Successful simultaneous liver-kidney transplantation for renal failure associated with hereditary complement C3 deficiency.

Hereditary complement C3 deficiency is associated with recurrent bacterial infections and proliferative glomerulonephritis. We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis, and end-stage renal failure. Following isolated kidney transplantation he would remain C3 deficient with a similar, or increased, risk of infections and glomerulonephritis. As C3 is predominantly synthesized in the liver, with a small proportion of C3 monocyte derived and kidney derived, he proceeded to simultaneous liver-kidney transplantation. The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow-up. Simultaneous liver-kidney transplant is a viable option to be considered in this rare setting.

Unification of a common biochemical failure definition for prostate cancer treated with brachytherapy or external beam radiotherapy with or without androgen deprivation.

PURPOSE: Minimal data are available regarding selection of an optimal biochemical failure (BF) definition for patients treated with brachytherapy, external beam radiotherapy (EBRT), and combinations of these treatments with or without androgen deprivation (AD). We retrospectively analyzed our institution's experience treating localized prostate cancer in an attempt to determine a BF definition that could be applied for these various treatment modalities. METHODS AND MATERIALS: A total of 2376 patients with clinical stage T1-T3 N0 M0 prostate cancer were treated with conventional dose (median, 66.6 Gy) EBRT (n = 1201), high-dose (median, 75.6 Gy) adaptive radiation therapy (n = 465), EBRT + high-dose-rate brachytherapy boost (n = 416), or brachytherapy alone (n = 294) between 1987 and 2003. A total of 496 patients (21%) received neoadjuvant AD with radiation therapy. There were 21924 posttreatment prostate-specific antigen (PSA) measurements. Multiple BF definitions were tested for their sensitivity, specificity, positive predictive value (+PV), and negative PV (-PV) in predicting subsequent clinical failure (CF) (any local failure or distant metastasis), overall survival (OS), and cause-specific survival (CSS). Median follow-up was 4.5 years. The date of BF was the date BF criteria were met (e.g., date of third rise). RESULTS: A total of 290 patients (12%) experienced CF at a median interval of 3.6 years (range, 0.2-15.2 years). The 5- and 10-year CF rates were 12% and 26%, respectively. Three consecutive rises yielded a 46% sensitivity and 84% specificity for predicting CF. The 10-year CF for those 475 patients who experienced three rises (BF) was 37% vs. 17% for those patients who did not meet these criteria (biochemically controlled [BC]). For all patients, the following definitions were superior to three rises for predicting CF for both +PV, and -PV: n + 1 (> or =1 ng/mL above nadir), n + 2, n + 3, threshold 2 (any PSA > or =2.0 ng/mL at or after nadir), threshold 3, threshold 4, and threshold 5. For the subset of patients treated with EBRT alone, the n + k definitions and threshold k definitions maintained superior predictive capacity. However, the threshold k definitions seemed to maintain a slightly greater separation in 10-year CF rates (43% for BF vs. 13% for BC = 30% difference for threshold 3). Surprisingly, all definitions generally had better predictive capacity for those patients who received brachytherapy or neoadjuvant AD vs. EBRT alone. The endpoints appeared similar for n + 1 vs. threshold 3 and n + 2 vs. threshold 4 in EBRT alone patients, but for brachytherapy or neoadjuvant AD patients, there were similarities for n + 2 vs. threshold 3 and n + 3 vs. threshold 4. This may be a reflection of the lower nadir levels in patients receiving AD (median <0.1 ng/mL vs. 0.2 ng/mL for brachytherapy vs. 0.8 ng/mL for EBRT alone, p < 0.01). When examining CF correlation for the various classes of BF definitions, the threshold k definitions clearly demonstrated the greatest area under the receiver operating characteristic curve, followed by the n + k definitions. For OS, the threshold k definitions again demonstrated the greatest area under the curve, followed by definitions based on specific nadir cutoffs (nadir > or =k ng/mL). CONCLUSIONS: Biochemical failure definitions applying a PSA threshold at or after the nadir (e.g., threshold 3) demonstrated the highest association with CF, OS, and CSS for all assessed treatment modalities. Definitions incorporating a PSA increase above the nadir value (e.g., nadir + 2 ng/mL) were also superior for all modalities. In general, BF definitions have greater predictive capacity for clinical outcome with brachytherapy or neoadjuvant AD than EBRT alone, possibly because of less "noise" from production of background PSA.

