrations of 5 CPAs (max = 8 M); dimethyl sulfoxide (Me(2)SO), glycerol (Gly), propylene glycol (PG), ethylene glycol (EG), and formamide (FM). Chondrocyte viability was determined by membrane integrity stains. Statistical analysis included t-tests and nonlinear least squares estimation methods. The dose-injury to chondrocytes relationships for all CPAs were found to be nonlinear (sigmoidal best fit). For the particular loading protocol in this study, the data identified the following CPA concentrations at which chondrocyte recoveries statistically deviated significantly from the control recovery; 1 M for Gly, 4 M for FM and PG, 6 M for Me(2)SO, and 7 M for EG. Comparison of individual means demonstrated that Gly exposure resulted in the lowest recovery, followed by PG, and then Me(2)SO, FM and EG in no specific order. The information from this study provides an order of damage to human chondrocytes in situ of commonly used CPAs for vitrification of AC and identifies threshold CPA concentrations for a stepwise loading protocol at which chondrocyte recovery is significantly decreased. In general, Gly and PG were the most damaging while DMSO and EG were among the least damaging.

Investigating cryoinjury using simulations and experiments. 1: TF-1 cells during two-step freezing (rapid cooling interrupted with a hold time).

There is significant interest in designing a cryopreservation protocol for hematopoietic stem cells (HSC) which does not rely on dimethyl sulfoxide (Me(2)SO) as a cryoprotectant. Computer simulations that describe cellular osmotic responses during cooling and warming can be used to optimize the viability of cryopreserved HSC; however, a better understanding of cellular osmotic parameters is required for these simulations. As a model for HSC, the erythroleukemic human cell line TF-1 was used in this study. Simulations, based on the osmotic properties of TF-1 cells and on the solution properties of the intra- and extracellular compartments, were used to interpret cryoinjury associated with a two-step cryopreservation protocol. Calculated intracellular supercooling was used as an indicator of cryoinjury related to intracellular ice formation. Simulations were applied to the two-step cooling protocol (rapid cooling interrupted with a hold time) for TF-1 cells in the absence of Me(2)SO or other cryoprotectants and optimized by minimizing the indicator of cryoinjury. A comparison of simulations and experimental measurements of membrane integrity supports the concept that, for two-step cooling, increasing intracellular supercooling is the primary contributor to potential freezing injury due to the increase in the likelihood of intracellular ice formation. By calculating intracellular supercooling for each step separately and comparing these calculations with cell recovery data, it was demonstrated that it is not optimal simply to limit overall supercooling during two-step freezing procedures. More aptly, appropriate limitations of supercooling differ from the first step to the second step. This study also demonstrates why high cell recovery after cryopreservation could be achieved in the absence of traditional cryoprotectants.

Postarteriographic femoral pseudoaneurysms: treatment with ultrasound-guided compression.

Pseudoaneurysms following femoral arterial catheterization are increasingly common and are related to factors such as catheter size, periprocedural anticoagulation, hypertension, and improper technique. Ultrasound-guided compression as a noninvasive technique for repair of these lesions was prospectively evaluated in 16 patients whose mean age was 61 years. Nine patients were on anticoagulants and six had hypertension. All patients presented with an enlarging groin hematoma, a pulsatile mass, and/or a bruit following femoral catheterization. Seventeen femoral artery pseudoaneurysms, including one with an associated arteriovenous fistula, were detected using color-flow Doppler imaging. Three pseudoaneurysms thrombosed spontaneously. The remaining 14 were managed with compressive therapy lasting from 20 to 100 minutes. No complications were encountered during the compressions and 10 false aneurysms (71%) responded completely (mean time to thrombosis of 38 minutes). Two lesions responded partially to compression and there were two failures, the latter associated with excessive anticoagulation in one patient and a well-established pseudoaneurysm in the second patient. Only one pseudoaneurysm (6%) in the series required surgical correction. Ultrasound-guided compression of acute pseudoaneurysms in the groin is a safe, inexpensive, and effective method of treatment.

Streptococcus mitis sepsis in bone marrow transplant patients receiving oral antimicrobial prophylaxis.

PURPOSE: Streptococcal infection has increasingly become a problem in neutropenic patients. We report on an outbreak of Streptococcus mitis sepsis in six bone marrow transplant patients receiving oral antimicrobial prophylaxis. PATIENTS AND METHODS: We performed an epidemiologic study of all patients in our bone marrow transplant program from 1986 to 1988. The hospital and microbiology records for all patients were reviewed. All bone marrow patients were treated according to specified protocols, including an oral prophylactic antimicrobial regimen that was changed in late 1987 from vancomycin/polymyxin/tobramycin to norfloxacin. Identification, susceptibility testing, and whole cell protein analysis of streptococcal isolates were performed at the Reference and Antimicrobial Investigations Laboratories at the Centers for Disease Control. RESULTS: We detected six cases of S. mitis sepsis among 21 patients undergoing bone marrow transplantation. No other concurrent pathogen was isolated from any patient at the time of the S. mitis bacteremia. Bacteremia developed within 72 hours of transplant in five of six patients and was associated with severe mucositis in four patients. An environmental study failed to reveal any common source for the outbreak, and whole cell protein analysis of all six S. mitis isolates revealed each to be distinct. Of 12 patients receiving oral vancomycin/polymyxin/tobramycin, one developed S. mitis bacteremia, versus five of nine patients receiving norfloxacin (p less than 0.03). CONCLUSION: We believe S. mitis bacteremia is a potential complication of bone marrow transplantation and is associated with antimicrobial prophylaxis with norfloxacin, especially in the setting of mucositis.

Reception of photoperiodic information by fetal Siberian hamsters: role of the mother's pineal gland.

