High-dose interleukin2 - a 10-year single-site experience in the treatment of metastatic renal cell carcinoma: careful selection of patients gives an excellent outcome.

BACKGROUND: VEGF-targeted therapy has become the mainstay of treatment for majority of mRCC patients. For most patients, benefit is short-lived and therefore treatment remains palliative in intent. HD IL2 is an effective immunotherapy treatment capable of durable remission in some patients but its unselected use has been difficult due to its modest response rate and considerable adverse effects. Using set pathology criteria as a selection tool in clinical practice, we have been able to show improved outcomes in our previous report. Here, we present an updated and extended report of this treatment and seek to explore any pathological, clinical and treatment variables likely to predict better outcomes. METHODS: This is an extension of a previously reported clinical audit, which includes mRCC cases treated with HD IL2 between 2003 and 2013. Since 2006, tumour specimens of potential candidates were routinely reviewed prospectively and stratified into Favourable or Other categories based on constitution of histological growth pattern, namely alveolar or solid versus papillary and/or sarcomatoid architecture; clear cell versus granular cell cytoplasmic morphology. HD IL2 was preferentially offered to patients with Favourable pathology. Outcome evaluation includes response rates, survival, and treatment tolerance. Multivariate analysis was performed to explore potential prognostic and predictive factors. RESULTS: Among prospectively selected patients with Favourable pathology (n = 106), overall response rate was 48.1 % (51/106) with CR rate of 21.6 % (23/106). Median OS was 58.1 months. Factors associated with significantly better response and/or survival includes favourable pathology pattern, higher cycle 1 tolerance and lower number of metastatic organ sites (<3). CAIX (Carbonic anhydrase 9) has prognostic value but is not predictive of response. Toxicities were those expected of IL2 but were manageable on general medical wards, with no treatment-related death. Importantly most complete responses were durable with 76 % (23/30) cases remained relapse-free (median 39 months follow up) and 2 of the seven who relapsed had had long-term disease free survival after resection of oligometastatic relapse. CONCLUSIONS: Our experience shows that HD IL2 remains an effective and safe treatment in well-selected cases of mRCC. The result in this single-institution patient series confirms similar outcomes to our previously reported retrospective series. Given the prospect of long-term remission, fit patients with Favourable histology and low disease burden should be considered for HD IL2 in an experienced centre. Better understanding has been gained from this in-depth analysis especially the examination of possible response predictors and strategies that can improve treatment outcome.

Diagnostic dental radiographs not allowed! A child with ataxia telangiectasia.

BACKGROUND: Ataxia telangiectasia (AT) is a rare neurodegenerative condition which has not previously been reported in the dental literature. It is a life threatening and debilitating disorder of progressive cerebellar ataxia and choreoathetosis, progressive oculocutaneous telangiectasias, immunodeficiency with susceptibility to sinopulmonary infections, impaired organ maturation, X-ray hypersensitivity, and a high incidence of malignancies. Of importance in dentistry is the contra-indication for taking diagnostic radiographs. CASE REPORT: A 5-year-old girl with AT was referred by her paediatrician for dental care as she had never been seen by a dentist. She presented with caries affecting a number of primary teeth. Diagnostic radiographs could not be taken due to her X-ray hypersensitivity. TREATMENT: She was given antibiotic prophylaxis for dental treatment under general anaesthetic. She had composite restorations, stainless steel crowns and extractions completed. FOLLOW-UP: She has been reviewed for over 2 years with ongoing enhanced prevention. CONCLUSION: This case reports a rare condition in which diagnostic dental radiographs are contra-indicated.

Case report: hypodontia and short roots in a child with Fraser syndrome.

