Detailed mapping of the complex fiber structure and white matter pathways of the chimpanzee brain.

Long-standing questions about human brain evolution may only be resolved through comparisons with close living evolutionary relatives, such as chimpanzees. This applies in particular to structural white matter (WM) connectivity, which continuously expanded throughout evolution. However, due to legal restrictions on chimpanzee research, neuroscience research currently relies largely on data with limited detail or on comparisons with evolutionarily distant monkeys. Here, we present a detailed magnetic resonance imaging resource to study structural WM connectivity in the chimpanzee. This open-access resource contains (1) WM reconstructions of a postmortem chimpanzee brain, using the highest-quality diffusion magnetic resonance imaging data yet acquired from great apes; (2) an optimized and validated method for high-quality fiber orientation reconstructions; and (3) major fiber tract segmentations for cross-species morphological comparisons. This dataset enabled us to identify phylogenetically relevant details of the chimpanzee connectome, and we anticipate that it will substantially contribute to understanding human brain evolution.

High angular resolution susceptibility imaging and estimation of fiber orientation distribution functions in primate brain.

Uncovering brain-tissue microstructure including axonal characteristics is a major neuroimaging research focus. Within this scope, anisotropic properties of magnetic susceptibility in white matter have been successfully employed to estimate primary axonal trajectories using mono-tensorial models. However, anisotropic susceptibility has not yet been considered for modeling more complex fiber structures within a voxel, such as intersecting bundles, or an estimation of orientation distribution functions (ODFs). This information is routinely obtained by high angular resolution diffusion imaging (HARDI) techniques. In applications to fixed tissue, however, diffusion-weighted imaging suffers from an inherently low signal-to-noise ratio and limited spatial resolution, leading to high demands on the performance of the gradient system in order to mitigate these limitations. In the current work, high angular resolution susceptibility imaging (HARSI) is proposed as a novel, phase-based methodology to estimate ODFs. A multiple gradient-echo dataset was acquired in an entire fixed chimpanzee brain at 61 orientations by reorienting the specimen in the magnetic field. The constant solid angle method was adapted for estimating phase-based ODFs. HARDI data were also acquired for comparison. HARSI yielded information on whole-brain fiber architecture, including identification of peaks of multiple bundles that resembled features of the HARDI results. Distinct differences between both methods suggest that susceptibility properties may offer complementary microstructural information. These proof-of-concept results indicate a potential to study the axonal organization in post-mortem primate and human brain at high resolution.

B 1 + $$ {B}_1

PURPOSE: Magnetization transfer saturation ( MTsat $$ \mathrm{MTsat} $$ ) is a useful marker to probe tissue macromolecular content and myelination in the brain. The increased B 1 + $$ {B}_1^{+} $$ -inhomogeneity at ≥ 7 $$ \ge 7 $$ T and significantly larger saturation pulse flip angles which are often used for postmortem studies exceed the limits where previous MTsat $$ \mathrm{MTsat} $$ B 1 + $$ {B}_1^{+} $$ correction methods are applicable. Here, we develop a calibration-based correction model and procedure, and validate and evaluate it in postmortem 7T data of whole chimpanzee brains. THEORY: The B 1 + $$ {B}_1^{+} $$ dependence of MTsat $$ \mathrm{MTsat} $$ was investigated by varying the off-resonance saturation pulse flip angle. For the range of saturation pulse flip angles applied in typical experiments on postmortem tissue, the dependence was close to linear. A linear model with a single calibration constant C $$ C $$ is proposed to correct bias in MTsat $$ \mathrm{MTsat} $$ by mapping it to the reference value of the saturation pulse flip angle. METHODS: C $$ C $$ was estimated voxel-wise in five postmortem chimpanzee brains. "Individual-based global parameters" were obtained by calculating the mean C $$ C $$ within individual specimen brains and "group-based global parameters" by calculating the means of the individual-based global parameters across the five brains. RESULTS: The linear calibration model described the data well, though C $$ C $$ was not entirely independent of the underlying tissue and B 1 + $$ {B}_1^{+} $$ . Individual-based correction parameters and a group-based global correction parameter ( C = 1 . 2 $$ C=1.2 $$ ) led to visible, quantifiable reductions of B 1 + $$ {B}_1^{+} $$ -biases in high-resolution MTsat $$ \mathrm{MTsat} $$ maps. CONCLUSION: The presented model and calibration approach effectively corrects for B 1 + $$ {B}_1^{+} $$ inhomogeneities in postmortem 7T data.

