Novel bioactive glass-AuNP composites for biomedical applications.

The bioactive glasses doped with gold nanoparticles (AuNPs) are very attractive materials due to their potential in medical applications. In the present study Pluronic-nanogold hybrid nanoparticles were introduced during the sol-gel route of the SiO2-CaO-P2O5 glasses preparation. The obtained samples were characterized by UV-vis spectroscopy, X-ray diffraction, FT-IR spectroscopy, transmission electron and scanning electron microscopy and afterwards they were investigated in terms of bioactivity, protein adsorption and cells viability. The in vitro bioactivity assessment shows the increase of the number of agglomerated spherical shapes of apatite layers for all Au containing samples, but apatite like structure sizes are influenced by the AuNP content. Beside the spherical shapes, three-dimensional flower-like nanostructures were observed on the surface of the glass with 0.2mol% Au2O. Zeta potential and fluorescence spectroscopy measurements evidenced that the amount of serum albumin adsorbed onto the composites surface increases with the AuNP content. FT-IR measurements point out that the secondary structure of the adsorbed proteins presents few minor changes, indicating biocompatibility of the AuNP doped glasses. The good proliferation rate of Human keratinocytes cells obtained in the presence of samples with 0.15 and 0.2mol% Au2O is comparable with the values achieved from free AuNP, fact that proves the preservation of AuNP properties after their incorporation inside the bioactive glass matrices.

Bioactive and biocompatible copper containing glass-ceramics with remarkable antibacterial properties and high cell viability designed for future in vivo trials.

In the present study our interest is focused on finding the efficiency of 60SiO2·(32 - x)CaO·8P2O5·xCuO (mol%) glass-ceramics, with 0 ≤ x ≤ 4 mol%, in terms of bioactivity, biocompatibility, antibacterial properties and cell viability in order to determine the most appropriate composition for their further use in in vivo trials. The sol-gel synthesized samples show a preponderantly amorphous structure with a few crystallization centers associated with the formation of an apatite and calcium carbonate crystalline phases. The Fourier Transform Infrared (FT-IR) spectra revealed slightly modified absorption bands due to the addition of copper oxide, while the information derived from the measurements performed by transmission electron microscopy, UV-vis and electron paramagnetic resonance spectroscopy showed the presence of ions and metallic copper species. X-Ray photoelectron spectroscopic analysis indicated the presence of copper metallic species, in a reduced amount, only on the sample surface with the highest Cu content. Regarding in vitro assessment of bioactivity, the results obtained by X-ray diffraction, FT-IR spectroscopy and scanning electron microscopy, demonstrated the formation of a calcium phosphate layer on all investigated sample surfaces. The inhibitory effect of the investigated samples was more significant on the Pseudomonas aeruginosa than the Staphylococcus aureus strain, the sample with the lowest concentration of copper oxide (0.5 mol%) being also the most efficient in both bacterial cultures. This sample also exhibits a very good bactericidal activity, for the other samples it was necessary to use a higher quantity to inhibit and kill the bacterial species. The secondary structure of adsorbed albumin presents few minor changes, indicating the biocompatibility of the glass-ceramics. The cell viability assay shows a good proliferation rate on samples with 0.5 and 1.5 mol% CuO, although all glass-ceramic samples exhibited a good in vivo tolerance.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).

BACKGROUND: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS: In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS: The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS: Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00544700.

The current and future role of the medical oncologist in the professional care for cancer patients: a position paper by the European Society for Medical Oncology (ESMO).

