Psychiatric disorders in internal medicine.

All patients admitted to one firm of the Department of Medicine were psychiatrically evaluated in terms of Diagnostic and Statistical Manual of Mental Disorders (DSM III, 1980) criteria. Thirty-three per cent of the patients had treatable psychiatric disorders while only 3.5% of admissions to a comparable firm of the same department were referred for psychiatric consultation (P < 0.05). These data support the need for a more comprehensive liaison psychiatric service than a mere consultation service in the general hospital.


When in vitro fertilization fails: a prospective view.

New reproductive technologies such as in vitro fertilization (IVF) offer much hope to infertile couples, yet the odds for success are not high. In this study we examine the experiences of a cohort of women undergoing IVF or a related technology at three points in time: before technological intervention, approximately one month after the first failed cycle, and six months later. We consider the women's expectations and experiences and discuss implications of the findings for social work practice.


Paediatric inter-facility transport: the parents' perspective.

A telephone survey was conducted to evaluate the impact on families of inter-facility paediatric transport to a tertiary care centre. The 54 families who responded were almost unanimous in their appreciation of the transport service and the expertise of the attendants. However, many experienced problems, including finances, child care, travel arrangements and accommodation. Most problems were encountered by those who did not accompany the child in the transport vehicle, lived at a distance so that they could not commute and did not use hospital accommodation. Further research is suggested to assess the extent of the problems families face and to determine appropriate solutions.


Driving and dementia: perspectives from an outpatient clinic.

This article explores issues related to automobile driving and dementia from the perspective of an outpatient medical clinic. A retrospective pilot study is presented with particular focus on the relationship between cognitive status and hazardous driving performance. Special attention is given to the practice considerations that confront social workers and other health care professionals who deal with this prevalent and difficult problem.


Searching for the doable in nursing home social work practice.

Nursing home social workers were asked to provide information about their current practice circumstances, and to rate relative importance of resident and family psychosocial needs and frequency of functions performed or overseen by social workers to meet these needs. Both consultant and full-time staff social workers practiced under severe time constraints. Practitioners viewed psychosocial needs similarly, but staff and consultants met these needs through somewhat different functions. Findings provide a profile of practice that can contribute to care improvement through a definition of realistic service expectations for which social workers can be accountable.


Maximizing the patient's uniqueness and strengths: a challenge for home health care.

Because of where services are provided, home health care programs offer rich opportunities for incorporating the patient's uniqueness and strengths in treatment planning. Operationalizing these in day-to-day practice may be inhibited by the traditional medical model governing most treatment decisions. A reflective model and strengths perspective are mechanisms which bolster efforts to individualize patient care. A case example illustrates the difference between traditional approaches and alternative opportunities open to the home health care social worker.


Cultural differences in health beliefs: implications for social work practice in health care settings.

Individuals of diverse ethnic backgrounds often have beliefs about health, disease and treatment which vary significantly from American scientific medical practice. Cultural and subcultural health beliefs also vary among blacks, Hispanics and Asians. Individual differences within cultural groups may be influenced by length of time in the United States, age and social economic status. Social work activities which can improve health care services to ethnic minorities are identified.


Towards an understanding of families with physically disabled adolescents.

This exploratory study examined the family environment of ten families, each with a physically disabled adolescent and at least one non-disabled adolescent. Family members completed the Moos Family Environment Scale (FES) and discussed with the interviewer their experiences as a family. Blind and independent ratings on the FES by social workers involved in the study provided a comparison with the families' self ratings. Family ratings on the FES gave no indication of distress, but showed slightly higher than average emphasis on cohesion and achievement orientation. Social work ratings, in contrast, indicated elevated levels of conflict, achievement orientation, and control. In this report, no attempt is made to generalize these specific findings to all families with disabled adolescents. Rather, results are interpreted, in the light of findings in the recent literature, to underscore the need for better designed research and to alert professionals to the danger of imposing the prevalent dysfunctional view upon families with disabled children and adolescents.


Early unplanned readmissions to social work of elderly patients: factors predicting who needs follow-up services.

There are some elderly patients who receive social work services during an initial hospitalization and experience an early unplanned readmission, when they again are in need of social work assistance. This research identified factors which differentiated social work patients who were readmitted to the hospital within one month and were again referred to social work services from those who were not readmitted. Three factors were found to be predictive of readmission to social work: longer length of stay in the initial hospitalization; presence of barriers which complicated the social work service plan undertaken in the first admission; and provision of social work services in the initial admission which were limited to information and referral only.


Treatment issues and treatment configurations for mentally ill homeless women.

This article reviews and discusses various issues pertinent to effective delivery of treatment services to mentally ill homeless women. The central emphasis is upon the gender-specific issues unique to this population and includes attention to distinctive features of effective case management, utilization of group therapy techniques, and greater integration of the psychiatrist into the treatment team. The article concludes with a discussion of the future issues relevant to community based services to homeless mentally ill women.


Workers' Sick Fund (Kupat Holim) hot-line therapeutic first intervention: a model developed in the Gulf War.

This paper describes the work of the Workers' Sick Fund (Kupat Holim) of the Labor Organization in Israel in the Gulf War. A model is presented which was developed in real time, in light of existing conditions. The distinctive feature of the model is its effectiveness: the model accomplished its objective although counselling was by telephone and limited to a single session only.


Social work ethics in the practice arena: a qualitative study.

This paper is a report of an exploratory qualitative study that examined the role that social work ethics plays in informing social work behavior, as compared to other influences of an extra-ethical nature. The paper begins with a review of the literature exploring how ethical principles are utilized in professional practice. A discussion of the methodology focuses upon the choice of a qualitative design. Excerpts from participants' responses to a fictional case history are presented and discussed. The reader is offered an understanding of the area of study through access to the "natural flow" of thoughts presented in the excerpts. This research demonstrates how ethical principles, as codified in the N.A.S.W. Code of Ethics, can be effective in informing practice decisions.


[An epidemiologic study of the value and limits of physical therapy/exercise therapy in Fontaine stage II arterial occlusive disease].

Using a questionaire the members of the German Society for Angiology (DGA) were interrogated on the use of physical training for the treatment of peripheral arterial occlusive disease; from a total of n = 431 as much as n = 156 responded, i.e. making up a response of 36%. 104 of them conduct physical training either on their own or assign patients to it (67%). In most of the institutions exclusively walking/interval training (83%) or medical exercise (74%) are performed. In most cases the training is conducted by physiotherapeutists (71%). 13% of the patients are admitted exclusively to physical training, 34% undergo combined therapy, i.e. physical training and vaso-active medication. 22% receive mere medical, 31% surgical treatment. A general evaluation on the success of the different therapies applied turned out following frequency: 1. combined therapy (medical treatment/physical training); 2. surgical procedures as a therapeutic measure; 3. physical training; 4. medical treatment. A further study performed at three ambulatory centres offering physical training were to show what kind and to which extent such training is useful. In 34% of the cases (from a total of n = 201 patients with peripheral arterial occlusive disease in state II according to Fontaine) contraindications argue against the application of physical training. From a rest of 66% as much as 36% of the patients refuse to undergo physical training the reasons of which were stated with large transport distances and time problems. The remaining rest accepts the offer, although 24% attend such training only sporadically. The results show that mainly contraindications and insufficient patient compliance account for the fact that only one third of the patients attend physical training. The results are discussed and proposals are made to improve patient compliance.


Techniques for in utero endoscopic surgery. A new approach for fetal intervention.

In utero open surgery can salvage many fetuses with life-threatening anomalies. This approach carries risks, especially from preterm labor induced by the hysterotomy incision. In an effort to decrease uterine injury during hysterotomy, we developed techniques for endoscopic manipulation of the fetus. We developed these methods in fetal lambs. The uterus was exposed and insufflated with CO2. As a model for in utero surgery, a simulated cleft lip was created and immediately repaired using intracorporeal suturing and knot-tying procedures. The techniques for endoscopic suture placement and knot-tying were based on microsurgical principles. We also designed and created several specialized instruments to facilitate precise work in this highly magnified surgical field. The novel techniques of endoscopic fetal surgery described here offer an alternate approach to fetal intervention. Our future goals include the application of these techniques to a nonhuman primate model and the development of percutaneous access methods.


The role of peritoneoscopy (laparoscopy) in the evaluation of the acute abdomen in critically ill patients.

Emergency peritoneoscopy (laparoscopy) to evaluate a suspected intraabdominal catastrophe was performed in ten critically ill patients over a 3-year period. The examination was negative in six cases, thereby avoiding celiotomy in this high-risk group. The examination was positive in four cases and, on this basis, celiotomy was recommended. Verification of the peritoneoscopic findings by clinical follow-up, operative findings, or autopsy was obtained in eight out of the ten cases. Based on our experience, we feel that peritoneoscopy is of value in defining the indications for celiotomy in this high-risk group of patients.


Comparison between echo-guided fine-needle aspiration cytology and microhistology in diagnosing pancreatic masses.

Echo-guided fine-needle aspiration biopsy of pancreatic masses is a well-established diagnostic procedure. However, there is no consensus as to the superiority of cytology or microhistology. We compared the results of cytology and microhistology in 50 consecutive patients who underwent fine-needle aspiration biopsy for pancreatic masses. Aspirates were positive for malignant disease in 42 patients; the other eight had chronic focal pancreatitis. In the 42 cases of cancer, cytology provided conclusive results in 40 (95.2%); sampling was inadequate in two. Microhistology proved accurate in 30 cases (71.4%); insufficient tissue was obtained in 12, giving a statistically significant difference in favor of cytology (P < 0.01). In the eight patients with benign disease both techniques ruled out malignancy; in five microhistology gave further indications confirming suspected chronic pancreatitis (fibrosis, lymphocyte and histiocyte-cell infiltrate). Our results show that cytology is the method of choice in diagnosing pancreatic carcinoma. Microhistology can be a useful adjunct in patients with suspected chronic pancreatitis.


Incision extension is the optimal method of difficult gallbladder extraction at laparoscopic cholecystectomy.

