Breast cancer therapy in women under 35 years and between 50 and 69 years: influence of the observation period.

PURPOSE: In recent years, therapeutic strategies based on tumour biology have increased significantly. We aimed to provide an overview of the recent changes in patient characteristics, treatment procedures and survival factors for two groups of patients: women younger than 35 years and women between 50 and 69 years. METHODS: We used data from the population-based Cancer Registry Magdeburg. Subjects included women with non-metastatic breast cancer treated between 2000 and 2015. We compared between two observation periods: 2000-2007 and 2008-2015. RESULTS: There was an increase in patient survival from the first to the second observation period. Tumour characteristics and treatment modalities changed, especially in the group of older patients. The proportion of prognostically more favourable tumour subtypes, such as Luminal A, increased significantly. Between 2008 and 2015, there were more hormone receptor-positive, lymph-node-negative, human epidermal growth factor receptor-2 (HER2)-negative and well-differentiated tumours. Surgical methods were associated with significantly reduced radicality, while the rate of neoadjuvant therapy increased in both groups. There was a decrease in cyclophosphamide, methotrexate and 5-fluoruracil (CMF) and anthracycline therapies, but taxane-containing chemotherapy increased. While tamoxifen was used more frequently in younger patients in the later observation period, its use was reduced in older patients, superseded by aromatase inhibitors. Furthermore, the use of immune therapy increased. CONCLUSION: In both age groups, but primarily in older patients, there were significant changes in tumour biology and treatment options between the two observation periods. These changes have led to a continuous improvement in patient outcomes.

Geant4 Monte Carlo simulation study of the secondary radiation fields at the laser-driven ion source LION.

At the Center for Advanced Laser Applications (CALA), Garching, Germany, the LION (Laser-driven ION Acceleration) experiment is being commissioned, aiming at the production of laser-driven bunches of protons and light ions with multi-MeV energies and repetition frequency up to 1 Hz. A Geant4 Monte Carlo-based study of the secondary neutron and photon fields expected during LION's different commissioning phases is presented. Goal of this study is the characterization of the secondary radiation environment present inside and outside the LION cave. Three different primary proton spectra, taken from experimental results reported in the literature and representative of three different future stages of the LION's commissioning path are used. Together with protons, also electrons are emitted through laser-target interaction and are also responsible for the production of secondary radiation. For the electron component of the three source terms, a simplified exponential model is used. Moreover, in order to reduce the simulation complexity, a two-components simplified geometrical model of proton and electron sources is proposed. It has been found that the radiation environment inside the experimental cave is either dominated by photons or neutrons depending on the position in the room and the source term used. The higher the intensity of the source, the higher the neutron contribution to the total dose for all scored positions. Maximum neutron and photon ambient dose equivalent values normalized to 109 simulated incident primaries were calculated at the exit of the vacuum chamber, where values of about 85 nSv (109 primaries)-1 and 1.0 µSv (109 primaries)-1 were found.

Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma.

AIM: To examine whether anesthesia exposure is associated with neurocognitive decline in pediatric medulloblastoma. METHODS: Patients were treated at St. Jude Children's Research Hospital and completed ≥2 protocol-directed neurocognitive assessments (n = 107) as part of a multisite clinical trial for pediatric medulloblastoma (NCT00085202). Patients received risk-adapted craniospinal photon irradiation, followed by four cycles of high-dose chemotherapy and stem cell rescue. Neurocognitive testing was completed at study baseline (after surgery and <2 weeks of starting radiation therapy) and annually for 5 years. Data on anesthesia exposure during treatment was abstracted from medical records. RESULTS: Patients were 10.2 years at diagnosis on average (SD = 4.5; 37% female, 73% average-risk). Mean cumulative anesthesia duration was 20.4 h (SD = 15.2; range 0.7-55.6 h). In the overall group, longer anesthesia duration was associated with greater declines in IQ (Estimate = -0.08, P < 0.001), attention (Estimate = -0.10, P < .001) and processing speed (Estimate = -0.13, P < 0.001). Similar results were shown in subgroups of patients who were <7 years at diagnosis (IQ = -0.14, P = 0.027; Attention = -0.25: P = 0.011), ≥7 years at diagnosis (Attention = -0.07, P = 0.039; Processing Speed = -0.08, P = 0.022), treated for high-risk disease (IQ = -0.09, P = 0.024; Attention = -0.11, P = 0.034; Processing Speed = -0.13, P = 0.001), or treated for average-risk disease (IQ = -0.05, P = .022; Attention = -0.08, P = 0.011; Processing Speed = -0.10, P < 0.001). CONCLUSION: Greater anesthesia exposure is a risk factor for clinically significant neurocognitive decline, in addition to factors of age at diagnosis and treatment risk arm. This result is notable as there are evidence-based strategies that can limit the need for anesthesia. Limiting anesthesia exposure, as feasible, may mitigate neurocognitive late effects, and thus, improve quality of life for survivors.