Treatment characteristics and outcomes of pure Acinar cell carcinoma of the pancreas - A multicentric European study on radically resected patients.

BACKGROUND: Acinar cell carcinomas (ACC) belong to the exocrine pancreatic malignancies. Due to their rarity, there is no consensus regarding treatment strategies for resectable ACC. METHODS: This is a retrospective multicentric study of radically resected pure pancreatic ACC. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Further endpoints were oncologic outcomes related to tumor stage and therapeutic protocols. RESULTS: 59 patients (44 men) with a median age of 64 years were included. The median tumor size was 45.0 mm. 61.0% were pT3 (n = 36), nodal positivity rate was 37.3% (n = 22), and synchronous distant metastases were present in 10.1% of the patients (n = 6). 5-Years OS was 60.9% and median DFS 30 months. 24 out of 31 recurred systemically (n = 18 only systemic, n = 6 local and systemic). Regarding TNM-staging, only the N2-stage negatively influenced OS and DFS (p = 0.004, p = 0.001). Adjuvant treatment protocols (performed in 62.7%) did neither improve OS (p = 0.542) nor DFS (p = 0.159). In 9 cases, radical resection was achieved following neoadjuvant therapy. DISCUSSION: Radical surgery is currently the mainstay for resectable ACC, even for limited metastatic disease. Novel (neo)adjuvant treatment strategies are needed, since current systemic therapies do not result in a clear survival benefit in the perioperative setting.

Towards a representative reference for MRI-based human axon radius assessment using light microscopy.

Non-invasive assessment of axon radii via MRI bears great potential for clinical and neuroscience research as it is a main determinant of the neuronal conduction velocity. However, there is a lack of representative histological reference data at the scale of the cross-section of MRI voxels for validating the MRI-visible, effective radius (reff). Because the current gold standard stems from neuroanatomical studies designed to estimate the bulk-determined arithmetic mean radius (rarith) on small ensembles of axons, it is unsuited to estimate the tail-weighted reff. We propose CNN-based segmentation on high-resolution, large-scale light microscopy (lsLM) data to generate a representative reference for reff. In a human corpus callosum, we assessed estimation accuracy and bias of rarith and reff. Furthermore, we investigated whether mapping anatomy-related variation of rarith and reff is confounded by low-frequency variation of the image intensity, e.g., due to staining heterogeneity. Finally, we analyzed the error due to outstandingly large axons in reff. Compared to rarith, reff was estimated with higher accuracy (maximum normalized-root-mean-square-error of reff: 8.5 %; rarith: 19.5 %) and lower bias (maximum absolute normalized-mean-bias-error of reff: 4.8 %; rarith: 13.4 %). While rarith was confounded by variation of the image intensity, variation of reff seemed anatomy-related. The largest axons contributed between 0.8 % and 2.9 % to reff. In conclusion, the proposed method is a step towards representatively estimating reff at MRI voxel resolution. Further investigations are required to assess generalization to other brains and brain areas with different axon radii distributions.

mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote KrasG12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis.

BACKGROUND & AIMS: Oncogenic KrasG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of KrasG12D, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. RESULTS: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote KrasG12D-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents KrasG12D-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. CONCLUSIONS: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.

Measuring the iron content of dopaminergic neurons in substantia nigra with MRI relaxometry.

In Parkinson's disease, the depletion of iron-rich dopaminergic neurons in nigrosome 1 of the substantia nigra precedes motor symptoms by two decades. Methods capable of monitoring this neuronal depletion, at an early disease stage, are needed for early diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is particularly suitable for this task due to its sensitivity to tissue microstructure and in particular, to iron. However, the exact mechanisms of MRI contrast in the substantia nigra are not well understood, hindering the development of powerful biomarkers. In the present report, we illuminate the contrast mechanisms in gradient and spin echo MR images in human nigrosome 1 by combining quantitative 3D iron histology and biophysical modeling with quantitative MRI on post mortem human brain tissue. We show that the dominant contribution to the effective transverse relaxation rate (R2*) in nigrosome 1 originates from iron accumulated in the neuromelanin of dopaminergic neurons. This contribution is appropriately described by a static dephasing approximation of the MRI signal. We demonstrate that the R2* contribution from dopaminergic neurons reflects the product of cell density and cellular iron concentration. These results demonstrate that the in vivo monitoring of neuronal density and iron in nigrosome 1 may be feasible with MRI and provide directions for the development of biomarkers for an early detection of dopaminergic neuron depletion in Parkinson's disease.

