Assessing response to treatment of bone metastases from breast cancer: what should be the standard of care?

Bone is the most common site for breast cancer metastases, occurring in up to 70% of those with metastatic disease. In order to effectively manage these patients, it is essential to have consistent, reproducible and validated methods of assessing response to therapy. We present current clinical practice of imaging response assessment of bone metastases. We also review the biology of bone metastases and measures of response assessment including clinical assessment, tumour markers and imaging techniques; bone scans (BSs), computed tomography (CT), positron emission tomography, magnetic resonance imaging (MRI) and whole-body diffusion-weighted MRI (WB DW-MRI). The current standard of care of BSs and CT has significant limitations and are not routinely recommended for the purpose of response assessment in the bones. WB DW-MRI has the potential to address this unmet need and should be evaluated in clinical trials.

Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer.

BACKGROUND: [(18)F]fluorothymidine (FLT) has been proposed as a positron emission tomography (PET)-imaging biomarker of proliferation for breast cancer. The aim of this prospective study was to assess the feasibility of FLT-PET-CT as a technique for predicting the response to neoadjuvant chemotherapy (NAC) in primary breast cancer and to compare baseline FLT with Ki-67. METHODS: Twenty women with primary breast cancer had a baseline FLT-PET-CT scan that was repeated before the second cycle of chemotherapy. Expression of Ki-67 in the diagnostic biopsy was quantified. From the FLT-PET-CT scans lesion maximum and mean standardised uptake values (SUVmax, SUVmean) were calculated. RESULTS: Mean baseline SUVmax was 7.3, and 4.62 post one cycle of NAC, representing a drop of 2.68 (36.3%). There was no significant association between baseline, post chemotherapy, or change in SUVmax and pathological response to NAC. There was a significant correlation between pre-chemotherapy Ki-67 and SUVmax of 0.604 (P=0.006). CONCLUSIONS: Baseline SUVmax measurements of FLT-PET-CT were significantly related to Ki-67 suggesting that it is a proliferation biomarker. However, in this series neither the baseline value nor the change in SUVmax after one cycle of NAC were able to predict response as most patients had a sizeable SUVmax reduction.

Disulfiram reaction in an artist exposed to solvents.

This case report describes an artist on treatment for alcoholism with disulfiram (Antabuse) who suffered chronic symptoms similar to those of a disulfiram alcohol reaction, which we attribute to his occupational exposure to products containing alcohol and other solvents. Symptoms abated with strict precautions to prevent exposure, although gradually returned over the course of months, causing him eventually to stop the medication. Medical practitioners should be aware of possible adverse interactions between occupational solvent exposures and disulfiram.

The Use of Palliative Radiotherapy in the Treatment of Lung Cancer.

There have been significant advances in the systemic treatment of stage IV lung cancer, which is now recommended first line in patients with adequate fitness. This includes some patients with brain metastases due to the increased understanding of the central nervous system penetration of targeted therapies. The trials evidence base for palliative radiotherapy pre-dated this routine use of systemic therapy in our practice, which means that the sequence and role of palliative radiotherapy are not currently well defined in the first-line treatment setting. However, due to its efficacy in symptom control, radiotherapy remains a core component in the palliative management of lung cancer, particularly in the second-line setting and those unsuited to primary systemic treatment. This overview focuses on the evidence behind palliative radiotherapy to the thorax and brain for non-small cell and small cell lung cancer and the potential for future studies, including the TOURIST Trial Platform, to guide the future direction of these treatments.

Acute disseminated encephalomyelitis due to Rickettsia conorii infection.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated acute inflammatory demyelinating disorder, which typically occurs after viral infections or immunisation. We present a case of a man with acute Rickettsia conorii infection whose diagnosis was delayed. He presented with fever, headache, an eschar and an acute paraplegia. The R. conorii IgM serum titre was 1:128. Magnetic resonance imaging showed multifocal lesions in the brain and spinal cord consistent with inflammatory demyelination. The patient responded well to doxycycline and a short course of high-dose corticosteroids. To our knowledge this is the first case of ADEM associated with Mediterranean spotted fever - we found a previous report of ADEM in a child with Rocky Mountain spotted fever, whose diagnosis of rickettsial infection was also delayed. We hypothesise that delayed diagnosis of spotted fever group rickettsial infections could rarely result in ADEM.

