Long-term experience on assisted suicide in Switzerland: dementia, mental disorders, age-related polymorbidity and the slippery slope argument.

OBJECTIVES: According to the Swiss medico-ethical guidelines valid between 2004 and 2018, the key criterion for assisted suicide (AS) was that the patients who wished to die suffered with a disease leading to death in the foreseeable future. Critics of AS fears that broadening of the medical indications will lead to an uncontrolled expansion to persons who are not terminally ill (slippery slope argument). We evaluated to what extent this broadening took place in practice over time. STUDY DESIGN: Retrospective national cohort study. METHODS: By using data of the Swiss Federal Statistical Office, we analyzed the long-term development of AS in Switzerland over a 20-year period (1999-2018; n = 8738 cases). We classified the cases into one of three categories regarding the aforementioned key criterion for AS. RESULTS: In 43.6% of AS cases, the criterion 'end of life is near' was met. In 5.3% of cases, this criterion was not met (4.7%: mental disorders; 0.6%: dementia). In 51.1% of cases, the reason underlying AS comprised several, mostly age-related diseases and/or functional impairments; the aforementioned key criterion, however, was probably not met in most of the cases. Over time, the number of cases doubled over each 5-year period; this increase occurred similarly for the three categories. CONCLUSION: The fact that many AS cases took place outside the valid medico-ethical guidelines might be interpreted as a development in the idea of the slippery slope argument. The fact that the percentage distribution of these cases remained unchanged over time argues against it.

Detailing the effects of polypharmacy in psychiatry: longitudinal study of 320 patients hospitalized for depression or schizophrenia.

Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today's acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: "F2x.x"; n = 94; "F2 patients") or depressive disorders (ICD-10: "F3x.x"; n = 226; "F3 patients"). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history¼ and «severity at baseline¼ played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2-3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the "natural" time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here.

Inflammatory processes linked to major depression and schizophrenic disorders and the effects of polypharmacy in psychiatry: evidence from a longitudinal study of 279 patients under therapy.

Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors "diagnosis", "previous history", "severity at baseline", "age", "gender", and "psychiatrist in charge"; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: "F3x.x"; n = 195) or schizophrenic disorders (ICD-10: "F2x.x"; n = 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data ("supervised learning"). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (p < 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of r = 0.746 (p = 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of r = 0.644 (p = 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today's acute treatment of psychiatric disorders. Given the large proportion of patients with unwanted side effects and the strong correlation between side effects and the number of drugs, polypharmacy approaches are not equally suited for every patient. In terms of efficacy, there are no advantages of polypharmacy over monotherapy. Most notably, our study appears to have cleared the way for the reliable identification of a subgroup of patients for whom the inflammatory response system is a promising target of therapeutic intervention.

"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

Assisted suicide in patients with cancer.

BACKGROUND: There are limited data on the long-term development and trends of assisted suicide (AS) among cancer patients. PATIENTS AND METHODS: Using data of the Swiss Federal Statistical Office, we analyzed AS trends over an 18-year period (1999-2016; total number of cases = 6553). RESULTS: Among patients who underwent AS, cancer was the most common underlying disease (n = 2704, 41.3% of all AS cases). The most common cancer types were lung (14.0% of cancer-related AS cases), breast (11.0%) and prostate (10.1%). There was a slight preponderance of men compared with women (51.5% versus 48.5%). The proportion of AS cases within cancer types did not change over time. The ratio of cancer-related AS cases in relationship with all cancer-related deaths increased from 0.3% at the beginning of the study period (1999-2003) to 2.1% from 2014 to 2016 (change of age-standardized rates for men: +488%; for women: +417%). At the end of the study period (2014-2016), there were only minor differences between cancer-specific ratios, highest and lowest range: 1.1% (liver cancer) and 2.8% (breast, esophageal and lip/oral cavity/oropharynx cancer). Individuals who underwent AS because of cancer were considerably younger than those who choose AS on account of other diseases (73 years versus 80 years). The median age of people with cancer-related AS was similar to that of all cancer-related deaths (74 years): for women, the median age of cancer-related AS was 72, whereas for men it was 75. The median age at which AS took place increased over time. CONCLUSIONS: During the study period, the proportion of people who chose cancer-related AS has approximately sextupled. However, AS among cancer patients remains rare and represents only ∼2% of all cancer-related deaths.