An unsolved problem of laparoscopic cholecystectomy is the optimal method of removing the gallbladder with thick walls and a large stone burden. Proposed solutions include fascial dilatation, stone crushing, and ultrasonic, high-speed rotary, or laser lithotripsy. Our observation was that extension of the fascial incision to remove the impacted gallbladder was time efficient and did not increase postoperative pain. We reviewed the narcotic requirements of 107 consecutive patients undergoing laparoscopic cholecystectomy. Fifty-two patients required extension of the umbilical incision, and 55 patients did not have their fascial incision enlarged. Parenteral meperidine use was 39.5 +/- 63.6 mg in the patients requiring fascial incision extension and 66.3 +/- 79.2 mg in those not requiring fascial incision extension (mean +/- standard deviation). Oral narcotic requirements were 1.1 +/- 1.5 doses vs 1.3 +/- 1.7 doses in patients with and without incision extension, respectively. The wide range of narcotic use in both groups makes these apparent differences not statistically significant. We conclude that protracted attempts at stone crushing or expensive stone fragmentation devices are unnecessary for the extraction of a difficult gallbladder during laparoscopic cholecystectomy.


Selection of the treatment for esophagogastric varices. Analyses of collateral structures by endoscopic ultrasonography.

In 57 cases with portal hypertensive disease, we investigated the intramural and extramural structure of the stomach and the esophagus by endoscopic ultrasonography (EUS). Variously developed intra- and extramural vascular structures had a relationship to the endoscopic variceal form, and communicating (inflow) vessels to varices were found in 28 of the 43 primary cases treated (65%). We then classified the esophagogastric varices into three types according to the vascular structure, such as the esophageal type, esophagogastric type, and solitary gastric type. Based on the analysis of these collateral structures, we selected the treatment as follows. In the esophageal type, which has a few inflow vessels, it is easy to eliminate the varices by obturating the inflow vessels by endoscopic injection sclerotherapy (EIS). In the esophagogastric type, which has many enlarged inflow vessels, the Hassab operation is effective in devascularizing the extramural inflow vessels, and the combination of EIS is necessary to sclerose the intramural varices. In the solitary gastric type, which is a part of the downward portosystemic shunt, the Hassab operation is recommended to prevent rupture of the varices for the subtype with intramural running vessels, but conservative therapy is enough for the subtype without.


The rotary gallstone lithotrite to aid gallbladder extraction in laparoscopic cholecystectomy.

During laparoscopic cholecystectomy, a large stone burden may cause difficulty when extracting the gallbladder through the abdominal wall. Currently, the alternatives available to the surgeon include increasing the incision, removing stones singly, or utilizing complex fragmentation techniques like the pulsed dye laser. We have employed an electromechanical rotary gallstone lithotrite (RGL) to fragment stones to an aspiratable size. Initially, cholesterol spheres were pulverized in a latex balloon to demonstrate the efficacy of the device. Then, human gallstones were placed in the balloon and reduced to fragments less than or equal to 1 mm from initial sizes of 4-24 mm. Human stones were then inserted in ex vivo porcine gallbladders in a controlled experiment and treated with the device. Ten out of 12 tests were completed within 30 s; one test required 49 s and one 105 s to achieve complete fragmentation. Blinded histological evaluation demonstrated that tissue abrasion caused by use of the device would not interfere with the diagnosis of unsuspected malignancy. Clinical trials have now commenced under the auspices of the hospital ethical committee.


A new method of recording endoscopic and operative findings in colorectal neoplasia.

A new method of recording 12 relevant facts concerning patients with colorectal neoplasia has provided a neoplastic profile for each patient. With this information recorded on an outline of the colon one can see at a glance the date, histology, and location of the initial lesion; the number and timing of both synchronous and metachronous lesions and their histology; the size, differentiation, and location of each lesion; plus a family tree. This method provides pertinent clinical facts in chronological order and characterizes each patient's neoplastic activity without the need to refer to operative notes and laboratory reports. With this method, it is easy to record and easy to interpret, and it has been extremely useful in the clinical assessment of patients with colorectal neoplasia and in arranging appropriate surveillance for these patients.


Periampullary duodenal diverticulum in a patient undergoing laparoscopic cholecystectomy.

Duodenal diverticulae are acquired lesions usually found near the papilla of Vater and associated with significant symptoms. We present a case of a patient with obstructive jaundice who had a diverticulum and cholelithiasis. The management of this scenario is explained in the era of laparoscopic cholecystectomy.


Combination therapy of laparoscopic cholecystectomy and endoscopic transpapillary lithotripsy for both cholecystolithiasis and choledocholithiasis.

This report describes five patients with cholecystolithiasis and choledocholithiasis who were treated by combination endoscopic extraction of common bile-duct stones with sphincterotomy (EST) and laparoscopic cholecystectomy (LC). Following this combination procedure the patients were relieved completely of obstructive jaundice and right upper quadrant pain, leaving only small trocar insertion scars made during the short course of hospitalization. The combination therapy of EST and LC will be recommended for this kind of patient as a minimally invasive procedure.


Dissection of the esophagus after dilatation of a cervical diaphragm.

The authors report a case of a very large esophageal mucosal dissection observed during an esophagoscopy performed 7 days after dilatation of a cervical esophageal web. They treated this dissection by positioning an endoesophageal balloon which obtained the fast, overlapping closure of the torn mucosal layers and at the same time allowed both gastric drainage and enteral feeding via a pump.


Endoscopic protector hood for safe removal of sharp-pointed gastroesophageal foreign bodies.

Endoscopic removal of sharp and pointed foreign bodies in the upper gastrointestinal tract still poses technical difficulties. Overtubes may be uncomfortable to the patients and only objects fitting within a lumen of about 11-15 mm can be removed. We present here our preliminary experience with a commercially available new endoscopic end protector hood having the unique characteristic of maintaining its bell portion inverted during the progression of the scope through the gut and flipping back to its original shape during withdrawal through the lower esophageal sphincter. This prevents exposure of the esophageal and pharyngeal wall to injuries from the edges of the foreign body. We used this device to remove nine large sharp or pointed gastroesophageal foreign bodies in six consecutive patients in whom conventional techniques were considered unsafe or not technically feasible owing to the size and shape of the objects. In all cases, removal was successful and easily performed without bowel damage. We believe that this device enhances the safe removal of a wide variety of potentially dangerous gastroesophageal foreign bodies.


Laparoscopic feeding jejunostomy: also a simple technique.

Placement of feeding tubes is a common procedure for general surgeons. While the advent of percutaneous endoscopic gastrostomy has changed and improved surgical practice, this technique is contraindicated in many circumstances. In some patients placement of feeding tubes in the stomach may be contraindicated due to the risks of aspiration, gastric paresis, or gastric dysmotility. We describe a technique of laparoscopic jejunostomy tube placement which is easy and effective. It is noteworthy that this method may be used in patients who have had previous abdominal operations, and it has the added advantage of a direct peritoneal view of the viscera. We suggest that qualified laparoscopic surgeons learn the technique of laparoscopic jejunostomy.


Metabolic mapping of the synergism between MK-801 and SKF 38393 in rats with unilateral lesions of the dopaminergic nigrostriatal pathway.

In rats with a unilateral lesion of the dopaminergic nigrostriatal pathway with 6-hydroxydopamine, blockade of N-methyl-D-aspartate receptors by MK-801 strongly potentiated the turning behavior induced by D-1 receptor stimulation. To determine the functional consequences of such positive interaction we measured the local rates of cerebral glucose utilization (lCMRglc) in lesioned rats treated with MK-801 (0.1 mg/kg) and the D-1 agonist SKF 38393 (1.5 mg/kg), either alone or in combination. Treatment with each drug separately did not induce any substantial change in lCMRglc besides an increase in the metabolic activity of the dorsomedial caudate and entopeduncular nucleus (EP) of the lesioned side of MK-801 treated rats, as compared to the same side of lesioned rats treated with vehicle. Combined administration of MK-801 + SKF 38393 increased lCMRglc in the EP (+77%) and in the substantia nigra pars reticulata (SNr) (+30%) of the lesioned side as compared with the intact side, while it decreased lCMRglc in the lateral habenula (-26%). These changes were also significant when compared to the lesioned side of vehicle treated rats. The results suggest that while the caudate putamen might be the primary site of MK-801 and SKF 38393 positive interaction, the EP and SNr are the striatal efferent areas where this positive interaction is expressed.


A simplified technique for percutaneous endoscopic gastrostomy.

Percutaneous endoscopic gastrostomy (PEG) is the preferred method of establishing long-term enteral access for feeding. Many patients requiring PEG are elderly and at risk for complications. Expeditious placement of the gastrostomy tube will minimize complications, but distorted esophageal anatomy can significantly lengthen the procedure. Some endoscopists abandon conventional repeat gastroscopy in difficult cases to accelerate the procedure. The authors describe a reliable method for quick reinsertion of the endoscope which shortens time required for PEG, and may reduce complications.


Dopaminergic regulation of cortical acetylcholine release.

The extent to which the activity of basal forebrain cholinergic neurons is influenced by dopamine (DA) was investigated using in vivo microdialysis of cortical acetylcholine (ACh). Systemic administration of the DA receptor agonist apomorphine significantly increased dialysate concentrations of ACh. Systemic, but not local, administration of d-amphetamine produced similar effects. Both D1 (SCH 23390) and D2 (haloperidol, raclopride) DA receptor antagonists attenuated the amphetamine-induced increase in cortical ACh release; however, only the D1 antagonist significantly reduced basal output of cortical ACh. These findings suggest that the activity of cortically projecting cholinergic neurons in the nucleus basalis is regulated in an excitatory manner by central dopaminergic neurons and that both D1 and D2 receptors are involved.


Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity.

The influence of subthalamic nucleus (STN) afferents on dopaminergic (DA) neurons of the rat substantia nigra (SN) was investigated. Hemisections of the brain placed between the STN and the SN or located anterior to the STN caused an increase in the firing rate of DA cells without producing significant changes in their firing pattern. In contrast, electrolytic and ibotenic acid lesions of the STN resulted in 93% and 49% reductions, respectively, in the level of burst firing without affecting the firing rate of DA cells recorded in the lateral SN. Furthermore, procedures which interrupted the STN input to the SN produced rapid pacemaker-like firing in 18% of the lateral SN DA neurons recorded. Activation of the STN using single pulses of electrical stimulation caused: 1) a 20-50 msec inhibition of DA cell firing followed by an excitation, which in 35% of DA cells was accompanied by spikes occurring in a burst-like pattern, and 2) a short-latency inhibition lasting 5-25 msec in 75% of non-DA SN zona reticulata (ZR) neurons. On the other hand, stimulation of the STN for 1 minute at 20 Hz resulted in an initial decrease in DA cell burst firing followed by elevated firing rates and increased burst firing by 30-60 minutes after the stimulation. Pharmacological activation of the STN by infusion of bicuculline caused a rapid inhibition of DA cells followed by a two-fold increase in burst firing 6-14 minutes later, whereas SN ZR cells responded with an elevation in firing rate which dissipated in 6-14 minutes. Muscimol-induced STN inhibition produced complimentary biphasic changes in SN neuron firing: 1) an initial increase followed by a decrease in burst firing and firing rate of DA neurons and 2) a rapid inhibition followed by an excitation of ZR cells over a similar time course. Thus, the STN appears to exert a dual action on SN DA cells: 1) initial inhibition possibly mediated through STN excitation of the inhibitory SN ZR projections to DA cells, and 2) a facilitation of burst firing which may be a direct effect of excitatory STN afferents.


