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PURPOSE: Most insulinomas are small solitary, benign neoplasms. Imaging and surgical techniques improved over the last 20 years. Thus, the aim of the present study was to analyze changes in diagnosis and surgery of insulinoma patients in a referral center over two decades. METHODS: Operated patients with a histologically proven insulinoma were retrieved from a prospective database. Clinico-pathological characteristics and outcomes were retrospectively analyzed with regard to the time periods 2000-2010 (group 1) and 2011-2020 (group 2). RESULTS: Sixty-one of 202 operated patients with pNEN had an insulinoma, 37 (61%) in group 1 and 24 (39%) in group 2. Of those 61 insulinomas, 49 (80%) were sporadic benign, 8 (13%) benign MEN1-associated insulinomas, and 4 (7%) sporadic malignant insulinomas. In 35 of 37 (95%) patients of group 1 and all patients of group 2, the insulinoma was preoperatively identified by imaging. The most sensitive imaging modality was endoscopic ultrasound (EUS) with correctly diagnosed and localized insulinomas in 89% of patients in group 1 and 100% in group 2. In group 1, significantly less patients were operated via minimally invasive approach compared to group 2 (19% (7/37) vs. 50% (12/24), p = 0.022). Enucleation was the most frequently performed operation (31 of 61, 51%), followed by distal resection (15 of 61, 25%) without significant differences between groups 1 and 2. The rate of relevant postoperative complications was not different between groups 1 and 2 (24% vs. 21%, p = 0.99). Two patients with benign insulinoma (1 out of each group) experienced disease recurrence and underwent a second resection. After a median follow-up of 134 (1-249) months, however, all 57 (100%) patients with benign insulinoma and 3 out of 4 patients with malignant insulinoma had no evidence of disease. CONCLUSION: Insulinoma can be preoperatively localized in almost all patients, allowing for a minimally invasive, parenchyma-sparing resection in selected patients. The long-term cure rate is excellent.

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BACKGROUND: For the increasingly diagnosed entity of small asymptomatic, sporadic, nonfunctional, pancreatic neuroendocrine neoplasms (pNEN), a negligible or at least unclear prognostic relevance of the disease for patient survival has often been observed. OBJECTIVE: Safety and acceptance of a watch-and-wait strategy versus surgical resection for small, asymptomatic nonfunctional (NF) pNEN. METHODS: Presentation and evaluation of the relevant literature as well as the corresponding national and European guidelines. RESULTS: Surgery of small NF-pNEN shows complication rates of 15-32% (Clavien-Dindo ≥ 3) and a mortality of 3.6%. Even for pNEN < 2 cm the presence of lymph node metastases has been observed in 11% of cases, while their prognostic relevance in G1-pNEN compared with active surveillance remains unclear. On average 14% of patients under active surveillance for small NF-pNEN, underwent a resection. Relevant tumor growth during surveillance was found in < 20% of cases. In all well-selected surveillance cohorts no metachronous lymphatic or distant metastases occurred during active surveillance and especially no cases of a metachronous no longer curable disease. CONCLUSION: Even small asymptomatic NF-pNEN have a certain metastatic potential but the clinical relevance has prospectively not yet been clearly determined. Controlled surveillance of these tumors is at least an alternative to immediate tumor resection. Especially patients above 70 years old do not seem to benefit from resection. The pros and cons of a resection should therefore be individually evaluated with the patient.

