Preliminary study on radioimmunodiagnosis of experimental tumor models using technetium-99m-labeled anti-C-erbB-2 monoclonal antibody

AIMS AND BACKGROUND: One of the great challenges of oncology is to improve methods for early tumor detection. Diagnosis of premalignant lesions and early stage primary tumors is crucial for the success of cancer therapy and increased survival rates. Growth factor receptors localized to the cell membrane play a vital role in cancer. Monoclonal antibodies labeled with radioisotopes have been used extensively for radioimmunodiagnosis and radioimmunotherapy of various malignancies. A preliminary study on immunoscintigraphy was carried out on animal tumor models using 99mTc-labeled monoclonal antibody CIBCgp185 generated against the CerbB-2 oncoprotein with a view to develop technologies for in vivo radioimmunodetection and localization of human breast cancer. METHODS: Mammary tumor xenografts induced using BT474 cells, a breast carcinoma cell line showing overexpression of C-erbB-2, were used for immunoscintigraphic studies. RESULTS: Scintigrams showed high radiolabel uptake by the tumor tissue of the mice belonging to the experimental group, whereas in control animals no radiolabel uptake was visualized. Biodistribution studies correlated well with scintiscans. CONCLUSIONS: The results indicate the potential application of this monoclonal antibody for in vivo diagnosis of occult malignancies of tumors with overexpression of C-erbB-2.     

Recommendations for surveillance of Clostridium difficile-associated disease.

BACKGROUND: The epidemiology of Clostridium difficile-associated disease (CDAD) is changing, with evidence of increased incidence and severity. However, the understanding of the magnitude of and reasons for this change is currently hampered by the lack of standardized surveillance methods. OBJECTIVE AND METHODS: An ad hoc C. difficile surveillance working group was formed to develop interim surveillance definitions and recommendations based on existing literature and expert opinion that can help to improve CDAD surveillance and prevention efforts. DEFINITIONS AND RECOMMENDATIONS: A CDAD case patient was defined as a patient with symptoms of diarrhea or toxic megacolon combined with a positive result of a laboratory assay and/or endoscopic or histopathologic evidence of pseudomembranous colitis. Recurrent CDAD was defined as repeated episodes within 8 weeks of each other. Severe CDAD was defined by CDAD-associated admission to an intensive care unit, colectomy, or death within 30 days after onset. Case patients were categorized by the setting in which C. difficile was likely acquired, to account for recent evidence that suggests that healthcare facility-associated CDAD may have its onset in the community up to 4 weeks after discharge. Tracking of healthcare facility-onset, healthcare facility-associated CDAD is the minimum surveillance required for healthcare settings; tracking of community-onset, healthcare facility-associated CDAD should be performed only in conjunction with tracking of healthcare facility-onset, healthcare facility-associated CDAD. Community-associated CDAD was defined by symptom onset more than 12 weeks after the last discharge from a healthcare facility. Rates of both healthcare facility-onset, healthcare facility-associated CDAD and community-onset, healthcare facility-associated CDAD should be expressed as case patients per 10,000 patient-days; rates of community-associated CDAD should be expressed as case patients per 100,000 person-years.     

Commentary on a phase III trial of bevacizumab plus XELOX or FOLFOX4 for first-line treatment of metastatic colorectal cancer: the NO16966 trial

Replacing infusional 5-fluorouracil (5-FU) leucovorin (LV) with oral capecitabine would be more convenient to patients, because it would lead to reduced hospital chair time and infusion-related toxicities. Previous trials with oral capecitabine-based regimens (other than XELOX [capecitabine/oxaliplatin]) have failed to demonstrate the equivalent efficacy of capecitabine based regimens to various 5-FU/oxaliplatin regimens (nonstandard FOLFOX [5-FU/LV/oxaliplatin] combinations); of note, these trials did not use the XELOX and standard FOLFOX regimens. An international phase III trial (NO16966) was initiated to demonstrate the noninferiority of XELOX to FOLFOX4 for the first-line treatment of metastatic colorectal cancer. The protocol was later amended to compare bevacizumab and chemotherapy versus placebo and chemotherapy. The efficacy data showed that XELOX was as effective as FOLFOX4 (progression-free survival [PPS; intent-to-treat population]: hazard ratio [HR], 1.04; 97.5% confidence interval, 0.93-1.16). Also, bevacizumab/chemotherapy(pooled with XELOX or FOLFOX) significantly prolonged PPS (HR 0.83; p=0.0023) compared with placebo and chemotherapy (XELOX/FOLFOX). In subgroup analysis, the addition of bevacizumab to XELOX (9.3 months vs. 7.4 months. HR.0.77; P=0.0026) and FOLFOX4(9.4 months vs. 8.6 months; HR, 0.89; P = 0.1871) prolonged PFS compared with respective placebo arms; however, it did not show statistical significance with the FOLFOX4 regimen. The adverse events were manageable and comparable between treatment arms.     

