The association of Greig syndrome and mastocytosis reveals the involvement of the hedgehog pathway in advanced mastocytosis.

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KIT D816V mutation is detected in ∼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3 and KIT mutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neoplastic MC proliferation in vitro and extend the survival time of mice with aggressive systemic mastocytosis (ASM). This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in mice with ASM, leading to the identification of new promising therapeutic targets.

Higher prevalence of vertebral fractures in systemic mastocytosis, but not in cutaneous mastocytosis and idiopathic mast cell activation syndrome.

Little is known about osteoporosis in mast cell disorders (MCDs) not related to systemic mastocytosis. We described osteoporosis and fractures in MCDs and showed that systemic mastocytosis was the only studied MCDs associated with osteoporotic vertebral fractures. INTRODUCTION: To describe osteoporosis (OP) and fragility fractures in mast cell disorders (MCDs). METHODS: We retrospectively analyzed data concerning all successive patients with systemic mastocytosis (SM), cutaneous mastocytosis (CM), and mast cell activation syndromes (MCAS) diagnosed in our mastocytosis expert center between 2004 and 2015. We collected data concerning demographic profiles, clinical signs of MCD, osteoporosis, fractures, densitometry, and biological assessment of MCD. We compared CM and MCAS patients with SM patients with regard to the characteristics of OP and fragility fractures. RESULTS: We assessed 89 SM patients, 20 CM patients, and 20 MCAS patients. Osteoporosis was less frequent in CM (15.0%) and MCAS (10.0%) than in SM (44.9%). Similarly, fractures were less frequent in non-SM MCDs, respectively 5.0%, 5.0%, and 28.1%. SM patients displayed high prevalence of vertebral fractures (22.5%), mostly multiple. Conversely, in non-SM patients, vertebral fractures appeared to be uncommon (5%) and more frequently associated with risk factors for osteoporosis. CONCLUSIONS: SM is associated with multiple vertebral osteoporotic fractures, whereas CM and MCAS do not appear to be associated with this phenotype.

Frequency of isolated cutaneous involvement in adult mastocytosis: a cohort study.

BACKGROUND: Mastocytosis is characterized by the accumulation/proliferation of abnormal mast cells. The frequency of isolated cutaneous involvement in adults with mastocytosis has not been fully determined. The main objective of our study was to assess the frequency of isolated cutaneous mastocytosis (CM) in adults with mastocytosis skin lesions. The second objective was to compare the clinical, histological, biological and imaging features in patients with isolated CM and patients with systemic mastocytosis (SM). METHODS: We included all patients with histology-proven mastocytosis skin lesions between January 2009 and December 2017. The mastocytosis diagnosis was made according to the international diagnostic criteria. All data were collected from a dedicated specific case report. RESULTS: Among 160 patients with mastocytosis skin lesions, 25 patients had isolated CM (15.6%), 105 had SM and 30 (18.7%) patients had undetermined mastocytosis. Skin KIT mutation (OR: 51.9, 95% CI: 3.9-678, P = 0.001) and high bone marrow tryptase (OR: 97.4, 95% CI: 10.3-915, P = 0.001) were strong predictors of SM. The prevalence of osteoporosis was higher in the SM population than in the isolated CM population. Moreover, a decrease in bone mineral density over a short period of follow-up (1-2 years) was associated with SM. There were no differences between the two groups regarding the frequency of mast cell activation symptoms, the presentation of skin lesions, the number of mast cells in the dermis and the level of serum tryptase. We propose considering the KIT mutation status and bone marrow tryptase levels to aid the diagnosis of isolated CM in adult mastocytosis patients. CONCLUSION: Only a small minority of adults with mastocytosis skin lesions has isolated cutaneous involvement. In 18.7% of mastocytosis cases, even complete workup does not allow for a precise classification of patients.

Paediatric mastocytosis: long-term follow-up of 53 patients with whole sequencing of KIT. A prospective study.