The hepatopulmonary syndrome: new name, old complexities.

On the basis of previous work, our own experience and findings, and the considerations discussed above, we propose a set of four diagnostic criteria for the hepatopulmonary syndrome: 1. presence of chronic hepatic disease (alcoholic, postnecrotic, or primary biliary cirrhosis or active chronic hepatitis)--severe liver dysfunction may not be mandatory; 2. absence of intrinsic cardiopulmonary disease, with normal chest radiograph or with nodular basal shadowing; 3. pulmonary gas exchange abnormalities--an increased alveolar-arterial oxygen gradient (> or = 2.0 kPa) with or without hypoxaemia; 4. the extrapulmonary appearance of intravenous radiolabelled microspheres or a positive contrast enhanced echocardiogram, suggesting intrapulmonary vascular abnormalities. Although these four criteria appear straightforward, there may be other features that are not always present--namely: 1. low transfer factor (diffusing capacity); 2. shortness of breath, with or without platypnoea and orthodeoxia; 3. increased cardiac output and reduced pulmonary vascular pressures; 4. small (or no) increase in pulmonary vascular resistance when the patient is breathing low oxygen mixtures. From the physiological viewpoint, the hepatopulmonary syndrome provides an excellent model for clinical research in the pathophysiology of pulmonary gas exchange. So far it has been possible to show that arterial hypoxaemia in this condition is (1) partitioned into components resulting from VA/Q mismatching, intrapulmonary shunt, and limitations of oxygen diffusion; (2) modulated by the interplay between the intrapulmonary and the extrapulmonary determinants of PaO2, such as cardiac output and minute ventilation; (3) vulnerable to the influence of inadequate pulmonary vascular tone; and (4) resolved when the injured liver is replaced and hepatic function is restored to within normal limits.


The accuracy of portable peak flow meters.

The variability of peak expiratory flow (PEF) is now commonly used in the diagnosis and management of asthma. It is essential for PEF meters to have a linear response in order to obtain an unbiased measurement of PEF variability. As the accuracy and linearity of portable PEF meters have not been rigorously tested in recent years this aspect of their performance has been investigated. The response of several portable PEF meters was tested with absolute standards of flow generated by a computer driven, servo controlled pump and their response was compared with that of a pneumotachograph. For each device tested the readings were highly repeatable to within the limits of accuracy with which the pointer position can be assessed by eye. The between instrument variation in reading for six identical devices expressed as a 95% confidence limit was, on average across the range of flows, +/- 8.5 l/min for the Mini-Wright, +/- 7.9 l/min for the Vitalograph, and +/- 6.4 l/min for the Ferraris. PEF meters based on the Wright meter all had similar error profiles with overreading of up to 80 l/min in the mid flow range from 300 to 500 l/min. This overreading was greatest for the Mini-Wright and Ferraris devices, and less so for the original Wright and Vitalograph meters. A Micro-Medical Turbine meter was accurate up to 400 l/min and then began to underread by up to 60 l/min at 720 l/min. For the low range devices the Vitalograph device was accurate to within 10 l/min up to 200 l/min, with the Mini-Wright overreading by up to 30 l/min above 150 l/min. Although the Mini-Wright, Ferraris, and Vitalograph meters gave remarkably repeatable results their error profiles for the full range meters will lead to important errors in recording PEF variability. This may lead to incorrect diagnosis and bias in implementing strategies of asthma treatment based on PEF measurement.


Randomised trial of inhaled steroids in preterm infants with respiratory symptoms at follow up.

Preterm infants often suffer from recurrent respiratory symptoms at follow up. Although these infants are responsive to treatment with bronchodilators some continue to wheeze or cough despite treatment. In a randomised double blind placebo controlled trial, the ability of inhaled steroids to reduce recurrent respiratory symptoms and the requirement for bronchodilator treatment in preterm infants less than two years of age has been assessed. Eighteen premature infants with mean gestational age 28 weeks and postnatal age 10.5 months were recruited. The study consisted of two six week treatment periods separated by a two week washout period. The infants received either 200 micrograms of beclomethasone dipropionate or placebo as one puff twice daily from an inhaler, through a spacer and a face mask. Parents kept a daily record of their infants' respiratory tract symptoms (wheeze and cough) and use of bronchodilators. Functional residual capacity (FRC) was measured at the beginning and end of each six week period. The symptom score was reduced by 37% in the active compared with the placebo period. During the active period the infants had a mean of 28 bronchodilator free days, compared with 22 days in the placebo period. The FRC improved significantly in the active but not the placebo period. Regular dosage with beclomethasone by inhalation is a useful treatment for preterm infants with respiratory symptoms.


Regional structure-function correlations in chronic obstructive lung disease measured with positron emission tomography.

Positron emission tomography, performed with isotopes of very short half life, can be used to relate local lung tissue density to local ventilation and to the ventilation:perfusion ratio. This method has been used in 10 patients with severe chronic airflow obstruction and differing values for carbon monoxide transfer factor (TLCO) and transfer coefficient (KCO). Ventilation (VA) and the ventilation:perfusion ratio (V/Q), lung density, and blood volume were measured regionally in a single transaxial section at mid-heart level with the patients in a supine position. Alveolar volume, extravascular tissue lung density, and perfusion (Q) were derived. Twenty five regions with abnormalities in the ventilation images were analysed. Tissue density showed a negative correlation with the ratio V/Q (r = 0.55) and a positive correlation with Q (r = 0.59) and blood volume (r = 0.65). In four patients with a low carbon monoxide transfer factor (TLCO) and transfer coefficient (KCO) < 50% predicted many regions with low VA had low tissue density and normal or high V/Q. On the other hand, in four patients with TLCO and KCO > 50% predicted many regions with low VA had normal or high tissue density and low values of V/Q. The other two patients had patterns between these two extremes. Individual ratios between mean values of tissue density and V/Q had a positive correlation with KCO (% pred; r = 0.79). These findings link structural differences with distinctive functional patterns; they reinforce the view that bronchial inflammation or oedema predominate in some patients with chronic airflow obstruction, whereas alveolar destruction is the major feature in others.


Inspiratory muscle strength and endurance during hyperinflation and histamine induced bronchoconstriction.

This study investigated whether the inspiratory muscles are susceptible to fatigue during acute airway narrowing because of increased airway resistance and hyperinflation. Asthmatic subjects performed up to four series (on separate days) of 18 maximal static inspiratory efforts of 10 seconds' duration with 10 second rest intervals (50% duty cycle; total duration six minutes): at functional residual capacity (FRC) (control); after histamine induced bronchoconstriction, which decreased forced expiratory volume in one second (FEV1) to a mean of 55% (SD 11%) of the initial value; at a voluntarily increased lung volume (initial volume held at 140% control); and after inhalation of histamine at a voluntarily increased lung volume. For the group of subjects the mean (SD) maximal inspiratory pressure (MIP) in the control experiments was 114 (22) cmH2O and the initial volume was 3.5 (1.2) 1. After histamine inhalation the initial lung volume for contractions increased to 118% (5%) of the control volume. In the high lung volume experiments initial volumes were 140% (12%) of the control (volume without histamine) and 140% (15%) (with histamine). The relation between MIP and initial absolute lung volume was determined for each subject before fatigue developed. When the inspiratory pressures for each contraction in the endurance test were normalised to the pressure expected for that lung volume, no significant differences were found between the four experimental conditions for MIP, or between pressures sustained over the 18 contractions. Histamine induced bronchoconstriction and hyperinflation had no detectable effect on inspiratory muscle strength or endurance in these asthmatic subjects.


Absence of seasonal variation in concentrations of the house dust mite allergen Der p1 in south Manchester homes.

House dust mite numbers and the concentration of its main allergen, Der p1, depend on ambient temperature and humidity and have been reported to show a seasonal variation in homes in the United States. A study was designed to find out whether Der p1 concentrations vary with the seasons in dust collected from homes in north west England. The concentration of Der p1 was measured in dust, collected every three months from April 1990 to April 1991, from mattresses and from bedroom and living room carpets in 40 houses in the south Manchester area. Twenty four hour recordings of indoor relative humidity were made in 20 houses during the sampling day. Mean concentrations of Der p1 from all three sources rose two to three fold in October. This was in contrast to the 1000 fold variation in concentrations of Der p1 present between houses within each season's sample and less than the 10 fold change considered to be of clinical importance. The autumn increase was paralleled by a rise in humidity. There was no statistical correlation, however, between Der p1 concentrations and relative humidity, house type, ventilation, or double glazing. The results suggest that seasonal variations in exposure to Der p1 exposure in north west England are small and unlikely to be of major clinical importance. The temperature and humidity data showed that the indoor environment remained relatively constant and conducive to mite growth throughout the year.


Intravenous pamidronate in the treatment of osteoporosis associated with corticosteroid dependent lung disease: an open pilot study.

