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Interleukin-2 in cancer treatment: disappointing or (still) promising? A review.

The central question to discuss in this review is whether the results of interleukin-2 (IL-2) treatment are still disappointing or again promising. Although in the (recent) past application of high doses of systemically applied rIL-2 has led to some success, the overall results are not as one had hoped. Considering these poor results it seems clear that the application of high systemic doses rIL-2 was not a good choice. IL-2 has been used more or less as a chemotherapeutic compound in the highest tolerable dose. This has led to a great number of unwanted toxic side-effects. In addition, these doses mainly stimulated nonspecific lymphokine-activated killer activity through low-affinity IL-2 receptors, which does not lead to systemic immunity. On the other hand, several groups have shown that application of intratumoral low doses of IL-2 can be highly effective against cancer and without toxic side-effects. Significant tumor loads constituting up to 6% of the total body weight of a mouse were eradicated after treatment with low-dose rIL-2 given locally. Furthermore local treatment can lead to eradication of a tumor at a distant site. This type of therapy is effective in many systems namely against different tumor types in mice, hepatocellular carcinoma in guinea-pigs and vulval papilloma and carcinoma and ocular carcinoma in cattle. Low-dose IL-2 is very effective in experimental animals if it is given relatively late after inoculation of the tumor cells. In other words, it seems necessary that some sort of immune reaction has started or is developing before low doses of rIL-2 effectively stimulate it. In fact there is strong evidence that T lymphocytes, both CD4+ and CD8+ cells, are directly involved in the process leading to induction of specific immunity. In our opinion rIL-2 therapy should therefore aim at the stimulation of such (originally weak) specific immune reaction. Under these conditions also systemic immunity can be induced. In conclusion, application of rIL-2 as a modality for cancer treatment is still promising. High priority should be given to a further delineation of the mechanisms involved after local application. The method of giving IL-2 systemically in the highest tolerable dose should be abandoned. Specific stimulation of the immune system by low-dose rIL-2 is a much more promising option.

Animals↗

Biofeedback training is useful in fecal incontinence but disappointing in constipation.

BACKGROUND: Successful biofeedback therapy has been reported in the treatment of fecal incontinence and constipation. It is uncertain which groups of incontinent patients benefit from biofeedback, and our impression has been that biofeedback is more successful for incontinence than for constipation. PURPOSE: This study was designed to review the results of biofeedback therapy at the Lahey Clinic. METHODS: Biofeedback was performed using an eight-channel, water-perfused manometry system. Patients saw anal canal pressures as a color bar graph on a computer screen. Assessment after biofeedback was by manometry and by telephone interview with an independent researcher. RESULTS: Fifteen patients (13 women and 2 men) with incontinence underwent a mean of three (range, 1-7) biofeedback sessions. The cause was obstetric (four patients), postsurgical (five patients), and idiopathic (six patients). Complete resolution of symptoms was reported in four patients, considerable improvement in four patients, and some improvement in three patients. Manometry showed a mean increase of 15.3 (range, -3-30) mmHg in resting pressure and 35.7 (range, 13-57) mmHg in squeezing pressure after biofeedback. A successful outcome could not be predicted on the basis of cause, severity of incontinence, or initial manometry. Twelve patients (10 women and 2 men) with constipation underwent a mean of three (range, 1-14) biofeedback sessions. Each had manometric evidence of paradoxic nonrelaxing external sphincter or puborectalis muscle confirmed by defography or electromyography. All patients could be taught to relax their sphincter in response to bearing down. Despite this, only one patient reported resolution of symptoms, three patients had reduced straining, and three patients had some gain in insight. CONCLUSIONS: Biofeedback helped 73 percent of patients with fecal incontinence, and its use should be considered regardless of the cause or severity of incontinence or of results on initial manometry. In contrast, biofeedback directed at correcting paradoxic external sphincter contraction has been disappointing.

Adolescent↗

Effects of nicotine and a cannabinoid receptor agonist on negative contrast: distinction between anxiety and disappointment?