The use of symptoms to predict colorectal cancer site. Can we reduce the pressure on our endoscopy services?

OBJECTIVE: Our objective was to determine the value of gastrointestinal symptoms and signs in predicting the site of colorectal cancer (CRC). These symptoms can subsequently be used in determining first-line investigation with either sigmoidoscopy or colonoscopy. METHOD: We interrogated the endoscopic and CRC databases ('Infoflex'), for patients diagnosed with CRC between April 2005 and March 2006 inclusive. These patients were cross-referenced with the pathology database and patient records. Information gathered from these databases include: age, gender, symptoms, site of cancer, histology, Duke's grading, blood parameters, diagnostic tool and treatment. RESULTS: One hundred fifty-three patients were diagnosed with CRC between April 2005 and March 2006. One hundred twenty-six were initially seen in the out-patient department, of whom 38 (29%) were right-sided (proximal to the splenic flexure), and 88 (70%) were left-sided (splenic flexure and beyond). Change in bowel habit (diarrhoea and constipation) and rectal bleeding were significantly associated with left-sided cancers (P < 0.0024 and P < 0.0001, respectively). Haemoglobin (P < 0.0001) and mean corpuscular volume (P < 0.0001) were significantly lower in right-sided cancers. Weight loss, pain and obstruction were not associated with cancer site. C-reactive protein, albumin and carcinoembryonic antigen are not predictive of cancer site, Duke's stage or influenced by patient age or gender. DISCUSSION: Symptoms can accurately predict site of cancer, allowing investigations to be tailored accordingly. We would recommend that patients with altered bowel habit and/or rectal bleeding, and no other symptoms, risk factors or anaemia, can be investigated with a flexible sigmoidoscopy to confirm or refute a diagnosis of colorectal cancer.

Impact of Peer Review in Reducing Uncertainty in the Definition of the Lung Target Volume Among Trainee Oncologists.

AIMS: To evaluate the impact of peer review and contouring workshops on reducing uncertainty in target volume delineation for lung cancer radiotherapy. MATERIALS AND METHODS: Data from two lung cancer target volume delineation courses were analysed. In total, 22 trainees in clinical oncology working across different UK centres attended these courses with priori experience in lung cancer radiotherapy. The courses were made up of short presentations and contouring practice sessions. The participants were divided into two groups and asked to first individually delineate (IND) and then individually peer review (IPR) the contours of another participant. The contours were discussed with an expert panel consisting of two consultant clinical oncologists and a consultant radiologist. Contours were analysed quantitatively by measuring the volume and local distance standard deviation (localSD) from the reference expert consensus contour and qualitatively through visual analysis. Feedback from the participants was obtained using a questionnaire. RESULTS: All participants applied minor editing to the contours during IPR, leading to a non-statistically significant reduction in the mean delineated volume (IND = 140.92 cm3, IPR = 125.26 cm3, P = 0.211). The overall interobserver variation was similar, with a localSD of 0.33 cm and 0.38 cm for the IND and IPR, respectively (P = 0.848). Six participants (29%) carried out correct major changes by either including tumour or excluding healthy tissue. One participant (5%) carried out an incorrect edit by excluding parts of the tumour, while another observer failed to identify a major contour error. The participants' level of confidence in target volume delineation increased following the course and identified the discussions with the radiologist and colleagues as the most important highlights of the course. CONCLUSION: IPR could improve target volume delineation quality among trainee oncologists by identifying most major contour errors. However, errors were also introduced after IPR, suggesting the need to further discuss major changes with a multidisciplinary team.

Palliative Lung Radiotherapy: Higher Dose Leads to Improved Survival?

