Pilot study to define criteria for Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of leading international centers.

PURPOSE: The Pituitary Society established the concept and mostly qualitative parameters for defining uniform criteria for Pituitary Tumor Centers of Excellence (PTCOEs) based on expert consensus. Aim of the study was to validate those previously proposed criteria through collection and evaluation of self-reported activity of several internationally-recognized tertiary pituitary centers, thereby transforming the qualitative 2017 definition into a validated quantitative one, which could serve as the basis for future objective PTCOE accreditation. METHODS: An ad hoc prepared database was distributed to nine Pituitary Centers chosen by the Project Scientific Committee and comprising Centers of worldwide repute, which agreed to provide activity information derived from registries related to the years 2018-2020 and completing the database within 60 days. The database, provided by each center and composed of Excel® spreadsheets with requested specific information on leading and supporting teams, was reviewed by two blinded referees and all 9 candidate centers satisfied the overall PTCOE definition, according to referees' evaluations. To obtain objective numerical criteria, median values for each activity/parameter were considered as the preferred PTCOE definition target, whereas the low limit of the range was selected as the acceptable target for each respective parameter. RESULTS: Three dedicated pituitary neurosurgeons are preferred, whereas one dedicated surgeon is acceptable. Moreover, 100 surgical procedures per center per year are preferred, while the results indicated that 50 surgeries per year are acceptable. Acute post-surgery complications, including mortality and readmission rates, should preferably be negligible or nonexistent, but acceptable criterion is a rate lower than 10% of patients with complications requiring readmission within 30 days after surgery. Four endocrinologists devoted to pituitary diseases are requested in a PTCOE and the total population of patients followed in a PTCOE should not be less than 850. It appears acceptable that at least one dedicated/expert in pituitary diseases is present in neuroradiology, pathology, and ophthalmology groups, whereas at least two expert radiation oncologists are needed. CONCLUSION: This is, to our knowledge, the first study to survey and evaluate the activity of a relevant number of high-volume centers in the pituitary field. This effort, internally validated by ad hoc reviewers, allowed for transformation of previously formulated theoretical criteria for the definition of a PTCOE to precise numerical definitions based on real-life evidence. The application of a derived synopsis of criteria could be used by independent bodies for accreditation of pituitary centers as PTCOEs.

The efficacy and safety of dupilumab in Chinese patients with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Dupilumab is an antibody against interleukin-4 receptor α, used in the treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of dupilumab in adult Chinese patients with moderate-to-severe AD. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, phase III study, conducted between December 2018 and February 2020, patients with AD received dupilumab (300 mg) or placebo once every 2 weeks for 16 weeks, and were followed up for 12 weeks. The primary efficacy endpoint was the proportion of patients with both an Investigator's Global Assessment score of 0-1 and a reduction from baseline of ≥ 2 points at week 16. RESULTS: Overall, 165 patients (mean age 30·6 years; 71·5% male patients) were randomized; 82 patients were randomized to dupilumab and 83 patients were randomized to placebo. At week 16, 26·8% of patients in the dupilumab group and 4·8% of patients in the placebo group achieved the primary endpoint [difference 22·0%, 95% confidence interval (CI) 11·37-32·65; P < 0·001]. Compared with placebo, higher proportions of patients in the dupilumab group achieved ≥ 75% reduction in the Eczema Area and Severity Index score (57·3% vs. 14·5%; difference 42·9%, 95% CI 29·75-55·97; P < 0·001) and had ≥ 3-point (52·4% vs. 9·6%; difference 42·8%, 95% CI 30·26-55·34; P < 0·001) and ≥ 4-point (39·0% vs. 4·8%; difference 34·2%, 95% CI 22·69-45·72; P < 0·001) reductions in weekly average daily peak daily pruritus numerical rating scale scores. The incidence of treatment-emergent adverse events during the treatment period was similar in the two groups. The incidence of conjunctivitis, allergic conjunctivitis and injection site reaction was higher in the dupilumab group than in the placebo group. CONCLUSIONS: In adult Chinese patients, dupilumab was effective in improving the signs and symptoms of AD and demonstrated a favourable safety profile.