Bisphosphonates have been shown to be effective agents in the treatment of postmenopausal osteoporosis. Because corticosteroid associated osteoporosis is often associated with increased bone turnover, the effect of intermittent intravenous infusions of pamidronate on this condition has been investigated. Seventeen patients (five male) with chronic corticosteroid dependent lung disease (15 asthma, two sarcoidosis) were treated with infusions of 30 mg pamidronate once every three months for one year. These patients had been taking an average of 14 (range 7.5-40) mg prednisolone a day for an average of 14 (range 3-30) years. Bone density measurements, by dual energy x ray absorptiometry, and radiography of the dorsolumbar spine were carried out before and one year after treatment. Bone formation was assessed by measurement of serum alkaline phosphatase and bone resorption by measurement of the fasting urinary hydroxyproline: creatinine ratio at the same time as densitometry and radiography were performed. Pretreatment density of L2-4 and the neck of the femur was significantly lower in these patients compared with a cohort of 100 age and sex matched controls (L2-4 (mean (SEM)): 0.906 (0.050) g/cm2 v 1.142 (0.016) g/cm2; neck of femur: 0.793 (0.030) g/cm2 v 0.936 (0.013)) g/cm2. After treatment there was a significant fall in serum alkaline phosphatase activity from (mean (SEM)) 220 (16) U/1 to 174 (9) U/1 (normal 80-280 U/1) and in the fasting urinary hydroxyproline:creatinine ratio from (mean (SEM) 0.040 (0.006) to 0.024 (0.003) (normal < 0.033). A significant rise was noted in L2-4 density to 0.927 (0.047) g/cm2; mean rise of 3.4%). No change was noted in density of the neck of the femur. Intermittent infusions of intravenous pamidronate would seem to be effective in both reducing turnover of bone and increasing bone density in corticosteroid induced osteoporosis associated with chronic lung disease. Longer term controlled studies are indicated.


Relation of serum elastin peptide concentration to age, FEV1, smoking habits, alcohol consumption, and protease inhibitor phenotype: an epidemiological study in working men.

In clinical investigations elastin peptide concentration has been proposed as one potential marker of lung elastin degradation. No epidemiological study has yet confirmed this hypothesis. The relation of elastin peptide concentration to some factors closely related to pulmonary emphysema (age, smoking habits, FEV1 alpha protease inhibitor (PI) phenotype) and to alcohol consumption was examined in an epidemiological study of 310 working men. The elastin peptides used for obtaining antibodies and as reference in an ELISA assay were prepared from chemically hydrolysed elastin. The elastin peptide concentration significantly decreased with age from 2.92 (1.54) micrograms/ml among subjects younger than 30 years to 2.18 (1.14) micrograms/ml among subjects older than 50. Elastin peptide concentration did not differ with smoking habits and was clearly unrelated to FEV1. A lower elastin peptide concentration was observed in all groups of subjects with a protease inhibitor phenotype other than PI MM (PI FM, IM, MP, MS, MZ, and S phenotypes). The results cast doubts on the usefulness of the elastin peptide concentration as a marker of lung destruction in middle aged, predominantly healthy men. Blood elastin peptide concentration may reflect both elastin degradation and resynthesis. The results of this analysis suggest that several factors (age, alcohol consumption, non-PI MM phenotype) may be associated with decreased resynthesis of lung elastin. Further studies, conducted in various age groups and including estimates of the degree of lung destruction, are needed to unravel the mechanisms underlying lysis and resynthesis of lung elastin.


Relation of measures of asthma severity and response to treatment to outcome in acute severe asthma.

It would be helpful if patients with asthma who require admission to hospital for an acute attack could be identified. The relation between the severity of an attack of asthma as determined by admission assessment and the eventual outcome was studied in 52 asthmatic patients aged 14 to 44 years and admitted to an asthma emergency room. The patient's history, including medication and previous admissions to hospital, was recorded and a clinical assessment, including a full inspiratory and expiratory flow-volume loop, was performed on four occasions: on admission, at two hours and at 12-18 hours after the start of a standardised treatment, and two weeks later on an outpatient basis. Patients who were discharged and who had an uneventful follow up at the two week assessment were defined as good responders. Patients who had to be admitted to hospital after 12 to 18 hours or were readmitted during the two weeks, or both, were defined as poor responders. Thirty eight patients were good responders and 14 were poor responders (seven admitted at 12 to 18 hours, seven returned to hospital). All four patients with a raised arterial carbon dioxide tension (PaCO2) (> or = 6 kPa) and the three with cyanosis were in the poor responder group, and this group had lower peak expiratory flow (PEF) values (21% v 30% predicted) on admission. There was, however, considerable overlap in PEF between the two groups and no clinical measure was able to distinguish between the good and the poor responders reliably. Poor responders had a history of more chronic systemic steroid administration, regular use of inhaled beta agonists, and asthma related hospital admissions. Nearly all the subjects showing a good response to standardised treatment had a PEF > 75% predicted and an FEV1 > 65% predicted 12 to 18 hours after the start of treatment. Prediction of outcome at admission was not possible in individual patients. A history of poor long term control of asthma, a PEF < 30% of predicted, a PaCO2 > or = 6 kPa, the presence of cyanosis, and lack of early response to treatment indicated a group of asthmatic patients who are less likely to respond to conventional emergency treatment over a short period.


Acute effect of inhaled bradykinin on tracheobronchial clearance in normal humans.

Bradykinin, a nonapeptide that contributes as a mediator to the pathogenesis of asthma, may affect lung mucociliary clearance, as it has been shown to be a potent secretagogue in canine airways and in human nasal mucosa in vivo. To evaluate this possibility the effect of inhaled bradykinin on mucociliary clearance has been studied in 10 healthy volunteers. Subjects attended the laboratory on two occasions to take part in tracheobronchial clearance studies using a non-invasive radioisotopic technique. Inhalation of radioaerosol was followed 30 minutes later by inhalation of either bradykinin (8 mg/ml) or vehicle placebo in a randomised, double blind fashion. After each inhalation the number of coughs was recorded. Whole lung radioactivity was measured every half hour for six hours with two collimated scintillation counters, and a tracheobronchial clearance curve was plotted for each subject on each occasion. Mucociliary clearance, expressed as the area under the tracheobronchial radioaerosol retention curve calculated for the first six hours (AUC0-6h), was greater in nine out of 10 subjects after inhalation of bradykinin than after placebo. The median values (range) for AUC0-6h were significantly reduced from 126% (78-232%)/h with placebo to 87% (51-133%)/h with bradykinin. It is concluded that acute exposure to inhaled bradykinin accelerates tracheobronchial clearance in normal human airways.


Respiratory disease in systemic lupus erythematosus: correlation with results of laboratory tests and histological appearance of muscle biopsy specimens.

In systemic lupus erythematosus, certain laboratory tests and evidence from muscle biopsy specimens of lymphocytic vasculitis reflect disease activity. A study was designed to determine if such indices predict respiratory lesions, and in particular whether the presence of vasculitis in quadriceps muscle reflects respiratory muscle function. Twenty seven 27 patients with systemic lupus erythematosus were studied, ten of whom were consecutive untreated patients and 17 having clinically active disease and being treated. They were prospectively evaluated on the basis of erythrocyte sedimentation rate, lymphocyte count, C3 degradation products, quadriceps muscle biopsy, spirometry, lung volumes, carbon monoxide transfer factor, and mouth pressure during a maximal sniff. Lung function test results were abnormal in 12 patients. Vital capacity was reduced in seven, carbon monoxide transfer factor capacity in five, and mouth pressure was low (< 70% predicted) in ten. Lymphocytic vasculitis was seen in the muscle biopsy specimens of ten patients. No correlation was found between laboratory tests and lung function or mouth pressure, or between the presence of lymphocytic vasculitis and mouth pressure. In untreated patients, those with lymphocytic vasculitis had lower spirometric values. In systemic lupus erythematosus, evidence from muscle biopsy specimens of lymphocytic vasculitis is not predictive of impaired inspiratory muscle function as measured by mouth pressure. In untreated patients there were relationships between some laboratory test results and respiratory function, but this was not the case for the whole group. In systemic lupus erythematosus, laboratory tests and evidence from muscle biopsy specimens of lymphocytic vasculitis are therefore unlikely to be helpful in the assessment of respiratory disease.


Measurement of maximal expiratory pressure: effect of holding the lips.

Minor differences in technique may account for the wide range of published normal values of maximum expiratory and inspiratory pressures. The effects of holding the lips while the subject performed a maximal expiratory pressure manoeuvre were investigated in this study. Maximum static expiratory pressures (PEmax) obtained with a cylindrical tube by means of lip compression by the subject and technician aided compression were compared in 20 men (mean age 27 years) and 20 women (mean age 28 years). Technician aided lip compression was associated with higher maximum expiratory pressure than compression by the subject in both men (195 v 110 cm H2O) and women (134 v 80 cm H2O). Compression of the lips and corners of the mouth should be performed by a trained technician for maximum expiratory pressure measurements when a cylindrical mouthpiece is used.


B lymphocyte accumulations in human pulmonary sarcoidosis.

Although cell mediated immunity is primarily thought to mediate the pathogenesis of sarcoidosis, the presence of immunoglobulins, immune complexes and complement suggests that processes of humoral immunity may contribute to immunopathology in sarcoid lesions. To test this hypothesis, the distribution of B lymphocytes in paraffin embedded sarcoid lesions in mediastinal lymph nodes and open lung biopsy specimens was investigated. Paraffin sections from eight open lung and 21 lymph node biopsies from sarcoid patients and five normal and five tuberculous lymph nodes from patients with tuberculosis were stained with a panel of monoclonal antibodies by means of avidin/biotin enhanced immunocytochemistry. Immunohistochemical analysis of the 29 biopsy specimens from the sarcoid patients revealed large numbers of B cells in the intergranulomatous regions. Further investigations in the open lung biopsy specimens indicated that these B cells were often organised into discrete circular or oval shaped aggregates with no germinal centre morphology, in which a few CD45RO memory T lymphocytes were scattered. The B cells were polyclonal, and a few plasma cells (IgM+, IgA+, IgG+) were identified. The finding of large numbers of B lymphocytes in sarcoid pulmonary lesions is in contrast to bronchoalveolar lavage studies, which have demonstrated proportions of 5% or less of B cells as a total of all immune cells, and therefore indicates that bronchoalveolar lavage may not correctly sample the immune cells of lung interstitial tissue in pulmonary sarcoidosis. The B cells at these sites are the possible origin of some of the humoral changes in the serum and lesions of sarcoid patients. They may also influence the pathogenesis of the disorder by presenting antigen(s) and forming immune complexes at sites of disease activity.


Carinal transplantation.

Current techniques of management of carinal lesions are not always satisfactory. Carinal transplantation, if feasible, would be valuable in certain circumstances. Carinal transplantation experiments were performed in dogs. In early cross transplant experiments there were problems in controlling ventilation and in obtaining satisfactory anastomoses, and the animals failed to live for even a few days. In seven subsequent experiments the carinal graft was removed from one dog and transplanted into a second dog. Two dogs lived for over four months with immunosuppression. The results suggest that carinal transplantation can succeed if (1) the calibre of the graft is matched with that of the recipient; (2) there is an abundant blood supply to the graft; (3) appropriate immunosuppression is provided; (4) ventilation is adequate during surgery.


