Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Working memory features are embedded in hippocampal place fields.

Hippocampal principal neurons display both spatial tuning properties and memory features. Whether this distinction corresponds to separate neuron types or a context-dependent continuum has been debated. We report here that the task-context ("splitter") feature is highly variable along both trial and spatial position axes. Neurons acquire or lose splitter features across trials even when place field features remain unaltered. Multiple place fields of the same neuron can individually encode both past or future run trajectories, implying that splitter fields are under the control of assembly activity. Place fields can be differentiated into subfields by the behavioral choice of the animal, and splitting within subfields evolves across trials. Interneurons also differentiate choices by integrating inputs from pyramidal cells. Finally, bilateral optogenetic inactivation of the medial entorhinal cortex reversibly decreases the fraction of splitter fields. Our findings suggest that place or splitter features are different manifestations of the same hippocampal computation.

Dose comparison of robustly optimized intensity modulated proton therapy (IMPT) vs IMRT and VMAT photon plans for testicular seminoma.

BACKGROUND: Patients with stage II seminoma have traditionally been treated with photons to the retroperitoneal and iliac space, which leads to a substantial dose bath to abdominal and pelvic organs at risk (OAR). As these patients are young and with excellent prognosis, reducing dose to OAR and thereby the risk of secondary cancer is of utmost importance. We compared IMPT to opposing IMRT fields and VMAT, assessing dose to OAR and both overall and organ-specific secondary cancer risk. MATERIAL AND METHODS: A comparative treatment planning study was conducted on planning CT-scans from ten patients with stage II seminoma, treated with photons to a 'dog-leg' field with doses ranging from 20 to 25 Gy and a 10 Gy sequential boost to the metastatic lymph node(s). Photon plans were either 3-4 field IMRT (Eclipse) or 1-2 arc VMAT (Pinnacle). Proton plans used robust (5 mm; 3.5%) IMPT (Eclipse), multi field optimization with 3 posterior fields supplemented by 2 anterior fields at the level of the iliac vessels. Thirty plans were generated. Mean doses to OARs were compared for IMRT vs IMPT and VMAT vs IMPT. The risk of secondary cancer was calculated according to the model described by Schneider, using excess absolute risk (EAR, per 10,000 persons per year) for body outline, stomach, duodenum, pancreas, bowel, bladder and spinal cord. RESULTS: Mean doses to all OARs were significantly lower with IMPT except similar kidney (IMRT) and spinal cord (VMAT) doses. The relative EAR for body outline was 0.59 for IMPT/IMRT (p < .05) and 0.33 for IMPT/VMAT (p < .05). Organ specific secondary cancer risk was also lower for IMPT except for pancreas and duodenum. CONCLUSION: Proton therapy reduced radiation dose to OAR compared to both IMRT and VMAT plans, and potentially reduce the risk of secondary cancer both overall and for most OAR.

Current evidence for moderate and ultra-hypofractionated radiation therapy in prostate cancer: a summary of the results from phase 3 randomised trials.

PROBLEM: A low α/ß ratio for prostate cancer (PCa) compared to surrounding normal tissue theoretically implies therapeutical advantages with hypofractionated treatment. Data from large randomised control trials (RCTs) comparing moderate hypofractionated (MHRT, 2.4-3.4 Gray/fraction (Gy/fx)) and ultra-hypofractionated (UHRT, >5 Gy/fx) with conventionally fractionated radiation therapy (CFRT, 1.8-2 Gy/fx) and the possible clinical implications have been reviewed. MATERIALS AND METHOD: We searched PubMed, Cochrane and Scopus for RCT comparing MHRT/UHRT with CFRT treatment of locally and/or locally advanced (N0M0) PCa. We found six RCTs, which compared different radiation therapy regimes. Tumour control and acute and late toxicities are reported. RESULTS: MHRT was non-inferior to CFRT for intermediate-risk PCa, non-inferior for low-risk PCa and not superior in terms of tumour control for high-risk PCa. Acute toxicity rates were increased compared to CFRT, especially an increase in acute gastrointestinal adverse effects was seen. Late toxicity related to MHRT seems to be comparable. UHRT was non-inferior in terms of tumour control in one RCT, with increased acute toxicity, but with comparable late toxicity. One trial, however, indicated increased late toxicity rates with UHRT. DISCUSSION AND CONCLUSION: MHRT delivers similar therapeutic outcomes compared to CFRT in terms of tumour control and late toxicity for intermediate-risk PCa patients. Slightly more acute transient toxicity could be tolerated in favour of a shorter treatment course. UHRT should be regarded as an optional treatment for patients with low- and intermediate-risk disease applied at experienced centres in concordance with international and national guidelines.