BACKGROUND: Mastocytosis is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells. The adult and paediatric forms differ in their clinical and genetic features and outcomes. OBJECTIVES: To describe the clinical evolution of a well-characterized cohort of paediatric mastocytosis (PM), and to analyse the relationship between KIT mutation and the clinical course. METHODS: This was a prospective cohort study performed at the National Clinical Reference Center for Mastocytosis. Diagnosis was confirmed by identification of KIT mutation on lesional skin biopsy. Mastocytosis subtype, mast cell mediator-related symptoms (MC MRS) and clinical course were recorded. Fifty-three patients with PM and > 4 years of disease course were enrolled. The mean ± SD age at the final evaluation was 13·2 ± 4·8 years. The main outcome was the type of KIT mutation as a predictor of evolution and clinical characteristics. RESULTS: Patients presented with maculopapular cutaneous mastocytosis (n = 44), diffuse cutaneous mastocytosis (n = 6) or mastocytoma (n = 3). The mean duration of disease was 12·1 years. Substantial or partial cutaneous regression (18 of 53 and 16 of 53), stabilization or aggravation (16 of 53) and complete cutaneous regression (three of 53) were noted. MC MRS mainly regressed (21 of 53). For 22 patients, evolution of MC MRS and evolution of cutaneous lesions were different. No significant association between evolution and KIT mutation or between evolution and type of cutaneous mastocytosis was found. A late onset of the disease (after 2 years) is associated with worse evolution. CONCLUSIONS: PM is not systematically self-regressive. MC MRS manifestations and cutaneous lesions can persist or increase overtime. KIT mutation is not a predictor of evolution.

General and specific combining abilities in a maize (Zea mays L.) test-cross hybrid panel: relative importance of population structure and genetic divergence between parents.

KEY MESSAGE: General and specific combining abilities of maize hybrids between 288 inbred lines and three tester lines were highly related to population structure and genetic distance inferred from SNP data. Many studies have attempted to provide reliable and quick methods to identify promising parental lines and combinations in hybrid breeding programs. Since the 1950s, maize germplasm has been organized into heterotic groups to facilitate the exploitation of heterosis. Molecular markers have proven efficient tools to address the organization of genetic diversity and the relationship between lines or populations. The aim of the present work was to investigate to what extent marker-based evaluations of population structure and genetic distance may account for general (GCA) and specific (SCA) combining ability components in a population composed of 800 inter and intra-heterotic group hybrids obtained by crossing 288 inbred lines and three testers. Our results illustrate a strong effect of groups identified by population structure analysis on both GCA and SCA components. Including genetic distance between parental lines of hybrids in the model leads to a significant decrease of SCA variance component and an increase in GCA variance component for all the traits. The latter suggests that this approach can be efficient to better estimate the potential combining ability of inbred lines when crossed with unrelated lines, and limits the consequences of tester choice. Significant residual GCA and SCA variance components of models taking into account structure and/or genetic distance highlight the variation available for breeding programs within structure groups.

Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis.

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

Bone marrow tryptase as a possible diagnostic criterion for adult systemic mastocytosis.

BACKGROUND: Mastocytosis is difficult to diagnose, especially when systemic mast cell activation symptoms are not present or involve only one extracutaneous organ. OBJECTIVE: The main objective was to evaluate the accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis in patients with a clinical suspicion of mastocytosis. METHODS: We included all adult patients evaluated in our centre between December 2009 and 2013 for suspected mastocytosis as part of a standardized procedure and who had a bone marrow and serum tryptase assay on the same day. The diagnosis of systemic mastocytosis was established on the basis of the World Health Organization criteria as the gold standard. The accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis was assessed by a receiver operating characteristics curve analysis. The different sensitivity and specificity values, corresponding to the set of possible bone marrow tryptase level cut-off values, were estimated with 95% confidence intervals. RESULTS: Seventy-three patients were included. The diagnosis of systemic mastocytosis was established in 43 patients (58.9%). The median bone marrow tryptase level was 423 µg/L [95% CI: 217-868] in the systemic mastocytosis group and 7.5 µg/L [95% CI: 4.6-17.1] in the non-systemic mastocytosis group (P < 0.001). A cut-off value of 50 µg/L for bone marrow tryptase identified systemic mastocytosis with a sensitivity of 93.0% [95% CI: 80.9-98.5%] and a specificity of 90.0% [95% CI: 73.5-97.9%]. CONCLUSION AND CLINICAL RELEVANCE: The bone marrow tryptase level appears to be a valuable diagnostic criterion for confirming systemic mastocytosis. If this diagnosis can reliably be excluded by evaluation of the bone marrow tryptase level, there would be no need to perform a bone marrow biopsy.

