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PurposeTherapy with [177Lu-DOTA,Tyr3]octreotate is effective in patients with grade I/II metastasized and/or inoperable bronchial neuroendocrine tumour (NET) or gastroenteropancreatic NET (GEP-NET). In this study, we investigated the efficacy and safety of salvage treatment with [177Lu-DOTA,Tyr3]octreotate.MethodsPatients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [177Lu-DOTA,Tyr3]octreotate over two cycles per retreatment with PRRT (R-PRRT) or re-retreatment with PRRT (RR-PRRT).ResultsThe safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0–98.2). Median cumulative doses were 44.7 GBq (range 26.3–46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2–≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4–16.9) following R-PRRT and 14.2 months (95% CI 9.8–18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0–95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed.ConclusionA cumulative dose of up to 60.5 GBq salvage PRRT with [177Lu-DOTA,Tyr3]octreotate is safe and effective in patients with progressive disease (relapse-PD) following I-PRRT with [177Lu-DOTA,Tyr3]octreotate. Safety appears similar to that of I-PRRT as no higher incidence of AML or MDS was observed. No grade III/IV renal toxicity occurred after retreatment.

BackgroundBRI is estimated to occur in 10% of skull-base surgery and 5% of aneurysm surgery. These estimates are based on a few studies with unclear methodology. The purpose of this study is to assess the rate of BRI occurrence, its risk factors, and the association between BRI and postoperative focal neurological deficit in patients that underwent elective aneurysm surgery in a single institution.MethodsAll patients that underwent elective aneurysm surgery in a single tertiary center in the Netherlands were included. BRI was defined as cortical hypodensities in the surgical trajectory not matching areas of large arterial infarction. Risk ratios were calculated between BRI and (a) the use of temporary parent artery occlusion during clipping, (b) anterior communicating artery (ACom), and (c) middle cerebral artery (MCA) location of the aneurysm, (d) presence of mentioned CVA risk factors, (e) the clipping of > 1 aneurysm during the same procedure, and (f) new focal neurological deficit. Statistical analysis further included t-tests and binary logistical regression analysis on the correlation between age and BRI.ResultsBRI was identified postoperatively in 42 of the 94 patients included in this study. A new focal neurological deficit was found in 7 patients in the BRI group. A total of 5 patients had persisting symptoms at 3-month follow-up, of which 2 were caused by BRI. Increasing age is a risk factor for developing BRI.ConclusionsThe high rate of BRI and significant risk of new postoperative focal neurological deficit in our patients should be considered when counseling patients for elective aneurysm surgery.

PurposePeptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction.MethodsThree independent 177Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2–12 months). PPQ (positive/negative) and NETest (0–100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan–Meier survival and standard statistics.ResultsOne hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST “responders” (− 47 ± 3%); in “non-responders,” it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02–0.07).PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (− 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03–0.12).CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS).ConclusionsPPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.

Background High flow bypass surgery can be a last resort procedure for patients suffering from complex neurovascular pathology. Temporary occlusion of a recipient artery in these patients could result in debilitating neurological deficits. We developed a sutureless, mechanical anastomotic connection device, the SELANA clip (Sutureless Excimer Laser-Assisted Non-occlusive Anastomosis clip: SEcl). In the present study, we aim to determine the long-term non-inferiority of the SEcl technique compared with historical data of the conventional ELANA anastomosis technique. Methods A total of 18 SEcl bypasses were created on the carotid artery in a porcine model in 6 different survival groups. Mean application times, flap retrieval rates, hemostasis, patency, flow, endothelialization, and remodeling were assessed. Results The mean application time of the SEcl anastomoses was 15.2 ± 9.6 min, which was faster compared with the conventional ELANA anastomoses. The flap retrieval rate of the SEcl anastomoses was 86% (32/37). Direct hemostasis was achieved in 89% (33/37) SEcl anastomoses. Patency in all surviving animals was 94% (17/18). Bypass flow after six months was 156.5 ± 24.7 mL/min. Full endothelialization of the SEcl pins was observed after 3 weeks. Conclusion The SEcl technique is not inferior to the ELANA technique regarding patency, flap retrieval rate, flow, and endothelialization. On the basis of a significantly shorter application time and superior hemostasis, the SEcl technique could be preferable over the ELANA technique. A pilot study in patients is a logical next step based on our current results.