RATIONALE: Animals trained to lick for a sucrose solution of a given incentive value that subsequently encounter an incentive downshift (i.e. 32-4% sucrose) display an exaggerated decrease in the amount consumed, relative to unshifted controls. This change has been classified as a successive negative contrast (SNC) effect. The emotional component to this robust behavioural change is dynamic and changes from post-shift day (PSD) 1 to 2. Anxiolytics block SNC, but the possible link between anxiety and SNC needs further exploration. Both nicotine and a cannabinoid receptor agonist have been reported to change anxiety and both have actions on the reward process, but their effects on SNC have not been investigated. OBJECTIVES: To determine: (1) whether exposure to SNC evokes an anxiogenic response; (2) whether an anxiolytic dose of nicotine has the same effects on SNC as those of chlordiazepoxide; (3) the effects of a low (anxiolytic) and a high (anxiogenic) dose of the cannabinoid receptor agonist CP 55,940 on SNC. METHODS: Two groups of animals were given access to high (32%) or low (4%) sucrose solutions for 5 min per day for 10 days. On PSD 1 and 2, the shifted group had access to a devalued incentive (from 32 to 4% sucrose) and the unshifted group remained at 4% sucrose. The volumes (ml) of sucrose solution consumed were measured pre-shift and on PSD 1 and 2. In experiment 1, immediately after SNC testing on PSD 1 and 2, the rats were tested in the social interaction and elevated plus-maze tests of anxiety. In experiment 2, the effects of chlordiazepoxide (5 and 7.5 mg/kg) and nicotine (0.1 mg/kg) were examined on PSD 1 and 2. In experiment 3, the effects of CP 55,940 (5 and 40 microg/kg) were examined on PSD 1 and 2. RESULTS: There were no anxiogenic effects of shift in either test of anxiety on either test day. However, on PSD 1, the shifted group had significantly higher locomotor activity and spent a higher percentage of time on the open arms, perhaps reflecting search strategies. Nicotine was without significant effect on SNC on either test day. On PSD 1, chlordiazepoxide (5 mg/kg) and CP 55,940 (5 and 40 microg/kg, IP) blocked SNC. On PSD 2, both doses of chlordiazepoxide and the low, anxiolytic dose of CP 55,940 (5 microg/kg) blocked SNC, the high dose of CP 55,940 was without effect. CONCLUSIONS: The pattern of results allows for the separation between effects on anxiety and SNC. The block of contrast on PSD 1 was independent of changes in anxiety, since both anxiolytic and anxiogenic drug doses were effective. It is suggested that this may provide an animal model of disappointment in which the cannabinoid system plays an important role. An anxiolytic action would seem to be a necessary, but not a sufficient, action to block SNC on PSD 2.

Animals↗

Towards professional autonomy: a commentary on "Expectations and disappointments' in development of the Royal College of Nursing.

The Royal College of Nursing of the United Kingdom has been engaged over recent years in a unique process of organizational change. Since 1973 sustained efforts have been made to mobilise widespread membership participation in shaping a new college structure which enables the Rcn to function effectively in representing the profession and in developing expertise on all aspects of nursing. A critical element has been creation of a network of "Rcn Centres' to provide a professional forum in each locality. A recent study by Bridget Ramsay has followed up this process. Its title, Expectations and Disappointments, reflects the mixed views of those involved on the progress which has been made. This article provides a commentary on Ramsay's analysis against the background of the complex situation of the Rcn in the early 1970s and the considerations which led the College to adopt an innovative approach to change. Particular attention is given to the influences which have made the growth of an active and integrated "Rcn at local level' quite problematic. It is suggested that the course Rcn development has taken in part reflects important elements in the nursing culture which members learn from their work in hospitals. Accordingly the Rcn experience has wider implications for the profession, not least for contemporary efforts, to achieve the greater professional autonomy necessary for nurses to implement more individualized patient care.

Humans↗

Disappointing results and low tolerability of photodynamic therapy with topical 5-aminolaevulinic acid in psoriasis. A randomized, double-blind phase I/II study.