Tuberculosis contact tracing: are the British Thoracic Society guidelines still appropriate?

The value of contact tracing in South Glamorgan for the period May 1987 to December 1989 was assessed. Tuberculosis was diagnosed in six (3.5%) of 170 close contacts. All were young and were detected in the initial screening. Tuberculosis was not found among 441 casual contacts. The value of follow up of contacts after the initial screening and of screening casual contacts in districts with a low prevalence of tuberculosis is questioned.


Unusual spinal tuberculosis after adequate chemotherapy for lymph node tuberculosis in an immunocompetent man.

A 35 year old man developed paraplegia due to an epidural mass 15 months after completion of a full chemotherapy course for pulmonary and lymph node Mycobacterium bovis infection. His cellular immune function was normal after treatment. It is suggested that the lesion was a granulomatous healing response rather than bacteriological recurrence.


Idiopathic pulmonary haemosiderosis: a form of microscopic polyarteritis?

Idiopathic pulmonary haemosiderosis remains a diagnosis of exclusion in patients who present with pulmonary alveolar haemorrhage. Systemic vasculitis developed in a patient with an eight year history of idiopathic pulmonary haemosiderosis. The diagnosis was confirmed by a rising titre of antineutrophil cytoplasmic antibodies directed against myeloperoxidase. Treatment with immunosuppressive agents resulted in complete resolution of symptoms and suppression of the antibodies. Measurement of antineutrophil cytoplasmic antibodies is recommended for all patients with pulmonary alveolar haemorrhage syndromes.


Extrinsic allergic alveolitis caused by goose feathers in a duvet.

A patient with extrinsic allergic alveolitis had precipitating antibodies to many avian antigens. A duvet containing goose feathers proved to be the source of antigenic material.


A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation.

Of 143 consecutive patients who survived at least 6 months after bone marrow transplantation (allogeneic [n = 131]; syngeneic [n = 5]; or autologous [n = 7]) and whose pulmonary function was evaluated before and on at least 2 occasions after BMT, 29 (20%) developed a chronic pulmonary syndrome without evidence for an infectious etiology. Twenty-eight (97%) presented with cough and 22 (76%) with dyspnea; abnormal chest signs were crackles in 23 (79%) and wheeze in 22 (76%). Chest roentgenogram showed pulmonary infiltrates in 15 (52%) cases but was normal in 14 (48%). All patients had major reductions in lung volumes (forced expiratory volume in 1 sec [FEV1]; relaxed vital capacity [VC]; and alveolar volume [VA]), and/or diffusing capacity (pulmonary diffusing capacity [TLCO] and single-breath carbon monoxide coefficient [KCO]). The obstructive component varied with only 18 (62%) patients developing overt airways obstruction (FEV1/VC < 75%), and in 6 of this group the fall in lung volumes preceded the onset of airways obstruction. Open lung biopsy (n = 4) showed both bronchiolitis obliterans and chronic patchy interstitial pneumonitis. The development of this syndrome was associated with acute (P < 0.001) and chronic (P < 0.0001) graft-versus-host disease of other organ systems. Twenty-four (83%) patients had a partial or complete response to immunosuppressive agents. Six (21%) have died, five (17%) of pulmonary complications. We suggest that this syndrome may be a manifestation of chronic GVHD involvement of the lung.


Lymphokine-activated killer cells in autologous bone marrow transplantation. Evidence against inhibition of engraftment in vivo.

Lymphokine activated killer cells have potent antitumor effect both in vitro and in vivo. They have been reported to suppress bone marrow (BM) progenitor cell activity (PCA) in vitro, thus raising concern about the feasibility of their use after autologous bone marrow transplantation. The present study was carried out to evaluate the effect of LAK cells on BM engraftment in a syngeneic BMT setting in mice. LAK cells supplemented with or without exogenous interleukin-2 therapy did not impair the hematopoietic reconstitution or survival of mice undergoing BMT. LAK cells also did not reduce the PCA of the engrafted BM. LAK cell therapy did not cause graft-versus-host disease. Finally, LAK cells supplemented with IL-2 therapy improved the graft-versus-leukemia effect. These findings suggest that LAK cells plus IL-2 therapy after BMT does not impede hematopoiesis and should be evaluated as an adjuvant therapy with the aim of eradication of minimal residual disease after autologous BMT.


The requirement for allogeneic chimerism for second transfer of tolerance from mixed allogeneic chimeras (A+B-->A) to secondary recipients.

We have applied the model of mixed allogeneic chimerism (A+B-->A), in which stem cells from both allogeneic and syngeneic donor engraft, to determine the in vivo cellular requirements for transfer of tolerance from mixed chimeras to secondary recipients. Using two approaches, we have demonstrated that the persistence of donor-specific transplantation tolerance is dependent on the presence of bone-marrow-derived cells. When untreated bone marrow from mixed chimeras was transferred to irradiated secondary recipient mice, most of the secondary recipients were rescued, but only 48% were demonstrably chimeric. This pattern of repopulation, therefore, allowed us to examine whether chimerism was required to maintain transplantation tolerance. In all of our studies, the presence of allogeneic chimerism was required for successful transfer of tolerance from mixed allogeneic chimeras to irradiated secondary recipients. Only those secondary recipients which repopulated with demonstrable allogeneic chimerism exhibited in vivo and in vitro evidence for transfer of donor-specific transplantation tolerance. These results were confirmed by using transfer of bone marrow from mixed chimeras depleted of allogeneic class I elements. In an attempt to identify a putative population of suppressor cells, second transfer of splenic lymphoid cells from mixed allogeneic chimeras, containing approximately 6 times more T-lymphocytes that were functionally tolerant to donor alloantigens, was also performed with similar results. These data suggest that the in vivo maintenance of tolerance to MHC transplantation alloantigens requires persistence of donor bone marrow-derived alloantigens.


The role of T suppressor cells in the maintenance of spontaneously accepted orthotopic rat liver allografts.

Orthotopic liver allografts from BN donors to LEW recipients are spontaneously accepted, and the recipients develop donor-specific immunological unresponsiveness. This unresponsiveness may be mediated by suppressor T cells. Immunomagnetically purified splenic T cells from LEW rats bearing BN liver grafts were shown to adoptively transfer suppression of skin, heart, and kidney graft rejection in a donor-specific manner, prolonging the survival of BN but not third-party DA grafts. However, the suppressor T cells were sessile, being resident in the spleen but not present in thoracic duct lymph. The presence of a nonrecirculating suppressor T cell in rats spontaneously accepting liver transplants is strongly suggestive of an important function in the maintenance of donor-specific unresponsiveness, although the contribution of other possible mechanisms of unresponsiveness has not been investigated.


The effects of rapamycin on humoral immunity in vivo. Suppression of primary responses but not of ongoing alloantibody synthesis or memory responses.

The effect of rapamycin on primary and secondary alloantibody responses to major histocompatibility complex class I antigens was investigated in inbred rat strains. Primary anti-MHC class I alloantibody responses, detected by indirect hemagglutination and complement-dependent cytotoxicity assays, were abrogated in high-responder WAG (RT1u) recipients of DA (RT1a) blood transfusions, given on days 0 and 7 of a 14-day course of rapamycin (3 mg/kg/day). Antibody class studies showed that both IgM and IgG responses were equally effectively inhibited. Moreover, when these animals were rechallenged with DA transfusions, 28 days after drug withdrawal, they exhibited donor-specific humoral unresponsiveness. Similar results were observed in cyclosporine-treated rats. In preimmunized high-responder LEW (RT1(1)) rats with high titer anti-DA class I alloantibodies, a 35-day course of rapamycin (3 mg/kg/day) had no significant suppressive effect on serum alloantibody levels when compared with untreated preimmunized control animals. WAG rats were immunized by DA transfusions and serum antibody levels then allowed to decay over 16 weeks. The animals were then challenged with a further DA transfusion given on the second day of a 14-day course of rapamycin (3 mg/kg/day). Alloantibody responses to the challenge transfusion in this group were not, however, significantly suppressed when compared with a non-drug-treated control group. The results of this study indicate that rapamycin is a potent inhibitor of primary alloantibody synthesis in high-responder rat strains, but does not significantly suppress alloantibody synthesis in animals with established humoral reactivity. These results may be of relevance if rapamycin is to be used in clinical renal transplantation, because in man similar antibodies mediate hyperacute rejection, and when they develop after transplantation are associated with very high rates of rejection.


Evidence that stimulator cell-derived IL-6 and IL-1 are released in the mixed lymphocyte culture but are not requisite for responder T cell proliferation.

We investigated whether IL-6 and (or) IL-1 are crucial costimulatory signals in the human MLC with purified responder T cells. With allogeneic PBMC as stimulators, IL-6 and IL-1 were rapidly produced, and reached plateau values of 100-300 U/ml and 200-500 pg/ml after 24 hr, respectively. Irradiated or mitomycin-c treated PBMC could easily be induced (with LPS) to produce IL-6 and IL-1 while no activity was measured after 48 hr in the supernatant of PHA-stimulated T cells, suggesting that in the MLC the monokines were entirely produced by stimulator PBMC. In cultures of responder T cells and stimulator B cells, no IL-6 and IL-1 activity was measured in the supernatant, and only a marginal proliferative response was found. Exogenous IL-6 and IL-1 increased in a dose-dependent way the B-cell-induced alloresponse and induced significant cytotoxicity in the responder cells. Antisera to IL-6 and IL-1 totally inhibited the induced response. The proliferation was accompanied by increased IL-2 production and IL-2R expression. Preincubation of B cells with IL-6 and IL-1 did not improve the proliferation, suggesting direct effects of IL-6 and IL-1 on the T cells. The proliferative responses induced by B cells and exogenous IL-6 and IL-1 represented a fraction of those induced by PBMC. Moreover, in PBMC-stimulated cultures exogenous IL-6 and IL-1 or antisera to these lymphokines did not significantly alter proliferative responses, cytotoxicity, IL-2 levels in the supernatant, or IL-2R expression on responder T cells. We conclude that a role for IL-6 and IL-1 in allogeneic T cell stimulation can be demonstrated in conditions of suboptimal stimulation with B cells. With PBMC, neutralizing antisera to these cytokines do not seem to inhibit the proliferative response, suggesting that these cells are superior in alloantigen presentation either by producing various costimulatory signals or by the fact that due to cell-cell contact stimulator cell-derived monokines cannot be blocked. This finding makes it unlikely that antimonokine therapy will be useful in transplantation.


