Pain-related changes in cutaneous innervation of patients suffering from bortezomib-induced, diabetic or chronic idiopathic axonal polyneuropathy

Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n = 22), painful diabetic neuropathy (PDN; n = 16), chronic i

Cerebellar plasticity and associative memories are controlled by perineuronal nets.

Perineuronal nets (PNNs) are assemblies of extracellular matrix molecules, which surround the cell body and dendrites of many types of neuron and regulate neural plasticity. PNNs are prominently expressed around neurons of the deep cerebellar nuclei (DCN), but their role in adult cerebellar plasticity and behavior is far from clear. Here we show that PNNs in the mouse DCN are diminished during eyeblink conditioning (EBC), a form of associative motor learning that depends on DCN plasticity. When memories are fully acquired, PNNs are restored. Enzymatic digestion of PNNs in the DCN improves EBC learning, but intact PNNs are necessary for memory retention. At the structural level, PNN removal induces significant synaptic rearrangements in vivo, resulting in increased inhibition of DCN baseline activity in awake behaving mice. Together, these results demonstrate that PNNs are critical players in the regulation of cerebellar circuitry and function

Mesoporous silica formation mechanisms probed using combined Spin-Echo Modulated Small Angle Neutron Scattering (SEMSANS) and Small Angle Neutron Scattering (SANS)

International audienceThe initial formation stages of surfactant-templated silica thin films which grow at the air−water interface were studied using combined spin−echo modulated small-angle neutron scattering (SEMSANS) and small-angle neutron scattering (SANS). The films are formed from either a cationic surfactant or nonionic surfactant (C16EO8) in a dilute acidic solution by the addition of tetramethoxysilane. Previous work has suggested a twostage formation mechanism with mesostructured particle formation in the bulk solution driving film formation at the solution surface. From the SEMSANS data, it is possible to pinpoint accurately the time associated with the formation of large particles in solution that go on to form the film and to show their emergence is concomitant with the appearance of Bragg peaks in the SANS pattern, associated with the two-dimensional hexagonal order. The combination of SANS and SEMSANS allows a complete depiction of the steps of the synthesis that occur in the subphase

Clinical, electrophysiological, and cutaneous innervation changes in patients with bortezomib-induced peripheral neuropathy reveal insight into mechanisms of neuropathic pain

Bortezomib is a mainstay of therapy for multiple myeloma, frequently complicated by painful neuropathy. The objective of this study was to describe clinical, electrophysiological, and pathological changes of bortezomib-induced peripheral neuropathy (BiPN) in detail and to correlate pathological changes with pain descriptors. Clinical data, nerve conduction studies, and lower leg skin biopsies were collected from 22 BiPN patients. Skin sections were immunostained using anti-protein gene product 9.5 (PGP9.5) and calcitonin gene-related peptide (CGRP) antibodies. Cumulative bortezomib dose and clinical assessment scales indicated light-moderate sensory neuropathy. Pain intensity >4 (numerical rating scale) was present in 77% of the patients. Median pain intensity and overall McGill Pain Questionnaire (MPQ) sum scores indicated moderate to severe neuropathic pain. Sural nerve sensory nerve action potentials were abnormal in 86%, while intraepidermal nerve fiber densities of PGP9.5 and CGRP were not significantly different from healthy controls. However, subepidermal nerve fiber density (SENFD) of PGP9.5 was significantly decreased and the axonal swelling ratio, a predictor of neuropathy, and upper dermis nerve fiber density (UDNFD) of PGP9.5, presumably representing sprouting of parasympathetic fibers, were significantly increased in BiPN patients. Finally, significant correlations between UDNFD of PGP9.5 versus the evaluative Pain Rating Index (PRI) and number of words count (NWC) of the MPQ, and significant inverse correlations between SENFD/UDNFD of CGRP versus the sensory-discriminative MPQ PRI/NWC were found. BiPN is a sensory neuropathy, in which neuropathic pain is the most striking clinical finding. Bortezomib-induced neuropathic pain may be driven by sprouting of parasympathetic fibers in the upper dermis and impaired regeneration of CGRP fibers in the subepidermal layer

Spinal Autofluorescent Flavoprotein Imaging in a Rat Model of Nerve Injury-Induced Pain and the Effect of Spinal Cord Stimulation

Nerve injury may cause neuropathic pain, which involves hyperexcitability of spinal dorsal horn neurons. The mechanisms of action of spinal cord stimulation (SCS), an established treatment for intractable neuropathic pain, are only partially understood. We used Autofluorescent Flavoprotein Imaging (AFI) to study changes in spinal dorsal horn metabolic activity. In the Seltzer model of nerve-injury induced pain, hypersensitivity was confirmed using the von Frey and hotplate test. 14 Days after nerve-injury, rats were anesthetized, a bipolar electrode was placed around the affected sciatic nerve and the spinal cord was exposed by a laminectomy at T13. AFI recordings were obtained in neuropathic rats and a control group of naýve rats following 10 seconds of electrical stimulation of the sciatic nerve at C-fiber strength, or following non-noxious palpation. Neuropathic rats were then treated with 30 minutes of SCS or sham stimulation and AFI recordings were obtained for up to 60 minutes after cessation of SCS/sham. Although AFI responses to noxious electrical stimulation were similar in neuropathic and naýve rats, only neuropathic rats demonstrated an AFI-response to palpation. Secondly, an immediate, short-lasting, but strong reduction in AFI intensity and area of excitation occurred following SCS, but not following sham stimulation. Our data confirm that AFI can be used to directly visualize changes in spinal metabolic activity following nerve injury and they imply that SCS acts through rapid modulation of nociceptive processing at the spinal level

