Abstract ▪785▪This icon denotes a clinically relevant abstract
FLT3 internal tandem duplications (FLT3-ITD) occur in about 25% of acute myeloid leukemia (AML), are associated with cooperating gene ...mutations (NPM1, DNMT3A), and confer an adverse prognosis. Several studies have indicated that the unfavorable impact of FLT3-ITD is influenced by a number of factors, such as the mutant to wild-type ratio (allelic ratio), insertion site of FLT3-ITD in the beta1 sheet of the tyrosine kinase domain 1, and the molecular background of cooperating mutations.
To evaluate the relative impact of FLT3-ITD allelic ratio and insertion site, as well as cooperating genetic lesions on prognosis and treatment decision making in a large cohort of homogeneously treated younger adult patients.
The basis of the study were 2377 younger adults (median age, 48 years; range, 16–62 years) with newly diagnosed AML enrolled on three prospective treatment trials of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. Patients with acute promyelocytic leukemia (n=99), core-binding factor AML (n=279) and AML with adverse-risk cytogenetics (n=436) according to the European LeukemiaNet recommendations were excluded. Based on material availability, the presence of FLT3-ITD could be analyzed in 1414 patients; NPM1 and DNMT3A mutational status was available in 97% and 84% of the patients, respectively. In FLT3-ITD positive AML (n=394), the allelic ratio, determined by Genescan-based fragment-length analysis, was available in 86% and the insertion site in 72%. Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission was performed in 41% and 29% of FLT3-ITD positive and negative patients, respectively.
We first evaluated the prognostic impact of the different FLT3-ITD characteristics within the subgroup of FLT3-ITD positive patients. The allelic ratio was categorized into quartiles ranging from low to high. For the endpoints event-free (EFS), relapse-free (RFS) and overall survival (OS), only the fourth quartile with the highest allelic ratio showed a prognostic impact for all endpoints, whereas no difference was identified between the other three quartiles. For further analyses, the allelic ratio was dichotomized comparing the fourth quartile versus the other three quartiles. FLT3-ITD insertion site in the beta1 sheet was significantly associated with an unfavorable outcome for all endpoints. Additionally, FLT3-ITD size was directly correlated with the insertion site: the more C-terminal the ITD inserted in the FLT3 gene the longer the FLT3-ITD size. There was no prognostic impact of FLT3-ITD size neither as continuous nor as quartile-categorized variable. Multiple FLT3-ITDs, present in 13% of AMLs, were associated with an unfavorable prognosis. The presence of either NPM1 and/or DNMT3A mutations in FLT3-ITD positive patients did not alter the original FLT3 prognosis. In multivariable models for the endpoint OS of the total cohort of intermediate-risk AML, an independent prognostic impact beyond the variable FLT3-ITD was shown for the allelic ratio (fourth quartile) HR, 1.4; p=0.037 and in trend for insertion site in the beta1 sheet HR, 1.33; p=0.06. Survival of patients exhibiting a high allelic ratio (n=43) or insertion site in the beta1 sheet (n=60) was comparable, with a median of 10 and 13 months and 4-year survival of 19% and 24%, respectively. Of note, outcome of patients with both high allelic ratio and insertion site in the beta1 sheet (n=21) was very poor with a median OS of 10 months and 4-year OS of 5%, respectively. In patients with FLT3-ITD positive AML without these unfavorable factors (n=144), median and 4-year OS were 15 months and 42%, respectively. Of note, a clear benefit of allogeneic HSCT in first CR was only seen in FLT3-ITD positive patients without these two unfavorable factors, with a 4-year OS of 63%. In comparison, the 4-year OS of the same subgroup of patients achieving a CR after induction therapy without proceeding to allogeneic HSCT during first CR was 35%. In contrast, outcome in patients with high allelic ratio and/or insertion site in the beta1 sheet remained poor despite allogeneic HSCT in first CR.
High FLT3-ITD allelic ratio and ITD insertion site in the beta1 sheet presented as prognostic indicators for poor outcome in patients with the presence of a FLT3-ITD. Only patients without these unfavorable FLT3-ITD features significantly benefitted from allogeneic HSCT.