BACKGROUND: Based on good results in the treatment of superficial skin tumours, since the early 1990s topical photodynamic therapy with aminolaevulinic acid (ALA PDT) has been used for disseminated, inflammatory dermatoses including psoriasis. However, there is still a lack of well-documented trials. OBJECTIVE: A prospective randomized, double-blind phase I/II intrapatient comparison study was conducted in 12 patients to investigate whether topical ALA PDT is an effective treatment for chronic plaque-type psoriasis. METHODS: In each patient three psoriatic plaques were randomly treated with a light dose of 20 J/cm(2) and 0.1%, 1% and 5% ALA, respectively. Treatment was conducted twice a week until complete clearance or for a maximum of 12 irradiations. Therapeutic efficacy was assessed by weekly determination of the psoriasis severity index (PSI). RESULTS: The mean percentage improvement was 37.5%, 45.6% and 51.2% in the 0.1%, 1% and 5% ALA-treated groups, respectively. Irradiation had to be interrupted several times because of severe burning and pain sensation. CONCLUSION: Topical ALA PDT did not prove to be an appropriate treatment option for plaque-type psoriasis due to disappointing clinical efficacy, the time-consuming treatment procedure and its unfavourable adverse event profile.

Administration, Topical↗

Disappointing sensitivity of endoscopic markers for villous atrophy in a high-risk population: implications for celiac disease diagnosis during routine endoscopy.

OBJECTIVE: Endoscopic markers of duodenal villous atrophy (VA) can facilitate diagnosis of celiac disease during routine upper GI endoscopy. We studied their sensitivity for VA in a large series of patients undergoing GI endoscopy specifically for duodenal biopsy. Poor sensitivity in this setting would have significant and adverse implications for their performance during routine endoscopy. METHODS: All patients with VA on duodenal biopsy performed for positive serum endomysial antibody (EmA) and/or clinical features suggestive of celiac disease were included. The second part of duodenum was inspected carefully for endoscopic markers using videogastroscopes. RESULTS: Of 129 patients studied, 99 (77%) had at least one endoscopic markers. The most commonly seen marker were a mosaic pattern mucosa (68 patients, 53%) and scalloping of duodenal folds (74 patients, 57%). The prevalence of markers was significantly lower for partial VA (15 of 26 patients, 58%) than for subtotal or total VA (84 of 103 patients, 82%) (p < 0.02). CONCLUSIONS: Endoscopic markers have disappointing sensitivity even in a population at high risk of celiac disease, particularly for partial VA. Their performance may be even poorer in an unselected dyspeptic population. Although they may help improve diagnosis rates among patients with nonspecific dyspeptic symptoms, many patients, particularly those with milder enteropathy, will be missed. As celiac disease is an important cause of dyspepsia, consideration should be given to serological screening to further improve diagnosis rates, as few centers will have the resources to routinely biopsy all patients.

Adolescent↗

Disappointing effect of endoscopic Teflon injection for female stress incontinence.

Twenty-two women were treated with endoscopic, transurethral, submucosal Teflon injection for moderate or severe urinary stress incontinence. The short-term effect was rather good, but he long-term results were disappointing. After 5 years, only 4 patients were completely or sufficiently continent and had not required any additional treatment for incontinence. Three major complications, paraurethral abscess, urethral diverticulum and Teflon granuloma with urethral wall prolapse occurred. Subsequent suprapubic urethropexy for the patients with inadequate response did not produce the usual good results.

Aged↗

Collective equipoise, disappointment, and the therapeutic misconception: on the consequences of selection for clinical research.

Private information induces individuals to self-select as subjects into clinical research trials, and it induces researchers to select which trials they conduct. The authors show that selection can induce ex ante therapeutic misconception and ex post disappointment among research subjects, and it undermines the rationale of collective equipoise as an ethical basis for clinical trials. Selection provides a reason to make nontrivial payments to subjects, and it implies that researchers should not design experiments to maximize statistical power.

Clinical Trials as Topic↗

Haglund's syndrome: disappointing results following surgery -- a clinical and radiographic analysis.