Advances and controversies in the classification and grading of pituitary tumors.

BACKGROUND: Pituitary tumors are common lesions, and they represent the second most frequent primary brain tumor. Their classification has undergone several changes over time. The World Health Organization conducts periodic expert review/consensus meetings and publishes the results as recommendations for changes in classification, based on advances in molecular and genetic advances. This paper summarizes the results of the 2017 WHO Classification, which recommends several important changes. PURPOSE: This paper provides a review of the major changes and issues leading to an understanding of the basis for a new pituitary tumor classification. They include the rejection and modification of prior conceptual and pathological characteristics of these neoplasms. There is also considerable concern related to invasive and recurrent pituitary tumors which follow a less benign course than the typical pituitary adenoma. METHODS: A review of the outcome data for the previously designated "atypical" pituitary tumor category revealed that the former criteria were not adequate to support their ability to predict with accuracy the clinical course of a given tumor. A similar review was accomplished regarding the role of the p53 tumor suppressor mutation. Again, there was no reliable contribution of p53 status to tumor aggressiveness. Other changes have occurred regarding the cytogenetic lineage of the various subtypes of pituitary adenoma. The transcription factors Pit-1, SF-1, and TPit play a major role in determining tumor subtypes and have become part of the classification criteria. RESULTS: These advances now help provide the background for more reliable and consistent classification of pituitary adenomas. Further definition of aggressive characteristics such as cavernous sinus and dural invasion remain to be considered in the quest to make more accurate prognostic projections based on histopathological analysis. CONCLUSIONS: The 2017 WHO Classification of Pituitary Tumors provides a more solid basis for accurate and reliable prognostic assessment of these lesions. Further progress undoubtedly will be made as the recommendations of this update are incorporated in to routine use.

Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.

Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. Objective To analyze the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. Methods We interbred PAR-1-deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APCMin/+ ) mice, which spontaneously develop intestinal adenomas. Results Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR-1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR-1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP-derived cells revealed that activated protein C-mediated PAR-1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell-intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APCMin/+ mice developed three-fold more adenomas than PAR-1-expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR-1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions Together, these results demonstrate a previously unrecognized role for PAR-1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long-term PAR-1 inhibition could increase malignancy risk in some contexts.

25-Hydroxy vitamin D3 serum concentration in dogs with acute polyradiculoneuritis compared to matched controls.

OBJECTIVES: To determine if dogs with acute polyradiculoneuritis have lower serum 25-hydroxy vitamin D3 concentration compared to a control group of dogs with idiopathic epilepsy. MATERIALS AND METHODS: Retrospective case-control study of 21 dogs with acute canine polyradiculoneuritis and 21 control dogs with idiopathic epilepsy matched for year and season of presentation from a referral hospital population in the UK. Serum concentration of 25-hydroxy vitamin D3 was compared between groups using Student's t-test. RESULTS: Dogs with acute canine polyradiculoneuritis had significantly lower (P=0·033) serum 25-hydroxy vitamin D3 concentration (87·1 nmol/L ±55·4 nmol/L) compared to a control group with idiopathic epilepsy (113 nmol/L ±66·3 nmol/L). CLINICAL SIGNIFICANCE: The cause and clinical significance of the altered vitamin D status in dogs with acute polyradiculoneuritis are not clear and require further investigation. Our findings pave the way for improved understanding of acute canine polyradiculoneuritis and, potentially, improved clinical management, if a causal role for 25-hydroxy vitamin D3 is defined.

A nano particle vector comprised of poly lactic-co-glycolic acid and monophosphoryl lipid A and recombinant Mycobacterium avium subsp paratuberculosis peptides stimulate a pro-immune profile in bovine macrophages.