Schlenk:Roche: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.
Background:Despite recent advances in identifying novel molecular targets in AML patients, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) still remains a ...cornerstone of AML therapy. However, outcome of HSCT depends on the availability of a donor and the donor type. Prior studies comparing HSCT from HLA-matched related donors (MRD) with matched unrelated donors (MUD), demonstrated conflicting results with regards to outcome. These conflicting results might be attributed to the genetic heterogeneity of AML.
Aims:To analyze outcome with respect to donor type of 952 AML patients who received HSCT in first complete remission (CR) and were treated within prospective AMLSG trials.
Methods:Within the AMLSG trials conducted between 1993 and 2013, of a total of 4991 patients (excluding acute promyelocytic leukemia), 3408 (2744 younger (<61 years old), 664 older (≥61 years old)) patients achieved a first CR after intensive double induction therapy. Of these, 867 (31%) younger and 85 (13%) older patients received HSCT in first CR. Distributions of donor types were 511 matched related donors (MRD), 435 matched unrelated donors (MUD) and 6 haplo-identical donors. The latter were grouped together with MUD.
Results:Distributions of donor type over time are illustrated in table 1 indicating two clear trends with increasing numbers of MUD transplants and increasing median age in MUD- and MRD-transplants in recent years. There was no significant difference in overall survival, cumulative incidence of relapse (CIR) and death (CID) all estimated at 4 years according to the three time periods for MRD (p=0.56, p=0.15, p=0.10, respectively) and MUD (p=0.27, p=0.20, p=0.88, respectively).
Table 1Time period1993-20022003-20072008-2013Total no.103611021270MRDNo.186 (18%)182 (17%)143 (11%)Median age42.7yrs46.0yrs51yrs4-yr-OS (95%-CI)59% (53-67)66% (59-73)61% (53-72)4-yr-CIR (SE)21% (3%)25% (3%)29% (4%)4-yr-CID (SE)25% (3%)15% (3%)18% (3%)MUDNo.42 (4%)131 (12%)268 (21%)Median age41.1yrs47.9yrs50.6yrs4-yr-OS (95%-CI)52% (39-70)46% (38-58)54% (47-61)4-yr-CIR (SE)21% (3%)25% (3%)29% (4%)4-yr-CID (SE)25% (3%)15% (3%)18% (3%)
Table 2ELN risk categorylowinter-1inter-2highTotal no.867711433318MRDNo.78 (9%)122 (17%)66 (15%)57 (18%)4-yr-OS (95%-CI)84% (76-93)50% (51-69)53% (41-67)57% (44-72)4-yr-CIR (SE)7% (3%)24% (4%)35% (6%)49% (7%)4-yr-CID (SE)13% (4%)23% (4%)23% (6%)12% (4%)MUDNo.21 (2%)139 (20%)76 (18%)109 (36%)4-yr-OS (95%-CI)69% (52-93)58 (49-68)52% (41 67)35% (26-46)4-yr-CIR (SE)0%28% (4%)32% (6%)44% (5%)4-yr-CID (SE)31% (11%)20% (4%)17% (5%)28% (4%)
There were no differences in stratified survival analyses for time period between MRD and MUD-transplants in the low, intermediate-1 and intermediate-2 risk groups with respect to OS (p=0.12, p=0.86, p=0.98), CIR (p=0.28, p=0.54, p=0.94) and CID (p=0.09, p=0.57, p=0.39). In the high risk group, OS was significantly superior after MRD-transplant compared to MUD-transplant (p=0.02), but without significant differences in CIR (p=0.74) and CID (p=0.08). Equivalent efficacy could also be shown in a subgroup analyses focusing on all FLT3-ITD positive patients (MRD, n=103, MRD, n=147) for OS (p=0.71), CIR (p=0.53) and CID (p=0.69).
Conclusions: Our results based on prospective interventional studies support the perception that MUD-transplants are equal to MRD-transplants in patients with AML in first CR. Only within the ELN high risk group, patients with MRD-transplants showed superior OS but without differences in CIR and CID as compared to MUD-transplants.