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The Gravity Recovery and Climate Experiment Follow-On (GRACE-FO), launched May 22, 2018 and collecting science data since June 2018, is extending the 15-year data record of Earth mass change established by its predecessor GRACE mission (2002-2017). The GRACE-FO satellites carry onboard a novel technology demonstration instrument for intersatellite ranging, the Laser Ranging Interferometer (LRI), in addition to the microwave interferometer (MWI) carried on GRACE. The LRI has out-performed its in-orbit performance requirements both in terms of accuracy as well as the duration of tracking. Here, we compare and validate LRI-based gravity solutions for January 2019 to September 2020 against the MWI solutions. The comparison between the two sets of gravity solutions shows great similarities in general and nearly perfect consistency at a large hydrologic basin spatial scale (100,000 km2 and above), commonly viewed as the spatial resolution established by GRACE. The comparison in the spectral domain shows differences at the higher degrees of the spectrum, with lower error in the zonal and near zonal terms for the LRI solutions. We conclude that the LRI observations can be used to recover time-varying gravity signals to at least the level of accuracy established by the MWI-based solutions. This is a promising finding, especially when considering the benefits of using the LRI over the MWI, such as the great stability of the instrument and the low occurrence of instrument reboot events.

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PURPOSE: The present study aimed to compare robotic-assisted versus laparoscopic distal pancreatic resection and enucleation for potentially benign pancreatic neoplasms. METHODS: Patients were retrieved from a prospectively maintained database. Demographic data, tumor types, and the perioperative outcomes were retrospectively analyzed. RESULTS: In a 10-year period, 75 patients (female, n = 44; male, n = 31; median age, 53 years [range, 9-84 years]) were identified. The majority of patients had pancreatic neuroendocrine neoplasms (n = 39, 52%) and cystic neoplasms (n = 23, 31%) with a median tumor size of 17 (3-60) mm. Nineteen (25.3%) patients underwent enucleation (robotic, n = 11; laparoscopic, n = 8) and 56 (74.7%) patients underwent distal pancreatic resection (robotic, n = 24; laparoscopic, n = 32), of those 48 (85%) underwent spleen-preserving procedures. Eight (10.7%) procedures had to be converted to open surgery. The rate of vessel preservation in distal pancreatectomy was significantly higher in robotic-assisted procedures (62.5% vs. 12.5%, p = 0.01). Twenty-six (34.6%) patients experienced postoperative complications (Clavien-Dindo grade > 3). Twenty (26.7%) patients developed a pancreatic fistula type B. There was no mortality. After a median follow-up period of 58 months (range 2-120 months), one patient (1.3%) developed local recurrence (glucagonoma) after enucleation, which was treated with a Whipple procedure. CONCLUSION: The robotic approach is comparably safe, but increases the rate of splenic vessel preservation and reduces the risk of conversion to open surgery.

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In Fig. 2 of this Analysis, the tick-mark labels on the colour bars in the second and third images from the top were inadvertently swapped. In addition, the citation at the end of the sentence, "On a monthly basis GRACE can resolve TWS changes with sufficient accuracy over scales that range from approximately 200,000 km2 at low latitudes to about 90,000 km2 near the poles" should be to ref. 4 not ref. 1. These errors have been corrected online.

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Freshwater availability is changing worldwide. Here we quantify 34 trends in terrestrial water storage observed by the Gravity Recovery and Climate Experiment (GRACE) satellites during 2002-2016 and categorize their drivers as natural interannual variability, unsustainable groundwater consumption, climate change or combinations thereof. Several of these trends had been lacking thorough investigation and attribution, including massive changes in northwestern China and the Okavango Delta. Others are consistent with climate model predictions. This observation-based assessment of how the world's water landscape is responding to human impacts and climate variations provides a blueprint for evaluating and predicting emerging threats to water and food security.

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Photonic crystals (PCs) are built to control the propagation of light within their structure. These can be used for an assortment of applications where custom designed devices are of interest. Among them, one-dimensional PCs can be produced to achieve the reflection of specific and broad wavelength ranges. However, their design and fabrication are challenging due to the diversity of periodic arrangement and layer configuration that each different PC needs. In this study, we present a framework to design high reflecting PCs for any desired wavelength range. Our method combines three stochastic optimization algorithms (Random Search, Particle Swarm Optimization and Simulated Annealing) along with a reduced space-search methodology to obtain a custom and optimized PC configuration. The optimization procedure is evaluated through theoretical reflectance spectra calculated by using the Equispaced Thickness Method, which improves the simulations due to the consideration of incoherent light transmission. We prove the viability of our procedure by fabricating different reflecting PCs made of porous silicon and obtain good agreement between experiment and theory using a merit function. With this methodology, diverse reflecting PCs can be designed for any applications and fabricated with different materials.

