An application framework for computer-aided patient positioning in radiation therapy

The importance of exact patient positioning in radiation therapy increases with the ongoing improvements in irradiation planning and treatment. Therefore, new ways to overcome precision limitations of current positioning methods in fractionated treatment have to be found. The Department of Medical Physics at the German Cancer Research Centre (DKFZ) follows different video-based approaches to increase repositioning precision. In this context, the modular software framework FIVE (Fast Integrated Video-based Environment) has been designed and implemented. It is both hardware- and platform-independent and supports merging position data by integrating various computer-aided patient positioning methods. A highly precise optical tracking system and several subtraction imaging techniques have been realized as modules to supply basic video-based repositioning techniques. This paper describes the common framework architecture, the main software modules and their interfaces. An object-oriented software engineering process has been applied using the UML, C + + and the Qt library. The significance of the current framework prototype for the application in patient positioning as well as the extension to further application areas will be discussed. Particularly in experimental research, where special system adjustments are often necessary, the open design of the software allows problem-oriented extensions and adaptations.     

Treating the drug user: considering the "demands" of therapeutic technologies and their implications for treatment planning, implementation, and outcome

Continued confusion regarding the actual and potential interface between technical issues (techniques/therapies) and ideological-theoretical considerations (treatment as a planned change process) results in built-in failure in the treatment of drug users. Only a limited number of currently available "therapies" are generally used for planned treatment intervention or for institutionalized reflexive reactions. Limited consideration has been given to the planning and implementation "demands" of a selected number of critical variables which affect the "therapies" currently in use and/or which can be chosen to be used. This note is designed as a catalytic cognitive resource to facilitate changing this situation by exploring some of the factors associated with this self-defeating, self-fulfilling prophecy.     

HIV/AIDS患者免疫重建炎性综合征的诊治

免疫重建炎性综合征（immune reconstitution inflammatory syndrome,IRIS）是部分HIV／AIDS患者在高效抗反转录病毒治疗后发生的一组疾病。IRIS主要与机体在免疫功能恢复过程中产生了针对残存活性／非活性抗原的过度免疫炎症反应以及免疫调节功能的缺失有关。临床多表现为抗病毒治疗后已有疾病的恶化或出现新发疾病。IRIS相关的感染原多见于分枝杆菌、新型隐球菌、巨细胞病毒等,临床上因特异性感染原的不同而表现各异。早期诊断、及时治疗IRIS,对更好地开展AIDS的抗病毒治疗非常重要。     

Transforming South–South Technical Support to Fight Noncommunicable Diseases

At the UN High-Level Meeting on non-communicable diseases (NCD) in September 2011, each member state was challenged to create a multisectoral national policy and plan for the prevention and control of non-communicable disease by 2013. Few low-income countries, however, currently have such plans. Their governments are likely to turn for assistance in drafting and implementation to multilateral agencies and Contract Technical Support Organizations recommended by development partners. Yet because many NCD seen in the lowest-income countries differ significantly from those prevalent elsewhere, existing providers of external technical support may lack the necessary experience to support strategic planning for NCD interventions in these settings. This article reviews currently available mechanisms of technical support for health sector planning. It places them in the broader historical context of post- World War II international development assistance and the more recent campaigns for horizontal “South-South” cooperation and aid effectiveness. It proposes bilateral technical assistance by low income-countries themselves as the natural evolution of development assistance in health. Such programs, it argues, may be able to improve the quality of technical support to low-income countries for strategic planning in the NCD area while directing resources to the regions where they are most needed.     

