TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept

There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU’s Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.     

Ovarian Brenner tumour: A morphologic and immunohistochemical analysis suggesting an origin from fallopian tube epithelium

BackgroundBrenner tumours (BTs), like other epithelial ovarian tumours, are thought to develop from the ovarian surface epithelium.Aim and MethodsWe hypothesised that BTs arise from transitional metaplasia near the tuboperitoneal junction which, when embedded in the ovary as Walthard cell nests, may progress to BTs. The aim of this study was to validate this hypothesis by a morphologic and immunohistochemical (IHC) analysis.ResultsThe IHC analysis revealed that fallopian tube secretory cells, transitional metaplasia, Walthard cell nests and the epithelial component of BTs shared a similar IHC profile, consistently expressing AKR1C3 (an enzyme involved in androgen biosynthesis) and androgen receptor, but not calretinin. The tumour stromal cells that immediately surrounded the epithelial nests showed strong expression of calretinin, inhibin and steroidogenic factor 1 (markers of steroidogenic cells) in the majority of BTs. Using a highly sensitive immunofluorescent staining method, we detected small groups of cilia in transitional metaplasia and Walthard cell nests, multifocal stretches of cilia and/or ciliated vacuoles in benign BTs and well-developed cilia in atypical proliferative BTs.ConclusionsOur findings suggest a tubal origin of BTs through transitional metaplasia and Walthard cell nests, based on their anatomic proximity, similar IHC profile and the presence of cilia. In addition, we hypothesise a role of androgenic stimulation in the pathogenesis of BT, based on the IHC staining pattern of calretinin, inhibin and steroidogenic factor 1 expressed in the luteinised stromal cells surrounding the epithelial nests of the tumours, and AKR1C3 and androgen receptor expressed in both the epithelial and stromal components.     

Dendritic cell-based approaches to cancer immunotherapy

Immunologic approaches to the treatment of malignancies are currently enjoying a resurgence of enthusiasm due to the discovery of tumour-associated antigens and the requirements for stimulating a tumour antigen-specific immune response. The goal of the newer strategies is to stimulate immunity against specific tumour-associated antigens, rather than to broadly, but non-specifically, stimulate the immune system. Since dendritic cells, professional antigen-presenting cells, play a central role in stimulating immune responses in vivo, there is considerable interest in immunising patients with autologous dendritic cells loaded with tumour antigens of interest. Methods for generating large numbers of dendritic cells under clinically-applicable conditions have been developed and it has been shown that they may be loaded with antigen in many different forms including proteins or peptides, RNA or DNA and cellular extracts. Ongoing research is seeking to optimise the purity, antigen loading and maturation of the dendritic cells. Phase I clinical trials have been initiated in order to study the safety and feasibility of immunisations with dendritic cells in humans with various malignancies. Phase II studies will be performed to establish which tumours and clinical scenarios will be most relevant for dendritic cell immunotherapy. Although the commercial applicability of dendritic cell-based immunotherapy has been recognised by the biotechnology industry, commercial availability of dendritic cell vaccines await phase III studies.     

Carbonic anhydrase IX inhibitors: fluorescent sulfonamides as therapeutic and diagnostic agents

This patent application discloses a novel class of strong carbonic anhydrase IX inhibitors bearing fluorescent tails. These compounds are claimed for use as therapeutic and imaging agents of hypoxic tumours, which are poorly responsive to classical chemo- and radiotherapies and constitute a novel strategy for cancer management.     

Pharmacokinetics and its relation to toxicity of pegylated‐liposomal doxorubicin in chinese patients with breast tumours

Objectives: Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin encapsulated with polyethylene glycol‐coated liposomes, which has prolonged circulation time and unique toxicity profile. This study deals with the pharmacokinetics and its relation to toxicity in Chinese patients with breast tumours. Methods: Twenty‐two Chinese female patients with breast tumours were received two PLD products in single dose of 50 mg/m² with a randomized, two‐period and cross‐over design. Blood was sampled immediately before and at 15, 30, 60 min, 1·17, 2, 5, 13, 25, 49, 73, 97, 121, 145 and 241 h after the PLD infusion. The plasma level of doxorubicin was determined with LC‐MS. Results: The pharmacokinetics of PLD was best described by a one‐compartment linear structural model with a long elimination T_1/2 (64 h), a slow clearance (0·025 L/h/m²) and a small volume of distribution (2·310 L/m²). The main toxicities were neutropenia (22/44), nausea (22/44), vomiting (8/44) and pigmentation (4/44). The nausea and neutropenia were positively correlated with AUC while negatively correlated with Cl (P < 0·05). Conclusions: The study confirms the different pharmacokinetic and toxicity profiles of PLD compared with non‐liposomal doxorubicin. The pharmacokinetic profiles in Chinese patients with breast tumours is different from those reported for European patients with metastatic breast cancer. The correlation between toxicities, neutropenia grade and nausea and two of the pharmacokinetic parameters, AUC and Cl, may be useful for guiding the dosing of the agent.     