AIMS: We evaluated the potential of a nanoparticle (NP) delivery system to improve methods of delivery of candidate peptide-based vaccines for Paratuberculosis in cattle. METHODS AND RESULTS: Peptides derived from Mycobacterium avium subsp. paratuberculosis (Map), and the pro-inflammatory monophosphoryl lipid A (MPLA) were incorporated in polymeric NPs based on poly (d,l-lactide-co-glycolide) (PLGA). The PLGA/MPLA NPs carriers were incubated with macrophages to examine their effects on survival and function. PLGA/MPLA NPs, with and without Map antigens, are efficiently phagocytized by macrophages with no evidence of toxicity. PLGA/MPLA NP formulations did not alter the level of expression of MHC I or II molecules. Expression of TNFα and IL12p40 was increased in Map-loaded NPs. T-cell proliferation studies using a model peptide from Anaplasma marginale demonstrated that a CD4 T-cell recall response could be elicited with macrophages pulsed with the peptide encapsulated in the PLGA/MPLA NP. CONCLUSIONS: These findings indicate PLGA/MPLA NPs can be used as a vehicle for delivery and testing of candidate peptide-based vaccines. SIGNIFICANCE AND IMPACT OF THE STUDY: These results will assist on more in depth studies on PLGA NP delivery systems that may lead to the development of a peptide-based vaccine for cattle.

An exploratory study into factors influencing development of acute canine polyradiculoneuritis in the UK.

OBJECTIVES: To investigate whether the development of acute canine polyradiculoneuritis is associated with various putative risk factors. MATERIALS AND METHODS: Retrospective case-control study with conditional logistic regression analysis from a referral hospital population in the UK where controls were matched for year of presentation. RESULTS: Forty-three cases were identified with acute canine polyradiculoneuritis and 86 controls were selected. Jack Russell terriers and West Highland white terriers were found to have a significantly greater odds of developing acute canine polyradiculoneuritis compared to a mixed baseline group of dogs. The odds of developing acute canine polyradiculoneuritis were greater in the autumn and winter compared to spring. Vaccination, rural/urban habitation, sex, neuter status and age were not associated with development of acute canine polyradiculoneuritis in our population of dogs. CLINICAL SIGNIFICANCE: Breed and season were associated with development of acute canine polyradiculoneuritis. However, this is a small sample and so this observation needs confirmation in further studies and other factors may also be involved. Nevertheless, these findings may be important in further understanding the aetiopathogenesis of this condition.

Prognostic Factors Associated with Recovery of Ambulation and Urinary Continence in Dogs with Acute Lumbosacral Spinal Cord Injury.

BACKGROUND: Limited information is available about prognostic factors for recovery after spinal cord injury (SCI) to the L4-S3 segments. Previous research suggests that L4-S3 SCI does not have a worse prognosis than T3-L3 SCI. HYPOTHESIS/OBJECTIVES: To elucidate prognostic factors for regaining urinary continence and ambulation in dogs with L4-S3 SCI and compare prognosis to T3-L3 SCI. ANIMALS/METHODS: A retrospective study on 61 nonambulatory dogs with L4-S3 SCI, matched to dogs with T3-L3 SCI, compared 3 weeks after onset. Prognostic factors explored using logistic regression and used for matching: nonchondrodystrophic dogs >15 kg versus dogs that were chondrodystrophic or <15 kg; compressive versus noncompressive lesions; presence versus absence of conscious pain perception (CPP); and lower vs upper motor neuron (LMN/UMN) incontinence. RESULTS: Fewer L4-S3 dogs regained continence compared to T3-L3 dogs (64 vs 85%, P = .0033), but no difference existed for regaining ambulation (66 vs 75%, P = .1306). In L4-S3 SCI dogs, fewer dogs regained continence with loss of CPP (P < .001), LMN incontinence (P = .004), and noncompressive lesions (P = .006). Negative prognostic factors for regaining ambulation included absent CPP (P < .001) and large nonchondrodystrophic breed (P = .022). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with L4-S3 SCI have a poorer short-term prognosis than do dogs with T3-L3 SCI. Dogs with L4-S3 SCI had a poor prognosis with loss of CPP, or noncompressive lesions combined with LMN incontinence. Small-breed or chondrodystrophic dogs with retained CPP, compressive lesions, and UMN incontinence had an excellent prognosis. These findings may help guide decision-making in L4-S3 SCI.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

Rapid Mass Spectrometry Imaging to Assess the Biochemical Profile of Pituitary Tissue for Potential Intraoperative Usage.