Clinical and radiographic data were analyzed for 49 surgical interventions of painful heel syndrome with a mean follow-up of 4 years and 7 months. In all patients the surgical procedure consisted of a triangular shaped resection of the posterosuperior portion of the calcaneus. The clinical evaluation showed disappointing results with complete relief of complaints in only 34 procedures (69.4%), and 7 patients (14.3%) with even a worsening of their symptoms. The time course of rehabilitation was long with an average of 6 months of functionally significant pain after surgery, reducing the willingness to undergo this operation again. Formerly published angular thresholds of radiographic calcaneal angles could not be confirmed to be predictors for the preoperative symptoms or the postoperative outcome. There was no accumulation of pathologic clinical foot shapes, only a slight increased calcaneal pitch in patients with isolated pain on the posterosuperior lateral part of the calcaneus. According to Haglund's description of painful heel syndrome, the clinical picture of our patients included affections of bone, tendon, peritendon, bursae, soft tissue and skin in different combinations. Based on this evaluation, we advise to be cautious to indicate the operation. All possibilities of conservative treatment should be performed prior to surgery.

Adolescent↗

Laparoscopic band repositioning for pouch dilatation/slippage after gastric banding: disappointing results.

BACKGROUND: Pouch dilatation with or without slippage of the band is a serious complication of gastric banding, often attributed to initial malpositioning of the band. Food intake is increased, and weight regain occurs. Progressive rotation of the band follows, leading to functional stenosis and dysphagia. Reoperation is necessary in most cases, and may consist of band removal, band change, band repositioning, or conversion to another bariatric procedure. MATERIAL AND METHODS: The study consisted of chart review of all patients who underwent laparoscopic repositioning of the band for pouch dilatation/slippage, and long-term follow-up through regular office visits and phone calls. RESULTS: Among 272 patients who had laparoscopic gastric banding, 20 (7.3%) developed pouch dilatation and/or slippage, of whom 19 underwent reoperation. Laparoscopic band repositioning was performed in 9 patients. One of them developed an intraabdominal collection postoperatively and required percutaneous CT-guided drainage. Recovery was uneventful in the other 8. Follow-up since reoperation varies from 13 to 42 months (mean 20 months). The result was good in 2 patients who lost further weight, satisfactory in 1 whose weight remained stable, and unsatisfactory in 6 patients. Weight loss was insufficient in 2, dilatation recurred in 2, and band infection or erosion developed each in 1 patient. 5 patients required further surgery: band removal in 3 and conversion to gastric bypass in 2. CONCLUSIONS: Laparoscopic band repositioning is feasible and safe if pouch dilatation and/or slippage develops after gastric banding. The mid-term results are disappointing in two-thirds of the patients. In some patients, pouch dilatation could result from poor adjustment to diet restriction rather than merely from original malplacement. Conversion to gastric bypass may be a better option in these cases.

Adult↗

Difficulties, disagreements, and disappointments in late-life marriages.

Although research has examined marital satisfaction in later life, little is known about the specific relationship challenges that older couples experience. Thus, the objective of the study was to explore the challenges older couples face. Data came from the USC Longitudinal Study of Generations. Qualitative analysis was conducted on 105 older couples, with an average age of 69, who responded in 1997 to an open-ended question about difficulties, disagreements, and disappointments in their marriage. Ten themes emerged from the data. In order of frequency, they were leisure activities, intimacy, finances, no problems, personality, intergenerational relations, household concerns, personal habits, health issues, and work/retirement. Comparisons in responses were made for age, gender, marital quality, length of marriage, and health. In addition, the dyadic data were examined for patterns within the relationship.

Aged↗

Challenges of internet recruitment: a case study with disappointing results.