Salvage Radiation Therapy After Radical Prostatectomy: Analysis of Toxicity by Dose-Fractionation in the RADICALS-RT Trial.

PURPOSE: Emerging data indicate comparable disease control and toxicity of normal postoperative fractionation and moderate hypofractionation radiation therapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66 Gy in 33 fractions (f) over 6.5 weeks or 52.5 Gy in 20f over 4 weeks. This non-randomized, exploratory analysis explored the toxicity of these 2 schedules in patients who had adjuvant RT. METHODS AND MATERIALS: Information on RT dose was collected in all patients. The Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, every 6 months until 5 years, then annually until 15 years. Patient-reported data were collected at baseline and at 1, 5, and 10 years using standard measures, including the Vaizey fecal incontinence score (bowel) and the International Continence Society Male Short-Form questionnaire (urinary incontinence). The highest event grade was recorded within the first 2 years and beyond 2 years and compared between treatment groups using the χ² test. RESULTS: Of 634 patients, 217 (34%) were planned for 52.5 Gy/20f and 417 (66%) for 66 Gy/33f. In the first 2 years, grade 1 to 2 cystitis was reported more frequently among the 66 Gy/33f group (52.5 Gy/20f: 20% vs 66 Gy/33f: 30%; P = .04). After 2 years, grade 1 to 2 cystitis was reported in 16% in the 66-Gy group and 9% in the 52.5-Gy group (P = .08). Other toxic effects were similar in the 2 groups, and very few patients had any grade 3 to 4 toxic effects. Patients reported slightly higher urinary and fecal incontinence scores at 1 year than at baseline, but no clinically meaningful differences were reported between the 52.5 Gy/20f and 66 Gy/33f groups. Patient-reported health was similar at baseline and at 1 year and similar between the 52.5 Gy/20f and 66 Gy/33f groups. CONCLUSIONS: Severe toxic effects were rare after prostate bed radiation therapy with either 52.5 Gy/20f or 66 Gy/33f. Only modest differences were recorded in toxic effects or in patient-reported outcomes between these 2 schedules.

Effect of docetaxel added to bicalutamide in Hormone-Naïve non-metastatic prostate cancer with rising PSA, a randomized clinical trial (SPCG-14).