Pituitary adenomas are relatively common intracranial neoplasms that are frequently treated with surgical resection. Rapid visualization of pituitary tissue remains a challenge as current techniques either produce little to no information on hormone-secreting function or are too slow to practically aid in intraoperative or even perioperative decision-making. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) represents a powerful method by which molecular maps of tissue samples can be created, yielding a two-dimensional representation of the expression patterns of small molecules and proteins from biologic samples. In this chapter, we review the use of MALDI MSI, its application to the characterization of the pituitary gland, and its potential applications for guiding the management of pituitary adenomas.

Enigmatic relationship between chlorophyll a concentrations and photosynthetic rates at Station ALOHA.

An ordinary least squares (OLS) analysis of the relationship between chlorophyll a (chl a) concentrations and photosynthetic rates at depths of 5 and 25 m at Station ALOHA produced a slope that was only 28% of the mean productivity index at those depths and an intercept at zero chl a that equaled 70% of the mean photosynthetic rate. OLS regression lines are known to produce a slope and intercept that are biased estimates of the true slope and intercept when the explanatory variable, X, is uncontrolled, but in this case the measurement errors and natural variability of the chl a concentrations were much too small to explain the apparent bias. The bias was traceable to the fact that the photosynthetic rates were determined by more than one explanatory variable, a source of variability that is typically overlooked in discussions of OLS bias. Modeling the photosynthetic rates as a function of the product of chl a and surface irradiance produced a much more accurate and realistic description of the data, but the OLS continued to be biased, presumably because the photosynthetic rates were functions of factors in addition to chl a and surface irradiance (e.g., temperature, macronutrients, trace metals, and vitamins). The results underscore the need to recognize that the absence of bias in an OLS when X is not controlled implies that all scatter in the data about the OLS is due to errors in the dependent variable, an unlikely scenario. In most cases, resolution of the bias problem will require identification of the explanatory variables in addition to X that determine the dependent variable.

Acromegaly: an endocrine society clinical practice guideline

OBJECTIVE: The aim was to formulate clinical practice guidelines for acromegaly. PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. CONCLUSIONS: Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.(AU)

Prominent human health impacts from several marine microbes: history, ecology, and public health implications.

This paper overviews several examples of important public health impacts by marine microbes and directs readers to the extensive literature germane to these maladies. These examples include three types of dinoflagellates (Gambierdiscus spp., Karenia brevis, and Alexandrium fundyense), BMAA-producing cyanobacteria, and infectious microbes. The dinoflagellates are responsible for ciguatera fish poisoning, neurotoxic shellfish poisoning, and paralytic shellfish poisoning, respectively, that have plagued coastal populations over time. Research interest on the potential for marine cyanobacteria to contribute BMAA into human food supplies has been derived by BMAA's discovery in cycad seeds and subsequent implication as the putative cause of amyotrophic lateral sclerosis/parkinsonism dementia complex among the Chamorro people of Guam. Recent UPLC/MS analyses indicate that recent reports that BMAA is prolifically distributed among marine cyanobacteria at high concentrations may be due to analyte misidentification in the analytical protocols being applied for BMAA. Common infectious microbes (including enterovirus, norovirus, Salmonella, Campylobacter, Shigella, Staphylococcus aureus, Cryptosporidium, and Giardia) cause gastrointestinal and skin-related illness. These microbes can be introduced from external human and animal sources, or they can be indigenous to the marine environment.

Guidelines for acromegaly management: an update.

OBJECTIVE: The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. PARTICIPANTS: The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. CONCLUSIONS: The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

Impacts of Hurricanes Katrina and Rita on the microbial landscape of the New Orleans area.