Bone remodeling in proximal HA-coated versus uncoated cementless SL-Plus((R)) femoral components: a 5-year follow-up study.

BACKGROUND AND PURPOSE: Bone resorption at the femoral stem due to stress shielding has been particularly observed secondary to cementless hip replacement. This prospective study of 126 total-hip replacements was performed to examine clinical outcomes and changes in peri-prosthetic bone density after implantation of a double-tapered cementless femoral component manufactured with versus without hydroxyapatite (HA) coating. METHODS: Sixty-seven femoral components with and 59 femoral components without proximal HA coating were implanted and examined after a mean follow-up of 5.8 (SD 1.1, 2.8-7.8) years. The Harris hip score (HHS) and plain radiographs were used for clinical and radiological follow-up evaluations. Possible changes in peri-prosthetic bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: Clinical outcome, measured by HHS, was similar in both groups. On plain radiographs, significantly less radiolucent lines were observed for the coated implants. DEXA revealed a significant increase in BMD at the proximal zones, along the medial side, and at the stem tips in the coated compared with the non-coated implants. INTERPRETATION: Hydroxyapatite-coated implants yield favorable radiographic characteristics, but no greater clinical benefit after 5 years' implantation.

Development of AFFITOPE vaccines for Alzheimer's disease (AD)--from concept to clinical testing.

Based on the notion that cerebral accumulation of certain Abeta species is central to AD pathogenesis and endowed with the knowledge that emerged during clinical testing of the first human Alzheimer vaccine, AN1792, we designed a new generation of Alzheimer vaccines. Rather than relying on full-length Abeta itself or fragments thereof, AFFITOPE vaccines use short peptides, mimicking parts of the native Abeta sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOPE-technology, at the same time provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are nonself, AFFITOPES don't need to break tolerance typically established against self proteins. This allows us to use aluminium hydroxide, the agent first approved as immunological adjuvant for human use and, thus, exhibiting an excellent safety profile. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Abeta-specific autoreactive T cells. Third, and above all, the AFFITOPE technology allows for controlling the specificity of the vaccine-induced antibody response focusing it exclusively on Abeta and preventing crossreactivity with APP. In a program based on two AFFITOPES allowing neoepitope targeting of Abeta (free N-terminus), this approach was taken all the way from concept to clinical application. Early clinical data support the safety concept inherent to AFFITOPE Alzheimer vaccines. Further clinical testing will focus on the identification of the optimal vaccine dose and immunization schedule. Together, result of these trials will provide a solid basis for clinical POC studies.

Long-term reduction of seclusion and forced medication on a hospital-wide level: Implementation of an open-door policy over 6 years.

BACKGROUND: Psychiatric inpatient treatment is increasingly performed in settings with locked doors. However, locked wards have well-known disadvantages and are ethically problematic. In addition, recent data challenges the hypothesis that locked wards provide improved safety over open-door settings regarding suicide, absconding and aggression. Furthermore, there is evidence that the introduction of an open-door policy may lead to short-term reductions in involuntary measures. The aim of this study was to assess if the introduction of an open-door policy is associated with a long-term reduction of the frequency of seclusion and forced medication. METHOD: In this 6-year, hospital-wide, longitudinal, observational study, we examined the frequency of seclusion and forced medication in 17,359 inpatient cases admitted to the Department of Adult Psychiatry, Universitäre Psychiatrische Kliniken (UPK) Basel, University of Basel, Switzerland. In an approach to enable a less restrictive policy, six previously closed psychiatric wards were permanently opened beginning from August 2011. During this process, a systematic change towards a more patient-centered and recovery-oriented care was applied. Statistical analysis consisted of generalized estimating equations (GEE) models. RESULTS: In multivariate analyses controlling for potential confounders, the implementation of an open-door policy was associated with a continuous reduction of seclusion (from 8.2 to 3.5%; ηp2=0.82; odds ratio: 0.88) and forced medication (from 2.4 to 1.2%; ηp2=0.70; odds ratio: 0.90). CONCLUSION: This underlines the potential of the introduction of an open-door policy to attain a long-term reduction in involuntary measures.

Mosquitoes (Diptera: Culicidae) from crepuscular period in an Atlantic Forest area in Southern Brazil.

