Modulation of peripheral immune responses by paclitaxel–ifosfamide–cisplatin chemotherapy in advanced non-small-cell lung cancer

Purpose

The aim of this study was to assess systemic immunological responses in non-small-cell lung cancer (NSCLC) patients with stage III/IV disease during treatment with paclitaxel–ifosfamide–cisplatin (TIP) chemotherapy.

Methods

Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (HD) (n = 20) and chemotherapy-naive NSCLC patients treated with TIP (n = 32) were tested for production of IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10, IL-12 and IL-2 upon polyclonal stimulation with anti-CD3 mAb. They were further assessed over a treatment period of twelve weeks (i.e., four treatment cycles).

Results

PBMCs from NSCLC patients produced higher IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10 and IL-12 levels, whereas IL-2 exhibited lower values compared to HD (p < 0.001 for all parameters). Of interest, patients who responded to treatment had significantly higher increases in IL-2 (p < 0.001) and significantly higher decreases in IL-1 (p < 0.001), TNF-α (p < 0.001), TNF-β (p < 0.001), IL-6 (p = 0.02), IL-8 (p < 0.001), IL-10 (p < 0.001) and IL-12 (p < 0.001) levels. Non-responders revealed post-therapeutically a significantly higher increase in IL-1, TNF-α, TNF-β, IL-6, IL-8, IL-10 and IL-12 secretion and a significantly higher decrease in IL-2 levels (p < 0.001 for all parameters). Patients who responded to treatment and had a significantly higher increase in IL-2 showed a significantly longer median survival (p value < 0.001, 26 vs. 7.5 months).

Conclusion

Our study indicates that monitoring cytokine dynamics in patients with advanced NSCLC and especially those of IL-2 in peripheral blood components in vitro could be used as a predictor of treatment-related outcome and overall survival in NSCLC.     

Fecal Calprotectin in Pediatric Inflammatory Bowel Disease: A Systematic Review

Background

Inflammatory bowel disease frequently begins during childhood or adolescence. Current tests and procedures for diagnosing and monitoring inflammatory bowel disease are invasive, uncomfortable and costly. Fecal calprotectin is an inflammatory marker tested in several studies including pediatric patients with inflammatory bowel disease.

Methods

A search for articles published up to October 2011 was conducted using MEDLINE and EMBASE databases. We included original English-written articles referred to pediatric patients with inflammatory bowel disease and measured fecal calprotectin levels. We extracted data concerning fecal calprotectin levels in patients with inflammatory bowel disease and in the controls groups, sensitivity, specificity, positive and negative likelihood ratio.

Results

Thirty-four studies were included. Fecal calprotectin levels of patients with inflammatory bowel disease are much higher than those of healthy controls or patients with functional disorders or other gastrointestinal diseases. The results vary greatly when taking all studies into consideration. Nevertheless, in cases of newly diagnosed and/or active inflammatory bowel disease, the results are more homogeneous, with high sensitivity and positive likelihood ratio, low negative likelihood ratio, but moderate specificity. Moreover, 50 μg/g seems to be the most proper cut-off point for the fecal calprotectin test.

Conclusions

The fecal calprotectin test could be used for supporting diagnosis or confirming relapse of inflammatory bowel disease in pediatric patients. A positive result could confirm the suspicion of either inflammatory bowel disease diagnosis or inflammatory bowel disease relapse, due to the high sensitivity of the test, but a negative result should not exclude these conditions, due to its moderate specificity.     

Sychronous anorectal malignant melanoma and rectal adenocarcinoma

BACKGROUND: Synchronous neoplasms of the rectum are an uncommon condition. The situation becomes more rare when tumors are of different origin. To the authors' knowledge, synchronous anorectal melanoma and adenocarcinoma of the rectum have not been reported in the literature before. METHODS AND RESULTS: A 67-year-old female patient with synchronous anorectal malignant melanoma and adenocarcinoma of the rectum is described. She had preoperative colonoscopic diagnosis. The different neoplasms' origin was histologically proven. Surgical management consisted of abdominoperineal resection of the rectum. Postoperatively, the patient received adjuvant chemotherapy of six cycles duration. At present, the patient has completed 32 months of follow-up. There is no evidence of recurrent disease or distant metastases. CONCLUSION: Review of the literature confirms the rarity of anorectal malignant melanoma. On the other hand, the rectum represents the most common site for development of colonic adenocarcinoma. We were unable to trace synchronous presentation of these two tumors. Prognosis should be defined by the most malignant neoplasm; therefore, management should be focused on treating the melanoma.     

