Evaluation of melanin-targeted radiotherapy in combination with radiosensitizing drugs for the treatment of melanoma

The incidence of malignant melanoma is rising faster than that of any other cancer in the United States. An [131I]-labeled benzamide - [131I]MIP-1145 - selectively targets melanin, reduces melanoma tumor burden and increases survival in preclinical models. Our purpose was to determine the potential of radiosensitizers to enhance the anti-tumor efficacy of [131I]MIP-1145. Melanotic (A2058) and amelanotic (A375 and SK-N-BE(2c)) cells were treated with [131I]MIP-1145 as a single agent or in combination with drugs with radiosenitizing potential. Cellular uptake of [131I]MIP-1145 and toxicity were assessed in monolayer culture. The interaction between radiosensitizers and [131I]MIP-1145 was evaluated by combination index analysis in monolayer cultures and by delayed growth of multicellular tumor spheroids. [131I]MIP-1145 was taken up by and was toxic to melanotic cells but not amelanotic cells. Combination treatments comprising [131I]MIP-1145 with the topoisomerase inhibitor topotecan or the PARP-1 inhibitor AG014699 resulted in synergistic clonogenic cell kill and enhanced delay of the growth of spheroids derived from melanotic melanoma cells. The proteasome inhibitor bortezomib had no synergistic cytotoxic effect with [131I]MIP-1145 and failed to enhance the delay of spheroid growth. Following combination treatment of amelanotic cells, neither synergistic clonogenic cell kill nor enhanced growth delay of spheroids was observed

Recent Advances in the Pathogenesis and Management of Cast Nephropathy (Myeloma Kidney)

Multiple myeloma is an incurable plasma cell malignancy that is often accompanied by renal failure; there are a number of potential causes of this, of which cast nephropathy is the most important. Renal failure is highly significant in myeloma, as patient survival can be stratified by the severity of the renal impairment. Consequently, there is an ongoing focus on the pathological basis of cast nephropathy and the optimal treatment regimens in this setting, including effective chemotherapy regimens to reduce light chain production and emerging extracorporeal techniques to remove circulating light chains. This paper bridges recent advances in the pathogenesis and management of cast nephropathy in multiple myeloma

Suicide and drought in New South Wales, Australia, 1970-2007

There is concern in Australia that droughts substantially increase the incidence of suicide in rural populations, particularly among male farmers and their families. We investigated this possibility for the state of New South Wales (NSW), Australia between 1970 and 2007, analyzing data on suicides with a previously established climatic drought index. Using a generalized additive model that controlled for season, region, and long-term suicide trends, we found an increased relative risk of suicide of 15% (95% confidence interval, 8%–22%) for rural males aged 30–49 y when the drought index rose from the first quartile to the third quartile. In contrast, the risk of suicide for rural females aged >30 y declined with increased values of the drought index. We also observed an increased risk of suicide in spring and early summer. In addition there was a smaller association during unusually warm months at any time of year. The spring suicide increase is well documented in nontropical locations, although its cause is unknown. The possible increased risk of suicide during drought in rural Australia warrants public health focus and concern, as does the annual, predictable increase seen each spring and early summer. Suicide is a complex phenomenon with many interacting social, environmental, and biological causal factors. The relationship between drought and suicide is best understood using a holistic framework. Climate change projections suggest increased frequency and severity of droughts in NSW, accompanied and exacerbated by rising temperatures. Elucidating the relationships between drought and mental health will help facilitate adaptation to climate change

A feldspar-nepheline achondrite clast in Parnallee

A feldspar-nepheline clast (FELINE) has been identified in Parnallee (LL3.6). Plagioclase is An_, Ab_ and nepheline contains 0.24-3.12wt% Cl. The calculated bulk composition is mildly alkaline, with 3.5wt% Na_2O. Plagioclase has heavy REE depletion and a positive Eu anomaly (Eu/Eu^*=65). Nepheline has lower total REE than plagioclase. On a three isotope plot, the oxygen isotope composition of FELINE falls near the Carbonaceous Chondrites Anyhdrous Minerals Line, beneath the Terrestrial Fractionation Line. This suggests that the parental material had carbonaceous chondrite affinities. It was derived from a melt with moderately enriched LREE and Eu (13.5×CI), which probably underwent an influx of Na-, Cl-rich fluids during crystallisation. This LREE-enrichment suggests that Ca-pyroxene crystallised in the parent body residue during a melt extraction event. REE abundances and the oxygen isotope signature are consistent with an origin as a lost plagiophile melt fraction complementary to the ureilites. FELINE provides further evidence that achondritic fragments with an igneous, exotic origin are an important component of chondritic meteorites