Background Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT “responders” from “non-responders”. This study clinically validates the utility of the PPQ in NETs. Methods The development and validation of the PPQ was undertaken in three independent 177 Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs ( n  = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany ( n  = 44), and Erasmus Medical Center, Rotterdam, Netherlands ( n  = 42). Each cohort included predominantly well differentiated, low grade (86–95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n  = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n  = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n  = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts ( n  = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: “predicted responder” (PPQ+); “predicted non-responder” (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses. Results In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64–79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10–14 months; HR: 18–77, p  < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47–50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10–12 months vs. PPQ-: 9–15 months). Conclusion The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.

Background Ankle valgus is a common deformity in patients with multiple hereditary exostoses (MHE) and a potential risk factor for early degenerative arthritis. In children, medial hemiepiphysiodesis of the distal tibia is a relatively simple surgical technique used to correct this deformity. We present here the first results of applying this procedure using the eight-Plate guided growth system (eight-Plate) for growth guidance. Methods Between 2006 and 2011 we performed hemiepiphysiodesis of the distal medial tibia in 30 ankles of 18 children with MHE using the eight-Plate. Weight-bearing total leg radiographs were obtained preoperatively, during follow-up and at the time of implant removal or when the distal tibial physis had closed. The lateral distal tibia angle (LDTA) was measured and fibular shortening assessed using the Malhotra classification. To evaluate the effect of hemiepiphysiodesis, we correlated the LDTA with age. Results The mean age at time of surgery was 12.6 (range 9.5–15.0) years, and the mean preoperative LDTA was 76.9° (range 68.5°–83.5°). During follow-up, the implant was removed in 12 extremities and the physis had closed in 18 extremities. The mean LDTA at the time of implant removal or at closure of the physis was 83.6° (range 76.5°–90.0°). Mean correction of LDTA was 6.9° after a mean follow-up period of 22 (range 3–43) months. During follow-up, no changes in the Malhotra classification were found in any of the patients. Correction of the valgus deformity of the ankle was significantly correlated (r = −0.506) (p = 0.004) with age in all patients. Conclusion Temporary medial hemiepiphyseodesis of the distal tibia seems to be an effective strategy for correcting ankle valgus in children with MHE. Timing of the intervention is, however, of importance. Hemiepiphyseodesis alone has no effect on the Malhotra classification. Level of evidence IV, retrospective review.

After peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with (90)Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [(177)Lu-DOTA(0),Tyr(3)]-Octreotate ((177)Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with (90)Y-radiolabelled somatostatin analogues. The annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed. Of the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5 - 3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (± SD) was 108 ± 5 ml/min and the estimated average annual decrease in CLR (± SD) was 3.4 ± 0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1 ± 4.9 Gy. Nephrotoxicity in patients treated with (177)Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with (90)Y-labelled somatostatin analogues, does not seem valid for PRRT with (177)Lu-octreotate.

The aim of this study was to obtain insight into which proportion of cancer patients is admitted to an Intensive Care Unit (ICU) and how their survival, demographic, and clinical characteristics relate to cancer patients not admitted to the ICU. Data from patients registered with cancer between 2006 and 2011 in four hospitals in the Netherlands were linked to the Dutch National Intensive Care Evaluation registry. About 36,860 patients with cancer were identified, of whom 2,374 (6.4%) were admitted to the ICU. Fifty‐six percent of ICU admissions were after surgery, whereas 44% were for medical reasons. The risk for ICU admission was highest among cancer patients treated with surgery either alone or combined with chemotherapy and/or radiation therapy. Only 80 of 1,073 medical ICU admissions (3.3%) were for cancer‐specific reasons. Although more women (54.0%) than men were registered with cancer, the proportion of male cancer patients admitted to an ICU was much higher (9.3 vs. 4.0%, P < 0.001). Five‐year survival of cancer patients admitted to the ICU was substantial (41%) although median survival was much lower (1,104 days) than in patients not admitted to the ICU (median survival time not reached, P < 0.001). These results show that one out of 16 cancer patients was admitted to an ICU and that ICU support for this group should not be considered futile. Although information about the influence of cancer on ICU outcome has become increasingly available during recent years, information on the proportion and characteristics of cancer patients from a general population that is admitted to an ICU is highly limited. To the best of our knowledge our investigation is the first to provide data hereon in a large cohort of patients with different cancer diagnoses.

