Nonpeptide Tachykinin Receptor Antagonists. III. SB 235375, a Low Central Nervous System-Penetrant, Potent and Selective Neurokinin-3 Receptor Antagonist, Inhibits Citric Acid-Induced Cough and Airways Hyper-reactivity in Guinea Pigs

In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of ()-(S)-N-(-ethylbenzyl)-3-(car-boxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neuro-kinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited 125I-[MePhe7]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a Ki 2.2 nM and antagonized competitively NKB-induced Ca2 mobilization in human em-bryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a Kb 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA2 8.1) and guinea pig ileal circular smooth muscles (pA2 8.3). SB 235375 was selective for the hNK-3

Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet - a population-based study

Background Rare cancers pose challenges for diagnosis, treatments, and clinical decision making. Information about rare cancers is scant. The RARECARE project defined rare cancers as those with an annual incidence of less than six per 100 000 people in European Union (EU). We updated the estimates of the burden of rare cancers in Europe, their time trends in incidence and survival, and provide information about centralisation of treatments in seven European countries. Methods We analysed data from 94 cancer registries for more than 2 million rare cancer diagnoses, to estimate European incidence and survival in 2000–07 and the corresponding time trends during 1995–2007. Incidence was calculated as the number of new cases divided by the corresponding total person-years in the population. 5-year relative survival was calculated by the Ederer-2 method. Seven registries (Belgium, Bulgaria, Finland, Ireland, the Netherlands, Slovenia, and the Navarra region in Spain) provided additional data for hospitals treating about 220 000 cases diagnosed in 2000–07. We also calculated hospital volume admission as the number of treatments provided by each hospital rare cancer group sharing the same referral pattern. Findings Rare cancers accounted for 24% of all cancers diagnosed in the EU during 2000–07. The overall incidence rose annually by 0.5% (99·8% CI 0·3–0·8). 5-year relative survival for all rare cancers was 48·5% (95% CI 48·4 to 48·6), compared with 63·4% (95% CI 63·3 to 63·4) for all common cancers. 5-year relative survival increased (overall 2·9%, 95% CI 2·7 to 3·2), from 1999–2001 to 2007–09, and for most rare cancers, with the largest increases for haematological tumours and sarcomas. The amount of centralisation of rare cancer treatment varied widely between cancers and between countries. The Netherlands and Slovenia had the highest treatment volumes. Interpretation Our study benefits from the largest pool of population-based registries to estimate incidence and survival of about 200 rare cancers. Incidence trends can be explained by changes in known risk factors, improved diagnosis, and registration problems. Survival could be improved by early diagnosis, new treatments, and improved case management. The centralisation of treatment could be improved in the seven European countries we studied. Funding The European Commission (Chafea)

Rare ovarian tumours: Epidemiology, treatment challenges in and outside a network setting

More than 50% of all gynaecological cancers can be classified as rare tumours (defined as an annual incidence of <6 per 100,000) and such tumours represent an important challenge for clinicians. Rare cancers account for more than one fifth of all new cancer diagnoses, more than any of the single common cancers alone. Reviewing the RARECAREnet database, some of the tumours occur infrequently, whilst others because of their natural history have a high prevalence, and therefore appear to be more common, although their incidence is also rare. Harmonization of medical practice, guidelines and novel trials are needed to identify rare tumours and facilitate the development of new treatments. Ovarian tumours are the focus of this review, but we comment on other rare gynaecological tumours, as the diagnosis and treatment challenges faced are similar. This requires European collaboration, international partnerships, harmonization of treatment and collaboration to overcome the regulatory barriers to conduct international trials. Whilst randomized trials can be done in many tumour types, there are some for which conducting even single arm studies may be challenging. For these tumours alternative study designs, robust collection of data through national registries and audits could lead to improvements in the treatment of rare tumours. In addition, concentring the care of patients with rare tumours into a limited number of centres will help to build expertise, facilitate trials and improve outcome