Cardiomyopathy responsive to gluten withdrawal in a patient with coeliac disease.

A 57-year-old man with iron deficiency anaemia developed general malaise, exertional dyspnoea and features of cardiac failure out of proportion to his anaemia (haemoglobin 120 g/L). Investigations showed a severely dilated left ventricle with an ejection fraction of 15%, due to dilated cardiomyopathy. He was treated with high-dose diuretics, ACE inhibitors and ß-blocker therapy. Subsequent investigation into his iron deficiency anaemia revealed a new diagnosis of coeliac disease. After starting a gluten-free diet, his cardiac function improved markedly, with ejection fraction reaching 70%, allowing his cardiac medications to be withdrawn. This case suggests a link between coeliac disease and cardiomyopathy.

Intrafraction variation of mean tumor position during image-guided hypofractionated stereotactic body radiotherapy for lung cancer.

PURPOSE: Prolonged delivery times during daily cone-beam computed tomography (CBCT)-guided lung stereotactic body radiotherapy (SBRT) introduce concerns regarding intrafraction variation (IFV) of the mean target position (MTP). The purpose of this study was to evaluate the magnitude of the IFV-MTP and to assess target margins required to compensate for IFV and postonline CBCT correction residuals. Patient, treatment, and tumor characteristics were analyzed with respect to their impact on IFV-MTP. METHODS AND MATERIALS: A total of 126 patients with 140 tumors underwent 659 fractions of lung SBRT. Dose prescribed was 48 or 60 Gy in 12 Gy fractions. Translational target position correction of the MTP was performed via onboard CBCT. IFV-MTP was measured as the difference in MTP between the postcorrection CBCT and the posttreatment CBCT excluding residual error. RESULTS: IFV-MTP was 0.2 ± 1.8 mm, 0.1 ± 1.9 mm, and 0.01 ± 1.5 mm in the craniocaudal, anteroposterior, and mediolateral dimensions and the IFV-MTP vector was 2.3 ± 2.1 mm. Treatment time and excursion were found to be significant predictors of IFV-MTP. An IFV-MTP vector greater than 2 and 5 mm was seen in 40.8% and 7.2% of fractions, respectively. IFV-MTP greater than 2 mm was seen in heavier patients with larger excursions and longer treatment times. Significant differences in IFV-MTP were seen between immobilization devices. The stereotactic frame immobilization device was found to be significantly less likely to have an IFV-MTP vector greater than 2 mm compared with the alpha cradle, BodyFIX, and hybrid immobilization devices. CONCLUSIONS: Treatment time and respiratory excursion are significantly associated with IFV-MTP. Significant differences in IFV-MTP were found between immobilization devices. Target margins for IFV-MTP plus post-correction residuals are dependent on immobilization device with 5-mm uniform margins being acceptable for the frame immobilization device.

Percentage of positive biopsy cores: a better risk stratification model for prostate cancer?

PURPOSE: To assess the prognostic value of the percentage of positive biopsy cores (PPC) and perineural invasion in predicting the clinical outcomes after radiotherapy (RT) for prostate cancer and to explore the possibilities to improve on existing risk-stratification models. METHODS AND MATERIALS: Between 1993 and 2004, 1,056 patients with clinical Stage T1c-T3N0M0 prostate cancer, who had four or more biopsy cores sampled and complete biopsy core data available, were treated with external beam RT, with or without a high-dose-rate brachytherapy boost at William Beaumont Hospital. The median follow-up was 7.6 years. Multivariate Cox regression analysis was performed with PPC, Gleason score, pretreatment prostate-specific antigen, T stage, PNI, radiation dose, androgen deprivation, age, prostate-specific antigen frequency, and follow-up duration. A new risk stratification (PPC classification) was empirically devised to incorporate PPC and replace the T stage. RESULTS: On multivariate Cox regression analysis, the PPC was an independent predictor of distant metastasis, cause-specific survival, and overall survival (all p < .05). A PPC >50% was associated with significantly greater distant metastasis (hazard ratio, 4.01; 95% confidence interval, 1.86-8.61), and its independent predictive value remained significant with or without androgen deprivation therapy (all p < .05). In contrast, PNI and T stage were only predictive for locoregional recurrence. Combining the PPC (≤50% vs. >50%) with National Comprehensive Cancer Network risk stratification demonstrated added prognostic value of distant metastasis for the intermediate-risk (hazard ratio, 5.44; 95% confidence interval, 1.78-16.6) and high-risk (hazard ratio, 4.39; 95% confidence interval, 1.70-11.3) groups, regardless of the use of androgen deprivation and high-dose RT (all p < .05). The proposed PPC classification appears to provide improved stratification of the clinical outcomes relative to the National Comprehensive Cancer Network classification. CONCLUSIONS: The PPC is an independent and powerful predictor of clinical outcomes of prostate cancer after RT. A risk model replacing T stage with the PPC to reduce subjectivity demonstrated potentially improved stratification.