Case mix, outcome and activity for patients admitted to intensive care units requiring chronic renal dialysis: a secondary analysis of the ICNARC Case Mix Programme Database

INTRODUCTION: This report describes the case mix, outcome and activity for admissions to intensive care units (ICUs) of patients who require prior chronic renal dialysis for end-stage renal failure (ESRF), and investigates the effect of case mix factors on outcome. METHODS: This was a secondary analysis of a high-quality clinical database, namely the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database, which includes 276,731 admissions to 170 adult ICUs across England, Wales and Northern Ireland from 1995 to 2004. RESULTS: During the eight year study period, 1.3% (n = 3,420) of all patients admitted to ICU were receiving chronic renal dialysis before ICU admission. This represents an estimated ICU utilization of six admissions (32 bed-days) per 100 dialysis patient-years. The ESRF group was younger (mean age 57.3 years versus 59.5 years) and more likely to be male (60.2% versus 57.9%) than those without ESRF. Acute Physiology and Chronic Health Evaluation II score and Acute Physiology Score revealed greater severity of illness on admission in patients with ESRF (mean 24.7 versus 16.6 and 17.2 versus 12.6, respectively). Length of stay in ICU was comparable between groups (median 1.9 days versus 1.8 days) and ICU mortality was only slightly elevated in the ESRF group (26.3% versus 20.8%). However, the ESRF group had protracted overall hospital stay (median 25 days versus 17 days), and increased hospital mortality (45.3% versus 31.2%) and ICU readmission (9.0% vs. 4.7%). Multiple logistic regression analysis adjusted for case mix identified the increased hospital mortality to be associated with increasing age, emergency surgery and nonsurgical cases, cardiopulmonary resuscitation before ICU admission and extremes of physiological norms. The adjusted odds ratio for ultimate hospital mortality associated with chronic renal dialysis was 1.24 (95% confidence interval 1.13 to 1.37). CONCLUSION: Patients with ESRF admitted to UK ICUs are more likely to be male and younger, with a medical cause of admission, and to have greater severity of illness than the non-ESRF population. Outcomes on the ICU were comparable between the two groups, but those patients with ESRF had greater readmission rates, prolonged post-ICU hospital stay and increased post-ICU hospital mortality. This study is by far the largest comparative outcome analysis to date in patients with ESRF admitted to the ICU. It may help to inform clinical decision-making and resource requirements for this patient population

European trial of free light chain removal by extended haemodialysis in cast nephropathy (EuLITE): A randomised control trial

<p>Abstract</p> <p>Background</p> <p>Renal failure is a frequent complication of multiple myeloma and when severe is associated with a greatly increased morbidity and mortality. The principal cause of severe renal failure is cast nephropathy, a direct consequence of high concentrations of monoclonal free light chains (FLCs) in patients' sera. FLC removal by extended haemodialysis, using a high cut-off dialyser, has recently been described as a novel therapeutic option.</p> <p>Methods</p> <p>The <b>EU</b>ropean trial of free <b>LI</b>ght chain removal by ex<b>TE</b>nded haemodialysis in cast nephropathy (EuLITE) trial is a prospective, randomised, multicentre, open label clinical trial to investigate the clinical benefits of FLC removal haemodialysis in patients with cast nephropathy, dialysis dependent acute renal failure and <it>de novo </it>multiple myeloma. Recruitment commenced in May 2008. In total, 90 patients will be recruited. Participants will be randomised, centrally, upon enrolment, to either trial chemotherapy and FLC removal haemodialysis or trial chemotherapy and standard high flux haemodialysis. Trial chemotherapy consists of bortezomib, doxorubicin and dexamethasone. FLC removal haemodialysis is undertaken with two Gambro HCO 1100 dialysers in series using an intensive treatment schedule. The primary outcome for the study is independence of dialysis at 3 months. Secondary outcomes are: duration of dialysis, reduction in serum FLC concentrations; myeloma response and survival.</p> <p>Hypothesis</p> <p>FLC removal haemodialysis will increase the rate of renal recovery in patients with severe renal failure secondary to cast nephropathy in <it>de novo </it>multiple myeloma.</p> <p>Trial registration</p> <p>ISRCTN45967602</p