Drug allergy and non-HIV immune reconstitution inflammatory syndrome

Non-HIV immune reconstitution inflammatory syndrome (non-HIV IRIS) is associated with the recovery from an immunocompromised condition. It is defined as inflammatory disorders caused by antigens, including drugs or pathogenic microorganisms present prior to immune recovery, or by the exacerbation of an inflammatory disorder that was already present. Drug-induced hypersensitivity syndrome is a prototype of IRIS, and the pathophysiology of non-HIV IRIS can be recognized in several disorders treated with corticosteroids, immunosuppressants, molecular-targeted drugs, TNF-α antibody drugs, immune checkpoint inhibitors, and dipeptidyl peptidase-4 inhibitors. This review focuses on the relationship between the immune mechanism of non-HIV IRIS and drug allergies, especially severe drug eruption. The antigen recognition mechanism in drug allergy varies depending on the clinical type and the causative drug. The p-i concept is the main mechanism in severe drug eruption such as Stevens-Johnson syndrome/toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Lymphocytes activated by an antigen other than a drug, such as a virus, can also develop drug allergy by the loose binding of drugs with immune receptors of T cells or human leukocyte antigen. Therefore, fluctuations in the immune environment affect the onset of severe drug eruption. Novel agents that cause major changes in immunity have been marketed mainly for autoimmune diseases and malignant tumors; therefore, it is necessary to consider their effects when treating severe drug eruptions. Moreover, although a list of diagnostic criteria for this syndrome has been drafted, predictive and diagnostic biomarkers for this syndrome needs to be urgently developed.     

Clinical and laboratory predictors and prevalence of immune reconstitution inflammatory syndrome in patients with Whipple's disease

Objectives

Whipple's disease (WD) is a rare and potentially fatal infectious disease caused by Tropheryma whipplei. It is characterized by a long prodromal phase that mimics a rheumatological disease, often leading to immunosuppressant treatment. Immune reconstitution inflammatory syndrome (IRIS) is currently the most important complication of WD, requiring prompt recognition and treatment as it can be fatal. However, epidemiological data on IRIS are scarce. We aimed to identify the clinical and laboratory predictors of IRIS at WD diagnosis and to evaluate whether the prevalence of IRIS has changed over time.

Methods

Forty-five patients with WD (mean age 52 ± 11 years; 10 females) were followed up between January 2000 and December 2021. Clinical and laboratory data at WD diagnosis were retrospectively collected and compared among patients who developed IRIS and those who did not.

Results

Erythrocyte sedimentation rate (ESR; 33.4 ± 11.8 mm/h vs 67.1 ± 26.3 mm/h, P < 0.01), platelet (PLT; 234 × 10⁹/L vs 363 × 10⁹/L, P < 0.01), and body mass index (22.0 ± 2.0 kg/m² vs 19.8 ± 3.0 kg/m², P = 0.04) differed significantly between patients who subsequently developed IRIS and those who did not. ROC analysis identified ESR ≤46 mm/h (AUROC 0.88, 95% CI 0.72–1.00) and PLT ≤ 327 × 10⁹/L (AUROC 0.85, 95% CI 0.70–1.00) as optimal cut-off values to discriminate WD patients at a high risk of developing IRIS. Prevalence of IRIS remained stable (22.2%) over time.

Conclusions

Low ESR and PLT count at diagnosis help identify WD patients at high risk of developing IRIS. Instead, a greater inflammatory response suggests a lower risk of IRIS. Prevalence of IRIS did not change over two decades.     

Selective expansion of polyfunctional pathogen-specific CD4(+) T cells in HIV-1-infected patients with immune reconstitution inflammatory syndrome

Since the introduction of highly active antiretroviral therapies (ART), the prognosis for HIV-1 patients has improved immensely. However, approximately 25% of patients can experience a variety of inflammatory symptoms that are collectively known as immune reconstitution inflammatory syndrome (IRIS). Studying the etiology and immunopathology of IRIS has been hampered by the fact that the symptoms and associated opportunistic infections are highly varied. We hypothesized that there is a common mechanism underlying IRIS pathogenesis and investigated a patient group with IRIS related to different pathogens. Functional and phenotypic characterization of PBMC samples was performed by polychromatic flow cytometry after in vitro stimulation with relevant antigenic preparations. In most patients, IRIS events were characterized by the robust increase of preexisting polyfunctional, highly differentiated effector CD4(+) T-cell responses that specifically targeted the antigens of the underlying co-infection. T-cell responses to HIV-1 or other underlying infections were not affected and did not differ between IRIS and non-IRIS patients. These data suggest that patients with IRIS do not have a generalized T-cell dysfunction; instead, IRIS represents a dysregulated CD4(+) T-cell response against residual opportunistic infection antigen. These studies were registered at www.clinical-trials.gov as NCT00557570 and NCT00286767.     