BACKGROUND: Historically, endocrine therapy was used in a range of scenarios in patients with rising PSA, both as a treatment for locally advanced non-metastatic prostate cancer and PSA recurrence following curative intended therapy. In the present study the objective was to investigate if chemotherapy added to endocrine therapy could improve progression-free survival (PFS). MATERIALS AND METHODS: Patients with hormone-naïve, non-metastatic prostate cancer and rising prostate-specific antigen (PSA), enrolled from Sweden, Denmark, the Netherlands, and Finland, were randomized to long-term bicalutamide (150 mg daily) or plus docetaxel (75 mg/m2, q3w, 8-10 cycles) without prednisone, after stratification for the site, prior local therapy or not, and PSA doubling time. The primary endpoint was 5-year PFS analyzed with a stratified Cox proportional hazards regression model on intention to treat basis. RESULTS: Between 2009 and 2018, a total of 348 patients were randomized; 315 patients had PSA relapse after radical treatment, 33 patients had no prior local therapy. Median follow-up was 4.9 years (IQR 4.0-5.1). Adding docetaxel improved PFS (HR 0.68, 95% CI 0.50-0.93; p = 0.015). Docetaxel showed an advantage for patients with PSA relapse after prior local therapy (HR 0.67, 95% CI 0.49-0.94; p = 0.019). One event of neutropenic infection/fever occurred in 27% of the patients receiving docetaxel. Limitations were slow recruitment, lack of enrolling patients without radical local treatment, and too short follow-up for evaluation of overall survival in patients with PSA relapse. CONCLUSION: Docetaxel improved PFS in patients starting bicalutamide due to PSA relapse after local therapy or localized disease without local therapy. Confirmatory studies of the efficacy of docetaxel in the setting of PSA-only relapse in addition to endocrine therapies may be justified if longer follow-up will show increased metastatic-free survival.

Movement is governed by rotational neural dynamics in spinal motor networks.

Although the generation of movements is a fundamental function of the nervous system, the underlying neural principles remain unclear. As flexor and extensor muscle activities alternate during rhythmic movements such as walking, it is often assumed that the responsible neural circuitry is similarly exhibiting alternating activity1. Here we present ensemble recordings of neurons in the lumbar spinal cord that indicate that, rather than alternating, the population is performing a low-dimensional 'rotation' in neural space, in which the neural activity is cycling through all phases continuously during the rhythmic behaviour. The radius of rotation correlates with the intended muscle force, and a perturbation of the low-dimensional trajectory can modify the motor behaviour. As existing models of spinal motor control do not offer an adequate explanation of rotation1,2, we propose a theory of neural generation of movements from which this and other unresolved issues, such as speed regulation, force control and multifunctionalism, are readily explained.

Patterns of relapse and long-term outcome in patients treated with a curative intent for advanced Hodgkin lymphoma.

BACKGROUND: Consolidation radiotherapy for advanced Hodgkin lymphoma (AHL) is controversial. Precise knowledge of the most likely relapse location is crucial for radiotherapy planning. We performed detailed patterns of relapse analyses and evaluated if initial bulky disease, initial 18F-fluoro-deoxy-glucose (FDG)-avidity and/or a residual mass on computed tomography (CT)-scan after chemotherapy are sites with a high risk of relapse. This information could provide guidance for optimal use of radiotherapy in AHL. MATERIAL AND METHODS: We included 133 patients treated with curatively intended chemotherapy for AHL. 23 patients received consolidation radiotherapy. For relapsed patients, imaging from diagnosis, response evaluation, relapse, and any radiotherapy planning, were retrieved and co-registered to determine the exact site(s) of relapse relative to initial site(s), residual mass(es) and to any irradiated volumes. Size and FDG-avidity of initial sites with later relapse, and residual CT-abnormalities after chemotherapy in these sites were registered. Survival analyses were done using the Kaplan-Meier method. RESULTS: Nine (6.8%) patients relapsed, eight in initially involved sites. One relapse was in an initially irradiated site (as well as other sites). Initial bulky disease, high initial FDG-uptake, and/or residual masses on CT-scan after chemotherapy did not predict sites with a high risk of relapse. Overall survival was 79.6% (95% CI, 72.7-86.5%) and 70.6% (95% CI, 62.4-78.8%) at 5 and 10 years, respectively. Time to progression analysis showed 91.8% (95% CI, 86.9-96.7%) and 90.7% (95% CI, 85.4-96.0%) without progression at 5 and 10 years, respectively. CONCLUSION: Current treatment strategies for AHL provide excellent disease control. Neither initial bulk, high initial FDG-uptake, nor a residual CT-abnormality post-chemotherapy seem to indicate sites with a high risk of relapse.

Characteristics of Patients in SPCG-15-A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer.

