Barrett's esophagus: treatment or observation of a major precursor factor of esophageal cancer?

Barrett's esophagus (BE) is a major precursor factor of esophageal cancer (EC). The appropriate management of patients with BE depends on the presence or not of dysplasia and the type of dysplasia that occurs. Due to the small proportion of BE patients that progress to cancer, the value of surveillance programs are a matter of debate. On the contrary, in high risk group of patients surveillance programs have significant impact. Large prospective trials are needed to define the optimal management strategy. Elucidation of carcinogenesis' steps and signal transduction pathways could reveal potential biomarkers in the order of early prediction for a highly malignant neoplasm with dismal prognosis. An efficacious tailored-made manner focusing to the safety profile and associated costs should be practised for less severe disease. In this review a thorough investigation of all available methods dealing with the clinical management of BE is provided.     

Chemoradiotherapy or chemotherapy as adjuvant treatment for resected gastric cancer: should we use selection criteria?

BackgroundThe management of gastric adenocarcinoma is essentially based on surgery followed by adjuvant treatment. Adjuvant chemotherapy (CT) as well as chemoradiotherapy (CTRT) have proven their effectiveness in survival outcomes compared to surgery alone. However, there is little data comparing the two adjuvant approaches. This study aimed to compare the prognosis and survival outcomes of patients with gastric adenocarcinoma operated and treated by adjuvant radio-chemotherapy or chemotherapyMaterials and methodsWe retrospectively evaluated 80 patients with locally advanced gastric cancer (LGC) who received adjuvant treatment. We compared survival outcomes and patterns of recurrence of 53 patients treated by CTRT and those of 27 patients treated by CT.ResultsAfter a median follow-up of 38.48 months, CTRT resulted in a significant improvement of the 5-year PFS (60.9% vs. 36%, p = 0.03) and the 5-year OS (55.9% vs. 33%, p = 0.015) compared to adjuvant CT. The 5-year OS was significantly increased by adjuvant CTRT (p = 0.046) in patients with lymph node metastasis, and particularly those with advanced pN stage (p = 0.0078) and high lymph node ratio (LNR) exceeding 25% (p = 0.012). Also, there was a significant improvement of the PFS of patients classified pN2–N3 (p = 0.022) with a high LNR (p = 0.018). CTRT was also associated with improved OS and PFS in patients with lymphovascular and perineural invasion (LVI and PNI) compared to chemotherapy.ConclusionThere is a particular survival benefit of adding radiotherapy to chemotherapy in patients with selected criteria such as lymph node involvement, high LNR LVI, and PNI.     

Synergistic anticancer effects of combined γ-tocotrienol with statin or receptor tyrosine kinase inhibitor treatment

Systemic chemotherapy is the only current method of treatment that provides some chance for long-term survival in patients with advanced or metastatic cancer. γ-Tocotrienol is a natural form of vitamin E found in high concentrations in palm oil and displays potent anticancer effects, but limited absorption and transport of by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and are an example of a promising cancer chemotherapeutic agent whose clinical usefulness has been limited due to high-dose toxicity. Similarly, erlotinib and gefitinib are anticancer agents that inhibit the activation of individual HER/ErbB receptor subtypes, but have shown limited clinical success because of heterodimerization between different EGF receptor family members that can rescue cancer cells from agents directed against a single receptor subtype. Recent studies have investigated the anticancer effectiveness of low-dose treatment of various statins or EGF receptor inhibitors alone and in combination with γ-tocotrienol on highly malignant +SA mouse mammary epithelial cells in vitro. Combined treatment with subeffective doses of γ-tocotrienol with these other chemotherapeutic agents resulted in a synergistic inhibition of +SA cell growth and viability. These findings strongly suggest that combined treatment of γ-tocotrienol with other anticancer agents may not only provide an enhanced therapeutic response but also provide a means to avoid the toxicity, low bioavailability, or limited therapeutic action associated with high-dose monotherapy.     