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Climate-driven changes in land water storage and their contributions to sea level rise have been absent from Intergovernmental Panel on Climate Change sea level budgets owing to observational challenges. Recent advances in satellite measurement of time-variable gravity combined with reconciled global glacier loss estimates enable a disaggregation of continental land mass changes and a quantification of this term. We found that between 2002 and 2014, climate variability resulted in an additional 3200 ± 900 gigatons of water being stored on land. This gain partially offset water losses from ice sheets, glaciers, and groundwater pumping, slowing the rate of sea level rise by 0.71 ± 0.20 millimeters per year. These findings highlight the importance of climate-driven changes in hydrology when assigning attribution to decadal changes in sea level.

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BACKGROUND: Resection with curative intention is the cornerstone of treatment in patients with neuroendocrine tumors. A proportion of patients will relapse after R0 resection, but the factors predictive of recurrence are not well understood. METHODS: A database established 1998 at the University Hospital Marburg was queried for all patients with documented R0 resection. Recurrence-free survival and overall survival were estimated using the Kaplan-Meier method. Uni- and multivariate analyses were performed. RESULTS: 180 patients with a median age of 52 years entered the analysis. We observed 77 recurrences after a median time of 2.9 years. 24% of the recurrences occurred later than 5 years after operation. Median recurrence-free survival of the whole cohort was 101 months. In univariate analysis grade by Ki-67, stage, high lymph node ratio and microangioinvasion were significant predictors of recurrence. On multivariate analysis these parameters were confirmed as independent prognostic parameters with stage and microangioinvasion being the most important predictors. CONCLUSIONS: After R0 resection of neuroendocrine tumors, postoperative surveillance should be extended to at least 10 years. Patients with distant metastases and microangioinvasion are at high risk of recurrence. Clinical trials of adjuvant treatment protocols are indicated in these patients.

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INTRODUCTION: Sentinel lymph node mapping (SLNM) with multilevel sections (MLS) and cytokeratin immunohistochemistry (CK-IHC) of sentinel lymph nodes (SLNs) upstages 15-20% of patients (pts). False-positive SLNs occur in breast cancer due to mechanical transport of cells during mapping procedures, or to pre-existing benign cellular inclusions. Our prospective study evaluated whether colorectal mapping procedures alone caused false positives. METHODS: A total of 314 pts underwent SLNM with blue dye. Ninety of the pts underwent a second mapping in normal bowel away from the primary tumor. The first 1-5 blue nodes near the primary tumor were marked as SLNs; those near the second injection site were marked as nontumor SLNs (nt-SLNs). All SLNs and nt-SLNs were evaluated by MLS and CK-IHC. RESULTS: Of 314 pts, 30 had benign tumor and 284 had invasive cancer. SLNM was successful in 274/284 (96.5%) invasive cancer pts, with 728 SLNs identified. Forty-six of the 274 pts (16.8%) had low-volume metastasis in 57 SLNs: 31 pts (11.3%) had 38 SLNs with micrometastasis (>0.2 mm,

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MR imaging is typically obtained during the work-up of patients who have undergone allogeneic hematopoietic stem-cell transplant who present with unexplained change in mental status, amnesia, or seizures. Although the differential diagnosis is broad in this setting, the presence of T2 prolongation limited to the medial aspect of one or both temporal lobes with or without associated reduced water diffusion may help limit the possible diagnoses. A frequent etiology seen in this context is human herpesvirus-6 (HHV6) infection. We report the evolution of MR imaging findings and clinical course in 4 patients with limbic encephalitis probably related to HHV6.