Diabetes and Weight Loss Are Associated With Malignancies in Patients With Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: The role of diabetes in intraductal papillary mucinous neoplasms (IPMNs) is not known. We investigated the prevalence of diabetes among patients with resected IPMNs and the association between diabetes, clinical and morphological features, and high-grade dysplasia or invasive cancer. METHODS: We collected clinical, pathology, laboratory, and demographic data from 134 patients who underwent pancreatic resection for IPMN from a referral center in Germany. We identified 50 patients with diabetes (37%). RESULTS: Higher proportions of patients with diabetes were male and older, but did not have increased body mass index, compared to patients without diabetes. Diabetes was significantly associated with main-duct involvement (odds ratio [OR], 2.827; 95% CI, 1.059-7.546; P = .038) and high-grade dysplasia or invasive carcinoma (OR, 2.692; 95% CI, 1.283-5.651; P = .009). Risk of high-grade dysplasia or invasive cancer was even higher in patients with new-onset or worsening diabetes (OR, 4.615; 95% CI, 1.423-14.698; P = .011). Fifty-eight percent of patients (18/31) with weight loss at diagnosis had diabetes vs 32% of patients (31/97) without weight loss (P = .009). However, when the analysis was restricted to IPMNs with low-grade dysplasia, weight loss and diabetes were no longer associated (42% [5/12] vs 21% [9/44]; P = .133). CONCLUSIONS: In patients with IPMNs, diabetes is associated with increased risk of main duct involvement and high-grade dysplasia or invasive carcinoma. Studies are needed to determine the relationship between diabetes and progression of IPMNs, which might lead to strategies for early detection and prevention of invasive cancer. Findings from this study should be considered in the guidelines for management of IPMN.

Kidney transplantation after rescue allocation-meticulous selection yields the chance for excellent outcome.

BACKGROUND: The small number of organ donors forces transplant centres to consider potentially suboptimal kidneys for transplantation. Eurotransplant established an algorithm for rescue allocation (RA) of kidneys repeatedly declined or not allocated within 5 h after procurement. Data on the outcomes and benefits of RA are scarce to date. METHODS: We conducted a retrospective 8-year analysis of transplant outcomes of RA offers based on our in-house criteria catalogue for acceptance and decline of organs and potential recipients. RESULTS: RA donors and recipients were both older compared with standard allocation (SA). RA donors more frequently had a history of hypertension, diabetes or fulfilled expanded criteria donor key parameters. RA recipients had poorer human leucocyte antigen (HLA) matches and longer cold ischaemia times (CITs). However, waiting time was shorter and delayed graft function, primary non-function and biopsy-proven rejections were comparable to SA. Five-year graft and patient survival after RA were similar to SA. In multivariate models accounting for confounding factors, graft survival and mortality after RA and SA were comparable as well. CONCLUSIONS: Facing relevant comorbidities and rapid deterioration with the risk of being removed from the waiting list, kidney transplantation after RA was identified to allow for earlier transplantation with excellent outcome. Data from this survey propose not to reject categorically organs from multimorbid donors with older age and a history of hypertension or diabetes to aim for the best possible HLA matching and to carefully calculate overall expected CIT.

Senile plaque calcification of the lamina circumvoluta medullaris in Alzheimer's disease.

Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus. Calcifications are not an inherent feature of Alzheimer's disease. On the other hand, a rare presenile type of dementia with symmetrical Fahr-type calcifications and numerous neurofibrillary tangles without senile plaques has been described by Kosaka in 1994 and was termed "diffuse neurofibrillary tangles with calcification" (DNTC). We here report a case of Alzheimer's disease with calcifications both in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus, differing from DNTC by the presence of senile plaques. The calcifications in the hippocampus were not only vascular in nature but also covered amyloid-ß- and phosphorylated tau-positive plaque-like structures that were linearly arranged along the dentate fascia in the CA1 sector, an unusual finding of pathogenetic interest.