Indefinite survival of MHC class I-deficient murine pancreatic islet allografts.

To examine the immune response to class I-deficient allogeneic tissue, we used beta 2-microglobulin-deficient mice as graft donors. These mice lack cell surface class I major histocompatibility complex antigen expression. Pancreatic islet allografts from class I-deficient donors survived indefinitely in a majority of fully allogeneic BALB/c recipients. In contrast, host recognition of graft class I antigen was unnecessary for prompt destruction of skin allografts of for autoimmune damage of transplanted pancreatic islet grafts in nonobese diabetic mice. These studies provide evidence that intentional genetic elimination of immunologically relevant donor antigens may prove an effective strategy for preventing allograft rejection.


Induction of specific unresponsiveness (tolerance) to skin allografts by intrathymic donor-specific splenocyte injection in antilymphocyte serum-treated mice.

Although chronic immunosuppression has been extremely successful in clinical organ transplantation, it is associated with severe complications such as opportunistic infections, spontaneous neoplasms, drug toxicities, metabolic complications, and the inability to control rejection. We therefore have investigated the ability of allogeneic donor lymphoid cells to produce specific tolerance following intrathymic (IT) injection into allograft recipients. Groups of B6AF1 mice received ALS on days -1 and +2 relative to C3H/He skin grafts on day 0; experimental groups received 1, 5, or 10 x 10(7) syngeneic (B6AF1) or allogeneic (C3H) spleen cells (SPCs) by IT injection on day +7. IT injection of C3H splenocytes significantly prolonged allograft survival at all cell doses tested when compared with ALS controls. The best survival was obtained following IT injection of 5 x 10(7) C3H cells (median survival time [MST] = 132 days; ALS controls = 21.5 days), with 8 of 13 skin grafts surviving longer than 100 days. IT injection of syngeneic splenocytes or third-party DBA/2 splenocytes did not prolong allograft survival beyond that observed in ALS controls. C3H spleen cells injected IT into ALS treated mice on day 0 relative to grafting of C3H skin also produced significant allograft survival (1, 5, or 10 x 10(7) SPCs = MSTs of 75, 47, and 35, respectively) but the results were inferior to those obtained by 5 x 10(7) SPCs IT on day +7. Spleen cells (1 or 5 x 10(7)) injected intraperitoneally or intravenously prolonged allograft survival beyond that seen in ALS controls but were inferior to IT injection at all doses and times studied. Bone marrow, thymocytes, or lymph node cells (5 x 10(7) cells) were substituted for SPCs for IT injection. IT injection of BM, LN or thymocytes all significantly prolonged graft survival over ALS controls. However none of these cell types was as effective as IT splenocytes. Eight B6Af1 recipients of IT splenocytes bearing C3H skin grafts for > 100 days received a second C3H skin graft as well as a simultaneous third-party B10.AKM skin graft. All rejected third-party grafts in normal first-set fashion. Three tolerated both 1st and 2nd C3H grafts without any sign of rejection; 1 rejected the 2nd C3H graft while tolerating the 1st graft; and 4 rejected the 2nd C3H graft in an attenuated fashion but also rejected the 1st graft at the same pace.(ABSTRACT TRUNCATED AT 400 WORDS)


Absence of hepatitis delta virus infection in chronic hemodialysis and kidney transplant patients in france.

Hemodialyzed patients and kidney recipients are frequently multiply-transfused and infected by hepatitis B virus (HBV). Hepatitis delta virus (HDV) has a symbiotic association with HBV. The prevalence of HDV infection has, surprisingly, not been assessed in patients in hemodialysis or renal transplantation setting. We retrospectively studied the prevalence of serum delta antigen and antidelta antibodies by a microenzyme-linked immunosorbent assay in 77 of the 80 HBsAg-positive patients who underwent a kidney transplantation over a 10-year period. Of these patients, 73% had active HBV replication as assessed by the presence of serum HBV DNA and 65% had a biopsy-proved chronic active hepatitis, including cirrhosis. None of our patients had any marker of HDV infection at the end of the hemodialysis period or at the end of follow-up in transplantation. These results establish that HDV superinfection has indeed been extremely rare during end-stage renal failure and kidney transplantation in France, in contrast to HBV reactivation or hepatitis C virus infection.


One-year monkey heart xenograft survival in cyclosporine-treated baboons. Suppression of the xenoantibody response with total-lymphoid irradiation.

The shortage of cadaveric human organs for transplantation could be alleviated by the use of xenografts. Long-term (> one-year) survival of xenografts in humans or experimental animals has not been achieved with previous immunosuppressive protocols. Poor results in xenotransplantation compared with allotransplantation have been attributed to a more potent antibody response rather than to cell-mediated responses. To investigate these issues a concordant heterotopic cardiac xenograft model was developed in conjunction with cyclosporine and/or total-lymphoid irradiation. Concordant models permit examination of xenoantigen induced antibody and cell-mediated responses since preformed humoral factors (in discordant models) do not cause hyperacute rejection. Four groups of baboon recipients received cervical heart transplants from cynomolgous monkeys. Group I (n = 2), untreated, mean survival (MS) = 6 days; group II (n = 5), CsA and methylprednisolone, MS = 25 days; group III (n = 3), preoperative TLI, MS = 29 days; group IV (n = 6), preoperative TLI and CsA+MP, MS = 255 days (> 77, > 108, > 142, 184, > 480, 540 days). Heart xenografts of CsA-MP-treated recipients appear to be destroyed predominantly by antibody (IgM)-mediated processes whereas cell-mediated rejection is likely the major reaction in TLI-treated recipients. CsA-MP-treated recipients had early immunohistochemical evidence of antibody and complement-mediated rejection (deposition of IgM and complement but not IgG on heart xenografts). In contrast IgM and complement deposits were not detected on heart xenografts in TLI- and TLI-CsA-treated recipients. IgG xenoantibodies were only detected on the two rejected heart grafts of TLI-CsA-treated recipients. CsA-MP-treated recipients rapidly developed high xenoantibody titers (1:256 to 1:512) that immediately preceded rejection. In contrast, TLI-treated animals developed lower levels of xenoantibody (< or = 1:8) and TLI-CsA-treated recipients had no detectable xenoantibody during the initial three months after transplantation (and titers no greater than 1:8 thereafter.) The lack of xenoantibody was likely not due to a generalized inhibitory effect of the immunosuppressants on B cell function since all classes of serum immunoglobulins were in the normal range. Intragraft cytolytic lymphocyte activity was detected in rejecting TLI- and TLI-CsA-treated recipients but could not be detected in xenografts of CsA-MP-treated recipients. One explanation for these data is that TLI (either directly or indirectly) induces a state of specific B cell unresponsiveness to monkey xenoantigens, thereby preventing IgM mediated rejection in the third week after transplantation.(ABSTRACT TRUNCATED AT 400 WORDS)


Prolonged adult skin allograft survival as a result of cotransplantation with neonatal tissue. The requirement for antigen sharing between graft and cotransplant.

The survival of an adult skin allograft can be prolonged by a cotransplant of neonatal, but not adult, skin on the same recipient. We demonstrated this phenomenon using a C3HeB/FeJ (H-2k; C3H) adult graft and neonatal cotransplant donors. The median survival time (MST) for adult graft survival on B6AF1 (H-2a/b) recipients was 59 days on recipients treated with antilymphocyte serum and donor bone marrow cells. With adult or neonatal cotransplants, the MSTs for adult graft survival were 55 and > 100 days, respectively. Our current experiments explore the specificity of this phenomenon by substituting neonatal cotransplants of several allogeneic and partially allogeneic strains. Cotransplants that do not share the antigens presented by the adult graft to the recipient as foreign do not produce any prolongation of adult graft survival. Thus, cotransplants of adult or neonatal C57BL/6J (H-2b) or A/J (H-2a) strain skins had no significant effect on adult C3H graft survival. In contrast to these results, neonatal (but not adult) cotransplants that share presented antigens produce a significant cotransplant effect. The presence, on a recipient, of a neonatal cotransplant of CBA/J (H-2k) resulted in significant prolongation of adult skin grafts (MST > 150 days; P < 0.05). As well, on a different recipient strain (CAF1; H-2a/d), neonatal C3H-H-2o2/SfSn (H-2o2) skin cotransplants, sharing only background antigens and H-2Dk with the adult graft donor, caused a significant prolongation of adult graft survival relative to that seen on recipients bearing only a single adult graft (MSTs = 53 and 31 days; P < 0.05). Our results suggest that this graft-prolonging effect of neonatal cotransplantation requires that the cotransplant shares antigens with the adult graft that are presented as foreign to the recipient.


Technetium-99m sulfur colloid accumulation as a predictor of acute renal transplant rejection.

Renal transplantation is the preferred treatment for end-stage renal disease in children. Most transplant failures are due to allograft rejection. To date, only histopathological findings on renal biopsy can establish this diagnosis. Prior to the availability of cyclosporine, technetium-99m sulfur colloid nuclear scans (TSC) were used in a limited number of institutions to detect rejection episodes. The purpose of this study was to determine whether TSC could predict acute rejection in the cyclosporine era. A prospective study involving 41 pediatric renal transplant patients (M = 25, F = 16) was conducted from 6/1/89 to 10/31/91. Patients who received a TSC and biopsy (41 patients, 62 studies) within one week of clinical and laboratory evidence of acute rejection were included in the study. A qualitative method of determining sulfur colloid uptake was used by comparing allograft uptake with that of the fifth lumbar vertebrae (L5) marrow uptake: 3(+)--allograft with greater than L5 marrow uptake, 2(+)--same as, 1(+)--less than, and 0--no allograft uptake. Transplant accumulation of > or = 2+ was considered consistent with acute rejection (P < 0.001). Acute rejection was noted in 53 of 62 renal biopsies. Of those with biopsy-proved acute rejection, SC was positive (> or = 2+) in 46 of 53. SC of > or = 2+ has proved to be a good predictor of acute rejection. This technique has a sensitivity of 98%, specificity of 53%, positive predictive value of 87%, and negative predictive value of 89%.


Impaired fibrinolysis in cyclosporine-treated renal transplant patients. Analysis of the defect and beneficial effect of fish-oil.

