Commentary on “Toxicity after external beam radiotherapy for prostate cancer: An analysis of late morbidity in men with diabetes mellitus.” Kalakota K,Liauw SL,Department of Radiation Oncology,Northwestern Memorial Hospital,Chicago, IL.: Urology 2013;81(6):1196–201. doi: 10.1016/j.urology.2013.01.047. [Epub 2013 Mar 26]

ObjectiveTo investigate the influence of diabetes mellitus (DM) on late genitourinary (GU) and gastrointestinal (GI) toxicity in patients treated with external beam radiotherapy (RT) for prostate cancer.Materials and methodsA total of 626 men were treated with curative-intent RT for prostate cancer from 1988 to 2008. Using the National Comprehensive Cancer Network risk category, the patients were considered to have low-risk (30%), intermediate-risk (42%), or high-risk (28%) prostate cancer. The median radiation dose was 74 Gy; 45% received androgen deprivation therapy for a median of 4 months. Late GU and GI Radiation Therapy Oncology Group toxicity was recorded prospectively at each visit after external beam RT. The median follow-up period was 55 months.ResultsOf the 626 men, 102 (16%) had DM that was controlled by diet (8%), oral medications (52%), or insulin (39%). The patients with DM were more likely to receive intensity-modulated RT and androgen deprivation therapy and to have a shorter follow-up duration (P≤.05 for all). Univariate analyses demonstrated that greater radiation dose, baseline urinary dysfunction, intensity-modulated RT, and DM were associated with grade 2 or greater GU toxicity, and transurethral resection of the prostate and DM were associated with grade 3 or greater GU toxicity. In addition, androgen deprivation therapy use, age≥70 years, and anticoagulation were associated with grade 2 or greater GI toxicity, and age≥70 years and anticoagulation were associated with grade 3 or greater GI toxicity. The multivariate analyses for late toxicity demonstrated a greater risk of grade 2 or greater (relative risk 1.36, P = .10) and grade 3 or greater GU toxicity (relative risk 2.74, P = .04) with DM.ConclusionA greater incidence of late GU toxicity was seen in patients with DM treated for prostate cancer. This relationship might be useful when considering the treatment of patients with DM, especially those receiving dose-escalated RT or with a history of transurethral resection of the prostate.     

High rates of advanced disease,complications, and decline of renal function after radical nephroureterectomy

ObjectivesRecurrences remain common following radical nephroureterectomy (RNU) for locally advanced upper-tract urothelial carcinoma (UTUC). We review a cohort of RNU patients to identify the incidence of locally advanced disease, decline in renal function, complications, and utilization of adjuvant chemotherapy (AC).MethodsInstitutional databases from 7 academic medical centers identified 414 RNU patients treated between 2003 and 2012 who had not received neoadjuvant chemotherapy. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation. Complications were classified according to the modified Clavien system. Cox proportional hazard modeling and Kaplan-Meier analysis determined factors associated with cancer-specific survival.ResultsOf 414 patients, 177 (43%) had locally advanced disease, including 118 pT3N0/Nx, 13 pT4N0/Nx, and 46 pTanyN+. Estimated 3- and 5-year cancer-specific survival was 47% and 34%, respectively. Only 31% of patients with locally advanced UTUC received AC. Mean estimated glomerular filtration rate declined from 59 to 51 ml/min/1.73 m² following RNU, including a new-onset decline below 60 and 45 ml/min/1.73 m² in 25% and 15% of patients, respectively (P<0.001 for both). Complications occurred in 46 of 177 (26%) patients, of which one-quarter were grade III or IV. Increasing age (Hazard Ratio (HR) 1.4, P = 0.03), positive surgical margins (HR 2.1, P = 0.01), and positive lymph nodes (HR 4.3, P<0.001) were associated with an increased risk of death from UTUC, whereas receipt of AC (HR 0.85, P = 0.05) was associated with a decrease in UTUC mortality.ConclusionsUnder one-third of RNU patients with locally advanced UTUC cancers received AC. Perioperative complications and decline in renal function may have contributed to this low rate. Such data further underscore the need for continued discussion regarding the use of chemotherapy in a neoadjuvant setting for appropriately selected patients with UTUC.     