Kobbe:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Petzer:Celgene: Honoraria, unrestricted grant Other. Lübbert:Cephalon / TEVA: Travel support Other. Greil:Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Döhner:Novartis: Research Funding. Döhner:TEVA: Research Funding.
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Overall survival (OS) in acute myeloid leukemia (AML) treated with intensive chemotherapy has improved over the last 20 year especially in younger adults (18-60 years) but still remains poor in ...older patients (>60 years) (Döhner et al. Blood 2010). The German-Austrian AMLSG performed controlled prospective treatment trials since 1993 starting with a risk-adapted approach (phase I, 1993-1997), followed by randomized and risk-adapted treatment strategies based on cytogenetic risk groups (phase II, 1997-2002); since 2003 addition of differentiating agents and HiDAC inhibitors to intensive induction therapy was evaluated (phase III, 2003-2007). Of note, until 2007 younger and older patients (> 60 years) were treated in separate protocols with significantly lower dosages of chemotherapy in older patients. Starting from 2008, risk-adapted therapies were replaced successively by a genotype-adapted approach and the artificial age cut-off at 60 years was abandoned (phase IV, 2008-2012).
To evaluate the outcome of adult AML patients within the different time periods.
The study included 4705 intensively treated adults (younger, n=3546; older, n=1159) with newly diagnosed AML enrolled on 11 AMLSG treatment trials between 1993 and 2012. Patients with acute promyelocytic leukemia were excluded. All patients received intensive induction and consolidation therapy. Analyzed outcome variables were first complete remission rates (CR1), relapse-free survival (RFS), survival after relapse (SAR) and OS. Analyses were performed according to age groups (18-60 vs. >60 yrs). In younger patients comparisons were performed for the 4 treatment phases (I-IV), whereas for older patients analyses were restricted to phase II-IV.
In younger patients CR rates did not improve over time (1993-2013) and varied between 72% and 77% (p=0.12), whereas early and hypoplastic (ED/HD) death rates significantly declined from 10% to 5% (p=0.0001). In older patients CR rates significantly improved over time from 44% to 50% between 1998 and 2007 to 67% after 2008 (p<0.0001); ED/HD rates gradually declined from 12% to 8%, but the difference was not statistically significant (p=0.17).
The proportion of younger patients receiving an allogeneic hematopoietic stem cell transplantation (alloHSCT) increased from 30% (15% in CR1) in phase I to 58% (29% in CR1) in phase III and remained there in phase IV with 53% (26% CR1), whereas the proportion of patients receiving an autologous HSCT constantly decreased from maximally 16% (15% in CR1) in phase II to 0.4% (0.2% in CR1) in phase IV; the proportion of older patients receiving an alloHSCT steadily increased from 4% (2% CR1) in phase II to 21% (12% CR1) in phase IV; autoHSCT was rarely performed. OS at 4 years in both age groups significantly improved (p<0.0001, each) from 41% to 56% and from 10% to 23% in younger and older patients, respectively. This beneficial effect on OS over time in younger patients was due to a better RFS (p=0.01) and SAR (p<0.0001), whereas in older patients no improvement in RFS (p=0.20) and only in trend for SAR (p=0.07) was noted. In cytogenetically high-risk patients, OS in younger (p=0.001) and in older (p=0.007) patients got better; in older patients mainly driven by increase in CR rates (p=0.001) and in younger patients by an improvement in RFS (p=0.02) and SAR (p=0.05). Nearly the same pattern was identified for cytogenetically intermediate risk patients with a better OS in younger (p<0.0001) and older patients (p=0.01) due to higher CR rates in older patients (p<0.0001), no improvement in RFS in both age groups and a significantly better SAR in younger patients (p=0.0002). In contrast, in low risk patients improvement in OS was only present in older patients (p=0.02), due to a better RFS in older patients (p=0.02) but without any progress in younger patients. Furthermore we performed two subgroup analyses in intermediate risk patients. In the subgroup of patients characterized by the genotype NPM1-mut/FLT3-ITDneg a significant better OS was present only in younger patients (p=0.03); in FLT3-ITD positive AML a better OS was seen in younger patients (p<0.0001) due to a better RFS (p=0.05) and SAR (p=0.01).