Decreased tryptophan and increased kynurenine levels in mastocytosis associated with digestive symptoms.

The main metabolism pathway of tryptophan is protein formation, but it can also be metabolized into serotonin and kynurenine. Indoleamine 2,3-dioxygenase (IDO) is the enzyme that catalyzes the degradation of tryptophan into kynurenine. Mastocytosis is a heterogeneous disease characterized by mast cell accumulation in various tissues with 57% of patients having gastrointestinal involvement. We studied tryptophan metabolism in mastocytosis patients displaying or not gastrointestinal features and healthy subjects (n = 26 in each group). Mastocytosis patients with digestive symptoms displayed significantly increased kynurenine level and IDO activity as compared to healthy controls and mastocytosis patients without digestive symptoms. This could be linked to mast cell-mediated digestive inflammation among patients with mastocytosis. This work is the first focusing on kynurenine pathway in a mast cell disease and could help to understand the pathogenesis of digestive features in mastocytosis as well as in other mast cell-mediated diseases.

A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.

BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

Activation of KIT modulates the function of tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) in mast cells.

BACKGROUND: Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation. MATERIAL AND METHODS: We sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis. RESULTS: MC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1. CONCLUSIONS: Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.

Paediatric mastocytosis: a systematic review of 1747 cases.

Paediatric mastocytosis was previously considered to be a benign and spontaneously regressing disease. However, this evolution is impossible to predict. To clarify the characteristics and course of paediatric mastocytosis, we performed a literature review of 1747 cases published between 1950 and April 2014. Lesions occurred before the age of 2 years in 90% of cases, and presented as urticaria pigmentosa (75% of cases), mastocytoma (20%) or diffuse cutaneous mastocytosis (5%). The male-to-female ratio was 1·4. KIT D816V mutation was detected in 34% of 215 tested patients. Clinical regression (complete or partial) occurred in 67% of cases and stabilization in 27%. However, the outcome was fatal in 2·9% of patients.

Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial.

BACKGROUND: Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance. PATIENTS AND METHODS: Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI. RESULTS: Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09-0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16-0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6-2.2, P = 0.833). CONCLUSIONS: Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit-risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.

Dent and Flint maize diversity panels reveal important genetic potential for increasing biomass production.

KEY MESSAGE: Genetic and phenotypic analysis of two complementary maize panels revealed an important variation for biomass yield. Flowering and biomass QTL were discovered by association mapping in both panels. The high whole plant biomass productivity of maize makes it a potential source of energy in animal feeding and biofuel production. The variability and the genetic determinism of traits related to biomass are poorly known. We analyzed two highly diverse panels of Dent and Flint lines representing complementary heterotic groups for Northern Europe. They were genotyped with the 50 k SNP-array and phenotyped as hybrids (crossed to a tester of the complementary pool) in a western European field trial network for traits related to flowering time, plant height, and biomass. The molecular information revealed to be a powerful tool for discovering different levels of structure and relatedness in both panels. This study revealed important variation and potential genetic progress for biomass production, even at constant precocity. Association mapping was run by combining genotypes and phenotypes in a mixed model with a random polygenic effect. This permitted the detection of significant associations, confirming height and flowering time quantitative trait loci (QTL) found in literature. Biomass yield QTL were detected in both panels but were unstable across the environments. Alternative kinship estimator only based on markers unlinked to the tested SNP increased the number of significant associations by around 40% with a satisfying control of the false positive rate. This study gave insights into the variability and the genetic architectures of biomass-related traits in Flint and Dent lines and suggests important potential of these two pools for breeding high biomass yielding hybrid varieties.

