Degenerative Changes in Aging Human Pelvic Lymph Nodes-A Reason to Rethink Staging and Therapy of Regional Malignancies?

Lymph node metastases are common in pelvic urological tumors, and the age-related remodeling process of the pelvic lymph nodes influences metastatic behavior. The aim of this work is to characterize age-related degenerative changes in the pelvic lymph nodes with respect to their occurrence and extent. A total of 5173 pelvic lymph nodes of 390 patients aged 44 to 79 years (median 68 years, IQR 62-71 years) were histologically examined for degenerative structural changes. Lymph node size, lipomatous atrophy, capsular fibrosis, framework fibrosis, and calcifications were recorded semi-quantitatively and evaluated by age group. Significantly more lymph nodes <10 mm were found in older patients (p = 0.001). The incidence of framework fibrosis, capsular fibrosis, and calcifications increased significantly with increasing patient age (p < 0.001). In lipomatous atrophy, an increase in mild to moderate lipomatous atrophy was observed with increasing age (p < 0.001). In this, the largest study to date on this topic, age-related degenerative changes in pelvic lymph nodes were proven. Due to the consecutive decrease in hte filtration function of pelvic lymph nodes with increasing age, staging and therapy of metastatic pelvic urologic carcinomas should be reconsidered.

[Prostate cancer in older men : Special features of the diagnostics and treatment]. / Prostatakarzinom beim älteren Mann : Besonderheiten der Diagnostik und Therapie.

Prostate cancer is the most frequent cancer in men. For localized prostate cancer, surgery and radiotherapy are the standard treatment, with active surveillance also used in low-risk cases. For advanced/metastatic disease, androgen deprivation treatment is carried out. Further options include inhibitors of the androgen receptor axis and taxane-based chemotherapy. The avoidance of side effects should be considered, e.g., by dose adjustment. New options include poly(ADP-ribose) polymerase (PARP) inhibitors, and radioligand treatment. The existing guidelines only provide a few treatment recommendations for older patients; however, the treatment of older patients should primarily consider not only chronological age but also the patient's psychological and physical condition and preferences. In this context, the geriatric assessment represents an important instrument for determining the treatment strategy.

PET/CT reading for relapse in non-small cell lung cancer after chemoradiotherapy in the PET-Plan trial cohort.

BACKGROUND: Current studies indicate that fluorine-18-fluorodeoxyglucose positron emission tomography/ computed tomography ([18F]FDG PET/CT) is the most accurate imaging modality for the detection of relapsed locally advanced non-small cell lung cancer (NSCLC) after curatively intended chemoradiotherapy. To this day, there is no objective and reproducible definition for the diagnosis of disease recurrence in PET/CT, the reading of which is relevantly influenced by post radiation inflammatory processes. The aim of this study was to evaluate and compare visual and threshold-based semi-automated evaluation criteria for the assessment of suspected tumor recurrence in a well-defined study population investigated during the randomized clinical PET-Plan trial. METHODS: This retrospective analysis comprises 114 PET/CT data sets of 82 patients from the PET-Plan multi-center study cohort who underwent [18F]FDG PET/CT imaging at different timepoints for relapse, as suspected by CT. Scans were first analyzed visually by four blinded readers using a binary scoring system for each possible localization and the associated reader certainty of the evaluation. Visual evaluations were conducted repeatedly without and with additional knowledge of the initial staging PET and radiotherapy delineation volumes. In a second step, uptake was measured quantitatively using maximum standardized uptake value (SUVmax), peak standardized uptake value corrected for lean body mass (SULpeak), and a liver threshold-based quantitative assessment model. Resulting sensitivity and specificity for relapse detection were compared to the findings in the visual assessment. The gold standard of recurrence was independently defined by prospective study routine including external reviewers using CT, PET, biopsies and clinical course of the disease. RESULTS: Overall interobserver agreement (IOA) of the visual assessment was moderate with a high difference between secure (ĸ = 0.66) and insecure (ĸ = 0.24) evaluations. Additional knowledge of the initial staging PET and radiotherapy delineation volumes improved the sensitivity (0.85 vs 0.92) but did not show significant impact on the specificity (0.86 vs 0.89). PET parameters SUVmax and SULpeak showed lower accuracy compared to the visual assessment, whereas threshold-based reading showed similar sensitivity (0.86) and higher specificity (0.97). CONCLUSION: Visual assessment especially if associated with high reader certainty shows very high interobserver agreement and high accuracy that can be further increased by baseline PET/CT information. The implementation of a patient individual liver threshold value definition, similar to the threshold definition in PERCIST, offers a more standardized method matching the accuracy of experienced readers albeit not providing further improvement of accuracy.