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

IntroductionA comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified.MethodsWe enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients’ outcome.ResultsThe cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule–positive (CD4⁺) programmed death 1–positive (PD-1⁺) (>5.2%) and CD8⁺PD-1⁺ (6.4%) cells, CD4⁺ lymphocyte activating 3–positive (LAG-3⁺) (>2.8% ) and CD8⁺LAG-3⁺ (>2.8%) cells, CD4⁺ T cell immunoglobulin and mucin domain 3–positive (TIM-3⁺) (>2.5%), and CD8⁺TIM-3⁺ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1⁺/LAG-3⁺/TIM-3⁺ CD4⁺ tumor-infiltrating lymphocytes correlated with overall survival.ConclusionsA clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients’ outcome.     

Developing in vitro assays to quantitatively evaluate the interactions of dressings with wounds

Evaluating interactions between dressing and wound is important for understanding wound management. This study quantitatively compared four polyurethane foam‐based wound dressings for their absorption profile, cell penetration, and adherence using two novel in vitro assays. The dressing with uniform pore sizes varying from 25~75 μm showed the highest absorption of both culture media and serum. The same dressing showed a 1.2‐ to 3.6‐fold lower cell adherence (3 hours) than the other dressings, and ~20‐fold lower cell penetration (5 days) than dressings with pore sizes varying from 55 to 343 μm. Additionally, cell and dressing interactions using a 3‐dimensional wound healing assay showed that the dressings with the smallest pore size of 25~75 μm maintained the highest cell viability (76.3%) and promoted cell migration into the wound site. This data suggest that polyurethane foam dressing with smaller and evenly distributed pores promotes wound healing with less cellular adhesion and penetration.     

Adoptive transfer of IL-4Rα+ macrophages is sufficient to enhance eosinophilic inflammation in a mouse model of allergic lung inflammation

Background

Cytokines and chemokines are key mediators of anti-malarial immunity. We evaluated whether Intermittent Preventive Treatment in infants with Sulfadoxine-Pyrimethamine (IPTi-SP) had an effect on the acquisition of these cellular immune responses in Mozambican children. Multiple cytokines and chemokines were quantified in plasma by luminex, and antigen-specific cytokine production in whole blood was determined by intracellular cytokine staining and flow cytometry, at ages 5, 9, 12 and 24 months.

Results

IPTi-SP did not significantly affect the proportion of CD3+ cells producing IFN-??, IL-4 or IL-10. Overall, plasma cytokine or chemokine concentrations did not differ between treatment groups. Th1 and pro-inflammatory responses were higher than Th2 and anti-inflammatory responses, respectively, and IFN-??:IL-4 ratios were higher for placebo than for SP recipients. Levels of cytokines and chemokines varied according to age, declining from 5 to 9 months. Plasma concentrations of IL-10, IL-12 and IL-13 were associated with current infection or prior malaria episodes. Higher frequencies of IFN-?? and IL-10 producing CD3+ cells and elevated IL-10, IFN-??, MCP-1 and IL-13 in plasma were individually associated with increased malaria incidence, at different time points. When all markers were analyzed together, only higher IL-17 at 12 months was associated with lower incidence of malaria up to 24 months.

Conclusions

Our work has confirmed that IPTi-SP does not negatively affect the development of cellular immune response during early childhood. This study has also provided new insights as to how these cytokine responses are acquired upon age and exposure to P. falciparum, as well as their associations with malaria susceptibility.