An experiment of the combined treatment of traditional Lei-huo-jiu therapy with Chinese medicine for the lacrimal gland of Sjögren’s syndrome

This experiment chooses nonobese diabetic (NOD) mouse as the animal model of Sjögren’s syndrome and investigates the morphologic changes, the expression of inflammatory factors and growth factors of this mouse’s lacrimal gland in response to a combined treatment of traditional Lei-huo-jiu therapy alone and in combination with Chinese medicine. The methods were to (1) use a morphological approach to directly observe pathological changes of the lacrimal gland in response to combined treatment and (2) to detect the level of tumor necrosis factor (TNF)-α, interleukin (IL)-1, and nuclear factor kappa B (NF-κB) in lacrimal gland tissue caused by the combined treatments using a immunohistochemical approach. There is a reduction of the mast cell’s degranulation and modulation of the level of cytokines in TNF-α, IL-1, and NF-κB in the combined therapy group. The combined treatment of traditional Lei-huo-jiu therapy with Chinese medicine can improve the pathological changes of the lacrimal gland tissue of the NOD mouse through modulating the level of TNF-α, IL-1, and NF-κB which results in improved tear secretion and function of the lacrimal gland.     

An experiment of the combined treatment of traditional Lei-huo-jiu therapy with Chinese medicine for the lacrimal gland of Sjögren’s syndrome

This experiment chooses nonobese diabetic (NOD) mouse as the animal model of Sjögren’s syndrome and investigates the morphologic changes, the expression of inflammatory factors and growth factors of this mouse’s lacrimal gland in response to a combined treatment of traditional Lei-huo-jiu therapy alone and in combination with Chinese medicine. The methods were to (1) use a morphological approach to directly observe pathological changes of the lacrimal gland in response to combined treatment and (2) to detect the level of tumor necrosis factor (TNF)-α, interleukin (IL)-1, and nuclear factor kappa B (NF-κB) in lacrimal gland tissue caused by the combined treatments using a immunohistochemical approach. There is a reduction of the mast cell’s degranulation and modulation of the level of cytokines in TNF-α, IL-1, and NF-κB in the combined therapy group. The combined treatment of traditional Lei-huo-jiu therapy with Chinese medicine can improve the pathological changes of the lacrimal gland tissue of the NOD mouse through modulating the level of TNF-α, IL-1, and NF-κB which results in improved tear secretion and function of the lacrimal gland.     

β-elemene combined with temozolomide in treatment of brain glioma

Temozolomide (TMZ) is a widely used chemotherapeutic agent for malignant glioma. β-Elemene has been reported to have the ability of passing through the blood-brain barrier and reverse multidrug resistance. In the present study, transport of drugs through the in vitro blood-brain barrier (BBB) model also suggested that β-elemene can assist in TMZ transport to the brain. Plasma and brain pharmacokinetics demonstrated that when β-elemene is used in combination with TMZ, the metabolic rate of TMZ in plasma is slowed, and mean residence time (MRT) in brain is prolonged. The brain tissue distribution at 1 h indicated that the combination of TMZ and β-elemene promotes the distribution of β-elemene in the brain but slightly reduces the distribution of TMZ in the brain. Furthermore the antitumor effect and toxicity in vivo were also investigated. The combination of β-elemene and TMZ was well tolerated and significantly inhibited tumor growth in glioma xenografts. In summary, the present study indicates a synergistic antitumor effect of β-elemene and TMZ in glioma.     

Effect of carnosine alone or combined with α-tocopherol on hepatic steatosis and oxidative stress in fructose-induced insulin-resistant rats