Based on the German-Austrian AMLSG experience the prognosis in younger and older AML patients has improved over time. In older patients this is mainly a result of higher CR rates and in younger patients of better RFS and SAR.
Schlenk:Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Greil:Novartis: Honoraria, Research Funding.
Background
The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) have focused on adult patients. Many of the previous recommendations have not ...been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1‐INH‐HAE.
Methods
During an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting.
Results
The symptoms of C1‐INH‐HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1‐INH‐HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1‐INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1‐INH‐HAE family member should be screened for C1‐INH deficiency. Pediatric patients should always carry a C1‐INH‐HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma‐derived C1‐INH, recombinant C1‐INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center.
Conclusions
The pediatric‐focused international consensus for the diagnosis and management of C1‐INH‐HAE patients was created.
The use of aprotinin to reduce blood loss after cardiopulmonary bypass is under debate. Concern has been raised about the renal effects of aprotinin. We administered a mean aprotinin dose of 4.2 x ...10(6) kallikrein-inhibiting units to 13 patients with coronary disease undergoing cardiopulmonary bypass for 74 +/- 5 minutes (mean +/- standard error of the mean); 13 comparable patients having cardiopulmonary bypass served as control subjects, and all were studied postoperatively for 24 hours. Aprotinin reduced postoperative blood loss by 50% (p = 0.0082). Two of the 13 patients who received aprotinin needed one red cell unit each versus a total of 18 units in eight of 13 control patients (p = 0.0096). Blood pressure, hemoglobin value and serum protein concentration were higher after operation in the aprotinin group (p less than 0.05 to p less than 0.01). Platelet counts did not differ, but plasma thromboxane was lower in aprotinin recipients (p less than 0.001). In control patients fibrinogen degradation products (D dimer) doubled, and alpha 2-antiplasmin activity was halved during and after cardiopulmonary bypass (p less than 0.01 to p less than 0.001), whereas aprotinin patients showed no changes. The complement breakdown products C4a, C3a, and C3dg as well as C9 neoantigen increased from prebypass baseline in both groups (p less than 0.001); the increment of C3a and C3dg was greater in the aprotinin than in the control patients (p less than 0.001). Serum electrolytes, osmolality, and creatinine remained normal in both groups of patients. Creatinine clearance was normal or above normal and virtually identical in both groups. Osmolar clearance and fractional sodium excretion were higher in the aprotinin group than in the control group shortly after cardiopulmonary bypass (p less than 0.05 to p less than 0.01); renal function was unremarkable the next morning. No adverse clinical effects attributable to aprotinin were seen. In summary, aprotinin offers advantages for cardiopulmonary bypass.
Impaired platelet function and a bleeding tendency are well-recognized complications of chronic renal failure. Because the fibrinogen receptor GPIIb-IIIa plays a central role in platelet aggregation ...and adhesion to the subendothelium, it was reasoned that a defect in this receptor may underlie the impaired platelet function in uremia. To test this hypothesis, the function of this receptor in the platelets of 11 uremic patients was studied. Aggregation studies were performed with flow cytometric techniques with anti-GPIIb-IIIa conformation-specific monoclonal antibodies (mAb) (anti-LIBS1 and anti-PMI-1). Antifibrinogen and antithrombospondin mAb were used to characterize fibrinogen binding to GPIIb-IIIa and the release of alpha-granules, respectively. Platelets from patients with chronic renal failure showed significantly decreased binding of conformation-dependent anti-LIBS1 mAb after ADP, phorbol myristate acetate, or RGD-peptide stimulation compared with normal controls, suggesting a defect related to the ability of the fibrinogen receptor to undergo a conformational change. Moreover, antifibrinogen and antithrombospondin binding to activated platelets were reduced in uremic patients, implying impairment of both ligand-binding and alpha-granule release. Hemodialysis partially restored GPIIb-IIIa function, which may account for the observed effects of this therapy in restoring platelet aggregation. These findings indicate that platelets of patients with chronic renal failure reveal an aggregation defect at least partially due to an intrinsic GPIIb-IIIa dysfunction and the presence of a putative uremic toxin that inhibits fibrinogen binding to GPIIb-IIIa.
