Diffusing alpha particles radiation treatment optimization in clinical settings

Alpha-particle emitters, notably used in 224Ra-DaRT, have emerged as effective in overcoming radiation resistance and providing targeted cancer therapy. These emitters cause DNA double-strand breaks, visualizable in human lymphocytes. The 224Ra DaRT technique, using a decay chain from seeds, extends alpha particle range, achieving complete tumor destruction while sparing healthy tissue. This thesis examines a biokinetic model, validated with patient data, and a feasibility study on skin squamous cell carcinomas are discussed. The study reports 75% tumor complete response rate and 48% patients experiencing acute grade 2 toxicity, resolving within a month. An observed abscopal effect (AE), where tumor regression occurs at non-irradiated sites, is examined, highlighting DaRT's potential in triggering anti-tumor immune responses. This effect, coupled with DaRT's high-linear energy transfer (LET), suggests its superiority over low-LET radiation in certain clinical scenarios. Improvements to DaRT, including the use of an external radio-opaque template for treatment planning, are explored. This advancement aids in determining source numbers for optimal tumor coverage, enhancing DaRT’s safety. The thesis outlines a typical DaRT procedure, from tumor measurements to source assessment and administration, emphasizing the importance of precise seed positioning. Furthermore, the thesis discusses DaRT's potential in treating prostate cancer, a prevalent global health issue, by offering an alternative to traditional salvage therapies. DaRT seeds, delivering alpha particle-based interstitial radiation, require precision in seed insertion due to their limited tissue range. In conclusion, the thesis advocates for DaRT's role in treating solid tumors, emphasizing its improved radiobiological potency and potential benefits over beta and gamma source-based therapies. Ongoing studies are assessing DaRT's feasibility in treating various solid tumors, including pancreatic, breast, prostate, and vulvar malignancies, suggesting a promising future in cancer treatment.

Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria

Background. A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation. METHODS: Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN beta1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years. RESULTS: We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m - last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m - last visit; CH: 0.29, NCH: 0.13). CONCLUSION: Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.

Optimization of HS-SPME/GC-MS analysis and its use in the profiling of illicit ecstasy tablets (Part 1)

A headspace solid-phase microextraction procedure (HS-SPME) was developed for the profiling of traces present in 3,4-methylenedioxymethylampethamine (MDMA). Traces were first extracted using HS-SPME and then analyzed by gas chromatography-mass spectroscopy (GC-MS). The HS-SPME conditions were optimized using varying conditions. Optimal results were obtained when 40 mg of crushed MDMA sample was heated at 80 °C for 15 min, followed by extraction at 80 °C for 15 min with a polydimethylsiloxane/divinylbenzene coated fibre. A total of 31 compounds were identified as traces related to MDMA synthesis, namely precursors, intermediates or by-products. In addition some fatty acids used as tabletting materials and caffeine used as adulterant, were also detected. The use of a restricted set of 10 target compounds was also proposed for developing a screening tool for clustering samples having close profile. 114 seizures were analyzed using an SPME auto-sampler (MultiPurpose Samples MPS2), purchased from Gerstel GMBH & Co. (Germany), and coupled to GC-MS. The data was handled using various pre-treatment methods, followed by the study of similarities between sample pairs based on the Pearson correlation. The results show that HS-SPME, coupled with the suitable statistical method is a powerful tool for distinguishing specimens coming from the same seizure and specimens coming from different seizures. This information can be used by law enforcement personnel to visualize the ecstasy distribution network as well as the clandestine tablet manufacturing.

