Intra-aortic metastases or intra-arterial thrombus?

Introduction: Intra-arterial malignancies are difficult to diagnose as they mimic other more common pathologies such as pulmonary embolus and vascular occlusive disease. Appropriate treatment may, therefore, be delayed. Case Report: We report a case of an occluded carotid artery and aortic mucosal thickening with a peduculated thrombus occurring in a patient with metastatic sarcomatoid carcinoma while anticoagulated. Conclusion: Diagnosis requires various imaging modalities and a consideration of an alternative diagnosis if not responding to initial therapy

Murine factor H co-produced in yeast with protein disulfide isomerase ameliorated C3 dysregulation in factor H-Deficient mice

Recombinant human factor H (hFH) has potential for treating diseases linked to aberrant complement regulation including C3 glomerulopathy (C3G) and dry age-related macular degeneration. Murine FH (mFH), produced in the same host, is useful for pre-clinical investigations in mouse models of disease. An abundance of FH in plasma suggests high doses, and hence microbial production, will be needed. Previously, Pichia pastoris produced useful but modest quantities of hFH. Herein, a similar strategy yielded miniscule quantities of mFH. Since FH has 40 disulfide bonds, we created a P. pastoris strain containing a methanol-inducible codon-modified gene for protein-disulfide isomerase (PDI) and transformed this with codon-modified DNA encoding mFH under the same promoter. What had been barely detectable yields of mFH became multiple 10s of mg/L. Our PDI-overexpressing strain also boosted hFH overproduction, by about tenfold. These enhancements exceeded PDI-related production gains reported for other proteins, all of which contain fewer disulfide-stabilized domains. We optimized fermentation conditions, purified recombinant mFH, enzymatically trimmed down its (non-human) N-glycans, characterised its functions in vitro and administered it to mice. In FH-knockout mice, our de-glycosylated recombinant mFH had a shorter half-life and induced more anti-mFH antibodies than mouse serum-derived, natively glycosylated, mFH. Even sequential daily injections of recombinant mFH failed to restore wild-type levels of FH and C3 in mouse plasma beyond 24 hours after the first injection. Nevertheless, mFH functionality appeared to persist in the glomerular basement membrane because C3-fragment deposition here, a hallmark of C3G, remained significantly reduced throughout and beyond the ten-day dosing regimen

Case report of interstitial nephritis induced by bevacizumab therapy for glioblastoma multiforme

Glioblastoma multiforme is an aggressive malignant brain tumor. The monoclonal antibody, bevacizumab, is active in recurrent disease via inhibition of angiogenesis. Proteinuria and renal thrombotic microangiopathy are known complications. We report a case of a patient developing acute renal failure with biopsy-proven interstitial nephritis while receiving bevacizumab for recurrent disease. The patient was otherwise well with a history of controlled hypertension. Renal function improved with discontinuation of bevacizumab and the administration of corticosteroid therapy

Exploring beamline momentum acceptance of a medical gantry to deliver optimized tumour tracking plans

Background: Tumour tracking is particularly challenging to realise when it comes to proton therapy. The difficulty of assessing anatomical changes reliably enough to offset the treatment settings on-the-fly, while taking into account the finite range of particles, is beyond the current capabilities of beam delivery and image guidance technologies. Methods: To implement fast range corrections, momentum acceptance (±0.6% dp/p) and global achromaticity of PSI Gantry2 has been exploited. Using a standard upstream degrader, the energy can be modulated around the mean value of the acceptance band without tuning the beamline magnets, overcoming the major source of dead-time in conventional treatments delivery. Being acceptance limited, such ultra-fast energy changes can only be of small magnitude, ~2mm WER. Therefore, at an early stage of planning, 4DCT images of the patient are used to generate a scan-path with dose spots sorted by energy, including tracking offsets, which can synchronized during delivery to the patient motion. Results: Beam properties within the momentum acceptance of our facility have been characterized between 150 MeV and 230 MeV. Using dedicated correction models for fine range control and compensation of beam intensity losses, a median energy switching time of 27ms could be achieved. Moreover, spot position errors in the transversal plane were below 1 mm across the 18x12 cm scan range. Conclusions: Rapid adaptation of beam range is essential to deliver tumour tracking plan following patients’ breathing. Fast energy modulation can be realized within the beamline acceptance preserving clinical level beam quality