Mycobacterium avium-intracellulare presenting as an endobronchial tumour due to immune reconstitution inflammatory syndrome

Mycobacterium avium-intracellulare (MAI) infection in an HIV-positive patient can present shortly after starting antiretroviral therapy, as a result of immune reconstitution inflammatory syndrome (IRIS). We report a case of a 33-year-old woman where MAI presented as an endobronchial tumour due to IRIS. She responded well to standard anti-MAI treatment (rifamycins, macrolide and ethambutol).     

Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis

Immune reconstitution inflammatory syndrome (IRIS) is a common and potentially serious complication occurring in HIV-infected patients being treated for tuberculosis (TB) using combined antiretroviral treatment. A role of adaptive immunity has been suggested in the onset of IRIS, whereas the role of natural killer (NK) cells has not yet been explored. The present study sought to examine the involvement of NK cells in the onset of IRIS in HIV-infected patients with TB and to identify predictive markers of IRIS. A total of 128 HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretroviral Drugs (CAMELIA) trial were enrolled in Cambodia. Thirty-seven of the 128 patients developed IRIS. At inclusion, patients had low CD4 cell counts (27 cells/mm(3)) and high plasma viral load (5.76 and 5.50 log/mL in IRIS and non-IRIS patients, respectively). At baseline, NK-cell degranulation capacity was significantly higher in IRIS patients than in non-IRIS patients (9.6% vs 6.38%, P < .005). At IRIS onset, degranulation capacity did not differ between patients, whereas activating receptor expression was lower in IRIS patients. Patients with degranulation levels > 10.84% had a higher risk of IRIS (P = .002 by log-rank test). Degranulation level at baseline was the most important IRIS predictor (hazard ratio = 4.41; 95% confidence interval, 1.60-12.16). We conclude that NK-degranulation levels identify higher IRIS risk in HIV-infected patients with TB.     

Immune reconstitution inflammatory syndrome associated with disseminated mycobacterial infection in patients with AIDS

Restoration of the immune system after highly active antiretroviral therapy (HAART) resulting from a quantitative and qualitative process of cell immune activity recovery may evolve with adverse clinical phenomena, known as the immune reconstitution inflammatory syndrome (IRIS). It can occur in association with several opportunist infections, although most reported cases have been related to mycobacterial infection caused by Mycobacterium tuberculosis and Mycobacterium avium. We describe three clinical cases of mycobacterial infection with different presentation patterns of IRIS after HAART. In each of these patients, immune reconstitution led to clinical manifestation of a latent infection, or clinical worsening of preexisting lesions, or manifestation of new lesions in the central nervous system. Clinical aspects of IRIS are presented in the paper and clinical management options for this event are carefully discussed.     

Non-invasive Renal Denervation: Update on External Ultrasound Approaches

In the last decade, intravenous renal denervation (RDN) has emerged as an alternative to pharmacological treatment in patients with resistant hypertension, but currently involves an invasive and technically challenging procedure. The Surround Sound? system utilises externally delivered ultrasound to achieve RDN using a completely non-invasive, automated real-time tracking system coupled with a therapeutic delivery module thereby addressing these limitations. A brief history, technical overview and summary of preclinical and clinical studies of the KonaMedical Surround Sound? system are presented. A literature search using the terms “renal denervation”, “resistant hypertension” and “external ultrasound” was performed using PubMed, and references retrieved were selected based on relevancy and year of publication (date range 1991–2015). The Surround Sound? system appears to be a promising approach to RDN which eliminates several of the factors currently limiting the intravenous approach. So far, it has demonstrated efficacy for reducing blood pressure in resistant hypertension patients with minimal adverse effects. Several double-blind, sham-controlled clinical trials are currently underway to confirm the validity of these findings.     