Impact of radiotherapy protocol adherence in NSCLC patients treated with concurrent chemoradiation: RTQA results of the PET-Plan trial.

INTRODUCTION: The success of intensification and personalisation of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy. Here, we evaluate the impact of radiotherapy protocol adherence in a prospective multicentre trial. METHODS: In the open-label, randomised, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by 1F-FDG PET and CT plus elective nodal irradiation (arm A) or target volumes informed by PET alone (arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organised quality assurance program (RTQA) included individual case review by predefined criteria. For evaluation, protocol adherence was scored as per protocol (pP), with minor (miD), intermediate (inD) and major (maD) deviations. In order to exclude biases through patients who discontinued treatment, patients who received ≥60 Gy were additionally analysed. RESULTS: Between 05/2009-11/2016, 205 patients were randomized, 204 patients started treatment according to protocol of which 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, p < 0.0001) and a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, p < 0.0001). These results were significant also in the subgroup of patients receiving ≥ 60 Gy. Patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (p = 0.006) although no higher incidence of grade ≥ 3 toxicities. CONCLUSIONS: Non-adherence to the radiotherapy protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA.

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION: 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Improved inter-observer agreement of an expert review panel in an oncology treatment trial--Insights from a structured interventional process.

PURPOSE: Oncologic imaging is a key for successful cancer treatment. While the quality assurance (QA) of image acquisition protocols has already been focussed, QA of reading and reporting offers still room for improvement. The latter was addressed in the context of a prospective multicentre trial on fluoro-deoxyglucose (FDG)-positron-emission tomography (PET)/CT-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: An expert panel was prospectively installed performing blinded reviews of mediastinal NSCLC involvement in FDG-PET/CT. Due to a high initial reporting inter-observer disagreement, the independent data monitoring committee (IDMC) triggered an interventional harmonisation process, which overall involved 11 experts uttering 6855 blinded diagnostic statements. After assessing the baseline inter-observer agreement (IOA) of a blinded re-review (phase 1), a discussion process led to improved reading criteria (phase 2). Those underwent a validation study (phase 3) and were then implemented into the study routine. After 2 months (phase 4) and 1 year (phase 5), the IOA was reassessed. RESULTS: The initial overall IOA was moderate (kappa 0.52 CT; 0.53 PET). After improvement of reading criteria, the kappa values improved substantially (kappa 0.61 CT; 0.66 PET), which was retained until the late reassessment (kappa 0.71 CT; 0.67 PET). Subjective uncertainty was highly predictive for low IOA. CONCLUSION: The IOA of an expert panel was significantly improved by a structured interventional harmonisation process which could be a model for future clinical trials. Furthermore, the low IOA in reporting nodal involvement in NSCLC may bear consequences for individual patient care.

Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome.

INTRODUCTION: Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by excessive tachycardia of unknown etiology. Our objective in this study was to evaluate the correlation between C-fiber involvement as shown by skin biopsy and adrenergic cardiac metaiodobenzylguanadine (MIBG) uptake in POTS patients. METHODS: Skin biopsies of 84 patients with POTS were examined by Protein Gene Product 9.5 (PGP9.5) immunohistochemistry and were compared with MIBG myocardial scintigraphy imaging data. RESULTS: Mean intraepidermal nerve fiber (IENF) density was in the lower normal age-adjusted range, 7.2 ± 2.9/mm (normal ≥ 7/mm), and was slightly below the normal range in 45% of POTS patients. MIBG uptake was reduced in 21% of patients. Low IENF density correlated with reduced cardiac MIBG uptake (r = 0.39, P = 0.001). CONCLUSIONS: A subset of neuropathic POTS patients may harbor mild small fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin associated with reduced myocardial postganglionic sympathetic innervation.