EPR/alanine dosimetry for two therapeutic proton beams

In this work the analysis of the electron paramagnetic resonance (EPR) response of alanine pellets exposed to two different clinical proton beams employed for radiotherapy is performed. One beam is characterized by a passive delivery technique and is dedicated to the eyes treatment (OPTIS2 beam line). Alanine pellets were irradiated with a 70 MeV proton beam corresponding to 35 mm range in eye tissue. We investigated how collimators with different sizes and shape used to conform the dose to the planned target volume influence the delivered dose. For this purpose we performed measurements with varying the collimator size (Output Factor) and the results were compared with those obtained with other dosimetric techniques (such as Markus chamber and diode detector). This analysis showed that the dosimeter response is independent of collimator diameter if this is larger than or equal to 10 mm. The other beam is characterized by an active spot-scanning technique, the Gantry1 beam line (maximum energy 230 MeV), and is used to treat deep-seated tumors. The dose linearity of alanine response in the clinical dose range was tested and the alanine dose response at selected locations in depth was measured and compared with the TPS planned dose in a quasi-clinical scenario. The alanine response was found to be linear in the dose in the clinical explored range (from 10 to 70 Gy). Furthermore, a depth dose profile in a quasi-clinical scenario was measured and compared to the dose computed by the Treatment Planning System PSIPLAN. The comparison of calibrated proton alanine measurements and TPS dose shows a difference under 1% in the SOBP and a ‘‘quenching” effect up to 4% in the distal part of SOBP. The positive dosimetric characteristics of the alanine pellets confirm the feasibility to use these detectors for ‘‘in vivo” dosimetry in clinical proton beams

A Novel Beam Optics Concept to Maximize the Transmission Through Cyclotron-based Proton Therapy Gantries

Most of the conventional beam optics of cyclotron-based proton gantries were designed to provide point-to-point focus in both planes with an imaging factor between 1 and 2 from the entrance of the gantry to the patient. This means that a small beam size at the gantry entrance is required to achieve the required small beam size at the patient. Due to the typically used beam emittance, this in turn results in large beam divergence at the gantry entrance, increasing the possibility of beam losses along the gantry as the beam envelope gets close to the apertures. To maximize transmission through the gantry, we propose a novel beam optics concept using 3:1 imaging. It reduces the beam divergence at the gantry entrance by factor 3 while still achieving a small beam size at the patient. The beam envelope is better controlled and keeps clear of the apertures compared to the 1:1 or 1:2 imaging beam envelope. For PSI Gantry 2, the novel 3:1 imaging beam optics increase the proton beam transmission for lower energies by 40% compare to 1:1 imaging beam optics. The usage of small imaging factors can help to maximize transmission for different gantry lattices, thus reducing treatment times

New Gantry Beam Optics Solution for Minimising Treatment Time in Cyclotron-based Proton Therapy Facilities

Treatment delivery time in proton therapy depends on beam-on time and the time required to change energy layers and/or lateral position. For cyclotron-based facilities, low energy beams (100-70 MeV) are inefficiently transported through beamlines due to their large emittance after the degrader (~400 pi*mm*mrad 2-sigma emittance), whereas the beamline and Gantry can only transport small emittances (e.g. 30 pi*mm*mrad for PSI Gantry 2) resulting in a low dose rate at the patient and increased beam-on time. In this work, we aim to maximize the emittance transported through the gantry for low energy beams. By choosing a small divergence, but large beam size, at the gantry entrance, it is possible to transport higher emittances through the gantry without compromising transmission. Additionally, in order to retrieve small beam sizes at the patient, we propose a 2:1 imaging of the gantry beam optics between the gantry coupling point and the patient. This concept has been experimentally validated on Gantry 2 at PSI. A beam with an emittance of 90 pi*mm*mrad and ~60% transmission was transported through the gantry. As we are transporting only a narrow part of the large Gaussian beam after the degrader, this 3 times higher emittance corresponds to ~3 times more transported particles. With this, treatment times for example cases (lung and liver) have been estimated to reduce by a factor of 2 to 3. Such a beam optic could therefore have substantial potential for reducing treatment times, and be of particular advantage for the treatment of moving targets

How much momentum acceptance is required to track breathing variability in NSCLC patients?

