Simple Summary: Contact X-ray brachytherapy (CXB) after neoadjuvant (chemo)radiotherapy for rectal cancer is applied in selected patients aiming at organ preservation. However, limited data exist... Show moreSimple Summary: Contact X-ray brachytherapy (CXB) after neoadjuvant (chemo)radiotherapy for rectal cancer is applied in selected patients aiming at organ preservation. However, limited data exist on features observed on endoscopy and MRI after treatment with CXB. On endoscopy, features observed in most patients 6 months after CXB are a flat, white scar, indicative for a clinical complete response (cCR), or tumor mass. On MRI, features indicative for a residual tumor are a focal tumor signal on T2W-MRI and a mass-like high signal on DWI. Due to treatment-related features observed early in follow-up, an irregular ulcer on endoscopy and a diffuse "reactive" mucosal signal on DWI, the distinction between a cCR and a residual tumor generally can be made at 6 months of follow-up. These results can help clinicians to interpret imaging features following CXB, ultimately, to identify patients with a cCR for Watch-and-Wait and to identify patients with a residual tumor for subsequent total mesorectal excision. After neoadjuvant (chemo)radiotherapy for rectal cancer, contact X-ray brachytherapy (CXB) can be applied aiming at organ preservation. This explorative study describes the early features on endoscopy and MRI after CXB. Patients treated with CXB following (chemo)radiotherapy and a follow-up of >= 12 months were selected. Endoscopy and MRI were performed every 3 months. Expert readers scored all the images according to structured reporting templates. Thirty-six patients were included, 15 of whom obtained a cCR. On endoscopy, the most frequently observed feature early in follow-up was an ulcer, regardless of whether patients developed a cCR. A flat, white scar and tumor mass were common at 6 months. Focal tumor signal on T2W-MRI and mass-like high signal on DWI were generally absent in patients with a cCR. An ulceration on T2W-MRI and "reactive" mucosal signal on DWI were observed early in follow-up regardless of the final tumor response. The distinction between a cCR and a residual tumor generally can be made at 6 months. Features associated with a residual tumor are tumor mass on endoscopy, focal tumor signal on T2W-MRI, and mass-like high signal on DWI. Early recognition of these features is necessary to identify patients who will not develop a cCR as early as possible. Show less
Marinkovic, M.; Pors, L.J.; Berg, V. van den; Peters, F.P.; Schalenbourg, A.; Zografos, L.; ... ; Horeweg, N. 2021
Simple Summary This study aims to assess cancer control and preservation of the eye and visual acuity after proton therapy abroad for eye melanoma. For this, medical files were reviewed of Dutch... Show moreSimple Summary This study aims to assess cancer control and preservation of the eye and visual acuity after proton therapy abroad for eye melanoma. For this, medical files were reviewed of Dutch uveal melanoma patients who were treated in Switzerland with proton therapy from 1987 to 2019. The tumours of these patients were too large and/or localised too close to the optic nerve to be treated with local plaque irradiation. There were 103 patients, of whom one had a uveal melanoma in both eyes. The tumours were relatively large and often localised around the central part of the retina. At five years after treatment, proton therapy had controlled the uveal melanomas of 94% of the patients and 81% had preserved their eye. Spread of the cancer beyond the eye was observed in 30% of the patients. Most patients (79%) became blind or had severe visual impairment after proton therapy; a small group of patients had mild or no visual impairment (17%). The size of the tumour, its localisation and the dose of proton therapy were important for the risk of decline in visual acuity. This study shows that proton therapy abroad for uveal melanoma is feasible and yields good results. Objective: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. Materials and Methods: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan-Meier's methodology and Cox proportional hazards models. Results: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6-26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. Conclusion: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy. Show less
Sande, M.E. van der; Maas, M.; Melenhorst, J.; Breukink, S.O.; Leerdam, M.E. van; Beets, G.L. 2021
Objective and Background: Watch-and-wait approach in rectal cancer relies on the identification of a clinical complete response (CR) after neoadjuvant (chemo)radiotherapy. This is mainly performed... Show moreObjective and Background: Watch-and-wait approach in rectal cancer relies on the identification of a clinical complete response (CR) after neoadjuvant (chemo)radiotherapy. This is mainly performed by rectal examination. magnetic resonance imaging, and endoscopy. Endoscopy has been less well studied, and the objective of the study is to assess the diagnostic value of endoscopy and the predictive value of endoscopic features for the identification of CR.Patients and Methods: A total of 161 patients with primary rectal cancer undergoing flexible sigmoidoscopy for response assessment after neoadjuvant (chemo)radiotherapy between January 2012 and December 2015 at a single institution were evaluated retrospectively. Three independent readers scored endoscopic features and a confidence level score for a CR. Diagnostic performance of endoscopy and positive predictive value (PPV) of endoscopic features for a CR were calculated. If available, biopsy results were revealed to the reader and a change in confidence level was noted. Reference standard was histology after surgery, or long-term outcome in a watch-and-wait policy.Results: Median time to endoscopy was 9 (interquartile range 8 12) weeks. Area under the receiver operator characteristic curve, sensitivity, specificity. PPV, and negative predictive value for a CR were 0.80 to 0.84, 72% to 94%, 61% to 85%, 63% to 78% and 80% to 89%, respectively. A flat scar was the most predictive feature of a CR (PPV 70%-80%). The PPV of small flat ulcers and large flat ulcers were 40% to 50% and 29% to 33%, respectively. The addition of biopsy results led to a significant change in confidence level score in 4% to 13% of patients.Conclusions: More than 70% of the patients with a luminal CR after neoadjuvant treatment for rectal cancer can be identified by endoscopy at +/- 9 weeks. Together with findings on digital rectal examination (DRE) and magnetic resonance imaging, specific endoscopic features can be used to select patients for an extended observation period to select for organ preservation. Show less
Normothermic machine perfusion (NMP) is emerging as a novel preservation strategy. During NMP, the organ is maintained in a metabolically active state that may not only provide superior organ... Show moreNormothermic machine perfusion (NMP) is emerging as a novel preservation strategy. During NMP, the organ is maintained in a metabolically active state that may not only provide superior organ preservation, but that also facilitates viability testing before transplantation, and ex situ resuscitation of marginal kidney grafts. Although the prevailing perfusion protocols for renal NMP are refined from initial pioneering studies concerning short periods of NMP, it could be argued that these protocols are not optimally tailored to address the putatively compromised metabolic plasticity of marginal donor grafts (i.e., in the context of viability testing and/or preservation), or to meet the metabolic prerequisites associated with prolonged perfusions and the required anabolic state in the context of organ regeneration. Herein, we provide a theoretical framework for the metabolic requirements for renal NMP. Aspects are discussed along the lines of carbohydrates, fatty acids, amino acids, and micronutrients required for optimal NMP of an isolated kidney. In addition, considerations for monitoring aspects of metabolic status during NMP are discussed. Show less
Pool, M.B.F.; Vos, J.; Eijken, M.; Pel, M. van; Reinders, M.E.J.; Ploeg, R.J.; ... ; Moers, C. 2020
Pretransplant normothermic machine perfusion (NMP) of donor kidneys offers the unique opportunity to perform active interventions to an isolated renal graft before transplantation. There is... Show morePretransplant normothermic machine perfusion (NMP) of donor kidneys offers the unique opportunity to perform active interventions to an isolated renal graft before transplantation. There is increasing evidence that mesenchymal stromal cells (MSCs) could have a paracrine/endocrine regenerative effect on ischemia-reperfusion injury. The purpose of this study was to determine which cytokines are secreted by MSCs during NMP of a porcine kidney. Viable porcine kidneys and autologous whole blood were obtained from a slaughterhouse. Warm ischemia time was standardized at 20 min and subsequent hypothermic machine perfusion was performed during 2-3 h. Thereafter, kidneys were machine perfused at 37 degrees C during 7 h. After 1 h of NMP, 0, 10(7)cultured human adipose tissue-derived MSCs, or 10(7)cultured bone marrow-derived MSCs were added (n = 5 per group). In a fourth experimental group, 7-h NMP was performed with 10(7)adipose tissue-derived MSCs, without a kidney in the circuit. Kidneys perfused with MSCs showed lower lactate dehydrogenase and neutrophil gelatinase-associated lipocalin levels in comparison with the control group. Also, elevated levels of human hepatocyte growth factor, interleukin (IL)-6, and IL-8 were found in the perfusate of the groups perfused with MSCs compared to the control groups. This study suggests that MSCs, in contact with an injured kidney during NMP, could lead to lower levels of injury markers and induce the release of immunomodulatory cytokines. Show less
Pool, M.; Eertman, T.; Parraga, J.S.; Hart, N. 't; Roemeling-van Rhijn, M.; Eijken, M.; ... ; Moers, C. 2019
Normothermic machine perfusion (NMP) of kidneys offers the opportunity to perform active interventions, such as the addition of mesenchymal stromal cells (MSCs), to an isolated organ prior to... Show moreNormothermic machine perfusion (NMP) of kidneys offers the opportunity to perform active interventions, such as the addition of mesenchymal stromal cells (MSCs), to an isolated organ prior to transplantation. The purpose of this study was to determine whether administering MSCs to kidneys during NMP is feasible, what the effect of NMP is on MSCs and whether intact MSCs are retained in the kidney and to which structures they home. Viable porcine kidneys were obtained from a slaughterhouse. Kidneys were machine perfused during 7 h at 37 C. After 1 h of perfusion either 0, 105, 106 or 107 human adipose tissue derived MSCs were added. Additional ex vivo perfusions were conducted with fluorescent pre-labelled bone-marrow derived MSCs to assess localisation and survival of MSCs during NMP. After NMP, intact MSCs were detected by immunohistochemistry in the lumen of glomerular capillaries, but only in the 107 MSC group. The experiments with fluorescent pre-labelled MSCs showed that only a minority of glomeruli were positive for infused MSCs and most of these glomeruli contained multiple MSCs. Flow cytometry showed that the number of infused MSCs in the perfusion circuit steeply declined during NMP to approximately 10%. In conclusion, the number of circulating MSCs in the perfusate decreases rapidly in time and after NMP only a small portion of the MSCs are intact and these appear to be clustered in a minority of glomeruli. Show less