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Sentinel lymph node (SLN) mapping accurately diagnoses the status of nodal basin with >95% accuracy in melanoma and breast cancer. A multicenter trial for SLN mapping was performed on 203 patients with colorectal cancer to determine accuracy, upstaging, skip metastasis, and aberrant drainage. Lymphazurin 1% was injected subserosally around the tumor and 1-4 blue staining nodes were marked as SLNs for detailed histological analysis. SLN mapping was successful in 98% of patients with an average of 1.7 SLNs per patient. SLNs were negative in 63% of the patients and positive in 37% of the patients. Skip metastasis was seen in 8 of the patients. Occult micrometastasis was found in 14% of patients. In 5% of the patients, unusual lymphatic drainage lead to an alteration of the extent of lymphadenectomy. This multicenter trial proved that SLN mapping in patients with colorectal cancer is simple, cost effective, and upstages at least 14% of patients from AJCC stage I/II to stage III. These patients may then benefit from adjuvant chemotherapy.

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PURPOSE: Approximately 30% of patients with American Joint Committee on Cancer stage I or II colorectal cancer (CRC) develop systemic disease. We hypothesized that multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of sentinel lymph nodes (SNs) draining a primary CRC could detect micrometastases not detected by conventional histopathologic analysis. PATIENTS AND METHODS: In a multi-institutional study, 40 patients with primary CRC underwent dye-directed lymphatic mapping at the time of colon resection. Each dye-stained SN was tagged, and the tumor and regional nodes were resected en bloc. All lymph nodes were examined by conventional hematoxylin and eosin (HE) staining. In addition, each SN was cut into multiple sections for cytokeratin immunohistochemical (CK-IHC) staining and for RT-PCR and electrochemiluminescent detection of three markers: beta-chain human chorionic gonadotropin, hepatocyte growth factor receptor, and universal melanoma-associated antigen. Whenever possible, RT-PCR assay was also performed on primary tumor tissue. The detection sensitivity of individual markers was 10(-3) to 10(-4) microg of RNA and one to five tumor cells in 10(7) lymphocytes of healthy donors. RESULTS: One to three SNs were identified in each patient. An average of 15 nodes were removed from each CRC specimen. No nonsentinel (untagged) node contained evidence of tumor if all tagged (sentinel) nodes in the same specimen were histopathology tumor-negative. HE staining of SNs identified tumor in 10 patients (25%), and CK-IHC of SNs identified occult micrometastases in four patients (10%) whose SNs were negative by HE. Of the remaining 26 patients with no evidence of SN involvement by HE or CK-IHC, 12 (46%) had positive RT-PCR results. The number of markers expressed in each SN correlated (P <.04) with the T stage of the primary tumor. There was 79% concordance in marker expression for the respective pairs (n = 38) of primary tumor and histopathologically positive SNs, and 86% (12 of 14) concordance between RT-PCR positive and histopathologically positive SNs. CONCLUSION: Identification and focused examination of the SN is a novel method of staging CRC. CK-IHC and RT-PCR identified occult micrometastases in 53% of patients whose SNs were negative by conventional staging techniques. These ultrasensitive assays of the SN can identify patients who may be at high risk for recurrence of CRC and therefore are more likely to benefit from systemic adjuvant therapy.