Prognostic value of total tumor volume in patients with colorectal liver metastases:A secondary analysis of the randomized CAIRO5 trial with external cohort validation

Background:This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment.Methods: Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center. Results:In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P &lt; 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008). Conclusion: Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS.</p

Deep learning models for automatic tumor segmentation and total tumor volume assessment in patients with colorectal liver metastases

Background: We developed models for tumor segmentation to automate the assessment of total tumor volume (TTV) in patients with colorectal liver metastases (CRLM). Methods: In this prospective cohort study, pre- and post-systemic treatment computed tomography (CT) scans of 259 patients with initially unresectable CRLM of the CAIRO5 trial (NCT02162563) were included. In total, 595 CT scans comprising 8,959 CRLM were divided into training (73%), validation (6.5%), and test sets (21%). Deep learning models were trained with ground truth segmentations of the liver and CRLM. TTV was calculated based on the CRLM segmentations. An external validation cohort was included, comprising 72 preoperative CT scans of patients with 112 resectable CRLM. Image segmentation evaluation metrics and intraclass correlation coefficient (ICC) were calculated. Results: In the test set (122 CT scans), the autosegmentation models showed a global Dice similarity coefficient (DSC) of 0.96 (liver) and 0.86 (CRLM). The corresponding median per-case DSC was 0.96 (interquartile range [IQR] 0.95–0.96) and 0.80 (IQR 0.67–0.87). For tumor segmentation, the intersection-over-union, precision, and recall were 0.75, 0.89, and 0.84, respectively. An excellent agreement was observed between the reference and automatically computed TTV for the test set (ICC 0.98) and external validation cohort (ICC 0.98). In the external validation, the global DSC was 0.82 and the median per-case DSC was 0.60 (IQR 0.29–0.76) for tumor segmentation. Conclusions: Deep learning autosegmentation models were able to segment the liver and CRLM automatically and accurately in patients with initially unresectable CRLM, enabling automatic TTV assessment in such patients. Relevance statement: Automatic segmentation enables the assessment of total tumor volume in patients with colorectal liver metastases, with a high potential of decreasing radiologist’s workload and increasing accuracy and consistency. Key points: • Tumor response evaluation is time-consuming, manually performed, and ignores total tumor volume. • Automatic models can accurately segment tumors in patients with colorectal liver metastases. • Total tumor volume can be accurately calculated based on automatic segmentations. Graphical Abstract: [Figure not available: see fulltext.]

Prognostic value of total tumor volume in patients with colorectal liver metastases: A secondary analysis of the randomized CAIRO5 trial with external cohort validation

Background: This study aimed to assess the prognostic value of total tumor volume (TTV) for early recurrence (within 6 months) and overall survival (OS) in patients with colorectal liver metastases (CRLM), treated with induction systemic therapy followed by complete local treatment. Methods: Patients with initially unresectable CRLM from the multicenter randomized phase 3 CAIRO5 trial (NCT02162563) who received induction systemic therapy followed by local treatment were included. Baseline TTV and change in TTV as response to systemic therapy were calculated using the CT scan before and the first after systemic treatment, and were assessed for their added prognostic value. The findings were validated in an external cohort of patients treated at a tertiary center. Results: In total, 215 CAIRO5 patients were included. Baseline TTV and absolute change in TTV were significantly associated with early recurrence (P = 0.005 and P = 0.040, respectively) and OS in multivariable analyses (P = 0.024 and P = 0.006, respectively), whereas RECIST1.1 was not prognostic for early recurrence (P = 0.88) and OS (P = 0.35). In the validation cohort (n = 85), baseline TTV and absolute change in TTV remained prognostic for early recurrence (P = 0.041 and P = 0.021, respectively) and OS in multivariable analyses (P < 0.0001 and P = 0.012, respectively), and showed added prognostic value over conventional clinicopathological variables (increase C-statistic, 0.06; 95 % CI, 0.02 to 0.14; P = 0.008). Conclusion: Total tumor volume is strongly prognostic for early recurrence and OS in patients who underwent complete local treatment of initially unresectable CRLM, both in the CAIRO5 trial and the validation cohort. In contrast, RECIST1.1 did not show prognostic value for neither early recurrence nor OS

Mesoporous Silica Formation Mechanisms Probed Using Combined Spin-Echo Modulated Small-Angle Neutron Scattering (SEMSANS) and Small-Angle Neutron Scattering (SANS)

The initial formation stages of surfactant-templated silica thin films which grow at the air-water interface were studied using combined spin-echo modulated small-angle neutron scattering (SEMSANS) and small-angle neutron scattering (SANS). The films are formed from either a cationic surfactant or nonionic surfactant (C16EO8) in a dilute acidic solution by the addition of tetramethoxysilane. Previous work has suggested a two stage formation mechanism with mesostructured particle formation in the bulk solution driving film formation at the solution surface. From the SEMSANS data, it is possible to pinpoint accurately the time associated with the formation of large particles in solution that go on to form the film and to show their emergence is concomitant with the appearance of Bragg peaks in the SANS pattern, associated with the two-dimensional hexagonal order. The combination of SANS and SEMSANS allows a complete depiction of the steps of the synthesis that occur in the subphase.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Instrumenten groepRST/Neutron and Positron Methods in MaterialsRST/Technici PoolTechnici Poo