Dysglycemia in non-functioning pancreatic neuroendocrine tumors (NF-PNET): Further insights into an under recognized entity.

Objective: Pancreatic neuroendocrine tumors (PNETs) are rare, but their incidence has risen significantly in recent years. Whereas diabetes mellitus (DM) is recognized in association with chronic pancreatitis and pancreatic cancer, it has not been well-characterized concerning non-functioning (NF)-PNETs.Study aim: to determine whether NF-PNETs are associated with DM/ Pre-DM and characterize the features of this putative association. Methods: Retrospective study to evaluate rate of Pre-DM /DM in subjects with NF-PNETs. Results: Study cohort of 129 patients with histologically confirmed NF-PNETs, ∼60% were men (M/F: 77/52). Abnormal glucose metabolism that preceded any treatment was seen in 70% of this cohort: overt DM in 34% and Pre-DM in 36% of the subjects. However, during follow-up, the overall prevalence rose to 80.6%, owing exclusively to newly diagnosed DM in subjects who received treatment.Patients with DM/Pre-DM were older (65 ± 11; 54 ± 14; p < 0.0001), the tumor was more commonly localized in the pancreatic body and tail (76.5% vs. 23.5% p = 0.03), while BMI (27 ± 6 vs. 28 ± 5 kg/m2), and tumor size (2.4 ± 2 vs. 2.9 ± 3.2 cm) were similar. The relative prevalence of DM in our cohort of NF-PNETs was 1.6 higher than that in the age and gender-adjusted general Israeli population (95 %CI: 1.197-2.212p = 0.03). Conclusions: We found a high rate of impaired glucose metabolism, either DM or Pre-DM, in a large cohort of NF-PNETs. The high prevalence of diabetes/pre-diabetes was unrelated to obesity or tumor size. This observation should increase awareness of the presence of DM on presentation or during treatment of "NF"-PNETs.

Esophagogastroduodenal Findings in Patients with Intraductal Papillary Mucinous Neoplasms.

The association between intraductal papillary mucinous neoplasms (IPMNs) and extra-pancreatic malignancies is controversial. This cross-sectional study compared esophagogastroduodenal findings in 340 IPMN patients to those of age- and gender-matched controls without known IPMNs who underwent esophagogastroduodenoscopies (EGDs) for similar clinical reasons. The presence of gastric and esophageal cancer, Barrett's esophagus, neuroendocrine tumors (NETs), gastrointestinal stromal tumors (GISTs), gastric adenomas, and ampullary tumors was assessed. The results showed that 4/340 (1.2%) of the IPMN patients had gastric cancer and 1/340 (0.3%) had esophageal cancer. The matched control group had a similar incidence of gastric cancer (5/340) (1.5%), with no esophageal cancer cases (p > 0.999). The overall incidence of other esophagogastroduodenal conditions did not significantly differ between the IPMN patients and the controls. However, the incidence of gastric cancer in the IPMN patients was higher than expected based on national cancer registry data (standardized incidence ratio of 31.39; p < 0.001; CI 8.38-78.76). In conclusion, IPMN patients have a significantly higher incidence of gastric cancer compared to the general population. However, the incidence of esophagogastroduodenal findings, including gastric and esophageal cancer, is similar between IPMN patients and those who undergo an EGD for similar clinical indications. Further research is needed to determine optimal surveillance strategies for IPMN patients regarding their risk of developing gastric cancer.

A Lymph Node Ratio Model for Prognosis of Patients with Pancreatic Neuroendocrine Tumors.

The objective of this study was to determine the prognostic value of lymph node (LN) involvement and the LN ratio (LNR) and their effect on recurrence rates and survival in patients with pancreatic neuroendocrine tumors (PNETs) undergoing surgery. This single-center retrospective study reviewed the medical records of 95 consecutive patients diagnosed with PNETs who underwent surgery at our medical center between 1997 and 2017. The retrieved information included patient demographics, pathology reports, treatments, and oncological outcomes. Results: 95 consecutive potentially suitable patients were identified. The 78 patients with PNETs who underwent surgery and for whom there was adequate data were included in the analysis. Their mean ± standard deviation age at diagnosis was 57.4 ± 13.4 years (range 20-82), and there were 50 males (64%) and 28 females (36%). 23 patients (30%) had LN metastases (N1). The 2.5- and 5-year disease-free survival (DFS) rates for the entire cohort were 79.5% and 71.8%, respectively, and their 2- and 5-year overall survival (OS) rates were 85.9% and 82.1%, respectively. The optimal value of the LNR was 0.1603, which correlated with the outcome (2-year OS p = 0.002 HR = 13.4 and 5-year DFS p = 0.016 HR = 7.2, respectively, and 5-year OS and 5-year DFS p = 0.004 HR = 9 and p = 0.001 HR = 10.6, respectively). However, the multivariate analysis failed to show that the LNR was an independent prognostic factor in PNETs. Patients with PNETs grade and stage are known key prognostic factors influencing OS and DFS. According to our results, LNR failed to be an independent prognostic factor.