Floodwaters in New Orleans from Hurricanes Katrina and Rita were observed to contain high levels of fecal indicator bacteria and microbial pathogens, generating concern about long-term impacts of these floodwaters on the sediment and water quality of the New Orleans area and Lake Pontchartrain. We show here that fecal indicator microbe concentrations in offshore waters from Lake Pontchartrain returned to prehurricane concentrations within 2 months of the flooding induced by these hurricanes. Vibrio and Legionella species within the lake were more abundant in samples collected shortly after the floodwaters had receded compared with samples taken within the subsequent 3 months; no evidence of a long-term hurricane-induced algal bloom was observed. Giardia and Cryptosporidium were detected in canal waters. Elevated levels of fecal indicator bacteria observed in sediment could not be solely attributed to impacts from floodwaters, as both flooded and nonflooded areas exhibited elevated levels of fecal indicator bacteria. Evidence from measurements of Bifidobacterium and bacterial diversity analysis suggest that the fecal indicator bacteria observed in the sediment were from human fecal sources. Epidemiologic studies are highly recommended to evaluate the human health effects of the sediments deposited by the floodwaters.

Consensus statement: medical management of acromegaly.

In November 2003, the Pituitary Society and the European Neuroendocrine Association sponsored a consensus workshop in Seville to address challenging issues in the medical management of acromegaly. Participants comprised 70 endocrinologists and neurosurgeons with international expertise in managing patients with acromegaly. All participants participated in the workshop proceedings, and the final document written by the scientific committee reflects the consensus opinion of the interactive deliberations. The meeting was supported by an unrestricted educational grant from Ipsen. No pharmaceutical representatives participated in the program planning or in the scientific deliberations.

Pituitary adenoma: a DNA flow cytometric study of 192 clinicopathologically characterized tumors.

A clinically, immunohistochemically and ultrastructurally characterized series of 192 pituitary adenomas was analyzed for DNA content by flow cytometry. Results were assessed not only relative to tumor immunotype, size, and invasiveness, but also with frequency of recurrence. Case selection was non-random; males predominated (1.8:1) and the ratio of macro-to-microadenomas was 4.2:1. Female patients were slightly younger and, in all adenoma categories, less often had invasive tumors: PRL (15%/30%), ACTH (17%/44%), LH/FSH (8%/27%) and null cell adenomas (0%/27%). With the exception of prolactin cell adenomas, similar proportions of macroadenomas and invasive tumors in all tumor subtypes were diploid and non-diploid. Prolactin adenomas differed in that tumors of males showed a high rate of non-diploidy (65%); such tumors were predominantly macroadenomas, but only 28% were invasive. Among GH-containing tumors 78% were macroadenomas, 40% were nondiploid, and the frequency of invasive macroadenomas was higher (49%) than in PRL tumors (21%). ACTH adenomas were mainly microadenomas (81%), their rate invasion (29%) and of non-diploidy being low (14%). Among "non-functioning" (LH/FSH, null cell adenomas), LH/FSH-producing tumors were all macroadenomas, but with low rates of invasion (23%) and non-diploidy (9%). Null cell adenomas, nearly all macroadenomas, had similar low invasion rate (21%), but were more often non-diploid (39%). In all adenoma subgroups S-phase fractions were higher in non-diploid adenomas by an overall ratio of 2.1:1. Prolactin adenomas showed the highest (15.2%) and LH/FSH adenomas the lowest (5.6%) mean S-phase fraction. When compared to long-term follow-up, neither this parameter nor ploidy correlated with tumor size or invasiveness. Lastly, long-term follow-up showed ploidy to be an unreliable predictor of tumor persistence or recurrence.

Surgical management of intracranial gliomas--does radical resection improve outcome?

UNLABELLED: This paper discusses the arguments for and against radical tumor resection as a strategy for treatment of cerebral gliomas. METHOD: Data from the Glioma Outcome Project were analyzed to determine whether survival could be related to extent of resection in 666 patients treated by biopsy or resection for malignant cerebral gliomas. FINDINGS: Consistent survival advantages were noted for those patients treated with resection. INTERPRETATION: This observational study, although undoubtedly reflecting selection bias, provides data that support resection as a major factor in survival after surgery for malignant gliomas.