Spontaneous resolution of symptomatic lumbar synovial cyst.

Lumbar synovial cyst arises from the facet joint and can lead to back pain, radiculopathy, neurogenic claudication or even cauda equina syndrome. Although most surgeons would consider surgery to be the treatment of choice, the natural history of the disease process remains unknown and uncertainty still exists regarding optimal management of this controversial entity. We illustrate a case of large L5/S1 synovial cyst for which surgery was initially planned. However, it resolved spontaneously without any treatment. We also provide a brief literature review regarding conservative, surgical and minimally invasive management of symptomatic lumbar synovial cyst with special reference to patient outcome.

Radiological and Pathological Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: A Brief Literature Review.

BACKGROUND: Early clinical response to neoadjuvant chemotherapy (NACT) in breast cancer correlates with pathological response at surgery. A tailored approach using biomarkers to predict response to NACT has become a research priority. Predictors of response can be divided into pathological and radiological biomarkers. Advances in gene expression profiling and diffusion-weighted MRI techniques are used to predict tumour response, and combinations thereof are the future of predicting response to NACT in early-stage breast cancer. METHODS: We searched Medline, CINAHL and Embase databases for studies on NACT. Key words used were NACT, breast cancer, pathological* complete response, primary chemotherapy, radiological*, predictor*, gene expression and biomarkers limited to the English language. Pathological markers such as tumour subtypes, topoisomerase IIα expression, Ki67, apoptosis-related markers and gene expression profiling were included. RESULTS: From 119 articles, 42 studies were reviewed; the majority of studies identified used pathological clinical response as an end point to NACT, whilst others used complete clinical response. Despite extensive studies, results regarding long-term survival following NACT and potential predictors are inconclusive. CONCLUSION: Future development of a predictive model combining key pathological and radiological biomarkers could provide personalised treatment regimens that improve pathological complete response rates and longer-term outcomes.

Atypical teratoid rhabdoid tumour of the spine: report of a case and literature review.

Atypical teratoid rhabdoid tumour (ATRT) is a rare and highly aggressive malignant neoplasm of the central nervous system (CNS), which occurs predominantly in children less than 2 years of age. There are less than 50 cases described in adult. We report a case of primary spinal ATRT in a 65-year-old male who presented to us with cauda equina syndrome. To the best of our knowledge, our patient is the (1) second oldest patient to be diagnosed with ATRT and only the third case of adult spinal ATRT report in the literature; (2) first reported case of CNS ATRT occurring in a patient with non-rhabdoid renal cancer; (3) first adult patient of ATRT to present with cauda equina syndrome.

Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

P2-P4 macrocyclic inhibitors of hepatitis C virus NS3-4A serine protease.

Synthesis and HCV NS3 serine protease inhibitory activity of 4-hydroxyproline derived macrocyclic inhibitors and SAR around this macrocyclic core is described in this communication. X-ray structure of inhibitor 38 bound to the protease is discussed.

Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles.

The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice for intensive drug discovery research. On the basis of an active pentapeptide inhibitor, 1, we envisioned that macrocyclization from the P2 proline to P3 capping could enhance binding to the backbone Ala156 residue and the S4 pocket. Thus, a number of P2 proline-based macrocyclic alpha-ketoamide inhibitors were prepared and investigated in an HCV NS3 serine protease continuous assay (K(i*)). The biological activity varied substantially depending on factors such as the ring size, number of amino acid residues, number of methyl substituents, type of heteroatom in the linker, P3 residue, and configuration at the proline C-4 center. The pentapeptide inhibitors were very potent, with the C-terminal acids and amides being the most active ones (24, K(i*) = 8 nM). The tetrapeptides and tripeptides were less potent. Sixteen- and seventeen-membered macrocyclic compounds were equally potent, while fifteen-membered analogues were slightly less active. gem-Dimethyl substituents at the linker improved the potency of all inhibitors (the best compound was 45, K(i*) = 6 nM). The combination of tert-leucine at P3 and dimethyl substituents at the linker in compound 47 realized a selectivity of 307 against human neutrophil elastase. Compound 45 had an IC(50) of 130 nM in a cellular replicon assay, while IC(50) for 24 was 400 nM. Several compounds had excellent subcutaneous AUC and bioavailability in rats. Although tripeptide compound 40 was 97% orally bioavailable, larger pentapeptides generally had low oral bioavailability. The X-ray crystal structure of compounds 24 and 45 bound to the protease demonstrated the close interaction of the macrocycle with the Ala156 methyl group and S4 pocket. The strategy of macrocyclization has been proved to be successful in improving potency (>20-fold greater than that of 1) and in structural depeptization.

Novel 2-oxoimidazolidine-4-carboxylic acid derivatives as hepatitis C virus NS3-4A serine protease inhibitors: synthesis, activity, and X-ray crystal structure of an enzyme inhibitor complex.

Synthesis and HCV NS3 serine protease inhibitory activity of some novel 2-oxoimidazolidine-4-carboxylic acid derivatives are reported. Inhibitors derived from this new P2 core exhibited activity in the low microM range. X-ray structure of an inhibitor, 15c bound to the protease is presented.

Novel dipeptide macrocycles from 4-oxo, -thio, and -amino-substituted proline derivatives.

Dipeptide macrocycles of type A have been constructed in a versatile manner from the corresponding 4-heteroatom-substituted proline derivatives using an intramolecular Mitsunobu strategy.