PD-1 Blockade Combined with Heated Intraperitoneal Chemotherapy Improves Outcome in Experimental Peritoneal Metastases from Colonic Origin in a Murine Model.

BACKGROUND: Heated intraperitoneal chemotherapy (HIPEC) was shown to induce immunogenicity of peritoneal metastases from colorectal cancer (PM-CRC) by induction of immunogenic cell death. We aimed to explore whether the addition of a checkpoint inhibitor would augment the effect of HIPEC in an experimental murine model of PM-CRC. METHODS: PM-CRC was established in C57BL mice by intraperitoneal inoculation of MC38 colon cancer cells. HIPEC was administered using the closed technique with mitomycin C (MMC). Clinical and immunological parameters were compared between animals treated with HIPEC alone and those treated with HIPEC + anti-programmed death receptor-1 (aPD-1). RESULTS: MMC-based HIPEC increased the overall survival of animals compared with sham-treated animals (22.8; 95% confidence interval [CI] 21.14-24.53 vs. 18.9 days; 95% CI 17.6-20.3, p < 0.001). The extent of peritoneal disease as measured by the modified peritoneal carcinomatosis index was also reduced by HIPEC. This clinical benefit was accompanied by increased infiltration of CD8+, CD68+, and CD20+ cells into tumor metastases in HIPEC-treated animals compared with sham-treated animals. We identified heat shock protein (HSP) 90 as a potential immunogenic cell death protein whose expression is increased under HIPEC conditions (fold change: 2.37 ± 1.5 vs. 1 without HIPEC, p < 0.05). Combined HIPEC + PD-1 treatment ameliorated survival compared with HIPEC alone and sham treatment (24.66; 95% CI 20.13-29.2 vs. 19; 95% CI 15.85-22.14 and 14.33 days; 95% CI 9.6-19.04, respectively; p = 0.008). This clinical effect was accompanied by increased CD8+ tumor infiltration. CONCLUSIONS: HIPEC induced the expression of immunogenic cell death signals that can support an anti-tumor immune response. This response can be further exploited by a checkpoint inhibitor.

The risk of PD-L1 expression misclassification in triple-negative breast cancer.

PURPOSE: Stratification of patients with triple-negative breast cancer (TNBC) for anti-PD-L1 therapy is based on PD-L1 expression in tumor biopsies. This study sought to evaluate the risk of PD-L1 misclassification. METHODS: We conducted a high-resolution analysis on ten surgical specimens of TNBC. First, we determined PD-L1 expression pattern distribution via manual segmentation and measurement of 6666 microscopic clusters of positive PD-L1 immunohistochemical staining. Then, based on these results, we generated a computer model to calculate the effect of the positive PD-L1 fraction, aggregate size, and distribution of PD-L1 positive cells on the diagnostic accuracy. RESULTS: Our computer-based model showed that larger aggregates of PD-L1 positive cells and smaller biopsy size were associated with higher fraction of false results (P < 0.001, P < 0.001, respectively). Additionally, our model showed a significant increase in error rate when the fraction of PD-L1 expression was close to the cut-off (error rate of 12.1%, 0.84%, and 0.65% for PD-L1 positivity of 0.5-1.5%, ≤ 0.5% ,and ≥ 1.5%, respectively, P < 0.0001). Interestingly, false positive results were significantly higher than false negative results (0.51-22.62%, with an average of 6.31% versus 0.11-11.36% with an average of 1.58% for false positive and false negative results, respectively, P < 0.05). Furthermore, heterogeneous tumors with different aggregate sizes in the same tumor, were associated with increased rate of false results in comparison to homogenous tumors (P < 0.001). CONCLUSION: Our model can be used to estimate the risk of PD-L1 misclassification in biopsies, with potential implications for treatment decisions.