AIMS: Choosing the optimal palliative lung radiotherapy regimen is challenging. Guidance from The Royal College of Radiologists recommends treatment stratification based on performance status, but evidence suggests that higher radiotherapy doses may be associated with survival benefits. The aim of this study was to investigate the effects of fractionation regimen and additional factors on the survival of palliative lung cancer radiotherapy patients. MATERIALS AND METHODS: A retrospective univariable (n = 925) and multivariable (n = 422) survival analysis of the prognostic significance of baseline patient characteristics and treatment prescription was carried out on patients with non-small cell and small cell lung cancer treated with palliative lung radiotherapy. The covariates investigated included: gender, age, performance status, histology, comorbidities, stage, tumour location, tumour side, smoking status, pack year history, primary radiotherapy technique and fractionation scheme. The overall mortality rate at 30 and 90 days of treatment was calculated. RESULTS: Univariable analysis revealed that performance status (P < 0.001), fractionation scheme (P < 0.001), comorbidities (P = 0.02), small cell histology (P = 0.02), 'lifelong never' smoking status (P = 0.01) and gender (P = 0.06) were associated with survival. Upon multivariable analysis, only better performance status (P = 0.01) and increased dose/fractionation regimens of up to 30 Gy/10 fractions (P < 0.001) were associated with increased survival. Eighty-five (9.2%) and 316 patients (34%) died within 30 and 90 days of treatment, respectively. CONCLUSION: In this retrospective single-centre analysis of palliative lung radiotherapy, increased total dose (up to and including 30 Gy/10 fractions) was associated with better survival regardless of performance status.

The Current Role of Radiotherapy in the Treatment of Small Cell Lung Cancer.

Radiotherapy has been shown to play a key role in the management of small cell lung cancer. There are well-established data in the literature for the use of concurrent chemoradiotherapy for stage I-III disease, although key questions remain over the timing of radiation, the optimal dose/fractionation and particularly once versus twice daily treatment, the use of elective nodal irradiation and drug combinations. Data for the use of thoracic radiation in stage IV disease, after chemotherapy, have recently become available and are leading to a change in practice. Prophylactic cranial irradiation has been shown to be of use in both stage I-III and stage IV disease, although uncertainties surround its use in the elderly population and the use of brain imaging before treatment. This overview will address the current available evidence and focus on areas for future research.

A Sensitivity Analysis of the Impact of Rain on Regional and Global Sea-Air Fluxes of CO2.

The global oceans are considered a major sink of atmospheric carbon dioxide (CO2). Rain is known to alter the physical and chemical conditions at the sea surface, and thus influence the transfer of CO2 between the ocean and atmosphere. It can influence gas exchange through enhanced gas transfer velocity, the direct export of carbon from the atmosphere to the ocean, by altering the sea skin temperature, and through surface layer dilution. However, to date, very few studies quantifying these effects on global net sea-air fluxes exist. Here, we include terms for the enhanced gas transfer velocity and the direct export of carbon in calculations of the global net sea-air fluxes, using a 7-year time series of monthly global climate quality satellite remote sensing observations, model and in-situ data. The use of a non-linear relationship between the effects of rain and wind significantly reduces the estimated impact of rain-induced surface turbulence on the rate of sea-air gas transfer, when compared to a linear relationship. Nevertheless, globally, the rain enhanced gas transfer and rain induced direct export increase the estimated annual oceanic integrated net sink of CO2 by up to 6%. Regionally, the variations can be larger, with rain increasing the estimated annual net sink in the Pacific Ocean by up to 15% and altering monthly net flux by > ± 50%. Based on these analyses, the impacts of rain should be included in the uncertainty analysis of studies that estimate net sea-air fluxes of CO2 as the rain can have a considerable impact, dependent upon the region and timescale.

Hypofractionated radiotherapy for localized prostate cancer using three-dimensional conformal radiotherapy technique: 3 years toxicity analysis.