BackgroundThe excimer laser-assisted non-occlusive anastomosis (ELANA) technique facilitates the construction of anastomoses without temporary occlusion of the recipient artery. Experiments aimed at simplifying the technique eventually resulted in a sutureless ELANA slide (SEsl) anastomosis. After the first clinical use, new insights lead to the application of a clip at the back of the device, the SELANA clip (SEcl). The SEcl offers a distinct advantage over the SEsl since no sealant is necessary. In this study, we determine the feasibility of the SEcl anastomosis in an in vivo rabbit model.Methods15 SEcl anastomoses and 15 conventional ELANA anastomoses were created on the abdominal aorta in 5 rabbits. Mean application times, flap retrieval rates, hemostasis, and burst pressures were assessed.ResultsThe mean application time of the SEcl anastomoses was 11.4 min versus 39.0 min for the ELANA anastomoses (mean difference, 27.6 min; 95% CI, 20.6–34.7). The flap retrieval rate of the SEcl anastomoses (14/15) was not inferior to the flap retrieval rate of the ELANA anastomoses (13/15). Direct hemostasis was achieved in 13/15 (87%) SEcl anastomoses and in 14/15 (94%) ELANA anastomoses. All SEcl anastomoses were resistant to provoked pressures until 250 mmHg.ConclusionThe SEcl anastomosis is technically feasible in in vivo experiments. Mean application time, flap retrieval rate, hemostasis, and burst pressure are not inferior to the conventional ELANA anastomosis. Further long term experiments should be performed to assess safety, patency, and reendothelialization.

BackgroundInformation on outcome of patients with occlusion of the internal carotid artery (ICA) is limited by the short duration of follow-up and lack of haemodynamic studies on the brain.MethodsThe authors prospectively investigated 117 consecutive patients with transient or moderately disabling cerebral or retinal ischaemia associated with ICA occlusion between September 1995 and July 1998, and followed them until June 2008. The authors determined the risk of recurrent ischaemic stroke and other vascular events and prognostic factors, including collateral pathways and transcranial Doppler CO2 reactivity.ResultsPatients (mean age 61±9 years; 80% male) were followed for a median time of 10.2 years; 22 patients underwent endarterectomy for contralateral ICA stenosis and 16 extracranial/intracranial bypass surgery. Recurrent ischaemic stroke occurred in 23 patients, resulting in an annual rate of 2.4% (95% CI 1.5 to 3.6). Risk factors for recurrent ischaemic stroke were age (HR 1.07, 1.02 to 1.13), cerebral rather than retinal symptoms (HR 8.0, 1.1 to 60), recurrent symptoms after documented occlusion (HR 4.4, 1.6 to 12), limb-shaking transient ischaemic attacks at presentation (HR 7.5, 2.6 to 22), history of stroke (HR 2.8, 1.2 to 6.7) and leptomeningeal collaterals (HR 5.2, 1.5 to 17) but not CO2 reactivity (HR 1.01, 0.99 to 1.02). The composite event of any vascular event occurred in 57 patients, resulting in an annual rate of 6.4% (95% CI 4.9 to 8.2).ConclusionThe prognosis of patients with transient ischaemic attack or minor stroke and ICA occlusion depends on age, several clinical factors and the presence of leptomeningeal collaterals. The long-term risk of recurrent ischaemic stroke is much lower than that of other vascular events.