Absence of circulating mast cell precursors in paediatric mastocytosis: could it reflect a different pathophysiology between adults and children with mastocytosis?

BACKGROUND: Mastocytosis is a heterogeneous disease whose different subtypes also vary in aggressivity. Children typically present with cutaneous mastocytosis. We identified, in our previous work, a peripheral CD34-c-Kit+mast cell precursor by flow cytometry in systemic forms but not in cutaneous forms of adult mastocytosis. OBJECTIVES: We wanted to know if such a mast cell precursor exists among children with mastocytosis. METHODS: We analysed 10 children with mastocytosis for c-Kit+CD34- mast cell precursors by flow cytometry. RESULTS: In contrast to adults with mastocytosis, we did not detect any circulating mast cell precursors by flow cytometry in the peripheral blood of children with mastocytosis. CONCLUSION: The clinical symptoms observed among children with cutaneous mastocytosis could be induced by cutaneous mast cell mediators and not by circulating mast cells. These results may help to better understand the differences between adult and childhood mastocytosis.

Metabolism of 2-hydroxy-4-(methylthio)butanoate (HMTBA) in lactating dairy cows.

The objectives of the current study were to determine the fate and contribution to Met kinetics of 2-hydroxy-4-(methylthio)butanoate (HMTBA) at the whole-body, splanchnic, and mammary levels. Four multicatheterized cows (31.3 kg of milk/d; 17.7 kg of DMI/d) were used in a crossover design, with two 1-wk periods, to determine the metabolic fate of HMTBA and its effect on Met metabolism. Over the last 2 d of each period, cows were infused, via a jugular vein, with saline or HMTBA (Alimet, Novus International Inc., St. Louis, Mo) at the rate of 36 g/d. During the last 8h, the HMTBA infusion was substituted by equimolar [1-(13)C]HMTBA (8.79 mmol/h) and l[methyl-(2)H(3)]Met (1.31 mmol/h) was infused in all cows. During the last 5h, hourly samples (n=6) were collected to determine plasma flows plus the isotopic enrichments (IE) and concentrations of HMTBA ((13)C) and Met (both (13)C and (2)H(3)) in plasma from an artery plus portal, hepatic, and mammary veins. The IE of [(13)C] and [(2)H(3)]Met were also determined in milk protein taken over the last 1h of infusion in HMTBA-infused cows. The infused HMTBA increased whole-body plasma flux of Met by 6.5 mmol/h (from 17.9 to 24.4 mmol/h). Based on enrichments of (13)C-labeled Met, 3.8 mmol/h of Met flow through plasma was derived directly from HMTBA. These 2 estimates accounted for between 43 to 74% of the HMTBA dose infused, contributing to increased whole-body Met availability. Although the portal-drained viscera, liver, and mammary gland (MG) extracted 11, 37, and 3.4%, respectively, of the infused HMTBA, tissue net Met fluxes were either unchanged (portal-drained viscera, MG) or even reduced (liver: -7.9 vs. -2.4±0.6 mmol/h). Therefore, net postsplanchnic supply of Met decreased from 7.0 to 2.9 mmol/h between control and HMTBA-infused cows, compared with needs for milk protein secretion of 7.6 and 8.1 mmol/h, respectively. The HMTBA provided directly 15% of the Met required for milk protein secretion, with 0.2 mmol/h synthesized within the MG, whereas 1.1 mmol/h originated from Met produced in other tissues and transported to the MG through blood circulation. Most of the remainder needed by the MG arose from unlabeled Met released from protein breakdown in extra-splanchnic tissues and that was not reused to support intracellular protein synthesis, as this function was performed by Met synthesized from HMTBA in situ. Absorbed HMTBA, therefore, both produces and spares Met for use by the MG.

Systemic mastocytosis and bone involvement in a cohort of 75 patients.