The rate of reproductive development in juvenile male Siberian hamsters is strongly influenced by daylength (photoperiod). Recent studies indicate that reception of photoperiodic cues begins during fetal life. The present experiments yielded a further demonstration that developing male Siberian hamsters receive information about the photoperiod to which their mother is exposed during pregnancy. The possibility that photoperiodic information is transmitted from mother to young after birth was investigated by cross-fostering young gestated on 12L and 16L to mothers from the other photoperiod. Litters were cross-fostered on the day of birth and then were transferred, along with their foster mothers, to 14L. We found no influence of the mother after birth, indicating that transmission of photoperiodic information from mother to young must occur during gestation. To determine if the pineal gland of the mother is required for this response, adult females were pinealectomized or sham-operated and paired with intact males in 12L, 14L, or 16L. After parturition parents and offspring were exposed to 14L. The influence of prenatal photoperiod on postnatal testicular development in 14L was blocked by pinealectomy of the mother. Postnatal testicular development was retarded in offspring that experienced a photoperiod transfer from either 15L to 14L or 8L to 12L at birth. In contrast, the inhibitory effect of a transfer from 16L to 14L at birth was abolished when juvenile males were exposed to a single long photoperiod (16.3 h light) at age 17-21 days and then were returned to 14L.

Interaction of bisantrene anti-cancer agents with DNA: footprinting, structural requirements for DNA unwinding, kinetics and mechanism of binding and correlation of structural and kinetic parameters with anti-cancer activity.

A topoisomerase I assay in conjunction with covalently closed circular DNA afforded unwinding angles for a series of eight analogs of the anti-cancer agent bisantrene. Values ranging from 33 degrees to zero comprised three classes wherein the extent of DNA interaction correlates with anti-cancer activity. The binding of bisantrene compounds to T4 DNA suggests at least partial interaction via the minor groove. MPE footprinting evaluation of bisantrene showed no evidence for selective protection of a Hind III-EcoRI fragment of pBR322 suggesting a sequence neutral binding mode. Stopped flow spectrophotometry studies indicate an association rate constant for bisantrene with DNA of greater than 1 x 10(7) M-1 S-1 at 20 degrees at ionic strength of 0.1 and is considerably slower than ethidium or propidium at all ionic strengths. At least two exponential components are required to match the kinetic curves indicating a biphasic mechanism and estimates of k1 and k2 were obtained for seven drugs. The ionic strength dependence of the surfactant driven dissociation of bisantrene is in accord with a competitive mechanism for intercalation of the drugs at alternative sites. The residence time and t1/2 (app) for bisantrene are slightly larger for poly d(G.C)2 than poly d(A.T)2 and calf thymus DNA is at an intermediate value. Considerations of structural factors in the drug dissociation kinetics permit a correlation with observed anti-cancer properties of these bisantrene analogs.

Role of short photoperiod and cold exposure in regulating daily torpor in Djungarian hamsters.

1. Male and female Djungarian hamsters (Phodopus sungorus) were gonadectomized or sham-operated after 12 weeks of exposure to short photoperiods (10L:14D). Half of the animals were single housed and transferred to a cold environment (7 degrees C) at week 13 of short days and half were transferred to cold at week 21. The time courses of short photoperiod induced seasonal changes in body weight, pelage color stage, and daily torpor were monitored periodically until the experiment was terminated after 34 weeks of short days. 2. The total duration of short photoperiod exposure was of primary importance compared to the duration of cold exposure in regulating seasonal changes in the frequency of daily torpor, body weight and pelage color exhibited by male and female Djungarian hamsters; that is, the change from long to short days was much more effective as a seasonal time cue than was the onset of cold exposure. 3. Gonadectomy did not prevent the occurrence of seasonal torpor in hamsters of either sex, indicating that these cycles are regulated by a time measuring mechanism (seasonal clock) that is largely independent of the gonadal cycle. However, castration did influence certain aspects of the body weight and torpor cycles exhibited by male hamsters. 4. Some castrated animals showed a delay in terminating the torpor season lending further support to the hypothesis that the spontaneous recrudescence of the testes which occurs toward the end of the torpor season may play a role in the termination of torpor in males.(ABSTRACT TRUNCATED AT 250 WORDS)

Metastatic patterns in small-cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients.

Postmortem material from 537 patients included in various protocols of intensive combination chemotherapy or chemoradiotherapy for the management of small-cell anaplastic carcinoma of the lung (SCLC) has been reviewed. Patterns of residual or recurrent disease were analyzed in relation to pretreatment clinical parameters. Residual primary tumor (P less than .05), regional lymph node involvement (P less than .01), hepatic (P less than .01), bone (P less than .05), and renal metastases (P less than .05) were all significantly less frequent among patients with initially limited-stage disease compared with extensively staged patients. The frequency of residual intrathoracic tumor and metastatic pattern did not significantly differ between partial responders (PRs) and nonresponders (NRs). Patients with limited disease achieving a complete remission had a lower frequency of intrathoracic tumor (P less than .001) at autopsy compared with limited-stage PRs. However, for extensive-stage patients the pattern of residual disease was essentially independent of tumor response. Prior surgery was associated with a reduced burden of metastases only in those who underwent a radical resection. The addition of radiotherapy to the primary tumor and mediastinum failed to modify the autopsy distribution of residual tumor compared with that in patients treated with chemotherapy alone. Metastatic patterns were similar with or without prophylactic abdominal radiotherapy, while prophylactic cranial irradiation (PCl) did not prevent the development of cerebral metastases in patients whose systemic response to treatment was either partial or nonexistent. However, a beneficial effect of PCl in compete responders (CRs) was not excluded.