The number of cancer patients in Europe is rising and significant advances in basic and applied cancer research are making the provision of optimal care more challenging. The concept of cancer as a systemic, highly heterogeneous and complex disease has increased the awareness that quality cancer care should be provided by a multidisciplinary team (MDT) of highly qualified healthcare professionals. Cancer patients also have the right to benefit from medical progress by receiving optimal treatment from adequately trained and highly skilled medical professionals. Built on the highest standards of professional training and continuing medical education, medical oncology is recognised as an independent medical specialty in many European countries. Medical oncology is a core member of the MDT and offers cancer patients a comprehensive and systemic approach to treatment and care, while ensuring evidence-based, safe and cost-effective use of cancer drugs and preserving the quality of life of cancer patients through the entire 'cancer journey'. Medical oncologists are also engaged in clinical and translational research to promote innovation and new therapies and they contribute to cancer diagnosis, prevention and research, making a difference for patients in a dynamic, stimulating professional environment. Medical oncologists play an important role in shaping the future of healthcare through innovation and are also actively involved at the political level to ensure a maximum contribution of the profession to Society and to tackle future challenges. This position paper summarises the multifarious and vital contributions of medical oncology and medical oncologists to today's and tomorrow's professional cancer care.

A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response.

Follicular lymphoma (FL) cells express CD20 and are associated in most cases with the t(14;18) chromosomal translocation. A multicentre study was undertaken between January 1997 and January 1998 to assess the complete response rate (CR) and overall response rate (RR) to rituximab, a chimaeric anti-CD20 monoclonal antibody. Seventy patients with previously treated FL received rituximab (375 mg/m2/week x4, by intravenous infusion). Restaging studies were performed 1 and 2 months after therapy. Molecular monitoring for the presence of cells harbouring the Bcl-2/JH gene rearrangement in the peripheral blood (PB) and bone marrow (BM) was performed before and after treatment using a two-step semi-nested polymerase chain reaction (PCR) assay. The overall RR was 32/70 (46%), being highest in patients who had received only one previous treatment (12/15, 80%). However, only two patients achieved a CR. The median duration of response was 11 months. Thirteen of 21 evaluable 'PCR-positive' patients (62%) became 'PCR-negative' in PB and/or BM samples 1 month after rituximab, although this did not correlate with clinical response. Treatment was generally well tolerated, although one patient developed Stevens-Johnson syndrome. Rituximab was shown to be active in FL, and in some cases PB and/or BM became PCR negative. Studies in combination with cytotoxic chemotherapy to increase the CR rate are warranted.

European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma.

PURPOSE: Mantle-cell lymphoma (MCL), immunocytoma (IMC), and small B-cell lymphocytic lymphoma (SLL) are B-cell malignancies that express CD20 and are incurable with standard therapy. A multicenter phase II study was conducted to assess the toxicity and the overall response rates (RR) and complete response (CR) rates to rituximab (chimeric anti-CD20 monoclonal antibody). PATIENTS AND METHODS: Between January 1997 and January 1998, 131 patients with newly diagnosed MCL (MCL1; n = 34) and previously treated MCL (MCL2; n = 40), IMC (n = 28), and SLL (n = 29) received rituximab 375 mg/m(2)/wk for 4 weeks via intravenous infusion. Restaging studies were performed 1 and 2 months after treatment. An analysis of the duration of response was conducted in December 1998. RESULTS: Eleven patients were unassessable, including one who died of splenic rupture after the first infusion. The RR among the 120 assessable patients was 30% (36 of 120 patients). The RR by histology was as follows: MCL1, 38%; MCL2, 37%; IMC, 28%; and SLL, 14%. Ten patients, all with MCL, achieved CR. The median duration of response in MCL was 1.2 years. Immediate side effects were common and usually responded to adjustments in the infusion rate. There were 31 episodes of infection after treatment; most cases were mild. Cardiac arrhythmia and ophthalmologic side effects occurred in 10 and nine patients, respectively, including one case of severe loss of visual acuity. CONCLUSION: Single-agent rituximab has moderate activity in MCL and IMC but only limited activity in SLL. The duration of response in MCL was similar to that previously reported in follicular lymphoma. Its use in combination with cytotoxic chemotherapy to increase the CR rate is warranted in MCL and IMC.

Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older.