Adaptive image-guided radiotherapy (IGRT) eliminates the risk of biochemical failure caused by the bias of rectal distension in prostate cancer treatment planning: clinical evidence.

PURPOSE: Rectal distension has been shown to decrease the probability of biochemical control. Adaptive image-guided radiotherapy (IGRT) corrects for target position and volume variations, reducing the risk of biochemical failure while yielding acceptable rates of gastrointestinal (GI)/genitourinary (GU) toxicities. METHODS AND MATERIALS: Between 1998 and 2006, 962 patients were treated with computed tomography (CT)-based offline adaptive IGRT. Patients were stratified into low (n = 400) vs. intermediate/high (n = 562) National Comprehensive Cancer Network (NCCN) risk groups. Target motion was assessed with daily CT during the first week. Electronic portal imaging device (EPID) was used to measure daily setup error. Patient-specific confidence-limited planning target volumes (cl-PTV) were then constructed, reducing the standard PTV and compensating for geometric variation of the target and setup errors. Rectal volume (RV), cross-sectional area (CSA), and rectal volume from the seminal vesicles to the inferior prostate (SVP) were assessed on the planning CT. The impact of these volumetric parameters on 5-year biochemical control (BC) and chronic Grades ≥2 and 3 GU and GI toxicity were examined. RESULTS: Median follow-up was 5.5 years. Median minimum dose covering cl-PTV was 75.6 Gy. Median values for RV, CSA, and SVP were 82.8 cm(3), 5.6 cm(2), and 53.3 cm(3), respectively. The 5-year BC was 89% for the entire group: 96% for low risk and 83% for intermediate/high risk (p < 0.001). No statistically significant differences in BC were seen with stratification by RV, CSA, and SVP in quartiles. Maximum chronic Grades ≥2 and 3 GI toxicities were 21.2% and 2.9%, respectively. Respective values for GU toxicities were 15.5% and 4.3%. No differences in GI or GU toxicities were noted when patients were stratified by RV. CONCLUSIONS: Incorporation of adaptive IGRT reduces the risk of geometric miss and results in excellent biochemical control that is independent of rectal volume/distension while maintaining very low rates of chronic GI toxicity.

Long-term patterns of in-breast failure in patients with early stage breast cancer treated with breast-conserving therapy: a molecular based clonality evaluation.

BACKGROUND: The clonality of ipsilateral breast tumor recurrences (IBTR) after breast-conserving therapy (BCT) was established using a polymerase chain reaction-based allelic imbalance assay of microsatellite loci to compare tumor suppressor gene alteration patterns. METHODS: The clonality of IBTRs relative to the initial invasive carcinomas were analyzed using a polymerase chain reaction-based allelic imbalance assay in 57 patients treated with BCT, including both whole breast irradiation and accelerated partial breast irradiation. RESULTS: Thirty-four IBTRs (60%) were clonally related to the initial carcinoma and 23 (40%) were clonally different. Clonally related IBTRs were more frequently higher grade (70% vs. 32%, P = 0.019) and developed sooner after initial treatment (mean time interval to IBTR was 5.1 years in clonally related versus 9.3 years in clonally different cases [P = 0.002]). Twelve patients subsequently developed distant metastases, of which 9 (75%) had clonally related IBTRs. Clinical IBTR classification and molecular clonality assay results differed in 44% of all cases. The proportion of IBTRs that were clonally related at 5, 10, and 15 years after BCT were 82%, 48%, and 33%, respectively. CONCLUSIONS: This analysis demonstrates the inaccuracy of clinically establishing the clonality of most IBTRs. Clonally related IBTRs occurred sooner than clonally different IBTRs, were more frequently associated with the development of distant metastases and had a worse prognosis. Molecular clonality assays provide a reliable means of identifying patients who may benefit from aggressive systemic therapy at the time of IBTR and provide an accurate assessment of the efficacy of various forms of local therapy.