ROS1-positive Inflammatory Myofibroblastic Tumor of the Small Bowel Causing Obstruction: A Case Report.

Inflammatory Myofibroblastic Tumors (IMTs) are rare fibroblastic/myofibroblastic neoplasms that affect predominately pediatric patients and young adults. Almost half of the patients with IMTs have a chromosomal abnormality in the Anaplastic Lymphoma Kinase 1 gene on chromosome 2p23. Although these tumors occur primarily in the lung, lesions have been reported in a variety of intra-abdominal organs like the liver, spleen, and mesentery. Small bowel IMTs are particularly rare. IMTs generally pursue a benign clinical course, however intra-abdominal and retroperitoneal tumors have typically shown higher local recurrence and even distant metastases. The most common presenting symptoms of an intra-abdominal IMT are abdominal pain and change in bowel habits. Laboratory results are nonspecific and can include anemia and minor elevation of inflammatory markers like C-reactive protein. We report an unusual case of IMT in the small bowel causing the obstruction.

Lymph Node Metastases from Visceral Peritoneal Colorectal Metastases are Associated with Systemic Recurrence.

BACKGROUND: Visceral peritoneal colorectal metastases (VPCMs) may further metastasize to lymph nodes that drain those organs. The rate of lymph node metastases (LNMs) from VPCMs and their clinical and prognostic significance are unknown. METHODS: This study retrospectively analyzed the authors' institutional databases of 160 patients with peritoneal colorectal metastases who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Patients with LNM-VPCM (n = 12) were identified by pathologic reports, and both their short- and long-term outcomes were compared with those of patients without LNM-VPCM. RESULTS: The clinical presentation and primary tumor pathologic characteristics did not differ between the two groups. The patients with LNM-VPCM had a higher tumor burden (measured by the peritoneal carcinomatosis index [PCI]) and visible remnant disease compared with those who had no LNM-VPI (10 vs 5.5 [p = 0.03] vs 33.3% vs 6.8% [p = 0.007], respectively). The postoperative outcomes also were comparable. The patients with LNM-VPCM had a shorter overall survival (OS) than those without LNM-VPCM (median OS, 22.5 months; 95% confidence interval [CI], 15.1-29.9 months vs 40.1 months; 95% CI, 38.1-42 months; p = 0.02). However, only tumor grade and PCI were predictors of OS in the multivariate analysis (hazard ratio [HR], 2.33 [p = 0.001]; 1.77 [p = 0.03], respectively). The study showed that LNM-VPCM was associated with systemic but not peritoneal recurrence compared with non-LNM-VPCM (81.8% vs 51.6% for systemic recurrence, respectively; p = 0.05). CONCLUSION: The small distinct group of patients defined by LNM-VPCM were prone to systemic recurrence. Given its correlation with systemic recurrence, LNM-VPCM may indicate the need for adjuvant treatment.

Automatic ganglion cell detection for improving the efficiency and accuracy of hirschprung disease diagnosis.

Histopathologic diagnosis of Hirschsprung's disease (HSCR) is time consuming and requires expertise. The use of artificial intelligence (AI) in digital pathology is actively researched and may improve the diagnosis of HSCR. The purpose of this research was to develop an algorithm capable of identifying ganglion cells in digital pathology slides and implement it as an assisting tool for the pathologist in the diagnosis of HSCR. Ninety five digital pathology slides were used for the construction and training of the algorithm. Fifty cases suspected for HSCR (727 slides) were used as a validation cohort. Image sets suspected to contain ganglion cells were chosen by the algorithm and then reviewed and scored by five pathologists, one HSCR expert and 4 non-experts. The algorithm was able to identify ganglion cells with 96% sensitivity and 99% specificity (in normal colon) as well as to correctly identify a case previously misdiagnosed as non-HSCR. The expert was able to achieve perfectly accurate diagnoses based solely on the images suggested by the algorithm, with over 95% time saved. Non-experts would require expert consultation in 20-58% of the cases to achieve similar results. The use of AI in the diagnosis of HSCR can greatly reduce the time and effort required for diagnosis and improve accuracy.

Laparoscopic sentinel lymph node dissection followed by open radical hysterectomy for early stage cervical cancer: A pilot study.