PURPOSE: The surgical treatment of colorectal cancer (CRC) in elderly patients (age 70 years or older) has improved, but data on adjuvant and palliative chemotherapy tolerability and benefits in this growing population remain scarce. Elderly patients are underrepresented in clinical trials, and results for older patients are seldom reported separately. PATIENTS AND METHODS: Using a prospective database, we analyzed demographics, chemotherapy toxicity, response rates, failure-free survival (FFS), and overall survival (OS) of CRC patients receiving chemotherapy at the Royal Marsden Hospital. The cutoff age was 70 years. RESULTS: A total of 844 patients received first-line chemotherapy with various fluorouracil (5-FU)-containing regimens or raltitrexed for advanced disease, and 543 patients were administered adjuvant, protracted venous infusion 5-FU or bolus 5-FU/folinic acid (FA) chemotherapy. Of the 1,387 patients, 310 were 70 years or older. There was no difference in overall or severe (Common Toxicity Criteria III to IV) toxicity between the two age groups, with the exception of more frequent severe mucositis in older patients receiving adjuvant bolus 5-FU/FA. For patients receiving palliative chemotherapy, no difference in response rates (24% v 29%, P =.19) and median FFS (164 v 168 days) were detected when the elderly were compared with younger patients. Median OS was 292 days for the elderly group and 350 days for the younger patients (P =.04), and 1-year survival was 44% and 48%, respectively. The length of inpatient hospital stay was identical. CONCLUSION: Elderly patients with good performance status tolerated adjuvant and palliative chemotherapy for CRC as well as did younger patients and had similar benefits from palliative chemotherapy.

Surgery plus chemotherapy or chemotherapy alone for primary intermediate- and high-grade gastric non-Hodgkin's lymphoma: the Royal Marsden Hospital experience.

Primary gastric lymphomas (PGL) have traditionally been treated with surgery followed by chemotherapy or radiotherapy. Surgery was thought to improve staging, optimise local disease control and reduce risk of perforation or bleeding, but recent studies question its role. In this study, patients with intermediate- or high-grade PGL who received chemotherapy from 1985 to 1996 at the Royal Marsden Hospital were identified using a prospectively accrued database. A total of 37 patients (6 with low-grade mucosa-associated lymphoid tissue lymphoma (MALT-L), 9 with high-grade MALT-L, 20 with diffuse large B-cell (DLBC) lymphoma and 2 other histologies), 17 of whom had localised disease, were treated with either surgery plus chemotherapy or chemotherapy alone. 5-year overall survival for localised and advanced PGL was 94 and 50%, respectively, with no differences between the two treatments over a 53 months median follow-up. No perforations or serious bleeding occurred. Surgery is associated with important morbidity and we detected no benefit of surgery prior to chemotherapy in this limited series of patients.

bcl-2 expression is reciprocal to p53 and c-myc expression in metastatic human colorectal cancer.

Apoptosis (programmed cell death) inhibition may be an important mechanism by which gastrointestinal mucosal cells containing damaged DNA evade normal clearance mechanisms and grow to become invasive tumours. Since bcl-2 is an apoptosis inhibitor, bcl-2 mRNA expression was measured in 21 metastases of colorectal cancer using reverse transcription-polymerase chain reaction analysis. The mean bcl-2 mRNA expression (0.45 U, P < 0.0001) was lower than that of normal mucosal controls (= 1 U). p53 expression was inversely correlated with bcl-2 expression (P = 0.021) in 19 evaluable samples, and in tumours where p53 expression was over twice that of normal colonic mucosal values, bcl-2 mRNA was significantly decreased (mean 0.30, P = 0.0052). c-myc was also inversely correlated with bcl-2 expression (P = 0.025). Decreased bcl-2 expression in metastatic colorectal cancer may be partly due to allelic loss, given the proximity of bcl-2 to the frequently deleted DCC gene on chromosome 18q. However, the inverse correlation to p53/c-myc suggests an active downregulation of bcl-2, possibly following delegation of its apoptosis inhibiting role to other genes.