Background: There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. Objective: To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design setting and participants: This study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. Intervention: Radical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysis: Cause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitations: The distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45-75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. Conclusions: We have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summary: This study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer.

A phase 2 trial of deep-inspiration breath hold in radiotherapy of gastric lymphomas.

Background and purpose: Radiotherapy (RT) is an important part in the treatment of gastric lymphomas and the prognosis after radiotherapy is very good with a good chance of long-term survival, so prevention of long-term adverse effects is important. In patients with gastric lymphomas cardiac late effects are of most concern. The aim of this study was to assess if the dose to the heart could be reduced with deep inspiration breath-hold (DIBH) without compromising the dose to the target or increasing the risk of other late effects. Methods and patients: Fifteen patients with gastric lymphoma were included. RT plans were made using DIBH and Free breathing (FB) scans. Clinical target volume (CTV) was the stomach plus 1 cm margin. The heart and surrounding organs at risk (OAR) were contoured. Two sets of plan comparisons were made, one with 1 cm CTV to planning target volume (PTV) margin in both DIBH and FB and one set with an additional 5 mm CTV to PTV margin in cranio-caudal direction with FB. Datasets were analysed with Wilcoxon signed rank test for non-parametric paired data. Results: All patients tolerated the procedures and were treated with volumetric arc therapy technique in DIBH. Target coverage was kept equal between FB and DIBH, while a statistically significant reduction of the estimated does to the heart was seen with DIBH. Median mean heart dose was reduced from 7.1 Gy (5.7-12) to a median of 3.2 Gy (1.2-7.0) and heart V20 from a median of 54 (17-106) cm3 to 15. (0.0-78) cm3. The estimated mean doses to the liver, duodenum, pancreas and spinal cord were at the same level. Conclusion: This clinical trial of RT with DIBH for gastric lymphomas showed that the heart dose could be reduced without compromising PTV coverage. The doses to abdominal OARs were similar with FB and DIBH.

Brain temperature affects quantitative features of hippocampal sharp wave ripples.

Biochemical mechanisms are temperature dependent. Brain temperature shows wide variations across brain states, and such changes may explain quantitative changes in network oscillations. Here, we report on the relationship between various hippocampal sharp wave ripple features to brain temperature. Ripple frequency, occurrence rate, and duration correlated with temperature dynamics. By focal manipulation of the brain temperature in the hippocampal CA1 region, we show that ripple frequency can be increased and decreased by local heating and cooling, respectively. Changes of other parameters, such as the rate of sharp wave-ripple complex (SPW-R) and ripple duration were not consistently affected. Our findings suggest that brain temperature in the CA1 region plays a leading role in affecting ripple frequency, whereas other parameters of SPW-Rs may be determined by mechanisms upstream from the CA1 region. These findings illustrate that physiological variations of brain temperature exert important effects on hippocampal circuit operations.NEW & NOTEWORTHY During physiological conditions, brain temperature fluctuates approximately 3°C between sleep and active waking. Here, we show that features of hippocampal ripples, including the rate of occurrence, peak frequency, and duration are correlated with brain temperature variations. Focal bidirectional manipulation of temperature in the hippocampal CA1 region in awake rodents show that ripple frequency can be altered in the direction expected from the correlational observations, implying that temperature plays a significant role.

A phase I/II study of acute and late physician assessed and patient-reported morbidity following whole pelvic radiation in high-risk prostate cancer patients.