CD28-mediated regulation of multiple myeloma cell proliferation and survival

Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFkappaB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)-induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM.     

Adenocarcinomas of the prostatic duct in necropsy material

The general consensus about prostatic duct adenocarcinomas is that they have a rather aggressive biological behavior. In addition, studies or reports of latent adenocarcinoma of the prostatic duct in necropsy material are scarce in the literature. We report here three cases of adenocarcinoma of the prostatic duct that were found incidentally among 39 cases of latent acinar prostate adenocarcinomas in necropsy material. We examined the morphologic and histological features of these prostatic duct adenocarcinomas, in order to better understand their biological behavior. We identified two cases of mixed ductal-acinar adenocarcinoma and one case of pure ductal adenocarcinoma. The pure form had a favorable histological differentiation, while the mixed forms had intermediate histological differentiation patterns. Invasiveness was related to both volume and histological differentiation. The finding of prostatic ductal adenocarcinomas among autopsy material, as well as some of their histological features, suggest that these tumors might have a similar biological potential as prostatic acinar cancer.     

Zebrafish models of cardiovascular disease

Cardiovascular disease (CVD) is one of the leading causes of death worldwide. The most significant risk factors associated with the development of heart diseases include genetic and environmental factors such as hypertension, high blood cholesterol levels, diabetes, smoking, and obesity. Coronary artery disease accounts for the highest percentage of CVD deaths and stroke, cardiomyopathies, congenital heart diseases, heart valve defects and arrhythmias follow. The causes, prevention, and treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies published on a weekly basis. Generating animal models of cardiovascular diseases is the main approach used to understand the mechanism of pathogenesis and also design and test novel therapies. Here, we will focus on recent advances to finding the genetic cause and the molecular mechanisms of CVDs as well as novel drugs to treat them, using a small tropical freshwater fish native to Southeast Asia: the zebrafish (Danio rerio). Zebrafish emerged as a high-throughput but low-cost model organism that combines the advantages of forward and reverse genetics with phenotype-driven drug screenings. Noninvasive imaging allows in vivo analyses of cardiovascular phenotypes. Functional verification of candidate genes from genome-wide association studies has verified the role of several genes in the pathophysiology of CVDs. Also, zebrafish hearts maintain their ability to regenerate throughout their lifetime, providing novel insights to understand human cardiac regeneration.     

Multiple Nevoid Hypertrichosis as An Isolated Developmental Defect

Abstract:   A 3-year-old girl presented with longer hair on the left side of her scalp, coarse hair of abnormal length on her extremities, and a tuft of hair in the lumbosacral region, with all hair distributed on normally pigmented skin. Neither similar or relevant family history nor associated extracutaneous abnormalities was detected after a thorough examination. Clinical diagnosis of patchy nevoid hypetrichosis was confirmed by histology. Nevoid hypertrichosis is a rare hair growth disorder that usually presents at or soon after birth. It is characterized by patches of hypertrichosis distributed in a segmental pattern. It may be accompanied by mental, ocular, or myoskeletal abnormalities. Cases of nevoid hypertrichosis with multiple patches presenting as a solitary developmental defect have been rarely described in the literature.     

Influence of 5-Fluorouracil on Serum Lipids

The effect of the cytotoxic drug 5-fluorouracil (5-FU) on plasma lipid levels was studied in patients and animals. Seven patients with metastatic carcinoma of the colon and three with advanced breast cancer were treated with 5-FU monotherapy by i.v. push at a dose of 500 mg/m²/d for 3-5 consecutive days. The animal group comprised 9 rabbits treated with 5-FU by i.v. push at 12-18 mg/kg/d for 2 consecutive days. Measurements of serum lipid levels were performed before and 2 and 4 weeks after 5-FU administration. No obvious change of diet, body weight and bowel habits occurred during the study period. A significant reduction of total plasma cholesterol was observed in both patients and animals. The triglyceride levels were also reduced in the rabbits. Maximal cholesterol-lowering effect was observed in patients and rabbits with higher baseline cholesterol levels. The results suggest that 5-FU might interfere with lipid metabolism.