Case mix, outcome and activity for patients admitted to intensive care units requiring chronic renal dialysis: a secondary analysis of the ICNARC Case Mix Programme Database

INTRODUCTION: This report describes the case mix, outcome and activity for admissions to intensive care units (ICUs) of patients who require prior chronic renal dialysis for end-stage renal failure (ESRF), and investigates the effect of case mix factors on outcome. METHODS: This was a secondary analysis of a high-quality clinical database, namely the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme Database, which includes 276,731 admissions to 170 adult ICUs across England, Wales and Northern Ireland from 1995 to 2004. RESULTS: During the eight year study period, 1.3% (n = 3,420) of all patients admitted to ICU were receiving chronic renal dialysis before ICU admission. This represents an estimated ICU utilization of six admissions (32 bed-days) per 100 dialysis patient-years. The ESRF group was younger (mean age 57.3 years versus 59.5 years) and more likely to be male (60.2% versus 57.9%) than those without ESRF. Acute Physiology and Chronic Health Evaluation II score and Acute Physiology Score revealed greater severity of illness on admission in patients with ESRF (mean 24.7 versus 16.6 and 17.2 versus 12.6, respectively). Length of stay in ICU was comparable between groups (median 1.9 days versus 1.8 days) and ICU mortality was only slightly elevated in the ESRF group (26.3% versus 20.8%). However, the ESRF group had protracted overall hospital stay (median 25 days versus 17 days), and increased hospital mortality (45.3% versus 31.2%) and ICU readmission (9.0% vs. 4.7%). Multiple logistic regression analysis adjusted for case mix identified the increased hospital mortality to be associated with increasing age, emergency surgery and nonsurgical cases, cardiopulmonary resuscitation before ICU admission and extremes of physiological norms. The adjusted odds ratio for ultimate hospital mortality associated with chronic renal dialysis was 1.24 (95% confidence interval 1.13 to 1.37). CONCLUSION: Patients with ESRF admitted to UK ICUs are more likely to be male and younger, with a medical cause of admission, and to have greater severity of illness than the non-ESRF population. Outcomes on the ICU were comparable between the two groups, but those patients with ESRF had greater readmission rates, prolonged post-ICU hospital stay and increased post-ICU hospital mortality. This study is by far the largest comparative outcome analysis to date in patients with ESRF admitted to the ICU. It may help to inform clinical decision-making and resource requirements for this patient population

Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure

<p>Abstract</p> <p>Background</p> <p>Monoclonal free light chains (FLCs) frequently cause rapidly progressive renal failure in patients with multiple myeloma. Immunoassays which provide quantitative measurement of FLCs in serum, have now been adopted into screening algorithms for multiple myeloma and other lymphoproliferative disorders. The assays indicate monoclonal FLC production by the presence of an abnormal κ to λ FLC ratio (reference range 0.26–1.65). Previous work, however, has demonstrated that in patients with renal failure the FLC ratio can be increased above normal with no other evidence of monoclonal proteins suggesting that in this population the range should be extended (reference range 0.37–3.1). This study evaluated the diagnostic sensitivity and specificity of the immunoassays in patients with severe renal failure.</p> <p>Methods</p> <p>Sera from 142 patients with new dialysis-dependent renal failure were assessed by serum protein electrophoresis (SPE), FLC immunoassays and immunofixation electrophoresis. The sensitivity and specificity of the FLC ratio's published reference range was compared with the modified renal reference range for identifying patients with multiple myeloma; by receiver operating characteristic curve analysis.</p> <p>Results</p> <p>Forty one patients had a clinical diagnosis of multiple myeloma; all of these patients had abnormal serum FLC ratios. The modified FLC ratio range increased the specificity of the assays (from 93% to 99%), with no loss of sensitivity. Monoclonal FLCs were identified in the urine from 23 of 24 patients assessed.</p> <p>Conclusion</p> <p>Measurement of serum FLC concentrations and calculation of the serum κ/λ ratio is a convenient, sensitive and specific method for identifying monoclonal FLC production in patients with multiple myeloma and acute renal failure. Rapid diagnosis in these patients will allow early initiation of disease specific treatment, such as chemotherapy plus or minus therapies for direct removal of FLCs.</p