Collateral effects of the SARS-CoV-2 pandemic on oncologic surgery in Bavaria.

BACKGROUND: The ongoing SARS-COV-2 pandemic has severe implications for people and healthcare systems everywhere. In Germany, worry about the consequences of the pandemic led to the deferral of non-emergency surgeries. Tumor surgery accounts for a large volume in the field of visceral surgery and cannot be considered purely elective. It is not known how the SARS-COV-2 pandemic has changed the surgical volume in tumor patients. METHODS: Retrospective analysis of the amount of oncological surgeries in three academic visceral surgery departments in Bavaria, Germany, in 2020. Procedures were split into subgroups: Upper Gastrointestinal (Upper GI), Colorectal, Hepato-Pancreato-Biliary (HPB), Peritoneal and Endocrine. Procedures in 2020 were compared to a reference period from January 1st, 2017 to December 31st 2019. Surgical volume was graphically merged with SARS-COV-2 incidence and the number of occupied ICU beds. RESULTS: Surgical volume decreased by 7.6% from an average of 924 oncologic surgeries from 2017 to 2019 to 854 in 2020. The decline was temporally associated with the incidence of infections and ICU capacity. Surgical volume did not uniformly increase to pre-pandemic levels in the months following the first pandemic wave with lower SARS-COV-2 incidence and varied according to local incidence levels. The decline was most pronounced in colorectal surgery where procedures declined on average by 26% following the beginning of the pandemic situation. CONCLUSION: The comparison with pre-pandemic years showed a decline in oncologic surgeries in 2020, which could have an impact on lost life years in non-COVID-19 patients. This decline was very different in subgroups which could not be solely explained by the pandemic.

Increased sensitivity and signal-to-noise ratio in diffusion-weighted MRI using multi-echo acquisitions.

Post-mortem diffusion MRI (dMRI) enables acquisitions of structural imaging data with otherwise unreachable resolutions - at the expense of longer scanning times. These data are typically acquired using highly segmented image acquisition strategies, thereby resulting in an incomplete signal decay before the MRI encoding continues. Especially in dMRI, with low signal intensities and lengthy contrast encoding, such temporal inefficiency translates into reduced image quality and longer scanning times. This study introduces Multi Echo (ME) acquisitions to dMRI on a human MRI system - a time-efficient approach, which increases SNR (Signal-to-Noise Ratio) and reduces noise bias for dMRI images. The benefit of the introduced ME-dMRI method was validated using numerical Monte Carlo simulations and showcased on a post-mortem brain of a wild chimpanzee. The proposed Maximum Likelihood Estimation echo combination results in an optimal SNR without detectable signal bias. The combined strategy comes at a small price in scanning time (here 30% additional) and leads to a substantial SNR increase (here white matter: ~ 1.6x, equivalent to 2.6 averages, grey matter: ~ 1.9x, equivalent to 3.6 averages) and a general reduction of the noise bias.

Meta-analysis and single-center experience on the protective effect of negative suction drains on wound healing after stoma reversal.

BACKGROUND: Compromised wound healing following stoma reversal is a frequent problem. The use of negative suction drainage for reduction of complications remains controversial. METHODS: The patient database of our center was reviewed for patients with ileostomy reversal between 2007 and 2017. Risk factors for wound complications were analyzed using multivariate regression analysis. Systematic review and meta-analysis was performed. Ultimately, results of this study were integrated into meta-analysis to assess the effect of drainage placement on wound healing. RESULTS: In our institutional analysis, a total of 406 patients with ileostomy reversal were included (n = 240 (59.1%) with drainage vs. n = 166 (40.8%) without drainage). In multivariate analysis, body mass index (BMI) was a risk factor for wound complications (odds ratio (95% CI) 1.06 (1.02-1.12)). Patients with drainage needed significantly fewer interventions than those without drainage (17.1% vs. 28.9%, p = 0.005). Placement of drainage significantly reduced the risk of wound complications even in the group with elevated BMI (odds ratio (95% CI) 0.462 (0.28-0.76), p = 0.003). Meta-analysis identified 6 studies with a total of 1180 patients eligible for further analysis (2 prospectively randomized trials; 4 retrospective cohort studies). Overall analysis revealed a significantly beneficial effect of wound drainage following ileostomy reversal (RR (95% CI) 0.47 (0.34, 0.66); p < 0.0001). CONCLUSION: In our institutional analysis as well as meta-analysis, the use of subcutaneous suction drains was beneficial for prevention of wound healing complications following ostomy reversal. Drainage placement is especially valuable in high-risk situations such as in obese patients.