OBJECTIVE: To propose a treatment algorithm, after the LACC trial, of laparoscopic sentinel lymph node biopsy with frozen section, followed by immediate open radical hysterectomy in node-negative cases, for early stage cervical cancer. METHODS: We retrospectively collected all cases of cervical cancer that were surgically treated between 2019-2020. In all cases, surgery began with laparoscopic sentinel lymph node biopsy ± ovarian transposition. Node-negative cases continued with open radical hysterectomy. In node-positive cases, surgery was discontinued, sparing the patient a laparotomy incision. RESULTS: Nine patients with cervical cancer were referred for surgery. Laparoscopic bilateral lymph node identification was achieved in all. In two cases, sentinel lymph nodes were positive for metastatic cancer and surgery was discontinued. For the other seven, node-negative patients, open radical hysterectomy was completed. Four patients had laparoscopic ovarian transposition. There were no cases where nodes were negative on frozen section but positive on final pathology. CONCLUSION: Laparoscopic sentinel lymph node biopsy before open radical hysterectomy may spare a considerable number of laparotomies on the one hand and bi-modal treatment with surgery and radiation on the other, for node-positive patients. The oncological safety of this approach is yet to be determined.

Protective Desmoplasia in Pancreatic Adenocarcinoma: High Vitamin D Receptor Expression and Collagen Content.

BACKGROUND/AIM: Vitamin D receptor (VDR) has been shown to suppress desmoplasia in pancreatic ductal adenocarcinoma (PDAC). Our aim was to assess the clinical effects of VDR expression and its correlation with collagen content in the desmoplasia of PDAC patients. PATIENTS AND METHODS: This is a retrospective analysis of 127 patients with peritumoral desmoplasia resected for PDAC. VDR expression and collagen content were assessed by immunohistochemistry and correlated with clinical outcome. RESULTS: Patients were classified into those with high and those with low VDR expression. High VDR expression was associated with improved overall survival (OS) in localized disease (N0) (median= 33; 95%CI=26.4-39.6 vs. 18; 15.5-20.5 months, p=0.01). Patients with high vs. low collagen content had improved OS [34, (range=22.3-45.6 months) vs. 17, (range=14.4-19.6 months), p<0.001]. The number of VDR+ cells was the same for patients with either high or low collagen content. CONCLUSION: Protective desmoplasia is associated with increased VDR expression and collagen content.

Spatial heterogeneity of PD-L1 expression and the risk for misclassification of PD-L1 immunohistochemistry in non-small cell lung cancer.

BACKGROUND: Intra-tumor heterogeneity for PD-L1 expression in non-small cell lung cancer (NSCLC) might lead to inaccurate stratification of patients to immunotherapy. The purpose of this research was to quantitate the effect of different factors on the risk of inaccurate diagnosis of PD-L1 expression. METHODS: MATLAB software was used to model tumor with a different fraction, distribution and clustering of PD-L1 protein expression and their effect on false positive and negative diagnosis in subsets of the modeled tumor (representing biopsies). Additionally, we evaluated the agreement between PD-L1 status in random segments and whole slides of PD-L1 stained clinical NSCLC cases. RESULTS: Our computer-based model showed a significant increase in error rate when the fraction of PD-L1 positive cells was closer to the cut-off value (error rate of 33.33 %, 0.45 % and 0.74 % for PD-L1 positivity in 40-60%, ≤20 % and ≥80 % of tumor cells, respectively, P < 0.0001). In addition, biopsy size showed negative correlation with error rate (P < 0.0001) and larger clusters of PD-L1 positive cells were associated with higher error rate (P < 0.0001). Analysis of the clinical samples supported those of the computer-based model with higher error rate in cases with positive PD-L1 expression closer to the cutoff value. Based on our computerized model and clinical analysis, we developed a model to predict error rate based on biopsy size and the fraction of PD-L1 positive cells in the biopsy. CONCLUSION: Analysis of small biopsies for PD-L1 expression might be associated with significant error rate. The model presented can be used to identify cases with increased risk for error in whom interpretation of the test results should be made with caution.

The accuracy of ascites cytology in diagnosis of advanced ovarian cancer in postmenopausal women prior to neoadjuvant chemotherapy.