Beam characterization and feasibility study for a small animal irradiation platform at clinical proton therapy facilities.

A deeper understanding of biological mechanisms to promote more efficient treatment strategies in proton therapy demands advances in preclinical radiation research. However this is often limited by insufficient availability of adequate infrastructures for precision image guided small animal proton irradiation. The project SIRMIO aims at filling this gap by developing a portable image-guided research platform for small animal irradiation, to be used at clinical facilities and allowing for a precision similar to a clinical treatment, when scaled down to the small animal size. This work investigates the achievable dosimetric properties of different lowest energy clinical proton therapy beams, manipulated by a dedicated portable beamline including active focusing after initial beam energy degradation and collimation. By measuring the lateral beam size in air close to the beam nozzle exit and the laterally integrated depth dose in water, an analytical beam model based on the beam parameters of the clinical beam at the Rinecker Proton Therapy Center was created for the lowest available clinical beam energy. The same approach was then applied to estimate the lowest energy beam model of different proton therapy facilities, Paul Scherrer Institute, Centre Antoine Lacassagne, Trento Proton Therapy Centre and the Danish Centre for Particle Therapy, based on their available beam commissioning data. This comparison indicated similar beam properties for all investigated sites, with emittance values of a few tens of mm·mrad. Finally, starting from these beam models, we simulated propagation through a novel beamline designed to manipulate the beam energy and size for precise small animal irradiation, and evaluated the resulting dosimetric properties in water. For all investigated initial clinical beams, similar dosimetric results suitable for small animal irradiation were found. This work supports the feasibility of the proposed SIRMIO beamline, promising suitable beam characteristics to allow for precise preclinical irradiation at clinical treatment facilities.

[Operability and Pathological Response of Non-Small Cell Lung Cancer (NSCLC) after Neoadjuvant Therapy with Immune Checkpoint Inhibition]. / Operabilität und pathologisches Ansprechen des Lungenkarzinoms nach neoadjuvanter Therapie mit Immun-Checkpoint-Inhibitoren.

BACKGROUND: The blockade of immune escape mechanisms (e. g. PD1 /PD-L1) using immune checkpoint inhibition (ICI) can significantly prolong survival and induce remission in patients with advanced non-small cell lung cancer (NSCLC). Less is known about neoadjuvant ICI in patients with resectable (UICC stage III) or oligometastatic (UICC stage IVa) NSCLC. METHODS: Tissue biopsies from patients with advanced or oligometastatic NSCLC were screened for PD-L1 expression. In case of PD-L1-expression > 50 %, ECOG status of 0 or 1 and expected operability, patients received ICI. After about four weeks, patients underwent thoracic surgical resection. In all patients, a complete staging, including PET-CT, cMRI, and endobronchial ultrasound, was performed. The tolerability, the radiological and the histopathological tumor response as well as the surgical and oncological outcomes were analyzed. FINDINGS: Four patients (2 male, 2 female, age 56 - 78 years, n = 3 adenocarcinoma, n = 1 squamous cell carcinoma) with local advanced tumors received ICI before surgical resection. In three cases the mediastinal lymph nodes were positive. One patient had a single cerebral metastasis which was treated with radiotherapy. All four patients underwent therapy with two to six cycles of ICI (3â€Š× pembrolizumab, 1â€Š× atezolizumab) without any complication, and ICI did not delay the time of surgical resection. According to iRECIST, three patients showed partial response (PR), one patient had stable disease (SD). All tumors were completely resected. The thoracic surgical procedures proved to be technically unproblematic despite inflammatory changes. There were neither treatment-related deaths nor perioperative complications. In the resectates, complete pathological response (CPR, regression grade III ) and regression grade IIb were detected twice. The average time of follow-up was 12 (1 - 24) months. Patients with PPR developed distant metastasis after six months or a local recurrence after four months. The CPR patient is relapse free to date. CONCLUSION: In selected patients, neoadjuvant therapy with ICI is well tolerated and can induce a complete remission of the tumor. Treatment with ICI has no negative impact on the surgical procedure. Prognosis seems to be promising in CPR and limited in PPR.