Influence of the extracellular matrix on water mobility in subcortical gray matter.

PURPOSE: Water mobility in tissues is related to the microstructure that modulates diffusion and spin relaxation. Previous work has shown that the extracellular matrix (ECM) impacts water diffusion in cartilage. To investigate if similar contributions to image contrast exist for brain, which is characterized by a substantially lower ECM content, diffusion and relaxation were studied in fixed samples from goat and human thalamus before and after enzymatic digestion of ECM compounds. Selected experiments in human corpus callosum were included for comparing subcortical gray matter and white matter. METHODS: Digestion of matrix components was achieved by treatment with hyaluronidase. Nonlocalized pulsed field gradient measurements were performed with b values between 0.6 and 18,000 s/mm2 at 3T and temperatures between 0°C and 20°C, in addition to T1 and T2 relaxation measurements. The data were fitted to multiexponential models to account for different water compartments. After the measurements, the samples were sliced and stained for ECM-sensitive markers to verify efficient digestion. RESULTS: Microstructural alterations associated with hyaluronan digestion did not lead to measurable effects on water diffusion or T 2 . However, T1 of the main relaxographic component, attributed to intra-/extracellular water, decreased by 7%. CONCLUSION: Investigations with very strong gradients did not reveal a detectable effect on water diffusion or T 2 after hyaluronan removal, indicating that the brain ECM content is too low to produce a detectable effect. The subtle alteration of T1 upon hyaluronidase treatment might reflect a modulation of intercompartmental water exchange properties.

Biophysically motivated efficient estimation of the spatially isotropic R2* component from a single gradient-recalled echo measurement.

PURPOSE: To propose and validate an efficient method, based on a biophysically motivated signal model, for removing the orientation-dependent part of R2* using a single gradient-recalled echo (GRE) measurement. METHODS: The proposed method utilized a temporal second-order approximation of the hollow-cylinder-fiber model, in which the parameter describing the linear signal decay corresponded to the orientation-independent part of R2* . The estimated parameters were compared to the classical, mono-exponential decay model for R2* in a sample of an ex vivo human optic chiasm (OC). The OC was measured at 16 distinct orientations relative to the external magnetic field using GRE at 7T. To show that the proposed signal model can remove the orientation dependence of R2* , it was compared to the established phenomenological method for separating R2* into orientation-dependent and -independent parts. RESULTS: Using the phenomenological method on the classical signal model, the well-known separation of R2* into orientation-dependent and -independent parts was verified. For the proposed model, no significant orientation dependence in the linear signal decay parameter was observed. CONCLUSIONS: Since the proposed second-order model features orientation-dependent and -independent components at distinct temporal orders, it can be used to remove the orientation dependence of R2* using only a single GRE measurement.

Developing 3D microscopy with CLARITY on human brain tissue: Towards a tool for informing and validating MRI-based histology.

Recent breakthroughs in magnetic resonance imaging (MRI) enabled quantitative relaxometry and diffusion-weighted imaging with sub-millimeter resolution. Combined with biophysical models of MR contrast the emerging methods promise in vivo mapping of cyto- and myelo-architectonics, i.e., in vivo histology using MRI (hMRI) in humans. The hMRI methods require histological reference data for model building and validation. This is currently provided by MRI on post mortem human brain tissue in combination with classical histology on sections. However, this well established approach is limited to qualitative 2D information, while a systematic validation of hMRI requires quantitative 3D information on macroscopic voxels. We present a promising histological method based on optical 3D imaging combined with a tissue clearing method, Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging compatible Tissue hYdrogel (CLARITY), adapted for hMRI validation. Adapting CLARITY to the needs of hMRI is challenging due to poor antibody penetration into large sample volumes and high opacity of aged post mortem human brain tissue. In a pilot experiment we achieved transparency of up to 8 mm-thick and immunohistochemical staining of up to 5 mm-thick post mortem brain tissue by a combination of active and passive clearing, prolonged clearing and staining times. We combined 3D optical imaging of the cleared samples with tailored image processing methods. We demonstrated the feasibility for quantification of neuron density, fiber orientation distribution and cell type classification within a volume with size similar to a typical MRI voxel. The presented combination of MRI, 3D optical microscopy and image processing is a promising tool for validation of MRI-based microstructure estimates.