OBJECTIVE: To evaluate the accuracy of ascites cytology in the diagnosis of epithelial ovarian cancer among postmenopausal women. METHODS: Ascites samples of women older than 51 years sent for cytology evaluation at our institution between 2010 and 2015 were retrospectively compared to final histology. The sensitivity, specificity, negative, and positive predictive values were calculated. Immunohistochemistry stain results were collected to determine diagnostic profiles. RESULTS: A total of 551 patients, 51 years and over had both cytology and diagnostic histology samples. Of those, 161 patients had pathology confirmed ovarian tumors, 155 of which were malignant. Of the 155 cases of ovarian cancer, 125 patients had malignant cells on cytology examination (true positive); in 30 cases, ascites was negative for malignancy (false negative). In six cases both ascites and final pathology were negative for malignancy (true negative). There were no cases of positive cytology and negative final pathology (ie, no false-positive cases). The sensitivity, specificity, positive, and negative predictive value for cytology diagnosis of ovarian cancer were 80.6%, 100%, 100%, and 16.7%, respectively. Immunohistochemistry was done on cell blocks in 79 cases of ovarian cancer, 75 (94.9%) had profiles diagnostic for ovarian origin. CONCLUSIONS: Ascites cytology for postmenopausal women older than 51 years with immunohistochemistry is highly accurate in diagnosis of ovarian cancer. Neoadjuvant chemotherapy can be safely prescribed based on paracentesis evaluations. : Video Summary:http://links.lww.com/MENO/A570.

Video Summary:http://links.lww.com/MENO/A570.

Tumor-to-Tumor Metastasis of Colorectal Adenocarcinoma to Ovarian Cystadenofibroma: A Case Report and Review of the Literature.

Tumor-to-tumor metastasis is being described in different types of tumors and in increasing amount of cases. Being aware of this phenomenon is important, as it affects disease stage and treatment approach. In this report, we descried an incidental histopathologic finding of metastatic adenocarcinoma to an ovarian cystadenofibroma and review cases published previously in the literature.

Size and lipid modification determine liposomal Indocyanine green performance for tumor imaging in a model of rectal cancer.

Localization of rectal tumors is a challenge in minimally invasive surgery due to the lack of tactile sensation. We had developed liposomal indocyanine green (Lip-ICG) for localization of rectal tumor. In this study we evaluated the effects of liposome size and lipid PEGylation on imaging. We used an endoscopically-guided orthotopic experimental rectal cancer model in which tumor fluorescence was determined at different time points after intravenous (i.v.) administration of Lip-ICG and PEGylated liposomes (PEG-Lip-ICG). Signal intensity was measured by tumor-to-background ratio (TBR), or normalized TBR (compared to TBR of free ICG). Fluorescence microscopy of tumor tissue was performed to determine fluorescence localization within the tissue and blood vessels. Liposomes of 60 nm showed an increased TBR compared with free ICG at 12 hours after i.v. injection: normalized TBR (nTBR) = 3.11 vs. 1, respectively (p = 0.006). Larger liposomes (100 nm and 140 nm) had comparable signal to free ICG (nTBR = 0.98 ± 0.02 and 0.78 ± 0.08, respectively), even when additional time points were examined (0.5, 3 and 24 hours). PEG-Lip- ICG were more efficient than Lip-ICG (TBR = 4.2 ± 0.18 vs. 2.5 ± 0.12, p < 0.01) presumably because of reduced uptake by the reticulo-endothelial system. ICG was found outside the capillaries in tumor margins. We conclude that size and lipid modification impact imaging intensity.

Desmoplasia in Lymph Node Metastasis of Pancreatic Adenocarcinoma Reveals Activation of Cancer-Associated Fibroblasts Pattern and T-helper 2 Immune Cell Infiltration.

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a peritumoral proliferation of fibroblasts and extracellular matrix production known as desmoplasia. We aimed to study desmoplasia in PDAC lymph node (LN) metastases. METHODS: We evaluated LNs from 66 patients with PDAC and LN metastases. We used immunohistochemistry and real-time polymerase chain reaction to phenotype the desmoplastic response. RESULTS: Desmoplasia was identified in 57% of patients with LN metastases (Des+). Cancer-associated fibroblasts (CAFs) in Des+ expressed α-smooth muscle actin and collagen 11A1. The latter expression was present only in CAFs but not in LN stroma or in LN metastases without desmoplasia (Des-). Desmoplasia was associated with upregulation of transforming growth factor ß messenger RNA. Whereas numbers of CD8+ in tumor vicinity were not different between Des+ and Des- patients (78 [standard deviation {SD}, 57] vs 92 [SD, 52], P = 0.48, respectively), the numbers of GATA-3+ cells, a marker of T-helper 2 immune response was significantly increased (3.7 [SD, 6.3] for Des+ vs 1.3 [SD, 2.7] for Des-, P < 0.05). CONCLUSIONS: Lymph node desmoplasia is associated with CAF pattern activation and Th2 infiltration. Therapeutic modulation of desmoplasia may be relevant in the metastatic phase and influence antitumor immune response.