Muscle motion and EMG activity in vibration treatment

The aim of this study is to highlight the relationship between muscle motion, generated by whole body vibration, and the correspondent electromyographic (EMG) activity and to suggest a new method to customize the stimulation frequency. Simultaneous recordings of EMG and tri-axial accelerations of quadriceps rectus femoris from fifteen subjects undergoing vibration treatments were collected. Vibrations were delivered via a sinusoidal oscillating platform at different frequencies (10-45 Hz). Muscle motion was estimated by processing the accelerometer data. Large EMG motion artifacts were removed using sharp notch filters centred at the vibration frequency and its superior harmonics. EMG-RMS values were computed and analyzed before and after artifact suppression to assess muscular activity. Muscles acceleration amplitude increased with frequency. Muscle displacements revealed a mechanical resonant-like behaviour of the muscle. Resonance frequencies and dumping factors depended on subject. Moreover, RMS of artifact-free EMG was found well correlated (R 2 = 0.82) to the actual muscle displacement, while the maximum of the EMG response was found related to the mechanical resonance frequency of muscle. Results showed that maximum muscular activity was found in correspondence to the mechanical resonance of the muscle itself. Assuming the hypothesis that muscle activation is proportional to muscle displacement, treatment optimization (i.e. to choose the best stimulation frequency) could be obtained by simply monitoring local acceleration (resonance), leading to a more effective muscle stimulation. Motion artifact produced an overestimation of muscle activity, therefore its removal was essential. © 2009 IPEM.

Produção de bioetanol a partir de um resíduo orgânico proveniente da central de compostagem da LIPOR