OBJECTIVES: To investigate bone involvement in a large cohort of systemic mastocytosis (SM) patients, and evaluate the efficacy of bisphosphonate therapy. PATIENTS AND METHODS: From 2000 to 2004, 75 patients with SM according to WHO criteria underwent skeletal x-rays and bone mineral density (BMD) assessment. Sequential BMD assessments were performed in nine patients treated with bisphosphonate (mean follow-up 65 months). RESULTS: 37 patients (49%) had bone involvement according to both x-rays and BMD evaluations: osteoporosis (23 patients, 31%, mean lumbar spine T score: -3 SD), with vertebral fracture (13 patients, 17%), axial skeleton osteosclerosis (six patients, 8%), mixed patterns (three patients), osteopenia with pre-existing fractures (four patients) and focal osteolytic lesion (one patient). Blood count abnormalities were associated with osteosclerosis (p=0.005). In nine patients with osteoporosis and bisphosphonate therapy, mean lumbar spine BMD increased from 0.83 to 0.92 g/cm(2) (+11.1%; ie, +2.05% per year) without recurrence of vertebral fracture. CONCLUSION: Half of adult patients with SM have bone involvement. Osteoporosis is the most prevalent bone manifestation in SM (31%). Bisphosphonate therapy seems efficient to improve lumbar spine BMD during SM-related osteoporosis. Spine x-ray and BMD should be performed in all SM patients to detect those who may benefit from anti-osteoporotic therapy.

The necessity of level IIb dissection for clinically negative neck oral squamous cell carcinoma.

AIM: Selective neck dissection reduces the incidence of complications associated with radical neck dissection while achieving the same oncological results, especially in clinically node-negative (cN0) cases. The most common complications associated with selective neck dissection are spinal accessory nerve dysfunction and shoulder disability, which result from level IIb dissection. The aim of the present study was to evaluate the incidence of level IIb lymph node metastasis in cN0 oral squamous cell carcinoma (OSCC) patients to determine the necessity of selective neck surgery. METHODS: The medical records of 138 consecutive OSCC cN0 patients seen from June 2012 to June 2017 were retrospectively reviewed for age, gender, tumor localization, and TNM classification. RESULTS: The incidence of occult metastasis was 29.7%, but level IIb nodes were not involved in any case. DISCUSSION: The lack of involvement of level IIb nodes in occult metastasis, and high prevalence of shoulder dysfunction caused by injury to the spinal accessory nerve during surgery, challenge the necessity of surgical IIb node clearance in cNO OSCC; this is true for all stages and especially for early T1 stage cases, when the likelihood of occult lymph node metastasis is low (15.6%).

Differences in splanchnic metabolism between late gestation and early lactation dairy cows.

In the transition from the pre- to postcalving state, the demands on the cow increase from support of gestation to high rates of milk production. This extra demand is met partly by increased intake but may also involve altered metabolism of major nutrients. Six multiparous Holstein cows were used to monitor changes in net fluxes of nutrients across the portal-drained viscera and liver (splanchnic tissues) between late gestation and early lactation. Blood samples were obtained simultaneously from the portal, hepatic, and subcutaneous abdominal veins and the caudal aorta 18 d before expected calving and 21 or 42 d after calving. On the day of blood sampling and the 3 d preceding sampling, cows were fed every 2 h. The precalving (1.63 Mcal of net energy for lactation/kg and 1,326 g of metabolizable protein/d) and postcalving (1.72 Mcal of net energy for lactation/kg and 2,136 g of metabolizable protein/d) diets were based on corn silage, alfalfa hay, and corn grain. Dry matter intake increased postcalving. Net splanchnic release of glucose increased postpartum because of tendencies for both increased portal absorption and net liver release. Increased removal of lactate, rather than AA, contributed to the additional hepatic gluconeogenesis. Although portal absorption of AA increased with intake at the onset of lactation, hepatic removal of total AA-N tended to decline. This clearly indicates that liver removal of AA is not linked to portal absorption. Furthermore, net liver removal relative to total liver inflow even decreased for Gly, His, Met, Phe, and Tyr. Together, these data indicate that in early lactation, metabolic priority is given to direct AA toward milk protein production rather than gluconeogenesis, in cows fed a corn-based ration.