BACKGROUND: The Internet provides tremendous opportunities for innovative research, but few publications on the use of the Internet for recruiting study participants exist. This paper summarizes our experiences from 2 studies in which we attempted to recruit teenagers on the Internet for a questionnaire study to evaluate a smoking-cessation website. OBJECTIVE: To evaluate strategies of recruiting teenagers for the evaluation of a smoking-cessation website through the Internet. METHODS: In Study 1 (Defined Community Recruitment), we sent invitation emails to registered members of a youth health website, CyberIsle. A total of 3801 email addresses were randomly divided into 2 groups. In the first group, emails indicated that the first 30 respondents would receive a Can dollars 20 electronic gift certificate for use at an online bookstore if they would go to the Smoking Zine website and respond to a short survey. For the second group, the email also indicated that respondents would receive an additional Can dollars 10 gift certificate if they referred their friends to the study. Reminder emails were sent 10 days after the sending of the initial invitation email. In Study 2 (Open Recruitment), we posted invitation messages on Web discussion boards, Usenet forums, and one specialized recruitment website, and attempted a snowball recruiting strategy. When potential participants arrived at the study site, they were automatically randomized into either the higher incentives group (Can dollars 15 electronic gift certificate) or lower incentive group (Can dollars 5 gift certificate). RESULTS: In Study 1 (defined community recruitment), 2109 emails were successfully delivered. Only 5 subjects (0.24%), including 1 referred by a friend, passed the recruitment process and completed the questionnaire; a further 6 individuals visited the information page of the study but did not complete the study. In Study 2 (open recruitment), the number of users seeing the advertisement is unknown. A total of 35 users arrived at the website, of whom 14 participants were recruited (8 from the Can dollars 15 gift certificate group and 6 from the Can dollars 5 gift certificate group). Another 5 were recruited from the general Internet community (3 from discussion boards and 2 from the Research Volunteers website). The remaining 9 participants were recruited through friend referrals with the snowball strategy. CONCLUSIONS: Overall, the recruitment rate was disappointingly low. In our case, recruitment using Internet technologies including email, electronic discussion boards, Usenet forums, and websites did not prove to be an effective approach for soliciting young subjects to participate in our research. Possible reasons are discussed, including the participants' perspective. A major challenge is to differentiate trustable and legitimate messages from spam and fraudulent misinformation on the Internet. From the researchers' perspective, approaches are needed to engage larger samples, to verify participants' attributes, and to evaluate and adjust for potential biases associated with Internet recruitment.

Adolescent↗

[AIDS prevention by a youth association in Ivory Coast: impact, successes and disappointments].

Over the last few years, the number of associations involved in AIDS prevention has dramatically increased in Ivory Coast, especially in Abidjan. This article describes an experiment in the prevention of AIDS and STDs among young people in Abidjan by means of peer education. It follows the management and progress of a youth organization for AIDS prevention, CESAM (Cellule Scolaire Anti-SIDA et MST), the School-based Anti-AIDS and STD Unit. Critical review of the activities of this association identifies a number of methodological, planning, human and material problems, which have received little attention in the past. CESAM is one of the first anti-AIDS associations in Ivory Coast to target young people and to have young members. This may be the reason for some of its successes and some of its failures and disappointments. The association's successes include the provision of information to more than 25,000 people between 1992 and 1996, and the overall satisfaction of the public and local AIDS institutions. The young people involved have taken on a new social identity, which has developed from the motivation of association members and the personal experiences of some with respect to AIDS, STDs and problems associated with contraception. However, this new identity is threatened by rivalry between members and the search for funding, as the substantial funding obtained in 1994-1995 can show it.

Acquired Immunodeficiency Syndrome↗

Why physicians are often disappointed with their practice administrators and managers.

This article provides a close look at why physicians often are disappointed with the practice administrator or manager they have hired or promoted. Reasons include: the wrong person was hired, such as one without the necessary qualifications and know-how, or the right person was hired, but wasn't given the authority to do the job. The article also provides practical tips on how to avoid mis-hires, how to evaluate the practice's managerial needs, and general differences between types of managers.

Administrative Personnel↗

[Osteosynthesis using resorbable plates in maxillofacial surgery: hopes and disappointments].