Mestrado em Engenharia Química

Optimização do tratamento por lamas activadas do efluente líquido da Mundotêxtil

A Mundotêxtil foi fundada em 1975 tendo iniciado a sua actividade na área comercial de produtos têxteis. Actualmente é o maior produtor nacional de atoalhados de felpo e emprega 575 colaboradores. Como resultado do seu crescimento e sobretudo da actividade de tingimento de fio e felpo, as necessidades de água são consideráveis e o volume de efluentes gerados nos processos industriais é cada vez maior a empresa avançou com a construção de uma estação de tratamento por lamas activadas, colocando-a em funcionamento em Setembro de 2004. Inicialmente surgiram dificuldades para a remoção da cor e da concentração da Carência Química de Oxigénio (CQO) de modo a cumprir os limites máximos de emissão permitidos nas normas de descarga no rio Ave e no Decreto-Lei nº 236/98, de 1 de Agosto. Com a descarga de parte dos efluentes no SIDVA e a utilização de um coagulante adicionado ao reactor o tratamento passou a apresentar melhores resultados. O intuito deste trabalho é o de apresentar soluções de modo a optimizar o funcionamento do tratamento biológico da Mundotêxtil. A optimização pode começar na concepção dos produtos, pode incidir no processo de fabrico para além de poder ser efectuada no seio da estação de tratamento biológico. Foi efectuado um estudo do tratamento biológico por lamas activadas no Laboratório de Tecnologia Química Profª Doutora Lída de Vasconcelos, laboratório tecnológico do Instituto Superior de Engenharia do Porto (ISEP) que decorreu nos meses de Maio, Junho e Julho de 2010. O estudo laboratorial foi efectuado para três situações distintas: 1) tratamento do efluente bruto sem qualquer tipo de pré-tratamento (ensaios 1 a 3); 2) tratamento do efluente bruto submetido a pré-tratamento com coagulante Ambifloc BIO MD (ensaios 4 e 5) e 3) tratamento com adição de fungos ao tanque de arejamento (ensaio 6). Foram utilizadas duas instalações de tratamento alimentadas a partir do mesmo tanque de alimentação. Os dois sistemas eram idênticos, diferiram nos caudais de alimentação de efluente que foram alterados ao longo do estudo. O efluente a tratar foi fornecido pela empresa Mundotêxtil, sendo recolhido por diversas vezes ao longo dos ensaios. Este efluente foi retirado após o pré-tratamento da empresa, ou seja este efluente é o mesmo que alimenta o tratamento biológico da Mundotêxtil. Devido a este facto o efluente usado no estudo laboratorial teve uma variabilidade no período em que decorreu o estudo, nomeadamente em termos de concentração de CQO e cor. A relação entre a Carência Bioquímica (CBO5) e a CQO situouse entre 0,47 e 0,63 o que traduz que está dentro dos valores típicos para um efluente têxtil. Os melhores resultados globais de remoção de CQO foram obtidos no ensaio 5 e estiveram compreendidos entre 73,2% e 77,5% para o ensaio 5.1 e entre 62,9 e 73,2% para o ensaio 5.2. Neste ensaio foi utilizado o coagulante. Todos os valores de concentração de CQO obtidos nos efluentes dos decantadores para os ensaios 2, 5 e 6 são inferiores aos valores limite de descarga definidos nas normas de descarga no rio Ave e o Decreto-Lei 236/98. Os valores de concentração de Sólidos Suspensos Totais (SST), pH, fósforo, CBO5 e cor nos decantadores cumpriram os limites de descarga definidos nas normas de descarga no rio Ave e no Decreto-Lei nº 236/98 em todos os ensaios. Os parâmetros cinéticos obtidos para os ensaios com descorante são os que melhor se ajustam ao projecto de uma instalação de tratamento biológico por lamas activadas do efluente da Mundotêxtil. Os valores obtidos, após ajuste, são os seguintes: k=0,015 L/(mgSSV*d); Sn=12 mg/L; a=0,7982 kgO2/kgCBO5; b=0,0233 [kgO2/(kgSSV*d); y=0,2253 kgSSV/kgCBO5; kd=0,0036 kgSSV/(kgSSV*d. Com base nos parâmetros cinéticos obtiveram-se os seguintes resultados para o projecto de uma estação de tratamento biológico por lamas activadas: · Tempo de retenção hidráulica no reactor de 1,79 d, · Volume do reactor igual a 3643 m3 · Consumo de oxigénio no reactor de 604 kg/d · Razão de recirculação igual a 0,8 · Volume total do decantador secundário igual a 540 m3 · Diâmetro do decantador secundário igual a 15 m A quantidade de oxigénio necessário é baixa e o valor mais adequado deverá ser da ordem de 1200 kg/d. Também foi efectuada uma análise aos produtos químicos consumidos pela empresa na área das tinturarias com a finalidade de identificar as substâncias com uma maior influência potencial no funcionamento da Estação de Tratamento Biológico. O encolante CB, Cera Têxtil P Líquida, Perfemina P-12, Meropan DPE-P, Meropan BRE-P, Indimina STS e Benzym TEC são os produtos químicos que têm uma influência potencial mais significativa na qualidade dos efluentes. Devido ao facto das temperaturas do efluente alimentado ao tratamento biológico da Mundotêxtil oscilarem entre 35 ºC e 43ºC efectuou-se um estudo às necessidades de água quente das tinturarias e por outro lado à capacidade de aquecimento dos efluentes disponíveis. Actualmente a racionalização dos consumos de água é cada vez mais premente, por isso também é apresentado neste trabalho um estudo para a substituição das máquinas convencionais das tinturarias com uma relação de banho 1:10 por máquinas de banho curto (1:6,5). Verifica-se a redução de consumos de 40% de água, 52% de energia eléctrica, 35% de produtos químicos, 51% das necessidades de vapor e por consequência um aumento da produtividade. A empresa pode reduzir os consumos de água em cerca de 280.000 m3/ano. A utilização do pré-tratamento com o coagulante permitirá baixar a concentração da CQO e reduzir a cor à entrada do reactor tratamento biológico. Deste modo é possível manter um tratamento eficiente à saída do tratamento biológico nas situações de descarga de cores carregadas e carga orgânica elevada. Com este conjunto de soluções, quer sejam aplicadas na totalidade ou não, a empresa Mundotêxtil pode enfrentar o futuro com mais confiança podendo estar preparada para fazer face à escassez de água e custos cada vez maiores da energia. Por outro lado pode tratar os seus efluentes a custos menores. A substituição das máquinas de tingimento por máquinas com relação de banho mais baixa (banho curto) implica investimentos elevados mas estes investimentos são necessários não só por motivos ambientais mas também devido à grande competitividade dos mercados.

Hit parade for adoptive cell transfer therapy: the best T cells for superior clinical responses.

Adoptive cell transfer (ACT) of T cells has great clinical potential, but the numerous variables of this therapy make choices difficult. A new study takes advantage of a novel technology for characterizing the T-cell responses of patients. If applied systematically, this approach may identify biomedical correlates of protection, thereby supporting treatment optimization.