BACKGROUND: Fraser syndrome is a rare autosomal recessive disorder of which there has only previously been one case reported in the dental literature. The main characteristics are cryptophthalmos, syndactyly and genital abnormalities. Orofacial findings reported are: facial asymmetry, cleft lip and palate, high arched palate, dental crowding, fusion of primary teeth, dental hypoplasia, malocclusion, and supragingival calculus. CASE REPORT: A 15 year old girl with Fraser syndrome attended Bradford and Airedale salaried dental services complaining of painful mandibular anterior teeth. On examination she presented with hypodontia, shortened roots, and the mandibular anteriors had a titanium trauma splint fixed to reduce the mobility. This had been placed 4 years previously by a paediatric specialist. However oral hygiene was poor around it and therefore the patient had calculus and gingivitis. TREATMENT: The splint was removed followed by subgingival scaling under local analgesia, fissure sealants of all posterior teeth, regular oral hygiene instruction and scaling, and occasional use of chlorhexidine gel. FOLLOW-UP: She has been reviewed regularly with frequent scalings over two years. CONCLUSION: This case reports the possibility of hypodontia and short roots being associated with Fraser syndrome.

Dynamical fluctuations in dense granular flows.

We have made measurements of force and velocity fluctuations in a variety of dense, gravity-driven granular flows under flow conditions close to the threshold of jamming. The measurements reveal a microscopic state that evolves rapidly from entirely collisional to largely frictional, as the system is taken close to jamming. On coarse-grained time scales, some descriptors of the dynamics-such as the probability distribution of force fluctuations, or the mean friction angle-do not reflect this profound change in the micromechanics of the flow. Other quantities, such as the frequency spectrum of force fluctuations, change significantly, developing low-frequency structure in the fluctuations as jamming is approached. We also show evidence of spatial structure, with force fluctuations being organized into local collision chains. These local structures propagate rapidly in the flow, with consequences far away from their origin, leading to long-range correlations in velocity fluctuations.

Phenomenological study of the North Dakota flood experience and its impact on survivors' health.

Grand Forks, North Dakota, was devastated by an unprecedented flood, forcing the evacuation of an entire community of 50,000 residents in 72 hours. A qualitative descriptive study with use of phenomenological methods was conducted 6 months after the flooding. Its purpose was to gain a deeper understanding of the meaning of a traumatic flood experience and its influence on the health of the residents of Grand Forks. Data were generated through interviews, observations, and media reports. The sample included 3 female and 3 male residents of the city of Grand Forks, North Dakota, who ranged in age from 26 to 77 years. Five essential themes were identified: (1) shock and disbelief, (2) uncertainty, (3) grief and loss, (4) emotional exhaustion, and (5) hope and meaning. The participants' descriptions of emotional exhaustion were similar to those found with survivors of posttraumatic stress disorder. Older adults appeared to be especially vulnerable. Nurses who are aware of the effects of natural disasters, particularly flooding, may be better able to identify vulnerable populations and understand the health needs of other survivors.

The neurokinin-1 and neurokinin-2 receptor binding sites of MDL103,392 differ.

Several small molecule non-peptide antagonists of the NK-1 and NK-2 receptors have been developed. Mutational analysis of the receptor protein sequence has led to the conclusion that the binding site for these non-peptide antagonists lies within the bundle created by transmembrane domains IV-VII of the receptor and differs from the binding sites of peptide agonists and antagonists. The current investigation uses site-directed mutagenesis of the NK-1 and NK-2 receptors to elucidate the amino acids that are important for binding and functional activity of the first potent dual NK-1/NK-2 antagonist MDL103,392. The amino acids found to be important for MDL103,392 binding to the NK-1 receptor are Gln-165, His-197, Leu-203, Ile-204, Phe-264, His-265 and Tyr-272. The amino acids found to be important for MDL103,392 binding to the NK-2 receptor are Gln-166, His-198, Tyr-266 and Tyr-289. While residues in transmembrane (TM) domains IV and V are important in both receptors (Gln-165/166 and His-197/198), residues in TM V and VI are more important for the NK-1 receptor and residues in TM VII play a more important role in the NK-2 receptor. These data are the first report of the analysis of the binding site of a dual tachykinin receptor antagonist and indicate that a single compound (MDL103,392) binds to each receptor in a different manner despite there being a high degree of homology in the transmembrane bundles. In addition, this is the first report in which a model for the binding of a non-peptide antagonist to the NK-2 receptor is proposed.