Crepuscular period is one of the factors that may influence the biting activity of mosquitoes. Many of these insects have a peak activity in this period. The purpose of this study was to investigate the afternoon crepuscular activity of Culicidae in a remaining area of Atlantic Forest in western Santa Catarina, southern Brazil. Moreover, the possible influence of abiotic factors, the abundance and species richness were verified. In order to better analyze the influence of crepuscular period in specific composition and abundance of mosquitoes, the dusk was divided into three periods: pre-sunset, sunset and post-sunset. At the end of the study, nine hundred and eight four specimens distributed in 12 genera and 23 species were collected. Trichoprosopon pallidiventer (Lutz, 1905) (59.76%), Aedes crinifer (Theobald, 1903) (8.13%), Ae. scapularis (Rondani, 1848) (5.89%) were the most abundant species. Spring time presented the greatest abundance and species richness. During the study, among the three periods evaluated, pre-sunset had the greatest abundance and post-sunset the lowest. Pre-sunset and sunset had the greatest similarity between species. Regarding to the abiotic factors evaluated seven and 15 days before sampling, they did not present significant correlation for the three most abundant species. However, temperature had a positive correlation to these species. Moreover, the correlation between collected species and its possible role as vectors of etiological agents of diseases was discussed.

Effect of cancer on the in vivo energy state of rat liver and skeletal muscle.

The effect of increasing tumor burden on host liver and skeletal muscle energy status was studied using P-31 nuclear magnetic resonance spectroscopy (NMR), in rats inoculated with a nonmetastasizing methylcholanthrene-induced sarcoma (TB), and compared to nontumor bearing (NTB) and pair-fed (PF) rats. During the 28-day study, serial measurements of body weight, food intake, and tumor volume were obtained. Using a 0.9-cm double-turn surface coil, weekly NMR measurements were obtained from liver and skeletal muscle. An increasing ratio of [Pi]/[ATP] was used as one measure of intracellular energy depletion. [Pi]/[ATP] in NTB rats remained constant over time at 0.78 +/- 0.10 in liver, and 0.30 +/- 0.10 in skeletal muscle. In TB rats, the [Pi]/[ATP] ratio increased significantly in liver (P = 0.00002) and skeletal muscle (P = 0.04) with increasing tumor burden. In PF rats, no significant change occurred in [Pi]/[ATP] in liver or skeletal muscle, indicating that declining food intake was not responsible for the change in [Pi]/[ATP] seen in TB rats. Surface-coil spectroscopy of liver and skeletal muscle permits serial measurement of visceral energy stores. Increasing tumor burden results in early, ongoing depletion of energy stores as reflected by increasing [Pi]/[ATP] in these organs.

Methodological Aspects of the Phase II Study AFF006 Evaluating Amyloid-beta -Targeting Vaccine AFFITOPE® AD02 in Early Alzheimer's Disease - Prospective Use of Novel Composite Scales.

BACKGROUND: Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer's disease related decline. AFFITOPE® AD02, is an amyloid-beta (Aß)-targeting vaccine to elicit anti-Aß antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. OBJECTIVES: To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. DESIGN: Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. RESULTS: Cognitive items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. CONCLUSION: To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers.

Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE® AD02 in Patients with Early Alzheimer's Disease.

OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE® AD02 following its repeated s.c. administration to patients with early Alzheimer´s disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25µg AD02 (in two different formulations) and 75µg AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE® AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions.

Immunologic host defense in melanoma: delineation of effector mechanisms involved and of strategies for the augmentation of their efficacy.

There exists substantial evidence that the immune system plays an important role in the prevention and control of cancer. This evidence includes 1) the occasional clinical observation of spontaneous tumor regression, 2) the correlation of this phenomenon with the presence of tumor-infiltrating lymphocytes, and 3) the in vitro demonstration of the specificity of tumor-infiltrating lymphocytes for the autologous tumor. Because of the only weak immunogenicity of and the occurrence of active immunosuppression by the cancer, this response often does not suffice to combat the neoplasm successfully. One strategy for amplifying the anti-tumor immune response is vaccination of patients or experimental animals with cancer cells, the immunogenicity of which has been enhanced by the introduction of genes encoding immunostimulatory molecules. Several investigators have shown that transfection of certain types of cancer cells with the interleukin-2 gene reduces their tumorigenicity and that immunization with interleukin-2-transduced cancer cells protects animals from challenge with a tumorigenic dose of wild-type cancer cells. We have recently established a murine melanoma model (M-3) and have used it to elucidate the mechanism by which interleukin-2-transfected cancer cells can induce protective immunity. We will demonstrate the following: 1) that the mechanisms leading to the loss of tumorigenicity of interleukin-2-expressing cancer cells are somewhat different from those leading to the rejection of wild-type cancer cells in immunized animals, 2) that immunity resides within both CD4- and CD8-positive T cells, and 3) that host antigen-presenting cells are probably important in the induction of this protective anti-tumor immunity.