Análise da fidelidade do traçado predictivo em pacientes submetidos à cirurgia ortognática em mandíbula

OBJETIVO: a proposta desse trabalho foi analisar a fidelidade dos traçados predictivos realizados para cirurgias ortognáticas, por meio de análise cefalométrica do pré e pós-operatório de sete dias, em pacientes submetidos à correção de deformidade mandibular. MÉTODOS: foram utilizadas telerradiografias cefalométricas de perfil de 17 pacientes submetidos à cirurgia ortognática de mandíbula. Foram realizados traçados cefalométricos do pré e do pós-operatório de 7 dias com marcação dos pontos côndilo (Co), pogônio (Pog), goníaco (Go), mento (Me), ponto B (B) e incisivo (I). A análise foi baseada na diferença obtida pela sobreposição dos traçados pré-operatório, predictivo e pós-operatório. Os pontos foram projetados em um plano cartesiano para medição das suas distâncias em milímetros. Os dados obtidos foram submetidos à análise estatística por meio do teste t de Student pareado (± = 0,05). RESULTADOS: no eixo horizontal, foi observada diferença média, entre a mudança planejada e a obtida nos traçados cefalométricos pós-operatórios, estatisticamente significativa nos pontos Pog (p = 0,014) e I (p = 0,008). No eixo vertical, não verificou-se diferença estatística significativa para os pontos cefalométricos marcados (p > 0,05). CONCLUSÕES: o traçado predictivo contribuiu para a avaliação pré-operatória do paciente e, consequentemente, para a otimização do tratamento. Entretanto, ele não se mostrou totalmente fiel nos casos analisados, com leve subestimação das alterações esqueléticas horizontais. Essas alterações devem ser consideradas no planejamento e acompanhamento pós-operatório dos pacientes submetidos à cirurgia ortognática em mandíbula.

Impact of comorbid migraine on the clinical course of bipolar disorder

Background: Recent evidence suggests an association between migraine and bipolar disorder (BD), although the impact of this association in the clinical course of BD is relatively unknown. Objective: This study aimed to compare 2 groups of individuals with BD (with vs without comorbid migraine) and evaluate differences in severity of clinical course. Methods: Three hundred thirty-nine adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition defined bipolar or II disorder were enrolled and divided into 2 groups: with and without comorbid migraine. Demographic and clinical data were obtained using standardized interviews. Results: Patients with comorbid migraines had more mood episodes, especially those with depressive polarity. In addition, comorbid migraine was associated with a higher prevalence of psychiatric and general medical comorbidities. Differences between the 2 groups in number of lifetime hospitalizations for depression/mania, rates of rapid cycling, and history of suicide attempts were not observed after Bonferroni correction. Conclusions: Comorbid migraine seems to be associated with poor outcomes in BD. Additional studies should be conducted to investigate shared vulnerabilities and pathophysiologic mechanisms as well as treatment optimization of both illnesses. (C) 2012 Elsevier Inc. All rights reserved.