Cyclosporine treatment has been associated with thrombotic vascular complications. We investigated the activity of the fibrinolytic system and its capacity to respond upon DDAVP stimulation in a group of 20 cyclosporine-treated patients as compared with a group of 9 azathioprine-treated patients. Furthermore, the effect of the administration of fish-oil to these patients on the endogenous fibrinolytic activity was studied in a double-blind randomized, placebo-controlled cross-over study. The cyclosporine-treated patients showed a significantly reduced plasminogen activator activity and plasmin generation response upon the infusion of DDAVP as compared with the azathioprine group. In the cyclosporine group 60% of the patients had an impaired fibrinolytic response, whereas this was found in only 11% of the azathioprine-treated patients (P < 0.05). The impairment of the endogenous fibrinolysis activity could be attributed either to a defective release of plasminogen activator from the vessel wall (67% of patients) or to high plasma levels of plasminogen activator inhibitor 1 (33% of patients). Administration of fish-oil resulted in a significant improvement of the impaired fibrinolysis in the cyclosporine group. Particularly, in patients with a defective release of plasminogen activator from the vessel wall, fish-oil treatment resulted in a normalization of the fibrinolytic activity. These results indicate that cyclosporine treatment induces an impaired fibrinolysis that may contribute to the frequent occurrence of thromboembolic complications and eventually the impairment of renal function in cyclosporine-treated patients. The beneficial effect of the administration of fish-oil on the endogenous fibrinolysis may result in a reduction of the adverse events associated with cyclosporine treatment.


Analyses of the risk and operative stress for donors in living-related partial liver transplantation.

Operative risk and stress were analyzed in 28 parent-donors whose children received partial liver transplantations at the Second Department of Surgery, Kyoto University Hospital between June 1990 and December 1991. Graft-harvesting operations were classified into three types: left lobectomy (group L, n = 12), left lateral segmentectomy (group S, n = 15), and right lobectomy (n = 1). Since donor safety is a primary concern, great care was taken to minimize potential damage to the remaining lobes of the donor liver as well as the graft liver by avoiding stressful maneuvers such as hepatic vascular clamping during the transection of the hepatic parenchyma. In all cases the arterial ketone body ratio, which reflects the hepatic mitochondrial redox potential, was maintained at over 0.7 throughout the donor operation as well as postoperatively. There was no significant difference in the postoperative RBC, WBC, serum GOT, and total bilirubin between groups L and S, although the abnormalities exhibited by the single right lobectomy case tended to be larger and more prolonged. All cases were within the range acceptable for immediate discharge, and all donors of groups L and S were subsequently discharged within 14 days without any postoperative complications. The single right lobectomy donor was discharged on POD17 because of transient slight icterus, which is the only postoperative complication encountered in this series thus far. The present analyses would indicate that the risk and operative stress to the donor in living-related partial liver transplantation can be minimal when the left lobe or left lateral segment of the liver is used for the graft.


Lipid status after combined pancreas-kidney transplantation and kidney transplantation alone in type I diabetes mellitus.

This study was designed to compare changes in lipid status following organ transplantation between type I diabetes mellitus (DM-I) patients receiving combined pancreas-kidney transplantation (PKT) with those receiving kidney transplantation alone (KTA). A retrospective chart review was used to identify pre- and posttransplantation fasting total cholesterol (TC) and triglycerides (TG) in three groups: DM-I patients receiving KTA (DM:KTA; n = 14), DM-I patients receiving PKT (DM:PKT; n = 20), and kidney transplant recipients without DM (NDM; n = 16). The groups were matched for age, gender, weight, duration of dialysis, smoking history, and duration of diabetes mellitus. Linear regression was used to analyze differences in lipid trends over time (up to 24 months posttransplantation) and the effects of prednisone dose, cyclosporine dose, and serum creatinine. Preoperative TC was significantly lower in the DM:KTA group (P < 0.05) compared with DM:PKT or NDM. There were no significant differences in preoperative TG between the three groups. TC and TG decreased over time only in DM:PKT (P = 0.0112, P = 0.0278, respectively). TC increased and TG was unchanged over time in DM:KTA (P = 0.0003, P = 0.1103, respectively). Neither TC nor TG changed over time in NDM. Trends of TC and TG for DM:PKT were significantly different from DM:KTA (P < 0.01 for both). Trend of TC for NDM was also significantly different from DM:PKT (P = 0.0061). Prednisone dose was significantly related to TC in DM:KTA and NDM (P < 0.01) while cyclosporine dose was significantly related to TC for DM:KTA only (P = 0.0013) in the presence of time. None of the variables tested (prednisone dose, cyclosporine dose, and serum creatinine) significantly affected TG in the presence of time. In summary, TC and TG decreased over time only in DM:PKT. In contrast, TC increased while TG was unchanged in DM:KTA over the same interval (0-24 months). If these trends continue, the beneficial change in lipids in the DM:PKT group may translate into a net improvement in atherosclerosis-mediated events for diabetic patients with chronic renal failure who receive PKT compared with those who do not.


Evidence that antihuman tumor necrosis factor monoclonal antibody prevents OKT3-induced acute syndrome.

We have used an antihuman tumor necrosis factor monoclonal antibody, CB006 (murine IgG1), to prevent the OKT3-induced acute clinical syndrome. This syndrome is due to the massive, although transient release in the circulation of various cytokines (TNF, interferon gamma, interleukin 2, interleukin 6) and represents one important side effect linked to in vivo use of OKT3. Fourteen kidney allograft recipients undergoing prophylactic OKT3 therapy were treated with CB006 in a single i.v. injection of either 0.4 mg/kg (group I, 7 patients) or 2 mg/kg (group II, 7 patients), 1 hr before the first OKT3 administration. Nineteen consecutive patients formed a historical control group. None of the CB006-pretreated patients showed any of the common, severe OKT3-associated symptoms (hypotension, respiratory distress, or neurotoxicity), which were observed in 10% of the historical controls. In addition, CB006-treated patients showed a lower frequency of pyrexia (> or = 39 degrees C) and gastrointestinal symptoms. None of the CB006-treated patients presented severe vomiting or diarrhea, defined as repeated episodes inducing significant fluid and electrolyte loss. Two out of the 7 patients in group I and group II had mild transitory diarrhea. Mild single vomiting episodes occurred in 2 group I patients and 3 group II patients. At variance in all controls, gastrointestinal symptoms were long lasting and associated with major prostration due to electrolyte and fluid loss. Importantly, CB006-treated patients who presented mild symptoms had detectable bioactive circulating TNF, showing incomplete inactivation of OKT3-induced TNF by CB006. CB006 was perfectly well tolerated, did not induce xenosensitization, and did not affect the biological or clinical effectiveness of OKT3.


Evolutionary and immunological aspects of xenotransplantation.

Immunological aspects in xenotransplantation are directly linked to evolutionary aspects. The immunological network with its high antigen specificity and species-specific interactions was developed to fight against the host's outside world including xenografts. The tremendous amount of reaction and mechanisms triggered by the performed natural antibody-endothelial cell reaction clearly indicates that only basic changes might overcome these problems. Even the introduction of transgenic donors might not be sufficient to modify more than one parameter, for example, complement activity. Total depletion of preformed natural antibodies is not compatible with normal life and the regulation of hormones and enzymes under xenogeneic conditions has just been discovered. Cellular mechanisms depend, as far as we know, on the delicate system of receptors, interleukins, and MHC antigens. From today's very early results we know that major changes exist already between closely related species. The investigation of xenogenic mechanisms has opened a totally new field of immunological interactions. Up to now there are no signs of solution to bridge clinically relevant times with xenogenic organs from widely divergent suitable donors with promising quality of life.


Some ethical issues in organ retrieval, 1982 to 1992.

The debate on incentive payments and related issues will continue so long as dialysis and cadaver donation remain out of the reach of physicians in developing countries. This article (from a Western doctor) steps outside the usual debate on these issues by making a practical suggestion which aims at easing the ethical tension of incentive donation rather than insisting on its abolition. "Donors' trusts" may help the situation in India, but should not be applied in any country where effective dialysis is generally available. Nor would I be happy for such a model to be developed in any country where the aim to introduce cadaveric organ donation was not being energetically pursued.


Effect of anti-HLA and anti-idiotypic antibodies on the long-term survival of heart and kidney allografts.

Long-term survival of heart and kidney allografts is threatened by the development of chronic rejection. Analysis of the relationship between reversible acute rejection episodes and actuarial survival at 5 years showed an inverse correlation suggesting that early cellular events may trigger antibody-mediated chronic rejection. In both heart and kidney allograft recipients producing anti-HLA antibodies we found a significant decrease in the 5-year graft survival rate. However, there was heterogeneity among anti-HLA antibody producers with respect to the development of anti-idiotypic antibodies. The actuarial 5-year graft survival was significantly higher in patients with Ab2 compared to patients without.


Effect of recipient gender and race on heart and kidney allograft survival.

Study of long-term survival of heart allografts shows that AA males and females have lower graft survival rates than those observed in NAC recipients. Primary kidney allografts in AA males, but not females, also display lower 5-year survival rates compared to those observed in the corresponding populations of NAC. Comparison of graft survival in the overall population of male and female recipients of kidney allografts shows that females have higher graft survival rates, probably as a result of better HLA matching. The level of alloantibody activity in posttransplantation sera is similar in the two populations, suggesting that factors other than HLA mismatching may contribute to the higher degree of graft failure in AA recipients.


Pathogenesis of human reactive-appearing "non-monomorphous" malignant lymphoproliferative disorders: a hypothesis.

Human reactive-appearing "non-monomorphous" malignant disorders, such as Hodgkin's disease, T-cell-rich B-cell lymphomas and angioimmunoblastic lymphadenopathy display a peculiar and unifying characteristic, which biologically differentiates them from "monomorphous" non-Hodgkin's lymphomas. It consists in the coexistence within the pathologic tissue of a polyclonal, normal-appearing, presumed reactive cellular component, mainly composed of T-lymphocytes together with a clonal cell component constituting a minority of the pathologic mass. To explain the long-lasting coexistence of such polymorphic cell populations in the pathologic tissue of synchronous and metachronous localizations of the disease, it is hypothesized that they are interconnected by "biological interactions" which determine and sustain the pathologic process. Based on the biological characteristics of an experimental model (the follicular center cell "lymphoma" of the SJL murine strain), it is suggested that these human "non-monomorphous" malignant diseases should be regarded as a continuous spectrum of lymphoproliferative disorders sustained by a biological loop which interconnects different cell populations able to stimulate each other for growth.