A diet high in fructose (HFr) induces insulin resistance in animals. Free radicals are involved in the pathogenesis of HFr-induced insulin resistance. Carnosine (CAR) is a dipeptide with antioxidant properties. We investigated the effect of CAR alone or in combination with α-tocopherol (CAR?+?TOC) on HFr-induced insulin-resistant rats. Rats fed with HFr containing 60 % fructose received CAR (2 g/L in drinking water) with/without TOC (200 mg/kg, i.m. twice a week) for 8 weeks. Insulin resistance, serum lipids, inflammation markers, hepatic lipids, lipid peroxides, and glutathione (GSH) levels together with glutathione peroxidase (GSH-Px) and superoxide dismutase 1 (CuZnSOD; SOD1) activities and their protein expressions were measured. Hepatic histopathological examinations were performed. HFr was observed to cause insulin resistance, inflammation and hypertriglyceridemia, and increased triglyceride and lipid peroxide levels in the liver. GSH-Px activity and expression decreased, but GSH levels and SOD1 activity and expression did not alter in HFr rats. Hepatic marker enzyme activities in serum increased and marked macro- and microvesicular steatosis were seen in the liver. CAR treatment did not alter insulin resistance and hypertriglyceridemia, but it decreased steatosis and lipid peroxidation without any change in the antioxidant system of the liver. However, CAR?+?TOC treatment decreased insulin resistance, inflammation, hepatic steatosis, and lipid peroxidation and increased GSH-Px activity and expression in the liver. Our results may indicate that CAR?+?TOC treatment is more effective to decrease HFr-induced insulin resistance, inflammation, hepatic steatosis, and dysfunction and pro-oxidant status in rats than CAR alone.     

Mesenchymal stem cells: weapons or dangers for cancer treatment?

Mesenchymal stem cells (MSC) have attracted recent attention for their cell therapy potential, based in particular on their immunosuppressive properties, which have served as the basis for the treatment of autoimmune diseases. Interestingly, MSC have been used in cell therapy strategies to deliver therapeutical genes. Cell therapy approaches taking advantages of MSC have been proposed, as MSC display a potential tropsim for tumors. However, all these strategies raise a series of questions about the safety of MSC, as MSC could enhance tumor growth and metastasis. This review summarizes recent findngs about MSC in carcinogenesis.     

Could preoperative short-course radiotherapy be the treatment of choice for localized advanced rectal carcinoma?

Short-course preoperative radiotherapy (RT) is widely used in northern Europe for locally advanced resectable rectal cancer, but its role in the era of advanced imaging techniques is uncertain. Here, we reviewed articles and abstracts on SCRT published from 1974 through 2013 with the goal of identifying patients who might be best suited for short-course RT. We included relevant articles comparing surgery with or without preoperative radiation published before and after the advent of total mesorectal excision. We also analyzed two randomized trials directly comparing short-course RT with conventionally fractionated chemoradiation (the Polish Colorectal Study Group and the Trans-Tasman Radiation Oncology Group) that compared short-course RT with conventional chemoradiotherapy. We conclude from our review that short-course RT can be generally applied for operable rectal cancer and produces high rates of pelvic control with acceptable toxicity; it reduces local recurrence rates but does not increase overall survival. SCRT seems to be best used for tumors considered “low risk,” i.e., those that are >5 cm from the anal margin, without circumferential margin involvement, and involvement of fewer than 4 lymph nodes. Whether sequential chemotherapy can further improve outcomes remains to be seen, as does the best time for surgery (immediately or 6–8 weeks after RT). We further recommend that selection of patients for short-course RT should be based on findings from magnetic resonance imaging or transrectal ultrasonography.     

The therapeutic potential of interleukin-1β in the treatment of chemotherapy or radiation-induced myelosuppression and in tumor therapy

In vivo administration of rHuIL-l selectively enhanced the recovery from granulocytopenia and thrombocytopenia caused by sublethal irradiation or 5-FU treatment. Granulopoiesis and thrombopoiesis were stimulated by rHuIL-l in a dose-dependent manner at doses ranging from 0.1 to 100 g/kg. In this study, we have observed IL-1 to induce at least two distinct types of hematopoietic growth factorsin vivo, namely GM-CSF and a thrombopoiessn-like factor. Various kinds of CSFs alone did not stimulate colony formation of primitive hematopoietic progenitor cells obtained from 5-FU treated mice. However, the pretreatment of primitive hematopoietic progenitor cells with IL-1in vitro orin vivo for 5 days accelerated the recovery of a cell population which respond to several types of CSFs. These data suggest that IL-1 may be useful clinically to enhance the recovery of granulocytes and platelets in myelosuppressed patients. In addition, we observed that rHuIL-1 is directly cytostatic for certain tumor cellsin vitro. Intratumoral or subcutaneous injection of rHuIL-l caused regression of a subcutaneous murine sarcoma by augmenting host antitumor responses. Together with the profound effects on hematopoiesis, these results point to potentially important uses of IL-l in treatment of disease.     