Volumetric modulated arc therapy for delivery of hypofractionated stereotactic lung radiotherapy: A dosimetric and treatment efficiency analysis.

PURPOSE/OBJECTIVE(S): Volumetric modulated arc therapy (VMAT) allows for intensity-modulated radiation delivery during gantry rotation with dynamic MLC motion, variable dose rates and gantry speed modulation. We compared VMAT plans with 3D-CRT for hypofractionated lung radiotherapy. MATERIALS/METHODS: Twenty-one 3D-CRT plans for Stage IA lung cancer previously treated stereotactically were selected. VMAT plans were generated by optimizing machine aperture shape and radiation intensity at 10 degrees intervals. A partial arc range of 180 degrees was manually selected to coincide with tumor location. The arc was resampled down to 5 degrees intervals to ensure dose calculation accuracy. Identical planning objectives were used for VMAT/3D-CRT. Parameters assessed included dose to PTV and organs-at-risk (OAR), monitor units, and multiple conformity and homogeneity indices. Plans were delivered to a phantom for time comparison. RESULTS: Lung V(20/12.5/10/5) were less with VMAT (relative reduction 4.5%, p = .02; 3.2%, p = .01; 2.6%, p = .01; 4.2%, p = .03, respectively). Mean/maximum-doses to PTV, dose to additional OARs, 95% isodose line conformity, and target volume homogeneity were equivalent. VMAT improved conformity at both the 80% (1.87 vs. 1.93, p = .08) and 50% isodose lines (5.19 vs. 5.65, p = .01). Treatment times were reduced significantly with VMAT (mean 6.1 vs. 11.9 min, p < .01). CONCLUSIONS: Single arc VMAT planning achieves highly conformal dose distributions while controlling dose to critical structures, including significant reduction in lung dose volume parameters. Employing a VMAT technique decreases treatment times by 37-63%, reducing the chance of error introduced by intrafraction variation. The quality and efficiency of VMAT is ideally suited for stereotactic lung radiotherapy delivery.

PSA bounce after prostate brachytherapy with or without neoadjuvant androgen deprivation.

PURPOSE: To assess the impact of PSA bounce (PB) on biochemical failure (BF) and clinical failure (CF) in brachytherapy patients treated with or without neoadjuvant androgen deprivation (AD). METHODS AND MATERIALS: From 1987 to 2003, 691 patients with clinical stage T1-T3N0M0 prostate cancer were treated with external beam radiotherapy (EBRT) and high-dose-rate (HDR) brachytherapy boost (n=407), HDR brachytherapy alone (n=93), or permanent seed implant (n=191). Three hundred seventeen patients (46%) received neoadjuvant/adjuvant AD with RT. BF was scored using 3 definitions (ASTRO--3 rises, nadir+2 ng/ml, and threshold 3 ng/ml) based on current and absolute nadir (AN) methodologies. PB was defined as any increase in PSA followed by a decrease to the prior baseline or lower. The median followup was 4.0 years. RESULTS: Forty-six patients (7%) experienced CF at 5 years. PB of >or=0.1, >or=1.0, and >or=2.0 ng/ml at any time after RT occurred in 330 (48%), 60 (9%), and 22 patients (3%) respectively. The use of an AN definition reduced the likelihood of scoring PB as BF across all levels. The patients receiving AD experienced significantly longer bounce duration. Bounce <1.0 ng/ml showed no association with CF. For bounce >or=1.0 ng/ml, 10% demonstrated CF vs. 6% without bounce of this amplitude (p=0.27). Bounces >or=1.0 ng/ml were more likely to be scored as BFs for definitions based on current nadir (3 rises: 20% vs. 13%, nadir+2: 43% vs. 11%, 3 at/after nadir: 57% vs. 12%) than those based on AN (3 rises: 8% vs. 10%, nadir+2: 18% vs. 11%, 3 at/after nadir: 13% vs. 11%). CONCLUSIONS: Bounces >or=1.0 ng/ml are rare after brachytherapy with or without neoadjuvant AD, occurring in less than 10% of patients. Low PBs have little impact on BF, but as PB amplitude increases, the BF rate increases. BF definitions based on AN are less sensitive to PB after brachytherapy.