Trial Registration

ClinicalTrials.gov: NCT00209795     

Phellinus rimosus (Berk.) pilat attenuates 7,12-dimethylbenz[a] anthracene induced and croton oil promoted skin papilloma formation in mice

The roles of 7,12-dimethylbenz[a]anthracene (DMBA), a polycyclic aromatic hydrocarbon (PAH), and 12-O-tetradecanoylphorbol-13-acetate (TPA) a skin tumor promoter present in croton oil, are clearly implicated in the formation of skin papilloma. The effect of ethyl acetate extract of Phellinus rimosus, a polypore macro fungus, against croton oil-induced skin inflammation, lipid peroxidation and tumor promotion was studied. The antiinflammatory and lipid peroxidation inhibiting activities were determined by topical application of extract of P. rimosus (10 and 20 mg) prior to the application of 0.1 ml of 50% croton oil in acetone. The tumor promotion inhibiting effect of P. rimosus was evaluated against DMBA-initiated, croton oil promoted two-stage carcinogenesis model in mouse skin. The results showed that topical application of the extract (10 and 20 mg) significantly (p < 0.01) and dose dependently attenuate the inflammatory edema as well as lipid peroxidation induced by croton oil. Similarly, topical application of extract (1 and 5 mg) effectively ameliorated the croton oil promoted skin papilloma formation. The results of this study concluded that ethyl acetate extract of P. rimosus showed antitumor activity against DMBA initiated, croton oil promoted skin papilloma formation which can be partially ascribed to the antiperoxidative and anti-inflammatory effects of the extract.     

Synergy of iron,high sensitivity C-reactive protein and ceruloplasmin with oxidative stress in non-diabetic normo-tensive South Indian obese men

BackgroundOxidative stress and inflammation are implicated in the pathogenesis of obesity and its related complications. Previous studies have suggested a potential link between obesity and altered iron metabolism. The present study was designed to evaluate iron, C-reactive protein, ceruloplasmin and oxidative stress and their association, if any, in non-diabetic normo-tensive South Indian obese men.Methods30 obese men and 30 age-matched males with normal body weight were recruited in the study. Serum iron, copper, ceruloplasmin, high sensitivity C-reactive protein (hs-CRP), malondialdehyde, protein carbonyl, total oxidant status and total antioxidant status were estimated in all the subjects.ResultsSerum iron, ceruloplasmin, high sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), protein carbonyl and total oxidant status were significantly increased and total antioxidant status was significantly reduced in obese men, compared to controls. Linear regression analysis shows highly significant positive association of iron with hs-CRP.ConclusionThe data from the present study concludes that oxidative stress parameters, hs-CRP, iron and ceruloplasmin were significantly elevated in obese Indian men, suggesting they are more prone to develop cardiovascular disease, than age-matched men with normal body weight.     

A case-control study of community-associated Clostridium difficile infection: no role for proton pump inhibitors

Background

The epidemiology of community-associated Clostridium difficile infection is not well known. We performed a multicenter, case-control study to further describe community-associated C. difficile infection and assess novel risk factors.

Methods

We conducted this study at 5 sites from October 2006 through November 2007. Community-associated C. difficile infection included individuals with diarrhea, a positive C. difficile toxin, and no recent (12 weeks) discharge from a health care facility. We selected controls from the same clinics attended by cases. We collected clinical and exposure data at the time of illness and cultured residual stool samples and performed ribotyping.

Results

Of 1041 adult C. difficile infections, 162 (15.5%) met criteria for community-associated: 66 case and 114 control patients were enrolled. Case patients were relatively young (median 64 years), female (56%), and frequently required hospitalization (38%). Antimicrobials, malignancy, exposure to high-risk persons, and remote health care exposure were independently associated with community-associated C. difficile infection. In 40% of cases, we could not confirm recent antibiotic exposure. Stomach-acid suppressants were not associated with community-associated infection, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors appeared protective. Prevalence of the hypervirulent NAP-1/027 strain was infrequent (17%).

Conclusions

Community-associated C. difficile infection resulted in a substantial health care burden. Antimicrobials are a significant risk factor for community-associated infection. However, other unique factors also may contribute, including person-to-person transmission, remote health care exposures, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. A role for stomach-acid suppressants in community-associated C. difficile infection is not supported.