Genetics of New-Onset Diabetes after Transplantation

New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic β-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in β-cell apoptosis. These results corroborate recent clinical evidence implicating β-cell dysfunction in the pathophysiology of new-onset diabetes after transplantation and support the pursuit of therapeutic strategies to protect β cells in the post-transplant period.One-year graft survival after renal transplantation is now excellent, exceeding 93% for organs donated after brain death and 96% for those from living donors.^1–3 Technical advancements in surgery, improved understanding of immunology, and innovative developments in pharmacology have altered the landscape of renal transplantation. The goal of preventing early graft loss has largely been achieved and arguably the greatest challenge now is the avoidance of late graft failure. Although there has been a considerable improvement in 1-year renal transplant survival, the rate of graft attrition after the first year remains frustratingly constant.^2,4New-onset diabetes after transplantation (NODAT) is a common and serious disorder that curtails recipient survival.^5–7 NODAT is associated with cardiovascular complications^8–11 and develops in 2%–50%¹² of renal transplant recipients. Approximately 50% of recipients with NODAT require insulin therapy.^{6–8,13–15} A number of clinical variables have been associated with NODAT, including black ethnicity, older recipient age, female sex, obesity, immunosuppression, and viral infections.^{5,6,8,13,16,17}Until recently, the pathophysiology of NODAT was considered to be analogous to type 2 diabetes mellitus. Renal transplant recipients have increased insulin resistance compared with transplant-naïve persons with normal renal function.¹⁸ In a nondiabetic renal transplant population, the main determinants of insulin resistance are obesity and corticosteroid therapy.¹⁹ Insulin resistance improves in renal transplant recipients after successful transplantation^20,21 and recipients have enhanced insulin sensitivity compared with dialysis patients.²² At 1 year, there is no significant difference in insulin resistance between renal transplant recipients with NODAT and those with normal glucose tolerance.^18,23 Furthermore, insulin resistance indices before transplantation and in the early post-transplant period do not predict NODAT development.¹¹Pancreatic β-cell dysfunction may prove to be the main pathologic contributor to NODAT. In glucose clamp studies, a deficit in insulin secretion was common to renal transplant recipients with NODAT.^18,20,21,24 There are a number of possible mechanisms for β-cell toxicity in renal transplantation, including hyperglycemia,²⁵ elevated free fatty acids,²⁶ and the effect of immunosuppressive medication.²⁷ A recent proof-of-concept clinical trial demonstrated that aggressive management of post-transplant hyperglycemia with insulin significantly reduced the 1-year incidence of NODAT.²⁸ This provides further evidence that post-transplant hyperglycemia plays a key role in NODAT development.This study investigates clinical and genetic factors associated with NODAT in a relatively large, white renal transplant population. Clinical variables were identified in a carefully phenotyped, ethnically homogeneous cohort. Initial exploratory analysis was conducted via a genome-wide association study (GWAS) in a subgroup of NODAT cases patients and controls to identify genetic variants associated with NODAT. De novo genotyping was then performed in a larger cohort of NODAT patients and controls to validate the findings.     

The variability of atlas-based targets in relation to surrounding major fibre tracts in thalamic deep brain stimulation

Background

In essential tremor (ET), the main target for deep brain stimulation (DBS) is the thalamic ventralis intermedius nucleus (Vim). This target cannot be identified on conventional magnetic resonance imaging (MRI). Therefore, targeting depends on probabilistic coordinates derived from stereotactic atlases. The goal of our study was to investigate the variability of atlas-based Vim targets in relation to surrounding major fibre tracts.

Methods

With the MRI and computed tomography (CT) scan data of ten patients who underwent DBS, we planned atlas based Vim targets in both hemispheres. We also performed deterministic fibre-tracking with diffusion tensor imaging (DTI) of the dentato-rubro-thalamic tract (DRTT), pyramidal tract (PT) and lemniscus medialis (LM) in all 20 hemispheres. Subsequently, we measured the distance from the atlas-based Vim target to each tract along the medial/lateral (x-coordinate), anterior/posterior (y-coordinate) and superior/inferior axis (z-coordinate).

Results

Seventeen out of 20 DRTTs could be depicted with our standardised DTI/fibre-tracking parameters. The PT and the LM could be displayed in all 20 hemispheres. The atlas-based Vim target was found inside the DRTT in 11 (concerning the x-coordinate) and 10 hemispheres (concerning the z-coordinate). Regarding the anterior/posterior direction, the target was posterior to the DRTT in 11 cases. In 19 hemispheres the Vim target was located medial and superior to the PT and in 17 hemispheres posterior to it. Concerning the LM, the Vim target was found inside the LM in 16 (regarding the x-coordinate) and in 14 cases (regarding the z-coordinate). In eight cases it was located inside and in 12 cases anterior to the LM concerning the y-coordinate.

Conclusions

We found a considerable variability of the location of atlas-based target points of the ventralis intermedius nucleus in relation to neighbouring major fibre tracts in individual patients. These results suggest that individualised targeting to structures not directly visible on conventional MRI is necessary.