A sorafenib-sparing effect in the treatment of thyroid carcinoma cells attained by co-treatment with a novel isoflavone derivative and 1,25 dihydroxyvitamin D3.

BACKGROUND: Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that isoflavone derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). METHODS: In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERß, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. RESULTS: 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 µg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 µg/ml) alone. CONCLUSIONS: The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.

Aging leads to impaired epicutaneous sensitization that causes attenuated allergy and pulmonary inflammation in mice.

Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)-mediated sensitization to environmental allergens. Yet, allergen-specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6-week-, 6-month-, and 18-month-old female BALB/c mice, underwent epicutaneous sensitization with ovalbumin (OVA) or phosphate buffered saline (PBS), followed by an inhaled OVA challenge. Blood OVA-specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids (BALF) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6-week-old (young) and 6-month-old (adult) groups. However, significantly decreased levels of systemic OVA IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18-month-old) mice compared to the other groups of mice. In addition, interleukin-10 (IL-10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA, possibly regulated by increased IL-10 levels.

Vitamin D receptor expression is linked to potential markers of human thyroid papillary carcinoma.

Genes regulated cell-cell and cell-matrix adhesion and degradation of the extracellular matrix (ECM) have been screened as potential markers of malignant thyroid nodules. The mRNA expression levels of two of them, the ECM protein-1 (ECM1) and the type II transmembrane serine protease-4 (TMPRSS4), were shown to be an independent predictor of an existing thyroid carcinoma. The vitamin D receptor (VDR) is expressed in epithelial cells of the normal thyroid gland, as well as in malignant dividing cells, which respond to the active metabolite of vitamin D by decreased proliferative activity in vitro. We evaluated the relationship between mRNA gene expressions of TMPRSS4, ECM1 and VDR in 21 papillary thyroid carcinoma samples and compared it to 21 normal thyroid tissues from the same patients. Gene expression was considered as up- or down-regulated if it varied by more or less than 2-fold in the cancer tissue relative to the normal thyroid tissue (Ca/N) from the same patient. We found an overall significant adjusted correlation between the mRNA expression ratio (ExR) of VDR and that of ECM1 in Ca/N thyroid tissue (R=0.648, P<0.001). There was a high ExR of VDR between Ca/N thyroid tissue from the same patient (3.06±2.9), which also exhibited a high Ca/N ExR of ECM1 and/or of TMPRSS4 (>2, P=0.05).The finding that increased VDR expression in human thyroid cancer cells is often linked to increased ECM1 and/or TPMRSS4 expression warrants further investigation into the potential role of vitamin D analogs in thyroid carcinoma.

Efficacy of dalbavancin in the treatment of MRSA rat sternal osteomyelitis with mediastinitis.

OBJECTIVES: Dalbavancin, a semi-synthetic lipoglycopeptide, is characterized by a long plasma half-life, which allows weekly dosing. Dalbavancin may be a good treatment option for patients with deep sternal wound infections owing to its improved pharmacokinetic profile and antibacterial activity compared with currently used antibiotics. Here we evaluated the efficacy of 7 or 14 days of treatment with dalbavancin, compared with vancomycin and with saline, in reducing sternal bone MRSA counts in a rat Staphylococcus aureus deep sternal wound infection model. METHODS: A mid-sternal wound was surgically induced in anaesthetized rats. A clinical strain of MRSA was injected into the sternum to establish infection. Rats were treated intraperitoneally for 7 or 14 days with dalbavancin, vancomycin or saline. The number of cfu per gram of sternum or spleen tissue was determined using viable counts. The antibacterial efficacy was determined by the reduction in bacterial counts per gram of sternum or spleen tissue in each treatment group. RESULTS: Treatment with dalbavancin was superior to treatment with saline for 7 days (0.75 log reduction in bone cfu) or 14 days (>3 log reduction in bone cfu) and similar to treatment with vancomycin. Additionally, dalbavancin was also effective in reducing systemic dissemination of MRSA. CONCLUSIONS: Dalbavancin is effective in the treatment of MRSA rat sternal osteomyelitis.