BACKGROUND: The aim of this study was to assess acute and late morbidity measured by the physician and patient-reported outcomes (PROs) in high-risk prostate cancer (PC) patients receiving whole pelvic intensity-modulated radiotherapy (IMRT) in the setting of a national clinical trial. MATERIAL AND METHODS: A total of 88 patients with adenocarcinoma of the prostate and high-risk parameters were enrolled from 2011 to 2013. All patients received 78 Gy in 39 fractions of IMRT delivering simultaneous 78 Gy to the prostate and 56 Gy to the seminal vesicles and lymph nodes. Physician-reported morbidity was assessed by CTCAE v.4.0. PROs were registered for gastro-intestinal (GI) by the RT-ARD score, genito-urinary (GU) by DAN-PSS, sexual and hormonal by EPIC-26, and quality of life (QoL) by EORTC QLQ-C30. RESULTS: Median follow-up (FU) time was 4.6 years. No persistent late CTCAE grade 3+ morbidity was observed. Prevalence of CTCAE grade 2+ GI morbidities varied from 0 to 6% at baseline throughout FU time, except for diarrhea, which was reported in 19% of the patients post-RT. PROs revealed increased GI morbidity (≥1 monthly episode) for "rectal urgency", "use of pads", "incomplete evacuation", "mucus in stool" and "bowel function impact on QoL" all remained significantly different (p < .05) at 60 months compared to baseline. CTCAE grade 2+ GU and sexual morbidity were unchanged. GU PROs on obstructive and irritative GU items (≥daily episode) increased during RT and normalized at 24 months. No clinically significant differences were found in sexual, hormonal, and QoL scores compared to baseline. CONCLUSIONS: Whole pelvic RT resulted in a mild to the moderate burden of late GI morbidities demonstrated by a relatively high prevalence of PROs. Whereas, physician-assessed morbidity revealed a low prevalence of late GI morbidity scores. This emphasizes the importance of using both PROs and physician-reported scoring scales when reporting late morbidity in clinical trials.

Prevention of Chemotherapy-Induced Nausea and Vomiting in the Older Patient: Optimizing Outcomes.

Chemotherapy-induced nausea and vomiting (CINV) are still two of the most feared side effects of cancer therapy. Although major progress in the prophylaxis of CINV has been made during the past 40 years, nausea in particular remains a significant problem. Older patients have a lower risk of CINV than younger patients, but are at a higher risk of severe consequences of dehydration and electrolyte disturbances following emesis. Age-related organ deficiencies, comorbidities, polypharmacy, risk of drug-drug interactions, and lack of compliance all need to be addressed in the older patient with cancer at risk of CINV. Guidelines provide evidence-based recommendations for the prophylaxis of CINV, but none of these guidelines offer specific recommendations for older patients with cancer. This means that the recommendations may lead to overtreatment in some older patients. This review describes the development of antiemetic prophylaxis of CINV focusing on older patients, summarizes recommendations from antiemetic guidelines, describes deficiencies in our knowledge of older patients, summarizes necessary precautions, and suggests some future perspectives for antiemetic research in older patients.

The role of motion management and position verification in lymphoma radiotherapy.

In the last decades, the substantial technical progress in radiation oncology offered the opportunity for more accurate planning and delivery of treatment. At the same time, the evolution of systemic treatment and the advent of modern diagnostic tools allowed for more accurate staging and consequently a safe reduction of radiotherapy (RT) target volumes and RT doses in the treatment of lymphomas. As a result, incidental irradiation of organs at risk was reduced, with a consequent reduction of severe late toxicity in long-term lymphoma survivors. Nevertheless, these innovations warrant that professionals pay attention to concurrently ensure precise planning and dose delivery to the target volume and safe sparing of the organs at risk. In particular, target and organ motion should be carefully managed in order to prevent any compromise of treatment efficacy. Several aspects should be taken into account during the treatment pathway to minimise uncertainties and to apply a valuable motion management strategy, when needed. These include: reliable image registration between diagnostic and planning radiologic exams to facilitate the contouring process, image guidance to limit positioning uncertainties and to ensure the accuracy of dose delivery and management of lung motion through procedures of respiratory gating and breath control. In this review, we will cover the current clinical approaches to minimise these uncertainties in patients treated with modern RT techniques, with a particular focus on mediastinal lymphoma. In addition, since uncertainties have a different impact on the dose deposition of protons compared to conventional x-rays, the role of motion management and position verification in proton beam therapy (PBT) will be discussed in a separate section.