Adjuvant chemotherapy for cancer of gastrointestinal tract: a critical review.

Surgery is the only curative therapeutic approach for gastrointestinal tumors. If the tumor is deeply infiltrating through serosa or invading regional lymph nodes, the 5-year patient's survival is about 60% and < 40%, respectively. The natural history and prognosis of neoplasms from colon, rectum and stomach are different. Despite the unsatisfactory results obtained with radical treatment of advanced disease, there are positive studies on adjuvant treatment of colon and rectal cancer, whereas the role of such an approach is still controversial for gastric cancer. The combination of fluorouracil containing chemotherapy with radiotherapy was suggested as the most effective adjuvant treatment for patients with Dukes' B and C rectal cancer. However, the choice of chemotherapeutic regimen is still debated. A recent report, from the North Central Cancer Tumor Group, stated survival and disease-free survival advantages for patients with Dukes' C colon cancer treated with FU + levamisole for 1 year after radical surgery. Since this regimen was not proven effective in advanced disease, ongoing adjuvant trials are comparing it with the combination of FU + biochemical modulator. The role of adjuvant therapy for gastric cancer is debated. The recent development of regimens active on advanced disease result in more promising future adjuvant trials.


Dietary habits, internal migration and social class in a sample of a northern Italian population.

The study of migrants has generated interesting hypotheses on the etiology of different types of cancer. In particular, it has been suggested that both colon and breast cancer could be related to living conditions, including diet, in the country of immigration. Considerable internal migration occurred in Italy in the sixties. We studied a random sample of 1,400 subjects living in the city of Torino and the province of Varese. They were interviewed with a detailed questionnaire about their dietary habits, and the consumption of several nutrients was considered according to the area of birth and social class. The hypothesis we tested was whether, after controlling for social class, there were different dietary habits among the migrants and the native population, and whether such differences could help in the formulation of etiologic hypotheses on cancer. We found that the intake of saturated fatty acids and cholesterol was lower among the migrants from the south, whereas they consumed higher levels of vegetables than people born in the north. The different intake of saturated fatty acids and cholesterol seemed to be attributable mainly to the consumption of butter, for which the south/north ratio was as low as 0.47 in men and 0.56 in women. Important gradients by social class were also suggested for several nutrients.


Spontaneous screening for cervical cancer and diagnostic histories of incident cases.

Cytologic and colposcopic histories of cases of invasive cervical cancer and cervical intraepithelial neoplasia grade III (CIN III) registered in Ravenna (northern Italy) between 1986 and 1990 were evaluated. During the 5 years prior to diagnosis, 10/49 invasive cancer patients and 25/61 CIN III patients had had at least one pap smear reported as negative. At the time of the most recent false-negative report, 9/10 and 17/25 of these cases had been recommended for a repeat smear within 2 to 6 months. Of the 9 patients with invasive cancer, 5 had also undergone an inconclusive colposcopy (with biopsy unperformed). Among invasive cancer patients aged under 50, half of incident cases (7/14) and most of those with some cytologic experience (7/8) had had a false-negative report; each of these patients (7/7) had been recommended for an early repeat smear. For invasive cancer patients as well as for CIN III patients, the suggested intervals for the early repeat were largely exceeded. Median delay in diagnosis was about 2 years. Although the frequency of negative reports recommending repeat smears within a few months was estimated to be some 10% of total screening patients, current concepts in cervical cytology suggest that cancer cases with such false-negative reports should be regarded as follow-up failures rather than laboratory errors. In fact, they passed quite unnoticed. In unplanned (spontaneous) cervical screening practice, sensitivity needs to be maximized, but even the occurrence of false-negative cases is not monitored. The present study points out what may result from such a contradiction.


Risk of infiltrating breast cancer subsequent to lobular carcinoma in situ. The Coordinating Center and Writing Committee of FONCAM (National Task Force for Breast Cancer).

The authors report on a retrospective consecutive multicentric series of 60 cases with histologic evidence of lobular carcinoma in situ (LCIS), followed for an average of 5.3 years. In the course of the follow-up, ipsilateral LCIS or infiltrating carcinoma occurred in 3 or 5 cases, respectively. Two LCIS reoccurrences and all ipsilateral infiltrating carcinomas were observed in 37 patients treated by limited surgery. Contralateral synchronous or metachronous carcinoma was observed in 3 or 2 cases, respectively (intraductal = 3, infiltrating = 2). Three patients died of breast cancer (2 with ipsilateral, 1 with ipsilateral and contralateral infiltrating carcinoma). The study confirms the higher risk of ipsilateral and contralateral cancer in LCIS patients and warns about the possible hazards of limited surgery in these cases.


Histopathologic classification of breast cancer in Sweden and Italy: a comparison between two pathologists.

Two large series of breast cancers (BC), identified in the Pathology Departments of Malmö (Sweden) and Florence (Italy), were independently reviewed by two experienced pathologists, one from each department. Overall, comparison of diagnoses of 372 BCs according to a simplified WHO histologic classification system (in four combined categories) revealed agreement for 74% of the cases. Concordance, as measured by the kappa statistic, was relatively good (0.53 overall). Kappa values for specific categories were also acceptable, being highest for "invasive lobular" BC (0.63) and lowest for "other types" (0.45). The kappa value for "noninvasive" versus all other categories of invasive BC was 0.53. Some BCs were systematically classified as "noninvasive" by one pathologist and as "invasive ductal with a predominant intraductal component" by the other. Invasive lobular BCs were also diagnosed more frequently by one pathologist. These findings suggest that when planning geographical or temporal comparisons of distribution for BC histologic categories, standardization of classification and a centralized review may play an important role.


Chromosome changes in renal cell carcinoma.

Cytogenetic studies have provided a great deal of useful information about the biology and diagnosis of renal cell tumors. Particularly papillary and non-papillary tumors seem to be characterized by different cytogenetic patterns. We report the cytogenetic and histologic analysis of 16 renal tumors, 5 of which showed clonal chromosome changes. Most had chromosome abnormalities which have so far been described as specific of particular histopathologic subgroups.


Reversal of resistance to doxifluridine and fluorouracil in metastatic colorectal cancer: the role of high-dose folinic acid.

The benefits from medical treatment in colorectal cancer are limited. Fluorouracil remains the only recognized drug, and how to treat unresponsive patients is still debated. To evaluate the role of folinic acid (FA) in circumvence resistance in colorectal cancer, 28 patients pretreated with fluoropyrimidine were candidated to receive one of the following schedules: fluorouracil (600 mg/m2) associated with FA (500 mg/m2) weekly for 6 weeks (Regimen A: 21 cases), or fluorouracil (370 mg/m2) plus FA (200 mg/m2) daily for 5 days every 4 weeks (Regimen B: 7 cases). Fourteen patients were pretreated with doxifluridine, a new fluoropyrimidine derivative with a peculiar mechanism of action, and the remaining 14 patients with fluorouracil. All but 2 patients were unresponsive to first-line treatments. When the treatment began, the median age of the patients was 60 years (range, 30-68). The performance status (ECOG) was 0/1 in 25 of them, and the primary tumor was in the colon and rectum in 19 and 9 patients, respectively. Sites of disease were liver (64%), lung (35%), local recurrence (10%) and peritoneum (10%). A median of 3 cycles (range, 1-7) was delivered, and no objective response was observed in the group of patients pretreated with doxifluridine or in the group pretreated with fluorouracil. In 5 cases a significant decrease in baseline CEA values was observed. Therapy was well tolerated, and no grade 4 toxicity was encountered. Severe toxicity was limited and included diarrhea (7 patients), stomatitis (1 patient) and nausea/vomiting (1 patient). High-dose FA has no role in reversing resistance to fluoropyrimidine, and other mechanisms of refractoriness are surely involved. FA should be associated with fluoropyrimidine as first-line therapy together with other biochemical modulators. Further rescue therapies need to be developed.


Hyperthermia in clinical practice: preliminary results and current problems in the treatment of 21 patients.

From February 1988 through February 1991, 21 patients were managed by superficial hyperthermia and radiotherapy. Nineteen patients had received previous treatment; the most common histology was breast carcinoma. Twenty-six cycles of combined hyperthermia and radiotherapy were delivered: 4 complete responses (15.4%), 17 partial responses (65.4%), 1 minimal partial response (3.8%), 3 stable diseases (11.6%) and 1 disease progression (3.8%) were obtained. The median duration of response was 7 months (range 1-16) for responding and 4 months (range 2.5-4) for non-responding patients. The toxicity encountered (confined mostly to epithelitis--7/21 patients) was completely reversible. In our experience, hyperthermia combined with radiotherapy proved to be an effective treatment. However, some problem that emerged during treatment planning and delivery showed the need for further development and research into hyperthermic devices and thermometry systems.


Deflazacort and fluoximesterone in advanced, pretreated breast cancer.

A very simple, low dose, orally administered regime (10 to 15 mg of fluoximesterone + 6 mg of deflazacort daily for periods of 1 to several months) resulting in mild-acceptable toxicity (essentially some weight gain) determined subjective improvement in 2/3 of 34 evaluable patients (out of 36 treated) and an objective measurable tumor reduction in 1/3, although most patients had been previously treated with chemotherapy and hormone treatment and proved primarily or secondarily refractory. The receptor status at the beginning of fluoximesterone+deflazacort treatment was not known, except in one negative-receptor patient, who responded to the combination after becoming resistant to tamoxifen (see photo). In some patients the condition of hormone refractoriness would suggest a no-treatment policy, but a trial with this regime is always convenient as it may improve both duration and quality of life.


Endobronchial metastases in colorectal adenocarcinoma.

Between 1982 and 1990, 2388 bronchoscopic examinations were carried out in patients with cancer in our hospital. A diagnosis of endobronchial metastasis was established in 30 patients (2.09%), with the following primary tumors in descending order of frequency: breast, large bowel, melanoma, neuroblastoma, leiomyosarcoma and endometrial. Despite the rarity of endobronchial metastases secondary to colon adenocarcinoma, we were able to study 3 cases from our Center. In one case the diagnosis of endobronchial metastasis was simultaneous with that of the primary tumor, and in the other 2 this metastatic complication occurred 16 and 42 months, after the original diagnosis. When this complication occurred, the stage of the disease was advanced in all 3 cases: 2 were Dukes' stage C and one stage D. Although this metastatic location usually implies a very negative prognosis as regards life expectancy, it did not seem to significantly reduce the latter in our patients.