Vibration as a method for muscular stimulation

Human reactions to vibration have been extensively investigated in the past. Vibration, as well as whole-body vibration (WBV), has been commonly considered as an occupational hazard for its detrimental effects on human condition and comfort. Although long term exposure to vibrations may produce undesirable side-effects, a great part of the literature is dedicated to the positive effects of WBV when used as method for muscular stimulation and as an exercise intervention. Whole body vibration training (WBVT) aims to mechanically activate muscles by eliciting neuromuscular activity (muscle reflexes) via the use of vibrations delivered to the whole body. The most mentioned mechanism to explain the neuromuscular outcomes of vibration is the elicited neuromuscular activation. Local tendon vibrations induce activity of the muscle spindle Ia fibers, mediated by monosynaptic and polysynaptic pathways: a reflex muscle contraction known as the Tonic Vibration Reflex (TVR) arises in response to such vibratory stimulus. In WBVT mechanical vibrations, in a range from 10 to 80 Hz and peak to peak displacements from 1 to 10 mm, are usually transmitted to the patient body by the use of oscillating platforms. Vibrations are then transferred from the platform to a specific muscle group through the subject body. To customize WBV treatments, surface electromyography (SEMG) signals are often used to reveal the best stimulation frequency for each subject. Use of SEMG concise parameters, such as root mean square values of the recordings, is also a common practice; frequently a preliminary session can take place in order to discover the more appropriate stimulation frequency. Soft tissues act as wobbling masses vibrating in a damped manner in response to mechanical excitation; Muscle Tuning hypothesis suggest that neuromuscular system works to damp the soft tissue oscillation that occurs in response to vibrations; muscles alters their activity to dampen the vibrations, preventing any resonance phenomenon. Muscle response to vibration is however a complex phenomenon as it depends on different parameters, like muscle-tension, muscle or segment-stiffness, amplitude and frequency of the mechanical vibration. Additionally, while in the TVR study the applied vibratory stimulus and the muscle conditions are completely characterised (a known vibration source is applied directly to a stretched/shortened muscle or tendon), in WBV study only the stimulus applied to a distal part of the body is known. Moreover, mechanical response changes in relation to the posture. The transmissibility of vibratory stimulus along the body segment strongly depends on the position held by the subject. The aim of this work was the investigation on the effects that the use of vibrations, in particular the effects of whole body vibrations, may have on muscular activity. A new approach to discover the more appropriate stimulus frequency, by the use of accelerometers, was also explored. Different subjects, not affected by any known neurological or musculoskeletal disorders, were voluntarily involved in the study and gave their informed, written consent to participate. The device used to deliver vibration to the subjects was a vibrating platform. Vibrations impressed by the platform were exclusively vertical; platform displacement was sinusoidal with an intensity (peak-to-peak displacement) set to 1.2 mm and with a frequency ranging from 10 to 80 Hz. All the subjects familiarized with the device and the proper positioning. Two different posture were explored in this study: position 1 - hack squat; position 2 - subject standing on toes with heels raised. SEMG signals from the Rectus Femoris (RF), Vastus Lateralis (VL) and Vastus medialis (VM) were recorded. SEMG signals were amplified using a multi-channel, isolated biomedical signal amplifier The gain was set to 1000 V/V and a band pass filter (-3dB frequency 10 - 500 Hz) was applied; no notch filters were used to suppress line interference. Tiny and lightweight (less than 10 g) three-axial MEMS accelerometers (Freescale semiconductors) were used to measure accelerations of onto patient’s skin, at EMG electrodes level. Accelerations signals provided information related to individuals’ RF, Biceps Femoris (BF) and Gastrocnemius Lateralis (GL) muscle belly oscillation; they were pre-processed in order to exclude influence of gravity. As demonstrated by our results, vibrations generate peculiar, not negligible motion artifact on skin electrodes. Artifact amplitude is generally unpredictable; it appeared in all the quadriceps muscles analysed, but in different amounts. Artifact harmonics extend throughout the EMG spectrum, making classic high-pass filters ineffective; however, their contribution was easy to filter out from the raw EMG signal with a series of sharp notch filters centred at the vibration frequency and its superior harmonics (1.5 Hz wide). However, use of these simple filters prevents the revelation of EMG power potential variation in the mentioned filtered bands. Moreover our experience suggests that the possibility of reducing motion artefact, by using particular electrodes and by accurately preparing the subject’s skin, is not easily viable; even though some small improvements were obtained, it was not possible to substantially decrease the artifact. Anyway, getting rid of those artifacts lead to some true EMG signal loss. Nevertheless, our preliminary results suggest that the use of notch filters at vibration frequency and its harmonics is suitable for motion artifacts filtering. In RF SEMG recordings during vibratory stimulation only a little EMG power increment should be contained in the mentioned filtered bands due to synchronous electromyographic activity of the muscle. Moreover, it is better to remove the artifact that, in our experience, was found to be more than 40% of the total signal power. In summary, many variables have to be taken into account: in addition to amplitude, frequency and duration of vibration treatment, other fundamental variables were found to be subject anatomy, individual physiological condition and subject’s positioning on the platform. Studies on WBV treatments that include surface EMG analysis to asses muscular activity during vibratory stimulation should take into account the presence of motion artifacts. Appropriate filtering of artifacts, to reveal the actual effect on muscle contraction elicited by vibration stimulus, is mandatory. However as a result of our preliminary study, a simple multi-band notch filtering may help to reduce randomness of the results. Muscle tuning hypothesis seemed to be confirmed. Our results suggested that the effects of WBV are linked to the actual muscle motion (displacement). The greater was the muscle belly displacement the higher was found the muscle activity. The maximum muscle activity has been found in correspondence with the local mechanical resonance, suggesting a more effective stimulation at the specific system resonance frequency. Holding the hypothesis that muscle activation is proportional to muscle displacement, treatment optimization could be obtained by simply monitoring local acceleration (resonance). However, our study revealed some short term effects of vibratory stimulus; prolonged studies should be assembled in order to consider the long term effectiveness of these results. Since local stimulus depends on the kinematic chain involved, WBV muscle stimulation has to take into account the transmissibility of the stimulus along the body segment in order to ensure that vibratory stimulation effectively reaches the target muscle. Combination of local resonance and muscle response should also be further investigated to prevent hazards to individuals undergoing WBV treatments.