3D-printed Recoverable Microdrive and Base Plate System for Rodent Electrophysiology.

Extracellular recordings in freely moving animals allow the monitoring of brain activity from populations of neurons at single-spike temporal resolution. While state-of-the-art electrophysiological recording devices have been developed in recent years (e.g., µLED and Neuropixels silicon probes), implantation methods for silicon probes in rats and mice have not advanced substantially for a decade. The surgery is complex, takes time to master, and involves handling expensive devices and valuable animal subjects. In addition, chronic silicon neural probes are practically single implant devices due to the current low success rate of probe recovery. To successfully recover silicon probes, improve upon the quality of electrophysiological recording, and make silicon probe recordings more accessible, we have designed a miniature, low cost, and recoverable microdrive system. The addition of a novel 3D-printed skull baseplate makes the surgery less invasive, faster, and simpler for both rats and mice. We provide detailed procedural instructions and print designs, allowing researchers to adapt and flexibly customize our designs to their experimental usage.

CellExplorer: A framework for visualizing and characterizing single neurons.

The large diversity of neuron types provides the means by which cortical circuits perform complex operations. Neuron can be described by biophysical and molecular characteristics, afferent inputs, and neuron targets. To quantify, visualize, and standardize those features, we developed the open-source, MATLAB-based framework CellExplorer. It consists of three components: a processing module, a flexible data structure, and a powerful graphical interface. The processing module calculates standardized physiological metrics, performs neuron-type classification, finds putative monosynaptic connections, and saves them to a standardized, yet flexible, machine-readable format. The graphical interface makes it possible to explore the computed features at the speed of a mouse click. The framework allows users to process, curate, and relate their data to a growing public collection of neurons. CellExplorer can link genetically identified cell types to physiological properties of neurons collected across laboratories and potentially lead to interlaboratory standards of single-cell metrics.

Effectiveness of Docetaxel for Metastatic Hormone-sensitive Prostate Cancer in Clinical Practice.

BACKGROUND: Addition of docetaxel to androgen deprivation therapy (ADT) for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has been proved to be effective with an overall survival (OS) benefit in phase III clinical trials. The effectiveness of docetaxel with ADT in the general patient population remains unknown. OBJECTIVE: The purpose of this study is to report the clinical experience in mHSPC patients treated with 3rd-weekly docetaxel plus ADT in routine practice at two Danish institutions. DESIGN SETTING AND PARTICIPANTS: A two-center retrospective study including consecutive mHSPC patients treated with 3rd-weekly docetaxel plus ADT was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes of interest were OS, and biochemical and clinical progression-free survival. RESULTS AND LIMITATIONS: A total of 173 consecutive patients with mHSPC who received docetaxel every 3rd week plus ADT between June 2015 and February 2018 were included. Most patients had high-volume disease (85%). All six planned docetaxel cycles were delivered in 149 cases (86%). Of the patients, 106 (61%) were alive at the last follow-up. At a median follow-up of 42 (37.8-58.6) mo, the median OS was 51.6 (41.5-56.3) mo. Castration-resistant prostate cancer (CRPC) developed in 46% within 1 yr, with a median time to CRPC of 15.6 (13.0-18.1) mo. Prostate-specific antigen nadir ≤0.2 ng/l was achieved in 15% of patients after 6 mo of ADT and in 19% after 12 mo. CONCLUSIONS: The effect of docetaxel for mHSPC patients treated in routine practice appears comparable with the overall efficacy reported in the literature. Selection of patients will influence the results in clinical practice and clinical studies. PATIENT SUMMARY: In this report, we looked at the clinical effectiveness of docetaxel combined with androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer (mHSPC) in a Danish population. We found the effect of docetaxel treatment for mHSPC in the general population to be comparable with the overall efficacy reported in published studies.