[Lupus nephritis]. / Lupusnephritis.

Lupus nephritis (LN) is the most frequent and one of the most severe organ manifestations of systemic lupus erythematosus. The central pathogenetic mechanism is characterized by the loss of immune tolerance against autoantigens of the cell nucleus, which can lead to renal inflammation via the formation of nuclear autoantibodies. The clinical manifestations of LN encompass nephritic syndrome with the special form of rapidly progressive glomerulonephritis, nephrotic syndrome and thrombotic microangiopathy. The diagnostic procedures consist of renal function and urine analysis as well as the determination of serum autoantibody profiles and complement components. An early renal biopsy enables a differentiation between the prognostically different forms of LN. In addition to supportive measures, a differentiated immunosuppressive treatment is the main approach for prognostically unfavorable forms. Important components are corticosteroids, cyclophosphamide and mycophenolate mofetil for induction treatment. Currently investigated treatment principles include next generation calcineurin inhibitors and anti-B cell treatment.

[Lung involvement in hematologic systemic diseases]. / Lungenbeteiligung bei hämatologischen Systemerkrankungen.

Pulmonary diseases can occur across the entire disease spectrum of malignant hematologic systemic diseases. Although infectious processes of the lungs are common in these immunosuppressed patient collectives, noninfectious causes account for up to half of the pulmonary manifestations found in hematologic malignancies. Besides the frequent infections including opportunistic pathogens, a broad differential diagnosis including drug-induced lung injury by cytostatic substances, cytokines, and innovative immunotherapeutic agents, rarer transfusion of blood products and intrathoracic manifestations of the hematologic malignancy itself, have to be kept in mind. Finally, vascular complications can also lead to pulmonary reactions. Early and consistent diagnostics and treatment of the bronchopulmonary, intrathoracic and vascular complications within the framwework of hematologic systemic diseases can be essential for the patient's prognosis.

Self-assembled Pt2L2 boxes strongly bind G-quadruplex DNA and influence gene expression in cancer cells.

Supramolecular Pt(ii) quadrangular boxes bind native and G-quadruplex DNA motifs in a size-dependent fashion. Three Pt molecular squares of distinct size show biological activity against cancer cells and heavily influence the expression of genes known to form G-quadruplexes in their promoter regions. The smallest Pt-box displays less activity but more selectivity for a quadruplex formed in the c-Kit gene.

[Rendu-Osler-Weber disease : More than just a nosebleed]. / Morbus Osler : Mehr als nur Nasenbluten.

A 72-year-old female patient presented with increasing dyspnea of unclear origin classified as New York Heart Association stage III (NYHA III). Using transesophageal echocardiography a patent foramen ovale (PFO) and right heart failure could be diagnosed. Right heart catheterization revealed a large left to right shunt due to an arteriovenous malformation in the liver. Because of additional telangiectasia of the lips the presumptive diagnosis was Rendu-Osler-Weber disease. Typical nosebleeds and other symptoms of the disease were lacking and only two out of four Curaçao criteria were positive; therefore, genetic testing was performed, which verified the clinical diagnosis. Off-label use of the angiogenesis inhibitor bevacizumab was initiated as the therapeutic strategy and led to an improvement in the symptomatic dyspnea.