Immune reconstitution inflammatory syndrome (IRIS) of the small bowel in an immunocompromised patient suffering from systemic lupus erythematosus and non-tuberculous mycobacteriosis

An overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens is termed immune reconstitution inflammatory syndrome (IRIS). It has mainly been described in patients with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy (HAART) who show a significant increase of low CD4 T cells (initially <50/microl). IRIS may lead to organ damage and differential diagnosis is often difficult. We report the case of a 38-year-old female patient who developed a Mycobacteria genavense infection of the liver and the bowel after several immunosuppressive therapies for systemic lupus erythematosus. CD4 T cell counts as low as 17/microl were found and immunosuppressive therapy was stopped. Despite several courses of antibiotic treatment and rising CD4 T cell counts, severe malabsorption persisted. Upper endoscopy revealed a continuous inflammation with pseudopolyps of the small bowel and histologically, a granulomatous infiltrate was detected. After exclusion of a persisting infection by Mycobacteria genavense, IRIS of the small bowel was suspected and treatment with prednisolone was started. The clinical and histological picture improved significantly, the number of CD25(+)CD4(+) cells decreased in the lamina propria of the duodenum under treatment with prednisolone and Foxp3+ regulatory T cells (Treg) accumulated around granulomas. This case shows that IRIS is not restricted to HIV patients but may also occur in otherwise immunosuppressed patients. Due to different treatment strategies, distinguishing IRIS from infectious diseases is essential. The role of Treg in IRIS has to be elucidated.     

Status report. Canadian strategy for cancer control

The Canadian Strategy for Cancer Control is a stakeholder-driven initiative, led by a partnership between the Canadian Cancer Society, National Cancer Institute of Canada, Canadian Association of Provincial Cancer Agencies and Health Canada. The planning process began in January 1999 and currently involves more than 130 health professionals and community representatives who are volunteering their time, experience and expertise. A crucial aspect of the strategy's successful implementation is early participation of the provincial/territorial ministries of health in the planning process. Working groups are addressing 11 areas of the cancer continuum: prevention, screening, diagnosis, treatment, supportive care/rehabilitation, palliative care, pediatric cancer, research, human resource planning, surveillance and informatics/technology. Two stakeholder conferences will engage all cancer stakeholders in helping develop recommendations and establishing priorities for cancer control in Canada.     

High-dose, stereotactic, one-time radiotherapy with curative intent for peripheral lung cancer

In peripheral non small cell lung cancer without metastasis, surgical resection achieves 5-year survival rates of at least 65%. In functionally inoperable patients radiation therapy offers the second best changes. However, in cases of severe emphysema with severely limited lung function even conventional radiation therapy is prohibited because of possible fibrotic reactions of the lung parenchyma. For such patients high dose rate stereotactic one-time radiation therapy may be an option. According to the study protocol of the DKFZ Heidelberg a dose rate of 24 Gy at the iso-center is applied with the linear accelerator in a single session. The recognisable tumour is irradiated with 22 Gy (90% isodose included). 20 Gy are applied to the tumour plus 6 millimeters safety margin. Prerequisites of such a therapy are a detailed computer-based planning using CT scans and an exact positioning with immobilisation of the patient. The irradiation is ideally performed under general anesthesia with high-frequency jetventilation to avoid movements due to breathing. We report on this new therapeutic modality in a patient with lung emphysema having a T2 tumour.     

Severe cryptococcal‐associated neurological immune reconstitution inflammatory syndrome in a renal transplant recipient treated with adalimumab

Cryptococcosis is a major concern in organ transplant recipients. A decrease in immunosuppressants following the initiation of antifungal therapy is currently recommended, but can occasionally be complicated by the onset of immune reconstitution inflammatory syndrome (IRIS). We report on a case of cryptococcosis in a kidney transplant recipient, compounded by severe neurological IRIS, the outcome of which was unfavorable despite the use of anti‐tumor necrosis factor‐alpha monoclonal antibodies.     