BACKGROUND: Hypofractionated radiotherapy in the radical treatment of localized prostate cancer has potential biological advantages relative to conventional fractionation. We report prospectively collected toxicity data from a cohort of patients treated with a 3D conformal technique (3DCRT). MATERIALS AND METHODS: 90 patients receiving curative intent hypofractionated radiotherapy with 57Gy in 19 daily fractions over 3.8 weeks were evaluated prospectively for the development of radiation related toxicity over a 3 year period. RESULTS: All patients completed treatment. Maximal acute toxicity experienced was 58.6, 10 and 1.1% for grade 1, 2 and 3 genitourinary (GU) toxicity respectively and 75.6, 9 and 0% for gastrointestinal (GI) toxicity. For late toxicity the three year actuarial rates of grade 1, 2 and 3 GU and GI toxicity respectively were 47.3, 2.4 and 0%; and 40, 9.3 and 4.7%. There were no grade 4 or worse acute or late toxicities. 97.6% of evaluable patients remained free of biochemical failure 36 months post radiotherapy. CONCLUSIONS: A 57Gy in 19 daily fraction radiotherapy schedule using 3D conformal radiotherapy for the definitive treatment of localized prostate cancer has acceptable early and late toxicity.

Stereotactic body radiotherapy (SBRT) in the management of extracranial oligometastatic (OM) disease.

OBJECTIVE: A review of stereotactic body radiotherapy (SBRT) for oligometastases defined as three or fewer sites of isolated metastatic disease. The aim was to identify local control, overall survival (OS) and progression-free survival (PFS) of patients receiving SBRT for oligometastatic (OM) disease. METHODS: Data were analysed for SBRT delivered between 01 September 2010 and 31 March 2014. End points included local control, PFS, OS and toxicity. RESULTS: 76 patients received SBRT. The median age was 60 years (31-89 years). 44 were male. Median follow-up was 12.3 months (0.2-36.9 months). Major primary tumour sites included colorectal (38%), the breast (18%) and the prostate (12%). The treatment sites included lymph nodes (42%), the bone and spine (29%) and soft tissue (29%). 42% were previously treated with conventional radiotherapy. 45% were disease free after SBRT. 4% had local relapse, 45% had distant relapse, and 6% had local and distant relapse. Local control was 89%. The OS was 84.4% at 1 year and 63.2% at 2 years. PFS was 49.1% at 1 year and 26.2% at 2 years. Toxicities included duodenal ulcer and biliary stricture formation. CONCLUSION: SBRT can achieve durable control of OM lesions and results in minimal radiation-induced morbidity. ADVANCES IN KNOWLEDGE: This cohort is one of the largest reported to date and contributes to the field of SBRT in oligometastases that is emerging as an important research area. It is the only study reported from the UK and uses a uniform technique throughout. The efficacy and low toxicity with durable control of local disease with this approach is shown, setting the foundations for future randomized studies.

Outcomes of primary lymphoma of the ocular adnexa (orbital lymphoma) treated with radiotherapy.

AIMS: Low-grade ocular adnexal lymphoma is a rare disease and often treated with local radiotherapy to varying doses. Most previously reported studies have a very heterogeneous patient population and treatments. We report the outcomes from a 10 year cohort of patients at our institution treated with primary radiation therapy. MATERIALS AND METHODS: We analysed a retrospective case series of patients with stage IE low-grade ocular adnexal lymphoma including a review of case notes, histological reports and radiotherapy charts. We assessed local and distant tumour control and relapse rates in addition to toxicity. Disease-free survival was estimated using the Kaplan-Meier method. RESULTS: In total, 81 patients and 85 orbits were treated with primary radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Seventy-nine per cent were treated with standard MV external beam radiotherapy to the whole orbit and 21% with a lens-sparing technique. The median follow-up was 4.4 years (range 0.2-10.4). Local control rates were 100%, with 5% of patients experiencing disease relapse elsewhere. No patients died from lymphoma. Cumulative acute toxicity rates were 51% (mainly erythema and conjunctivitis) and late toxicity rates were 8% (mainly cataract). The lens-sparing technique was associated with a significant reduction in cataract rate (P = 0.013) and an increase in acute toxicity (P < 0.001). CONCLUSIONS: This study has shown excellent local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks.