Therapeutisches drug monitoring bei antidepressiver Pharmakotherapie

Therapeutisches Drug Monitoring (TDM) umfasst die Messung von Medikamentenspiegeln im Blut und stellt die Ergebnisse in Zusammenhang mit dem klinischen Erscheinungsbild der Patienten. Dabei wird angenommen, dass die Konzentrationen im Blut besser mit der Wirkung korrelieren als die Dosis. Dies gilt auch für Antidepressiva. Voraussetzung für eine Therapiesteuerung durch TDM ist die Verfügbarkeit valider Messmethoden im Labor und die korrekte Anwendung des Verfahrens in der Klinik. Ziel dieser Arbeit war es, den Einsatz von TDM für die Depressionsbehandlung zu analysieren und zu verbessern. Im ersten Schritt wurde für das neu zugelassene Antidepressivum Duloxetin eine hochleistungsflüssig-chromatographische (HPLC) Methode mit Säulenschaltung und spektrophotometrischer Detektion etabliert und an Patienten für TDM angewandt. Durch Analyse von 280 Patientenproben wurde herausgefunden, dass Duloxetin-Konzentrationen von 60 bis 120 ng/ml mit gutem klinischen Ansprechen und einem geringen Risiko für Nebenwirkungen einhergingen. Bezüglich seines Interaktionspotentials erwies sich Duloxetin im Vergleich zu anderen Antidepressiva als schwacher Inhibitor des Cytochrom P450 (CYP) Isoenzyms 2D6. Es gab keinen Hinweis auf eine klinische Relevanz. Im zweiten Schritt sollte eine Methode entwickelt werden, mit der möglichst viele unterschiedliche Antidepressiva einschließlich deren Metaboliten messbar sind. Dazu wurde eine flüssigchromatographische Methode (HPLC) mit Ultraviolettspektroskopie (UV) entwickelt, mit der die quantitative Analyse von zehn antidepressiven und zusätzlich zwei antipsychotischen Substanzen innerhalb von 25 Minuten mit ausreichender Präzision und Richtigkeit (beide über 85%) und Sensitivität erlaubte. Durch Säulenschaltung war eine automatisierte Analyse von Blutplasma oder –serum möglich. Störende Matrixbestandteile konnten auf einer Vorsäule ohne vorherige Probenaufbereitung abgetrennt werden. Das kosten- und zeiteffektive Verfahren war eine deutliche Verbesserung für die Bewältigung von Proben im Laboralltag und damit für das TDM von Antidepressiva. Durch Analyse des klinischen Einsatzes von TDM wurden eine Reihe von Anwendungsfehlern identifiziert. Es wurde deshalb versucht, die klinische Anwendung des TDM von Antidepressiva durch die Umstellung von einer weitgehend händischen Dokumentation auf eine elektronische Bearbeitungsweise zu verbessern. Im Rahmen der Arbeit wurde untersucht, welchen Effekt man mit dieser Intervention erzielen konnte. Dazu wurde eine Labor-EDV eingeführt, mit der der Prozess vom Probeneingang bis zur Mitteilung der Messergebnisse auf die Stationen elektronisch erfolgte und die Anwendung von TDM vor und nach der Umstellung untersucht. Die Umstellung fand bei den behandelnden Ärzten gute Akzeptanz. Die Labor-EDV erlaubte eine kumulative Befundabfrage und eine Darstellung des Behandlungsverlaufs jedes einzelnen Patienten inklusive vorhergehender Klinikaufenthalte. Auf die Qualität der Anwendung von TDM hatte die Implementierung des Systems jedoch nur einen geringen Einfluss. Viele Anforderungen waren vor und nach der Einführung der EDV unverändert fehlerhaft, z.B. wurden häufig Messungen vor Erreichen des Steady State angefordert. Die Geschwindigkeit der Bearbeitung der Proben war im Vergleich zur vorher händischen Ausführung unverändert, ebenso die Qualität der Analysen bezüglich Richtigkeit und Präzision. Ausgesprochene Empfehlungen hinsichtlich der Dosierungsstrategie der angeforderten Substanzen wurden häufig nicht beachtet. Verkürzt wurde allerdings die mittlere Latenz, mit der eine Dosisanpassung nach Mitteilung des Laborbefundes erfolgte. Insgesamt ist es mit dieser Arbeit gelungen, einen Beitrag zur Verbesserung des Therapeutischen Drug Monitoring von Antidepressiva zu liefern. In der klinischen Anwendung sind allerdings Interventionen notwendig, um Anwendungsfehler beim TDM von Antidepressiva zu minimieren.

Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML)

In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with 1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with 35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with 1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks.

Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874

Toward stratified treatments for bipolar disorders

In bipolar disorders, there are unclear diagnostic boundaries with unipolar depression and schizophrenia, inconsistency of treatment guidelines, relatively long trial-and-error phases of treatment optimization, and increasing use of complex combination therapies lacking empirical evidence. These suggest that the current definition of bipolar disorders based on clinical symptoms reflects a clinically and etiologically heterogeneous entity. Stratification of treatments for bipolar disorders based on biomarkers and improved clinical markers are greatly needed to increase the efficacy of currently available treatments and improve the chances of developing novel therapeutic approaches. This review provides a theoretical framework to identify biomarkers and summarizes the most promising markers for stratification regarding beneficial and adverse treatment effects. State and stage specifiers, neuropsychological tests, neuroimaging, and genetic and epigenetic biomarkers will be discussed with respect to their ability to predict the response to specific pharmacological and psychosocial psychotherapies for bipolar disorders. To date, the most reliable markers are derived from psychopathology and history-taking, while no biomarker has been found that reliably predicts individual treatment responses. This review underlines both the importance of clinical diagnostic skills and the need for biological research to identify markers that will allow the targeting of treatment specifically to sub-populations of bipolar patients who are more likely to benefit from a specific treatment and less likely to develop adverse reactions.

The Comparative Effectiveness of EEG Biomarkers in Antidepressant Response and Illness Prediction in Major Depressive Disorder

Background: There is growing evidence that individual EEG differences may aid in classifying patients with major depressive disorder (MDD) and also help predict clinical response to antidepressant treatment. This study aims to compare the effectiveness of EEG frequency band power, alpha asymmetry and prefrontal theta cordance towards escitalopram response prediction and MDD diagnosis, in a multi-site initiative. Methods: Resting EEG (eyes open and closed) was recorded from 64 electrodes in 44 depressed patients and 20 healthy controls at baseline, 2 weeks post-treatment and 8 weeks post-treatment. Clinical response was measured as change from baseline MADRS of 50% or more. EEG measures were analyzed (1) at baseline (2) at 2 weeks post-treatment and (3) as an ‘‘early change” variable defined as change in EEG from baseline to 2 weeks post-treatment. Results: At baseline, responders exhibited greater absolute alpha power in the left hemisphere versus the right while non-responders showed the opposite. Responders further exhibited a cortical asymmetry of greater right relative to left activity in parietal areas. Groups also differed in baseline relative delta power with responders showing greater power in the right hemisphere versus the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to right and the opposite was noted for non-responders. The opposite pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reduction in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance. Absolute delta power helped distinguish MDD patients from healthy controls. Conclusions: Hemispheric asymmetries in the alpha and delta bands at pre-treatment baseline and at 2 weeks post-treatment have moderate to moderately strong predictive utility towards antidepressant treatment response. These findings have significant potential for improving clinical practice in psychiatry by eventually guiding clinical choice of treatments. This would greatly benefit patients awaiting relief from depressive symptoms as treatment optimization would help overcome problems associated with delayed recovery. Our results also indicate that resting EEG activity may have clinical utility in predicting MDD diagnosis.