The use of absorbable osteosynthesis material has two advantages in maxillofacial surgery: suppressing the possible biological effects of implanted metallic foreign bodies, making second surgery for material removal useless. Although the biotolerance of currently used materials is well known, the authors intended to test their use in the specific conditions of maxillofacial surgery, in which simply extrapolating the data collected in general surgery leads to erroneous conclusion. The authors report the results of a preliminary clinical study on 21 cases of osteosynthesis of the upper third of the face using absorbable plates (18 fractures of the zygomatic bone, 3 maxillary osteotomies). The biotolerance of the material is very good, after more than 3 years for the oldest cases. The mechanical stability of the assembly is sufficient for the selected indications. As regards disappointments, these include the thickness of the plates, the difficulty to adapt them to bony surfaces, the fragility of the screws and the slow resorption of the material.

Biocompatible Materials↗

Why have drug treatments been so disappointing?

The title of this contribution involves two consecutive questions: have the effects of medication in autism indeed been disappointing? And if so, why? The answer to the first question depends on whether one focuses on the core social and communicative deficits of autism, or on various complicating behaviour problems. Attempts over the past decades to develop drugs that specifically improve social and communicative functioning have failed. Among the most ambitious attempts were medical interventions in the endogenous opioid system that were motivated from animal models on the involvement of this system in various aspects of social behaviour. By contrast, medications such as the newer antipsychotics, psychostimulants, presynaptic noradrenergic blocking agents (clonidine and guanfacine) and selective serotonin reuptake inhibitors were shown to reduce impairing complicating symptoms of affective instability, irritability, hyperactivity and inattentiveness, aggression, self-injury and stereotypies. The explanation for the medication-refractory status of social and communicative deficits should be sought in at least two related factors: (1) the as yet unidentified neurochemical basis of autism, and (2) the obvious lack of involvement of the main neurotransmitter systems (dopamine, noradrenaline and serotonin) in the pathophysiology of social and communicative behaviour.

Adolescent↗

[My current options in cervicofacial lift. Results, disappointments and development from 1980 to 1990].

Based on a series of 100 cases of cervicofacial face lift selected at random over a period of 10 years, the author describes the development of her personal technique together with the results and disappointments responsible for this development. She distinguishes 3 surgical periods. The first period (1980-1984) was characterised by very extensive subcutaneous undermining associated with reduced detachment of the facial SMAS, systematic anterior and variable posterior platysmaplasty. The second period (1984-1986) was distinguished by abandonment of the systematic submental approach, a persistent extensive subcutaneous undermining especially in the neck, more pronounced dissection of the facial SMAS and a systematic posterior platysmaplasty. The third period (1986-1990) was marked by a trend toward more limited subcutaneous undermining and more dissection-section-resection-retention of the facial and cervical SMAS and the current tendency consists of total platysmaplasty.

Esthetics↗

Treprostinil: new drug. Pulmonary artery hypertension: just another (disappointing) prostacycline analogue.

(1) Standard treatment for pulmonary artery hypertension usually combines a calcium channel blocker with an anticoagulant, supplemental oxygen, a digitalin and a diuretic, with only limited efficacy. When added to this standard treatment, long-term continuous intravenous epoprostenol (prostacycline) infusion improves survival time and quality of life in patients with severe primary pulmonary artery hypertension, but at a cost of many adverse effects, some of which can be serious. Bosentan, an endothelin receptor antagonist, is an oral alternative. (2) Following the approval of inhaled iloprost, another prostacycline analogue, treprostinil, has been approved for use as a continuous subcutaneous infusion. (3) Its clinical evaluation is based on 2 randomised double-blind placebo-controlled trials with disappointing clinical results: the 6-minute walking distance increased by only 10 meters after 12 weeks of treatment. This modest degree of improvement in an intermediate outcome is unlikely to translate into a tangible improvement in quality of life. (4) The only available comparison with epoprostenol is a clinical pharmacology study in about 20 patients, with no tangible clinical benefit. (5) The adverse effect profile of treprostinil is the same as that of epoprostenol, and is mainly due to its vasodilatory properties (diarrhoea, ankle swelling). In addition, pain and other local reactions are very frequent at the point of infusion. (6) Treprostinil must be administered as a continuous subcutaneous infusion; this is not convenient, but it is easier to set up than central intravenous epoprostenol infusion.

Antihypertensive Agents↗