Intracutaneous genetic immunization with autologous melanoma-associated antigen Pmel17/gp100 induces T cell-mediated tumor protection in vivo.

Using the differentiation antigen Pmel17/gp100 to genetically immunize C57BL/6 mice (H-2(b)), we and colleagues noticed that only mice that had received the human homolog but not animals injected with the murine counterpart were protected against the growth of syngeneic B16 melanoma cells. The goal of this study was to determine whether the state of nonresponsiveness to the autoantigen Pmel17/gp100 can be broken by immunization with a plasmid DNA construct encoding the autologous form of the molecule. A construct containing the murine form of Pmel17 was administered intradermally to DBA/2 mice (H-2(d)), which were then investigated for the presence of Pmel17/gp100-specific immunity. We show that administration of plasmid DNA coding for the autologous melanoma-associated antigen Pmel17/gp100 protects DBA/2 mice against the growth of Pmel17-positive M3 melanoma cells but not against Pmel17-negative M3 melanoma cells or unrelated P815 mastocytoma cells. Cell depletion experiments demonstrated that this protective effect is mediated by T lymphocytes. The notion that Pmel17/gp100 represents the biologically relevant target in this system was supported by the observations (i) that recipients of Pmel17/gp100 DNA mount an antigen-specific cytotoxic T lymphocyte response and (ii) that M3 tumors growing in mice immunized with autologous Pmel17/gp100 had lost expression of this melanoma-associated antigen whereas M3 melanomas appearing in control-vector-treated animals were still Pmel17/gp100-positive. These results indicate that intracutaneous genetic immunization with autologous melanoma-associated antigen Pmel17/gp100 encoding plasmid DNA can lead to protection against melanoma cells as a result of the induction of a melanoma-associated antigen-specific and protective T-cell-mediated immune response. J Invest Dermatol 115:1082-1087 2000

Edge deepithelialization: a method to prevent leakage when tubed free skin flap is used for pharyngoesophageal reconstruction.

BACKGROUND: Anastomosis leakage remains a major source of morbidity and mortality in patients who receive pharyngoesophageal reconstruction, especially when a free skin flap is used as the substitute. This makes free skin flaps less favored than other substitutes in pharyngoesophageal reconstruction. However, a free skin flap provides many advantages for pharyngoesophageal reconstruction and, in some circumstances, may be the only choice. To reduce the incidence of postoperative leakage, we developed a technical modification called edge-deepithelialization for skin flap to ensure a more secure anastomosis. METHODS: Twenty-four patients who received tubed free skin flaps for cervical esophagus or hypopharynx reconstruction during a 7-year period were included in this study. Group 1 (n = 12) received flap edge-deepithelialization before undergoing the anastomosis, and Group 2 (n = 12) received the conventional anastomosis method. Preoperative nutritional status was evaluated by serum albumin level. All the patients were followed up for at least 1 year (1 approximately 14 years; mean, 7.3 years). Postoperative leakage was detected by clinical symptoms and signs or by routine esophagography. RESULTS: Postoperative anastomosis leakage developed in 1 patient in Group 1 (8.3%) and 5 patients in Group 2 (41.67%). The difference in the leakage rate between these groups was of statistical significance (P =.0001). There were no significant differences in the preoperative serum albumin level noted between these 2 groups (t test, P >.05). Older age was not associated with a higher leakage rate. Among the 6 leakage cases, 1 was treated conservatively, and the other 5 needed an additional 1 to 5 procedures for the management of leakage. All the leakages were cured during the follow-up period. CONCLUSIONS: With the flap edge deepithelialized, a more secure and reliable anastomosis can be obtained. This makes the free skin flap an easier and safer alternative in pharyngoesophageal reconstruction, especially when laparotomy and enteric flaps are contraindicated.

The arterial vascularization of the humeral head. An anatomical study.