[The Influence of Laparoscopic Fundoplication on Reflux-Associated Cough]. / Einfluss der laparoskopischen Fundoplikation auf den mit gastroösophagealem Reflux assoziierten Husten.

Introduction: The gastrooesophageal reflux disease (GERD) is a possible cause of chronic cough. The laparoscopic fundoplication is well established in the treatment of GERD. In a retrospective study, the effectivity of this operation on the GERD associated cough was examined and possible preoperative predictive factors concerning the post-surgical therapy effect were characterized. Patients and Methods: 85 patients after laparoscopic fundoplication due to GERD treated with proton pump inhibitors without (RS-H: n = 31) or with associated cough (RS+H: n = 54) were evaluated in a three-month follow-up by data analysis regarding an indication point score from typical symptoms as well as findings (gastroscopy, histology, 24-hour oesophagus pH-metry). Results: For the leading symptoms of heartburn and regurgitation a complete freedom from complaints was reached with 98.8 % of all patients postal-surgically. In the group RS+H 70.4 % of the patients were free of cough after 3 months, other 22.2 % with significant improvement and 7.4 % with unchanged irritant cough. Higher values of the typical reflux symptoms and a therapy resistance to proton pump inhibitors (PPI) were clearly seen in the RS-H patients. The RS+H patients showed less reflux complaints with lower PPI resistance, frequent allergies as well as significantly more often an acid or bitter taste and hoarseness. After further subdivision of the RS+H patients into the subgroups RS>H (mainly reflux, n = 31) and H>RS (mainly cough), the lowest values for heartburn, regurgitation and PPI resistance were found in subgroup H>RS. Diagnostics did not show any significiant differences between the groups although a trend could be seen towards fewer duodenogastric bile reflux, larger hiatus hernias and higher DeMeester scores in RS+H and H>RS. Also smokers, non-allergic asthmatics and polyallergic sufferers with cough profited from the intervention. Conclusion: Patients with reflux-associated respiratory symptoms present an own entity with good PPI therapy response to heartburn, but not to cough. They should be considered more often for surgery. Since the cough symptoms in more than two-thirds of appropriately selected patients disappear in a short time after surgery, laparoscopic antireflux surgery should also be considered from pneumological aspects. There are no individual predictors for the success of antireflux surgery, only the sum of all relevant individual case history and clinical criteria, as they are combined in the used score, can provide a reliable indication for surgery.

Arc expression identifies the lateral amygdala fear memory trace.

Memories are encoded within sparsely distributed neuronal ensembles. However, the defining cellular properties of neurons within a memory trace remain incompletely understood. Using a fluorescence-based Arc reporter, we were able to visually identify the distinct subset of lateral amygdala (LA) neurons activated during auditory fear conditioning. We found that Arc-expressing neurons have enhanced intrinsic excitability and are preferentially recruited into newly encoded memory traces. Furthermore, synaptic potentiation of thalamic inputs to the LA during fear conditioning is learning-specific, postsynaptically mediated and highly localized to Arc-expressing neurons. Taken together, our findings validate the immediate-early gene Arc as a molecular marker for the LA neuronal ensemble recruited during fear learning. Moreover, these results establish a model of fear memory formation in which intrinsic excitability determines neuronal selection, whereas learning-related encoding is governed by synaptic plasticity.

[Position Paper: Significance of the Forced Vital Capacity in Idiopathic Pulmonary Fibrosis]. / Positionspapier zur Bedeutung der forcierten Vitalkapazität für Patienten mit idiopathischer Lungenfibrose (IPF).

Spirometry is a highly standardized method which allows to measure the forced vital capacity (FVC) with high precision and reproducibility. In patients with IPF FVC is directly linked to the disease process which is characterized by scaring of alveoli and shrinkage of the lungs. Consequently, there is ample evidence form clinical studies that the decline of FVC over time is consistently associated with mortality in IPF. As for the first time effective drugs for the treatment of IPF are available it becomes obvious that in studies which could demonstrate that the drug reduces FVC decline, a numerical effect on mortality was also observed, while in one study where a significant effect on FVC decline was missed, there was also no change in mortality. Based on these studies FVC decline is a validated surrogate of mortality in IPF. It is concluded that FVC decline is not only accepted as an endpoint of clinical treatment trials in IPF but is also valid as a patient related outcome parameter which should be considered for the assessment of the efficacy of an IPF drug.