PET Scan in Head and Neck Tumours in a Developing Country Like India: Is It a Must?

To study the impact of Positron emission tomography (PET) and its incremental value in diagnosing an unknown primary tumour with secondaries in the head and neck; recurrent head and neck cancers (confirmation of suspected recurrences and re-staging); and staging of head and neck tumours. This was a prospective observational study where 60 patients of head and neck tumours under the clinical settings as described above were evaluated. Thorough clinical examination and necessary radiological and histopathological investigations were done. All patients underwent a PET scan, the results of which were correlated with histopathological examination. Sensitivities, specificities, positive and negative predictive values, false positives and false negatives of PET scan in the different indications were calculated. The study included 11 patients of unknown primary, 28 patients with suspected recurrent tumours and 21 patients where PET scan was done for initial staging. PETCT scan was able to detect the primary in 3 out of 11 patients (27.27 %) who presented with cervical metastases with an unknown primary. In 2 of the 8 patients where a primary tumour was not found, PETCT detected distant metastases. For recurrent tumours, PETCT scan showed sensitivity, specificity, positive predictive value and negative predictive value as 100, 72.72, 85 and 100 % respectively. In restaging of recurrent disease, 4 out of 28 patients were detected to have distant metastases. In 7 cases of locoregionally advanced tumors, where PETCT scan was used for pre-treatment staging, it detected distant metastases in 4 of 7 patients. In the patients with N0 neck status PETCT scan showed a sensitivity, specificity, positive predictive value and negative predictive value of 100, 66.67, 50 and 100 % respectively. PETCT scan was able to alter the plan of management in 15 out of 60 patients. Thus, in carefully selected patients PETCT scan can provide incremental information that proves invaluable in these circumstances even in a developing country like India. In all the settings, PETCT scan demonstrated a very high negative predictive value. Hence, negative PETCT scan could be interpreted as absence of disease with reasonable assurance.     

Metachronous bilateral mucoepidermoid carcinoma of the parotid gland

We report a very rare case of bilateral muco-epidermoid carcinoma of the parotid gland that underwent bilateral parotidectomy with neck dissections and radiotherapy. This case has done well for three years and suggests that metachronous bilateral mucoepidermoid carcinoma of the parotid gland, if treated as per the merits of each side, has a reasonable survival.     

Rhabdomyosarcoma arising in mediastinal teratoma in an adult man: a case report.

We report a case of rhabdomyosarcoma which occurred in a mediastinal teratoma in a 44-year-old man. Presentation symptoms were chest pain, hoarseness and a cough. Diagnosis was fortuitous, performed by the histological and immunohistochemical study of a mediastinal tumour biopsy specimen that showed embryonal carcinoma and yolk sac tumour components associated with the rhabdomyosarcoma. After cisplatin-based chemotherapy (bleomycin-etoposide-cisplatin), surgical resection of the residual mediastinal tumour was performed. Histological and immunohistochemical study of this tumour confirmed the presence of mature teratoma and embryonal rhabdomyosarcoma. Evolution was marked by a local extension of the mediastinal tumour, occurrence of multiple metastases and bone marrow involvement. The patient died 8 months after diagnosis despite chemotherapy and radiotherapy. A review of the literature reveals that the development of rhabdomyosarcoma in primary mediastinal teratomas is unusual in adults. The diagnostic, therapeutic and prognostic implications of such an association are reviewed.     

The Relationship Between Changes in Tumour Volume, Tumour Cell Density and Parenchymal Cord Radius in a Human Melanoma Xenograft Exposed to Single Dose Irradiation

A human melanoma xenograft, in which the viable tumour tissue formed cylindrical cuffs around blood vessels, was irradiated with single doses of 7.5 Gy and 15.0 Gy respectively. The nuclear density, the frequency of giant cells and the mean par-enchymal cord radius were measured and compared to the tumour growth response. After 7.5 Gy, the growth rate was only slightly reduced and there were no significant changes in the nuclear density or the mean parenchymal cord radius. After 15.0 Gy the mean parenchymal cord radius decreased the first week. This coincided with swelling of endothelial cell nuclei and reduced density of functional capillary-like vessels. Although the number of tumour cells declined, the tumour volume increased the first days after irradiation with 15.0 Gy since the cell density was reduced.