Deep radiomic model based on the sphere–shell partition for predicting treatment response to chemotherapy in lung cancer

BackgroundThe prognosis of chemotherapy is important in clinical decision-making for non-small cell lung cancer (NSCLC) patients.ObjectivesTo develop a model for predicting treatment response to chemotherapy in NSCLC patients from pre-chemotherapy CT images.Materials and MethodsThis retrospective multicenter study enrolled 485 patients with NSCLC who received chemotherapy alone as a first-line treatment. Two integrated models were developed using radiomic and deep-learning-based features. First, we partitioned pre-chemotherapy CT images into spheres and shells with different radii around the tumor (0–3, 3–6, 6–9, 9–12, 12–15 mm) containing intratumoral and peritumoral regions. Second, we extracted radiomic and deep-learning-based features from each partition. Third, using radiomic features, five sphere–shell models, one feature fusion model, and one image fusion model were developed. Finally, the model with the best performance was validated in two cohorts.ResultsAmong the five partitions, the model of 9–12 mm achieved the highest area under the curve (AUC) of 0.87 (95% confidence interval: 0.77–0.94). The AUC was 0.94 (0.85–0.98) for the feature fusion model and 0.91 (0.82–0.97) for the image fusion model. For the model integrating radiomic and deep-learning-based features, the AUC was 0.96 (0.88–0.99) for the feature fusion method and 0.94 (0.85–0.98) for the image fusion method. The best-performing model had an AUC of 0.91 (0.81–0.97) and 0.89 (0.79–0.93) in two validation sets, respectively.ConclusionsThis integrated model can predict the response to chemotherapy in NSCLC patients and assist physicians in clinical decision-making.     

Leptin role in advanced lung cancer. A mediator of the acute phase response or a marker of the status of nutrition?

Leptin is an anorexia inductor peptide produced by adipocytes and related to fat mass. Leptin is also produced by fat under proinflammatory cytokine action. Our objective is to study serum leptin levels in relation to nutritional status and acute phase response in advanced-stage non-small cell lung cancer.Seventy-six patients newly diagnosed of non surgical non-small cell lung cancer before chemotherapy treatment and 30 healthy controls were included. BMI, serum leptin and cholesterol levels and lymphocyte count were decreased in lung cancer patients. Cytokine IL-6, TNF-alpha, sTNF-RII, sIL-2R, IL-12, IL-10 and IFN-gamma, and other acute phase reactants as alpha1 antitrypsin, ferritin, CRP and platelets were all raised in patients, whereas the IL-2 was decreased. We found a direct relationship between leptin and other indicators of the status of nutrition, especially total fat mass. We also found a close relationship between the status of nutrition and the performance status (Karnofsky index). However, serum leptin and nutritional status were inversely correlated with acute phase proteins and proinflammatory cytokines, suggesting a stress-type malnutrition. Although serum leptin levels, nutritional status and Karnofsky index are related to survival, at multivariate analysis they all were displaced by the acute phase reaction markers.These results suggest that cancer anorexia and cachexia are not due to a dysregulation of leptin production. Circulating leptin concentrations are not elevated in weight-losing cancer patients and are inversely related to the intensity of the inflammatory response. In advanced lung cancer patients serum leptin concentrations only depend on the total amount of fat.     

Piggy-backing the concept of cancer drugs for schistosomiasis treatment: a tangible perspective?

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. Recent studies of signaling proteins in schistosomes uncovered a way of achieving this goal relatively quickly. It was shown that protein kinases (PKs) control important biological processes in schistosomes. Concurrently, the involvement of mutant forms of PKs was demonstrated in the etiology of cancer. Therefore, different anticancer drugs have been developed to inhibit deregulated PKs. These can also inhibit schistosome PKs, thus blocking parasite development. Recent studies characterizing schistosome PKs are summarized and we discuss the concept of PK inhibitors, including approved cancer drugs, as novel candidate anti-schistosome agents. This is also likely to be of significance for other worm infections.