R0 Versus R1 Resection Matters after Pancreaticoduodenectomy, and Less after Distal or Total Pancreatectomy for Pancreatic Cancer.

OBJECTIVE: The aim of this study was to decipher the true importance of R0 versus R1 resection for survival in pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: PDAC is characterized by poor survival, even after curative resection. In many studies, R0 versus R1 does not result in different prognosis and does not affect the postoperative management. METHODS: Pubmed, Embase, and Cochrane databases were screened for prognostic studies on the association between resection status and survival. Hazard ratios (HRs) were pooled in a meta-analysis. Furthermore, our prospective database was retrospectively screened for curative PDAC resections according to inclusion criteria (n = 254 patients) between July 2007 and October 2014. RESULTS: In the meta-analysis, R1 was associated with a decreased overall survival [HR 1.45 (95% confidence interval, 95% CI 1.37-1.52)] and disease-free survival [HR 1.44 (1.30-1.59)] in PDAC when compared with R0. Importantly, this effect held true only for pancreatic head resection both in the meta-analysis [R0 ≥0 mm: HR 1.21 (1.05-1.39) vs R0 ≥1 mm: HR 1.66 (1.46-1.89)] and in our cohort (R0 ≥0 mm: 31.8 vs 14.5 months, P < 0.001; R0 ≥1 mm, 41.2 vs 16.8 months; P < 0.001). Moreover, R1 resections were associated with advanced tumor disease, that is, larger tumor size, lymph node metastases, and extended resections. Multivariable Cox proportional hazard model suggested G3, pN1, tumor size, and R1 (0 mm/1 mm) as independent predictors of overall survival. CONCLUSION: Resection margin is not a valid prognostic marker in publications before 2010 due to heterogeneity of cohorts and lack of standardized histopathological examination. Within standardized pathology protocols, R-status' prognostic validity may be primarily confined to pancreatic head cancers.

Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer.

BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions. METHODS: Plasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC (n = 36) and chronic pancreatitis (CP) (n = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls (n = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters. RESULTS: TIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed. CONCLUSION: This retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice.

Subthalamic nucleus volumes are highly consistent but decrease age-dependently-a combined magnetic resonance imaging and stereology approach in humans.

The subthalamic nucleus (STN) is a main target structure of deep brain stimulation (DBS) in idiopathic Parkinson's disease. Nevertheless, there is an ongoing discussion regarding human STN volumes and neuron count, which could potentially have an impact on STN-DBS. Moreover, a suspected functional subdivision forms the basis of the tripartite hypothesis, which has not yet been morphologically substantiated. In this study, it was aimed to investigate the human STN by means of combined magnetic resonance imaging (MRI) and stereology. STN volumes were obtained from 14 individuals (ranging from 65 to 96 years, 25 hemispheres) in 3 T MRI and in luxol-stained histology slices. Neuron number and cell densities were investigated stereologically over the entire STN and in pre-defined subregions in anti-human neuronal protein HuC/D-stained slices. STN volumes measured with MRI were smaller than in stereology but appeared to be highly consistent, measuring on average 99 ± 6 mm3 (MRI) and 132 ± 20 mm3 (stereology). The neuron count was 431,088 ± 72,172. Both STN volumes and cell count decreased age-dependently. Neuron density was different for the dorsal, medial and ventral subregion with significantly higher values ventrally than dorsally. Small variations in STN volumes in both MRI and stereology contradict previous findings of large variations in STN size. Age-dependent decreases in STN volumes and neuron numbers might influence the efficacy of STN-DBS in a geriatric population. Though the study is limited in sample size, site-dependent differences for the STN subregions form a morphological basis for the tripartite theory. Hum Brain Mapp 38:909-922, 2017. © 2016 Wiley Periodicals, Inc.