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BACKGROUND: The identification of lymph node metastases in colorectal resection specimens is necessary for accurate tumor staging. However, routine lymph node dissection by the pathologist yields only a subset of nodes removed surgically and may not include those nodes most directly in the path of lymphatic drainage from the tumor. Intraoperative mapping of such sentinel lymph nodes (SLNs) has been reported in cases of melanoma and breast cancer. We applied a similar method to cases of colorectal carcinoma, with emphasis on the pathology of the SLNs. METHODS: Eighty-three consecutive patients with colorectal carcinoma were evaluated after intraoperative injection of 1 to 2 mL of 1% isosulfan blue dye (Lymphazurin) into the peritumoral subserosa. Blue-stained lymph nodes were suture-tagged by the surgeon within minutes of the injection for identification by the pathologist, and a standard resection was performed. Designated SLNs were sectioned at 10 levels through the block; a cytokeratin immunostain (AE1) was also obtained. To evaluate the possibility that increased detection of metastases in the SLN might be solely due to increased histologic sampling, all initially negative non-SLNs in the first 25 cases were sectioned also at 10 levels. RESULTS: Sentinel lymph nodes were identified intraoperatively in 82 (99%) of 83 patients and accounted for 152 (11.9%) of 1275 lymph nodes recovered, with an average of 1.9 SLNs per patient. A total of 99 positive lymph nodes (38 positive SLNs and 61 positive non-SLNs) were identified in 34 node-positive patients. The SLNs were the only site of metastasis in 17 patients (50%), while 14 patients (41%) had both positive SLNs and non-SLNs. Three patients (9%) had positive non-SLNs with negative SLNs, representing skip metastases. In patients with positive SLNs, 91 (19%) of 474 total lymph nodes and 53 (12%) of 436 non-SLNs were positive for metastasis. In patients with negative SLNs, 8 (1%) of 801 total lymph nodes and 8 (1.2%) of 687 non-SLNs were positive for metastasis. Multilevel sections of 330 initially negative non-SLNs in the first 25 patients yielded only 2 additional positive nodes (0. 6%). All patients with positive SLNs were correctly staged by a combination of 4 representative levels through the SLN(s) together with a single cytokeratin immunostain. CONCLUSIONS: Intraoperative mapping of SLNs in colorectal carcinoma identifies lymph nodes likely to contain metastases. Focused pathologic evaluation of the 1 to 4 SLNs so identified can improve the accuracy of pathologic staging.

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Self- and partner-ratings on trait affect and the Big Five were obtained from 74 married and 136 dating couples. The relationship satisfaction of each person (the "target") was correlated with four sets of ratings: (a) target's self-rated personality, (b) target's partner-rated personality, (c) partner's self-rated personality, and (d) partner's target-rated personality. Self- and partner-ratings of the target's personality yielded very similar results. Negative and positive affectivity were consistent predictors of satisfaction in both samples. Conscientiousness and agreeableness were reliably related to satisfaction in the dating couples, whereas extraversion consistently correlated with satisfaction in the married couples. These traits jointly predicted as much as 34% (self-ratings) and 26% (partner-ratings) of the variance in satisfaction. In contrast, the partner's personality played a lesser role in satisfaction.

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BACKGROUND: Sentinel lymph node (SLN) mapping for melanoma and breast cancer has greatly enhanced the identification of micrometastases in many patients, thereby upstaging a subset of these patients. The purpose of this study was to see if SLN mapping technique could be used to identify SLNs in colorectal cancer and to assess its impact on pathological staging and treatment. METHODS: At the time of surgery, 1 ml of Lymphazurin 1% was injected subserosally around the tumor without injecting into the lumen. The first to fourth blue nodes identified were considered the SLNs, which have the highest probability to contain metastases. A standard oncological resection of the bowel was then performed. Multilevel microsections of the SLNs, including a detailed pathological examination of the entire specimen, was performed. RESULTS: SLN was successfully identified in 85 (98.8%) of 86 patients. In 85 patients, there were 1,367 (16 per patient) lymph nodes examined, of which 140 (1.6 per patient) were identified as SLNs. In 53 (95%) of 56, of whom the SLNs were without metastases (negative), all other non-SLNs also were negative. In 29 (34% of 85) patients, SLNs were positive for metastases; in 14 of the 29 patients, other non-SLNs also were positive in addition to the SLNs. In the other 15 of the 29 patients (18% of 85 patients), SLNs were the only site of metastases, and all other non-SLNs were negative. In 7 patients (8.2% of 85 patients), micrometastases were identified only in 1 or 2 of the 10 sections of a single SLN. In five of seven patients, such micrometastases were detected by hematoxylin and eosin staining and immunohistochemistry; in the other two patients, it was detected only by immunohistochemistry. In patients with negative SLNs, the rate of occurrence of micrometastases in non-SLNs was 5 (0.4%) of 1,184 lymph nodes. CONCLUSIONS: SLN mapping can be performed easily in colorectal cancer patients, with an accuracy of more than 95%. The identification of submicroscopic lymph node metastases by this technique may have upstaged these patients (18%) from stage I/II to stage III disease, who may then benefit from further adjuvant chemotherapy.