[German guideline for diagnosis and management of idiopathic pulmonary fibrosis]. / S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis is a fatal lung disease with a variable and unpredictable natural history and limited treatment options. Since publication of the ATS-ERS statement on IPF in the year 2000 diagnostic standards have improved and a considerable number of randomized controlled treatment trials have been published necessitating a revision. In the years 2006 - 2010 an international panel of IPF experts produced an evidence-based guideline on diagnosis and treatment of IPF, which was published in 2011. In order to implement this evidence-based guideline into the German Health System a group of German IPF experts translated and commented the international guideline, also including new publications in the field. A consensus conference was held in Bochum on December 3rd 2011 under the protectorate of the "Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP)" and supervised by the "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF). Most recommendations of the international guideline were found to be appropriate for the german situation. Based on recent clinical studies "weak negative" treatment recommendations for pirfenidone and anticoagulation were changed into "weak positive" for pirfenidone and "strong negative" for anticoagulation. Based on negative results from the PANTHER-trial the recommendation for the combination therapy of prednisone plus azathiorpine plus N-acetlycsteine was also changed into strong negative für patients with definite IPF. This document summarizes essential parts of the international IPF guideline and the comments and recommendations of the German IPF consensus conference.

Rayleigh-Taylor instability of an ultrathin foil accelerated by the radiation pressure of an intense laser.

We report experimental evidence for a Rayleigh-Taylor-like instability driven by radiation pressure of an ultraintense (10(21) W/cm(2)) laser pulse. The instability is witnessed by the highly modulated profile of the accelerated proton beam produced when the laser irradiates a 5 nm diamondlike carbon (90% C, 10% H) target. Clear anticorrelation between bubblelike modulations of the proton beam and transmitted laser profile further demonstrate the role of the radiation pressure in modulating the foil. Measurements of the modulation wavelength, and of the acceleration from Doppler-broadening of back-reflected light, agree quantitatively with particle-in-cell simulations performed for our experimental parameters and which confirm the existence of this instability.

An isolated hand tumour as primary manifestation of sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic disorder with unknown etiology, characterized by non-caseating granulomas in numerous organs and tissues. In 90% of patients lung and lymph nodes are involved. The incidence of sarcoidal granulomas in the upper extremities is low. Here we present the case of a primary hand manifestation of sarcoidosis without clinical systemic involvement. OBJECTIVES: A young woman presented with a painful swelling in her right hand. There were no signs of inflammation. Normal perfusion, mobility and sensibility were found. Magnetic resonance imaging (MRI) revealed a tumour infiltrating the muscles and flexor tendons of the third digit around the metacarpal bone and with pathological signal enhancement after administration of contrast medium. RESULTS: Intraoperatively, nodular masses and fat tissue were seen. Histological examination after radical tumour resection showed sarcoidal granulomas. Postoperative staging diagnostics with computed tomography (CT) demonstrated multiple thoracic lymph node swellings in the mediastinum and bilateral hill. Follow-up after one year we saw normal scars in the palmar hand. There was no sign of local recurrence. The pulmological care is still going on. CONCLUSIONS: Sarcoidosis is a rare, often asymptomatic disease. Patients present with dyspnoe and cough caused by the inflammation of the lung. The first clinical manifestation of sarcoidosis as a tumor in the palmar hand is unusual. Extrapulmonary systemic or progressive sarcoidosis is regarded as an indication for therapy with glucocorticosteroids. This case demonstrates that surgical excision enabled complete local cure without necessity of systemic and/or local treatment with steroids.

[Intralobar pulmonary sequestration with aspergillosis in an asymptomatic 39-year-old man]. / Intralobulärer Lungensequester mit Aspergillose bei einem beschwerdefreien 39-jährigen Mann.