In twenty-nine specimens from fresh cadavera, we performed an anatomical study of the arteries of the humeral head to determine their intraosseous distributions. A radiopaque suspension was injected into the anterior circumflex, posterior circumflex, suprascapular, thoracoacromial, or subscapular artery and then the specimens were dissected and were analyzed macroscopically, and radiographs were made in three mutually perpendicular projections. In addition, sixteen of the specimens were cut into four-millimeter slices and were studied microradiographically. The humeral head was shown to have been perfused by the anterolateral ascending branch of the anterior circumflex artery in all specimens. That vessel ran parallel to the lateral aspect of the tendon of the long head of the biceps and entered the humeral head where the proximal end of the intertubercular groove met the greater tuberosity. When the intraosseous (terminal) part of the anterolateral branch, the so-called arcuate artery, had been perfused, almost the entire epiphysis was radiopaque. The posterior circumflex artery vascularized only the posterior portion of the greater tuberosity and a small posteroinferior part of the head. Anastomoses between the different arteries were abundant, but vascularization of all of the humeral head was possible only through the anterolateral branch of the anterior circumflex artery.

Semiconstrained total elbow replacement for the treatment of post-traumatic osteoarthrosis.

Forty-one consecutive patients were managed for post-traumatic osteoarthrosis or dysfunction of the elbow with use of a non-customized semiconstrained Coonrad-Morrey total elbow prosthesis. The average age at the time of the operation was fifty-seven years (range, thirty-two to eighty-two years). The patients were followed for an average of five years and eight months (range, two to twelve years). Radiographs were made at least two years postoperatively (average, five years and one month; range, two to twelve years) for thirty-nine of the forty-one patients. According to the Mayo elbow performance score, sixteen patients (39 per cent) had an excellent result, eighteen (44 per cent) had a good result, five (12 per cent) had a fair result, and two (5 per cent) had a poor result. Thirty-six (95 per cent) of the thirty-eight patients who had a functioning implant at the time of follow-up considered the outcome to be satisfactory. Preoperatively, thirty-seven patients (90 per cent) had moderate or severe pain; postoperatively, thirty (73 per cent) had no or only mild discomfort. Motion improved from an average arc of flexion of 40 to 118 degrees preoperatively to an average arc of flexion of 27 to 131 degrees postoperatively. All thirty-eight functioning implants rendered the elbow stable. Eleven patients (27 per cent) had a major complication. Nine of them (22 per cent of the series) needed an additional operation. There was no aseptic loosening, and most of the complications were primarily due to so-called mechanical failure. The ulnar component fractured in five patients (12 per cent), and the polyethylene bushings wore out in two (5 per cent). These complications were attributed principally to the performance of strenuous physical labor, such as lifting more than ten kilograms on a regular basis, against the advice of the surgeon; excessive preoperative deformity of the joint; or an unstable traumatic injury. Two patients (5 per cent) had an infection. Semiconstrained joint replacement of the elbow can be a reliable form of treatment, and frequently is the only viable option, for the difficult problems encountered with post-traumatic destruction of a joint. Restoration of function, relief of pain, and patient satisfaction can be achieved even when a patient is less than sixty years old if that patient has low demands and a low level of activity. However, the mechanical failures underscore the fact that this procedure is relatively contraindicated in patients who anticipate strenuous physical activity or who are not expected to comply with the postoperative protocol. This observation reflects the tendency for increased and excessive use of a previously functionless joint, after it has been rendered stable and pain-free, to lead to mechanical failure.

Experimental rotator cuff repair. A preliminary study.