Local recurrence of a primary pancreatic lymphoma 18 years after complete remission.

Primary pancreatic lymphoma is exceedingly rare, with fewer than 40 patients reported in the English literature, mostly in single case publications. It comprises under 0.2 per cent of pancreatic tumours in one surgical series, but represents a disease that may be curable even in advanced stages and thus should be distinguished from other pancreatic malignancies. We report on a patient with lymphoma initially presenting in the pancreas in 1978, achieving complete remission (CR) and re-presenting with pancreatic lymphoma 18 years after treatment, with immunohistochemical and molecular studies suggesting recurrence of the original phenotype.

High-dose chemotherapy and autologous transplantation in lymphomatous polyposis in second remission: three case reports and literature review.

Lymphomatous polyposis is a rare primary gastrointestinal lymphoma. It morphologically and immunohistochemically resembles mantle cell lymphoma, with which it shares a disappointing response rate and duration following conventional anthracyclin-containing combination chemotherapy, with a short median survival and virtually no long-term survivors. We report the use of high-dose chemotherapy with autologous stem cell transplantation in second partial remission in three patients with lymphomatous polyposis treated at the Royal Marsden Hospital. All patients achieved a complete response, and one patient remains well and disease-free 64 months following transplantation and 76 months after diagnosis.

New approaches to the treatment of gastro-intestinal cancer.

A number of new cytotoxic agents are currently being assessed for the treatment of gastro-intestinal cancers. Colorectal cancer has been successfully treated with several direct thymidylate synthase inhibitors, oral 5-fluorouracil analogues, irinotecan, and oxaliplatin, alone and in combination regimens. Upper gastro-intestinal malignancies are also proving responsive to combinations including irinotecan and the taxanes. Pancreatic cancer, while remaining relatively chemoresistant, is proving treatable with the new direct thymidylate synthase inhibitors, docetaxel, and gemcitabine, improvements in quality of life being an important outcome. New strategies of treatment delivery are also proving beneficial. Neo-adjuvant chemotherapy is well tolerated for the treatment of gastric cancer and results in tumour downstaging. Randomized trials will show whether this translates into a survival advantage. Combination chemoradiation for oesophageal, pancreatic, and rectal cancers also appears to be an effective strategy. Biological therapies including hormonal manipulation, immunotherapy, angiogenesis inhibition, and gene-directed therapies are the subjects of intensive research at present, with many approaches being applied in early clinical trials. These have demonstrated the tolerability of many of these treatments with evidence for activity in some cases.

Tissue-specific regulation of vasoactive intestinal peptide messenger ribonucleic acid levels by estrogen in the rat.

The early and chronic effects of 17 beta-estradiol on vasoactive intestinal peptide (VIP) gene expression in rats were examined. Total RNA of four VIP-producing tissues were subjected to Northern blot analysis 15 and 30 min, and 1, 3, 6, and 24 h after a single injection of 17 beta-estradiol (100 micrograms/kg ip). Pituitary, hypothalamus, brain, and ileum VIP messenger RNA (mRNA) levels rose in a time-dependent manner after estrogen treatment. In the pituitary, the increase was maximal at 30-60 min, whereas in the hypothalamus, the increase reached significance only at 3 h but then persisted until at least 24 h. In the brain, a transient increase in VIP mRNA was observed at 30 min, whereas VIP mRNA levels in the ileum responded in a biphasic pattern; the initial early increase was followed by a second elevation occurring at 6 h. A smaller 1-kilobase VIP-related transcript particularly abundant in the pituitary was regulated in parallel with the 1.7-kilobase mature VIP mRNA species. Continuous estrogen stimulation for 7 weeks dramatically increased both mRNA species in the pituitary but did not affect VIP mRNA levels in the other tissues. These data suggest that the regulation of VIP gene expression by transient increases in estrogen levels is rapid and that the pattern of induction is tissue specific.