HISTORY AND CLINICAL FINDINGS: During a screening examination a pulmonary mass in the left lower lobe was detected in a 39-year-old man. The patient was asymptomatic and had hitherto been healthy. CT pulmonary angiography revealed an intralobar pulmonary sequestration with an afferent arterial branch from the thoracic aorta. DIAGNOSIS, TREATMENT AND COURSE: Thoracotomy with resection of the sequestration was performed. On the first postoperative day hemiparesis of the left side occurred because of an infarction of the arteria cerebri media. After aspiration of the thrombus and intraarterial thrombolysis the patient recovered completely. Histology of the sequestration showed invasive growth of aspergillus and severe inflammation, caused by invasive mycosis. Subsequently the patient received voriconazol for four weeks. CONCLUSION: Diagnosis of pulmonary sequestration in adults is rare. In asymptomatic patients there is still controversy about the treatment. Surgery, arterial embolisation and a "watch and wait" strategy can be taken into account. Because of the risk of infection an operative approach should be favoured.

[Drug-induced lung diseases]. / Medikamentös induzierte Lungenerkrankungen.

Adverse effects of drug therapy may induce a wide variety of bronchopulmonary disorders. The spectrum of drug induced lung and bronchial diseases include simple cough, bronchial obstruction, and obstructive bronchiolitis. Lung parenchyma may be affected by alveolitis/pneumonitis or lung fibrosis. Further damage patterns are noncardiac pulmonary oedema, diffuse alveolar damage, diffuse alveolar haemorrhage, eosinophilic lung diseases, pulmonary vascular disorders as well as pleural affections. These side effects rarely have pathognomonic features. Therefore they are relevant differential diagnoses of genuine pulmonary diseases. Diagnostics is based mainly on the verification of a compatible disease pattern, exclusion of differential diagnoses, and assessment of the temporal relationship and the consequences of drug abstention. Reexposure is rarely indicated. Strict elimination of the responsible drugs is the most important therapeutic measure. Additional drug therapy, mostly with glucocorticosteroids, may be indicated.

Acceleromyography to assess neuromuscular recovery: is calibration before measurement mandatory?

BACKGROUND: Acceleromyography has been shown to be an appropriate method in the detection of residual paralysis. However, the clinical importance of an individual calibration of the device in the single patient to improve reliability in detecting residual paralysis remains unclear. METHODS: Observational study in 100 patients undergoing general anaesthesia with endotracheal intubation and a neuromuscular block with atracurium. In all patients, an individually calibrated acceleromyograph was used to estimate a possible residual block at the end of surgery. Immediately after finishing the calibrated measurements at the end of surgery, a non-calibrated measurement was performed. Agreements between the two measurements were tested using Cohen's κ and a Bland-Altman analysis. RESULTS: Data from 96 patients were analysed. At the end of surgery, a discordance in the calibrated and the non-calibrated train-of-four ratio was found in 88 patients. Bland-Altman analysis showed a mean (bias) of 0.01, with limits of agreement of 0.15/-0.15. κ was calculated with κ=0.84 for the absence or presence of a potential residual block if defined as a train-of-four ratio of 1.0 as a threshold. CONCLUSIONS: The results imply a good agreement in the detection of the presence or absence of a residual neuromuscular block between calibrated and non-calibrated acceleromyography if a train-of-four ratio of 1.0 has been chosen as the threshold. However, the estimated train-of-four values are not transferable between calibrated and non-calibrated measurements.

Monoenergetic proton beams accelerated by a radiation pressure driven shock.

We report on the acceleration of impurity-free quasimononenergetic proton beams from an initially gaseous hydrogen target driven by an intense infrared (λ=10 µm) laser. The front surface of the target was observed by optical probing to be driven forward by the radiation pressure of the laser. A proton beam of ∼MeV energy was simultaneously recorded with narrow energy spread (σ∼4%), low normalized emittance (∼8 nm), and negligible background. The scaling of proton energy with the ratio of intensity over density (I/n) confirms that the acceleration is due to the radiation pressure driven shock.