Mucocutaneous blood contact: blood release behavior of safety peripheral intravenous catheters.

BACKGROUND: Protection against needlestick injuries has significantly improved in recent years thanks to so-called "safety devices." However, a potential drawback occasionally reported by users is a risk of blood splashing. If this blood comes in contact with the mucous membranes, it could lead to an infection. METHODS: Five safety peripheral intravenous catheter brands were examined in a laboratory test. To simulate the extreme situations, which may arise through human use, the introducer needle was withdrawn from the catheter at 2 different angles whereby an industrial robot was used to simulate the sequence of this movement. Each brand was tested 30 times. The experiment was carried out using radioactively labeled human whole blood. The measurements for the transmitted volume of blood was taken both from an artificial head and from a surface measuring 18.5 cm by 26.5 cm at a height of 30 cm above the catheter; scintigraphy was used to take the measurements. RESULTS: The volume of blood droplets potentially splashing into the mucous membranes was in the range of 1 nL. CONCLUSION: For normal virus concentrations in the blood of sick patients, this dose is too small to cause hepatitis C and HIV.

Abnormal neuroendocrine response to clomipramine in hereditary affective psychosis.

BACKGROUND: Blunting of prolactin response after serotonergic stimulation during a major depressive episode has been described by several investigators. In this study, the neuroendocrine responses to clomipramine were assessed in remitted patients suffering from hereditary depression. METHODS: Twenty remitted patients from 11 large families with multigenerational, multiple cases of major affective disorder (bipolar disorder n=15, recurrent depression n=5, according DSM-IV) and 12 healthy relatives were investigated. After intravenous application of 12.5 mg of the serotonin re-uptake inhibitor clomipramine, serum prolactin and cortisol levels were analysed. RESULTS: Patients and comparison group did not differ significantly with respect to age, baseline prolactin and cortisol concentrations. A gender effect was found in an exploratory analysis for prolactin but not for cortisol and therefore the data for prolactin were analysed separately. After clomipramine infusion, the increase of cortisol was significantly lower in patients than in the comparison group (P=.046). For prolactin, this effect could be found in the male (P=.012) as well as in the female (P=.007) subsample. CONCLUSIONS: These results suggest that blunted prolactin and cortisol responses to serotonergic stimulation are characteristic for remitted depressive patients with previous episodes of major affective disorders.

Influence of synaptic serotonin level on [18F]altanserin binding to 5HT2 receptors in man.

The feasibility of in vivo serotonin 5HT(2) receptor binding measurement using [18F]altanserin as a radioligand has been well established. In this study, the postsynaptic receptor binding potential of this ligand was examined as a possible indicator of synaptic serotonin content after pharmacological challenge. Studies were performed in 11 subjects with a history of recurrent major depression. Six of them received serotonergic antidepressive treatment at the time of the experiment, the other five patients were untreated. Two PET measurements were carried out in each subject within 2 or 3 days. Before one of the measurements, 25 mg of the serotonin re-uptake inhibitor clomipramine were given intravenously, the other measurement was done without pharmacological challenge. The data were analyzed using non-linear least-square regression and Logan's graphical method. In the whole group of subjects, binding potential and distribution volume of altanserin decreased following clomipramine challenge. The decrease was between 14 (P=0.03) and 23% (P=0.004). This effect was mainly seen in subjects not on antidepressive medication. Clomipramine challenge probably increased the synaptic serotonin level, which competed with altanserin leading to the lowered binding potential. The paradigm might, thus, be useful to estimate serotonin release in vivo. Pretreatment with serotonergic antidepressants reduces the effect of clomipramine.