Human keratinocytes lack the components to produce leukotriene B4.

The cellular origin of leukotriene B4 (LTB4), a potent pro-inflammatory molecule present in psoriatic lesions, has yet to be determined. In the present study, cultured human keratinocytes were evaluated for their ability to produce LTB4. Keratinocytes stimulated under a variety of conditions did not produce detectable amounts of LTB4, as measured by enzyme immunoassay and liquid chromatographic techniques. Prostaglandin E2 and 15-hydroxyeicosatetraenoic acid were the only eicosanoids detected. The capacity of keratinocytes to synthesize 5-lipoxygenase (5-LO) products, or lack thereof, was further evaluated by preparing subcellular fractions and examining them for the presence of 5-LO activity and the proteins responsible for LTB4 production. Using Western blot analysis, we detected no bands that migrated with the 78-kDa 5-LO enzyme. Subcellular fractions were also examined for the presence of the 5-LO-activating protein (FLAP). This protein, which is essential to 5-LO activity, could not be detected in any keratinocyte preparation examined. Consistent with the absence of proteins, the mRNAs for 5-LO and FLAP were undetectable by reverse transcriptase polymerase chain reactions analysis. These results demonstrate that human keratinocytes lack the crucial proteins necessary for LTB4 production.

Investigation of urea cycle enzyme disorders by 1H-NMR spectroscopy.

High resolution proton nuclear magnetic resonance spectroscopy (1H-NMR) has been used to study patients with inborn errors of the urea cycle to evaluate further the diagnostic potential of this technique. The 1H-NMR metabolic profile from the urine of patients with citrullinaemia and argininosuccinic aciduria consistently demonstrated the presence of the diagnostic metabolites citrulline, N-acetylcitrulline and argininosuccinate, respectively. The profile from the urine of patients with ornithine carbamoyl transferase deficiency, is potentially diagnostic, but orotate was only detected in samples from three out of four patients. The characteristic fingerprint that each of the metabolites produces is unlike that of any other we have seen, including analogues of the metabolites which are structurally very similar such as arginine, ornithine and aspartate. The level of excretion of the metabolites from the patients with citrullinaemia and argininosuccinic aciduria has been well within the range of NMR detection.

Generalized lymphangiomatosis and chylothorax in the pediatric age group.

Four patients with generalized lymphangiomatosis presenting with chylothoraces are described. All four had bone involvement, two had involvement of the spleen, and one of the pericardium. The diagnosis was confirmed by typical radiology, histology, and in three patients by immunohistochemistry. Treatment was mainly palliative. Three patients died within 1/2 to three years of presentation.

Routine clinical data predict survival after palliative radiotherapy: an opportunity to improve end of life care.

AIMS: Estimating the prognosis of cancer patients with incurable disease remains an important and difficult task for clinicians. Radiotherapy is a commonly used modality for palliation of symptoms, and we investigated whether we could predict differences in overall survival after the first course of palliative radiotherapy using routinely available data. MATERIALS AND METHODS: We examined variations in survival in 1226 patients after their first course of palliative radiotherapy in relation to cancer type, site treated, age, gender and socioeconomic status, and developed a multivariate model based on these. RESULTS: The median overall survival after the first course of palliative radiotherapy was 5.2 months. Large differences in survival were seen, depending on the primary tumour and the site treated. Survival was much better in those with breast (median overall survival 11.4 months) or prostate cancer (8.4 months, hazard ratio = 1.3) than in those with oesophageal/gastro-oesophageal junctional tumours (4.6 months, hazard ratio = 2.3) or lung (3.9 months, hazard ratio = 2.5). The treated site was an important prognostic factor (primary tumour versus bone metastases, hazard ratio = 1.3; versus brain metastases, hazard ratio = 2.1). CONCLUSIONS: The median overall survival after a first course of palliative radiotherapy was less than 6 months. Simple data, provided as part of routine radiotherapy practice, clearly discriminate between patients with very different prognoses. Such data could therefore be used to trigger appropriate end of life care.