Immune reconstitution inflammatory syndrome in the lung in non-human immunodeficiency virus patients

BackgroundWe evaluated immune reconstitution inflammatory syndrome (IRIS) in the lung in non-human immunodeficiency virus (HIV) patients.MethodsWe reviewed articles related to IRIS occurrence in the lung in non-HIV patients using a PubMed search. The keywords used for the search were “immune reconstitution syndrome” and “non-HIV.” Only patients with lung involvement were included. Those with suggested IRIS caused by white blood cell recovery were excluded.ResultsThere were 37 cases of IRIS in the lung in non-HIV patients. Complicating infections included tuberculosis (n = 17), histoplasmosis (n = 9), aspergillosis (n = 5), cryptococcosis (n = 4), and Pneumocystis pneumonia (n = 2). We also evaluated the underlying diseases, IRIS pathogenesis, management, and prognosis. IRIS was most commonly encountered in patients treated with anti-tumor necrosis factor (TNF) antibody who developed disseminated or extrapulmonary tuberculosis, leading to treatment discontinuation.ConclusionsThe diagnosis and management of IRIS in the lung in non-HIV patients should be investigated further, especially in the era of anti-TNF treatment.     

AIDS-related Mycobacterium avium infection dissemination in a patient with endobronchial lesions associated with immune reconstitution inflammatory syndrome

Highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of HIV-1-associated morbidity and mortality. During the initial months of HAART, immune reconstitution inflammatory syndrome (IRIS), an adverse consequence of restoration of the pathogen-specific immune response, often occurred in terminal-stage in patients, with MAC infection the most frequently implicated in IRIS. In August 2004, a 26-year-old Japanese woman with fever and general lymphadenopathy was diagnosed with AIDS (HIV-1 RNA 5.7 x 10(5) copies/mL, CD4+ T cell count 10/microL) and disseminated Mycobacterium avium (M. avium) infection, for which antimycobacterial treatment was initiated. The M. avium infection responded well to two months of this treatment, and HAART was begun. Despite good virologic response to HAART (HIV-1 RNA <50 copies/mL), she contracted pulmonary disease with parenchymal lung changes, endobronchial lesions, and localized supraclavicular lymphadenitis, which are M. avium-associated IRIS. Good immunological response (CD4+ T cell count 136/microL) and a stronger antimycobacterial treatment helped her overcoming M. avium-associated IRIS without systemic corticosteroids or the discontinuation of HAART. The possibility of IRIS should always be watched for when treating AIDS patients with HAART and an antimycobacterial treatment regimen formulated that considers potential drug interactions with HAART.     

Immunrekonstitutionssyndrom des Dünndarms bei einer immunsupprimierten Patientin mit systemischem Lupus erythematodes und nichttuberkulöser Mykobakteriose

An overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens is termed immune reconstitution inflammatory syndrome (IRIS). It has mainly been described in patients with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy (HAART) who show a significant increase of low CD4 T cells (initially <50/μl). IRIS may lead to organ damage and differential diagnosis is often difficult. We report the case of a 38-year-old female patient who developed a Mycobacteria genavense infection of the liver and the bowel after several immunosuppressive therapies for systemic lupus erythematosus. CD4 T cell counts as low as 17/μl were found and immunosuppressive therapy was stopped. Despite several courses of antibiotic treatment and rising CD4 T cell counts, severe malabsorption persisted. Upper endoscopy revealed a continuous inflammation with pseudopolyps of the small bowel and histologically, a granulomatous infiltrate was detected. After exclusion of a persisting infection by Mycobacteria genavense, IRIS of the small bowel was suspected and treatment with prednisolone was started. The clinical and histological picture improved significantly, the number of CD25⁺CD4⁺ cells decreased in the lamina propria of the duodenum under treatment with prednisolone and Foxp3+ regulatory T cells (Treg) accumulated around granulomas. This case shows that IRIS is not restricted to HIV patients but may also occur in otherwise immunosuppressed patients. Due to different treatment strategies, distinguishing IRIS from infectious diseases is essential. The role of Treg in IRIS has to be elucidated.     

Immunrekonstitutionssyndrome

The immune reconstitution inflammatory syndrome (IRIS) represents a heterogeneous group of conditions. Whilst they typically present in HIV-infected patients with advanced immunodeficiency, IRIS have also been described in HIV-negative patients with immune reconstitution due to other causes of immunosuppression. Frequently IRIS results from an immune response against underlying infection (pathogen-associated IRIS). However, IRIS might become evident during immune reconstitution without an underlying pathogen such as a sarcoid-like illness or an autoimmune thyropathy. Here we report on the epidemiology and risk factors of IRIS along with diagnosis and management of this clinically important inflammatory syndrome.