BACKGROUND: The repair of chronic, massive rotator cuff tears is associated with a high rate of failure. Prospective studies comparing different repair techniques are difficult to design and carry out because of the many factors that influence structural and clinical outcomes. The objective of this study was to develop a suitable animal model for evaluation of the efficacy of different repair techniques for massive rotator cuff tears and to use this model to compare a new repair technique, tested in vitro, with the conventional technique. METHODS: We compared two techniques of rotator cuff repair in vivo using the left shoulders of forty-seven sheep. With the conventional technique, simple stitches were used and both suture ends were passed transosseously and tied over the greater tuberosity of the humerus. With the other technique, the modified Mason-Allen stitch was used and both suture ends were passed transosseously and tied over a cortical-bone-augmentation device. This device consisted of a poly(L/D-lactide) plate that was fifteen millimeters long, ten millimeters wide, and two millimeters thick. Number-3 braided polyester suture material was used in all of the experiments. RESULTS: In pilot studies (without prevention of full weight-bearing), most repairs failed regardless of the technique that was used. The simple stitch always failed by the suture pulling through the tendon or the bone; the suture material did not break or tear. The modified Mason-Allen stitch failed in only two of seventeen shoulders. In ten shoulders, the suture material failed even though the stitches were intact. Thus, we concluded that the modified Mason-Allen stitch is a more secure method of achieving suture purchase in the tendon. In eight of sixteen shoulders, the nonaugmented double transosseous bone-fixation technique failed by the suture pulling through the bone. The cortical-bone-augmentation technique never failed. In definite studies, prevention of full weight-bearing was achieved by fixation of a ten-centimeter-diameter ball under the hoof of the sheep. This led to healing in eight of ten shoulders repaired with the modified Mason-Allen stitch and cortical-bone augmentation. On histological analysis, both the simple-stitch and the modified Mason-Allen technique caused similar degrees of transient localized tissue damage. Mechanical pullout tests of repairs with the new technique showed a failure strength that was approximately 30 percent of that of an intact infraspinatus tendon at six weeks, 52 percent of that of an intact tendon at three months, and 81 percent of that of an intact tendon at six months. CONCLUSIONS: The repair technique with a modified Mason-Allen stitch with number-3 braided polyester suture material and cortical-bone augmentation was superior to the conventional repair technique. Use of the modified Mason-Allen stitch and the cortical-bone-augmentation device transferred the weakest point of the repair to the suture material rather than to the bone or the tendon. Failure to protect the rotator cuff post-operatively was associated with an exceedingly high rate of failure, even if optimum repair technique was used. CLINICAL RELEVANCE: Different techniques for rotator cuff repair substantially influence the rate of failure. A modified Mason-Allen stitch does not cause tendon necrosis, and use of this stitch with cortical-bone augmentation yields a repair that is biologically well tolerated and stronger in vivo than a repair with the conventional technique. Unprotected repairs, however, have an exceedingly high rate of failure even if optimum repair technique is used. Postoperative protection from tension overload, such as with an abduction splint, may be necessary for successful healing of massive rotator cuff tears.

Effect of tendon release and delayed repair on the structure of the muscles of the rotator cuff: an experimental study in sheep.

BACKGROUND: Ruptures of the tendons of the rotator cuff lead to profound and possibly irreversible changes in the structure and physiological properties of the rotator cuff muscles. Muscle atrophy and fatty infiltration are important prognostic factors that affect the natural history and outcome of treatment. The purpose of this study was to examine the amount of muscle atrophy and fatty infiltration in an animal model and to determine whether the repair of a long-standing tendon tear can reverse these changes. METHODS: The infraspinatus tendon in six sheep was released and encased in a silicone tube to prevent spontaneous healing. The musculotendinous unit was allowed to retract for forty weeks. Throughout this period, the muscular changes were studied with use of computed tomography, histological analysis, and electron microscopy. At forty weeks, the elasticity, intramuscular pressure, and perfusion were measured intraoperatively and a tendon repair was carried out. The structural changes of the muscle were studied for thirty-five weeks after the repair. The animals were then killed, and the musculotendinous units were examined macroscopically and by computed tomography, histological analysis, and electron microscopy. RESULTS: At the time of the tendon release, the infraspinatus showed no fatty changes. The force needed to cause a tendon excursion of 1 cm was a mean (and standard deviation) of 6.8 +/- 1 N. The application of tension on the tendon did not alter the perfusion and decreased the intramuscular pressure. After the tendon release, muscular atrophy developed and there was a significant increase (p < 0.001) in interfascicular and intrafascicular fat, representing fatty infiltration rather than fatty degeneration. Furthermore, there was an increase of interstitial connective tissue. At the time of the tendon repair, between forty and forty-two weeks after the release, there was a sevenfold poorer elasticity of the musculotendinous unit but preserved muscle perfusion. The structural changes increased six weeks after the repair and then recovered partially at twelve and thirty-five weeks thereafter but only to the amount demonstrated before the repair. CONCLUSIONS: Musculotendinous retraction induced by tendon release is associated with profound changes in the structure and function of the affected muscle. Vascularization, intramuscular pressure, and individual fiber composition are not markedly affected, and muscle fibers do not appear to degenerate. However, muscle atrophy, infiltration by fat cells, and an increase of interstitial connective tissue lead to impairment of the physiological properties of the muscle. These changes were irreversible under the conditions of this experiment with the repair technique used.