Purpose Fast energy change within beamline momentum acceptance is investigated as an option to track organ motion in pencil beam scanning proton therapy. Although prior knowledge of the patient’s organ motion can be used to optimize scan paths that minimize acceptance requirements, allowance has to be made to account for breathing variability. We investigate how much variation in beam momentum (dp/p) is required to track lung tumors under realistic breathing scenarios. Methods Treatments were simulated for three NSCLC patients provided with repeated (5x) 4DCT imaging. Tumor tracking plans were optimized on the first image set and the remaining ones combined via deformable image registration to mimic the breathing variability happening during beam delivery. Ideal tumor tracking with unconstrained energy offset was compared with respiratory synchronized tracking, minimizing energy corrections based on prior considerations of the organ motion. For both strategies, the amount of dp/p required to track tumors under irregular breathing was quantified together with the assessment of quality indexes such target dose-coverage (V95) and homogeneity (D5-D95). Results For all patients, organ motion was predominantly in superior-inferior direction, with an amplitude ranging between 2.5mm and 13.9mm on the planning images and increasing up to 37% of that value due to breathing variability during treatment delivery simulations. Beamline acceptance requirements were found to be reduced for respiratory-synchronized tracking (dp/p=0.39%) compared to ideal approaches (dp/p=0.59%) while ensuring comparable dose-coverage and homogeneity, respectively 90.9% and 27.9% for respiratory-synchronized tracking and 90.6% and 30.4% for ideal one. Conclusion To minimize demands on beamline technology, whilst ensuring treatment quality, respiratory-synchronized tumor tracking should be further investigated as a concrete option to bring this motion mitigation technique one step closer to clinical implementation

A supportive care intervention for people with metastatic melanoma being treated with immunotherapy : a pilot study assessing feasibility, perceived benefit, and acceptability

Introduction: Increasing numbers of metastatic melanoma (MM) patients are receiving immunotherapy treatment, including pembrolizumab, and the impact on their well-being is underexplored. Objectives: To assess the feasibility of a multimodal supportive care program to MM patients being treated with pembrolizumab. Methods: This pre-post-test feasibility cohort study recruited MM participants treated with pembrolizumab: (i) supportive care intervention with usual care and (ii) usual care. The intervention comprised comprehensive medical assessment by supportive care physician (SCP), exercise physiologist (EP), and dietitian then a tailored supportive care program. Programs included exercise, dietary advice, non-invasive complementary therapies, and psychology consultation. Outcome measures included adherence, patient-reported symptoms, anxiety and depression, and toxicity. Descriptive data are reported. Results: We recruited 28 participants: 13 intervention and 15 control; three did not complete the study. Most were male, with median age 66 (range 42–85) years. All intervention participants completed baseline assessments with SCP, EP, and dietitian. Two missed follow-up with EP or dietitian. Symptoms most troubling at baseline were as follows: fatigue (n = 6), sleep (n = 6), general aches and pains (n = 5), and memory (n = 4). All intervention participants were prescribed 16 exercise sessions; 8 (50%) completed all; overall exercise adherence was 85%. Integrative therapies were accessed by 85% (11) participants. Immunotherapy-related adverse event rates were low and SCP consultation identified symptoms not captured by CTCAE 4.0. Conclusions: A holistic supportive care intervention tailored to individual needs is feasible. The symptom burden in MM patients was low. Further investigation of the intervention is warranted, focused on populations with higher symptom burden to improve outcomes