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Self- and other-ratings on the Big Five and a comprehensive inventory of trait affect were obtained from 74 married couples, 136 dating couples, and 279 friendship dyads. With the exception of Surprise, all scales showed significant self-other agreement in all 3 samples, thereby establishing their convergent validity. Consistent with the trait visibility effect, however, the Big Five consistently yielded higher agreement correlations than did the affectivity scales. Conversely, the affective traits consistently showed stronger evidence of assumed similarity (i.e., the tendency for judges to rate others as similar to themselves) than did the Big Five. Cross-sample comparisons indicated that agreement was significantly higher in the married sample than in the other 2 groups; however, analyses of 3 potential moderators in the dating and friendship samples failed to identify the source of this acquaintanceship effect.

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BACKGROUND: Only a small number of case reports have described medical treatment of interstitial ectopic pregnancies. Almost all of the reported patients were treated with repeated high doses (1 mg/kg) of methotrexate. CASE: At 6 weeks of gestation, a 31-year-old woman, gravida 5, para 4, was diagnosed with a 0.96 x 1.36-cm right cornual pregnancy. As the patient desired future fertility, she received 100 mg of intramuscular methotrexate (50 mg/m2). She was then followed on an outpatient basis, with serum human chorionic gonadotropin values appropriately declining. Serial ultrasound also showed decreasing size of the gestational sac. Twenty-one days after the methotrexate dose, the patient experienced rupture of the right posterior cornu, necessitating exploratory laparotomy. CONCLUSION: Extreme caution should be used when treating interstitial gestations with single-dose methotrexate. All patients should be extensively counseled regarding the significantly increased risk of failure, possibility of rupture and need for emergency surgery.

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The global regulator Lrp (leucine-responsive regulatory protein), in some cases modulated by its co-regulator leucine, has been shown to regulate more than 40 genes and operons in Escherichia coli. Leucine modulates Lrp regulation of leucine-responsive operons. The level of sensitivity of these operons to leucine varies greatly, but the basis for this variation is only partially understood. One operon controlled by Lrp that is relatively insensitive to leucine is gltBDF, which includes genes specifying the large (GltB) and small (GltD) subunits of glutamate synthase. Earlier gel mobility shift assays have demonstrated that Lrp binds to a fragment of DNA containing the gltBDF promoter region. To further define the nature of this Lrp-gltBDF interaction, DNase I footprinting experiments were performed. The results indicate that Lrp binds cooperatively to three sites quite far upstream, spanning the region from -140 to -260 base-pairs relative to the start of transcription. Phased hypersensitivity is observed throughout the entire binding region, suggesting that Lrp bends the DNA. To determine the relative importance of these three sites for the transcriptional activation of gltBDF, a series of site-directed mutations was generated. The effects of these mutations on Lrp binding were determined both by DNase I footprinting and by quantitative mobility shift assays, while their effects on transcription in vivo were examined by measuring beta-galactosidase activity levels of chromosomal gltB::lacZ operon fusions. Our results indicate that all three sites are required for maximal gene expression, as is the proper phasing of the sites with one another and with the start of transcription. Our results suggest that Lrp binds a central palindromic site, interacting predominantly with the major groove of its DNA target, and that additional dimers bind to flanking sites to form a nucleoprotein activation complex.

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Appendiceal endometriosis is a very uncommon clinical entity. We describe a 33-yr-old white female who presented with painless profuse rectal bleeding. Emergency colonoscopy revealed bleeding from the appendiceal opening. An emergency appendectomy was performed which controlled her bleeding. The histopathological examination demonstrated appendiceal endometriosis. Painless bleeding from appendiceal endometriosis is extremely rare; however, it should be considered when evaluating young women of reproductive age who present with rectal bleeding.

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