Aberrant subclavian artery (ASA) and Kommerell's diverticulum (KD) are rare vascular anomalies that may be associated with lifestyle-limiting and life-threatening complications. The aim of this study ...is to report contemporary outcomes after invasive treatment of ASA/KD using a large international dataset.
Patients who underwent treatment for ASA/KD (2000-2020) were identified through the Vascular Low Frequency Disease Consortium, a multi-institutional collaboration to investigate uncommon vascular disorders. We report the early and mid-term clinical outcomes including stroke and mortality, technical success, and other operative outcomes including reintervention rates, patency, and endoleak.
Overall, 285 patients were identified during the study period. The mean patient age was 57 years; 47% were female and 68% presented with symptoms. A right-sided arch was present in 23%. The mean KD diameter was 47.4 mm (range, 13.0-108.0 mm). The most common indication for treatment was symptoms (59%), followed by aneurysm size (38%). The most common symptom reported was dysphagia (44%). A ruptured KD was treated in 4.2% of cases, with a mean diameter of 43.9 mm (range, 18.0-100.0 mm). An open procedure was performed in 101 cases (36%); the most common approach was ASA ligation with subclavian transposition. An endovascular or hybrid approach was performed in 184 patients (64%); the most common approach was thoracic endograft and carotid-subclavian bypass. A staged operative strategy was employed more often than single setting repair (55% vs 45%). Compared with endovascular or hybrid approach, those in the open procedure group were more likely to be younger (49 years vs 61 years; P < .0001), female (64% vs 36%; P < .0001), and symptomatic (85% vs 59%; P < .0001). Complete or partial symptomatic relief at 1 year after intervention was 82.6%. There was no association between modality of treatment and symptom relief (open 87.2% vs endovascular or hybrid approach 78.9%; P = .13). After the intervention, 11 subclavian occlusions (4.5%) occurred; 3 were successfully thrombectomized resulting in a primary and secondary patency of 95% and 96%, respectively, at a median follow-up of 39 months. Among the 33 reinterventions (12%), the majority were performed for endoleak (36%), and more reinterventions occurred in the endovascular or hybrid approach than open procedure group (15% vs 6%; P = .02). The overall survival rate was 87.3% at a median follow-up of 41 months. The 30-day stroke and death rates were 4.2% and 4.9%, respectively. Urgent or emergent presentation was independently associated with increased risk of 30-day mortality (odds ratio OR, 19.8; 95% confidence interval CI, 3.3-116.6), overall mortality (OR, 3.6; 95% CI, 1.2-11.2) and intraoperative complications (OR, 8.3; 95% CI, 2.8-25.1). Females had a higher risk of reintervention (OR, 2.6; 95% CI, 1.0-6.5). At an aneurysm size of 44.4 mm, receiver operator characteristic curve analysis suggested that 60% of patients would have symptoms.
Treatment of ASA/KD can be performed safely with low rates of mortality, stroke and reintervention and high rates of symptomatic relief, regardless of the repair strategy. Symptomatic and urgent operations were associated with worse outcomes in general, and female gender was associated with a higher likelihood of reintervention. Given the worse overall outcomes when symptomatic and the inherent risk of rupture, consideration of repair at 40 mm is reasonable in most patients. ASA/KD can be repaired in asymptomatic patients with excellent outcomes and young healthy patients may be considered better candidates for open approaches versus endovascular or hybrid modalities, given the lower likelihood of reintervention and lower early mortality rate.
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Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI can detect tissue-resident macrophage activity and identify cellular inflammation within tissues. We hypothesised that ...USPIO-enhanced MRI would provide a non-invasive imaging technique that would improve the diagnosis and management of patients with acute myocarditis.
Ten volunteers and 14 patients with suspected acute myocarditis underwent T2, T2* and late gadolinium enhancement (LGE) 3T MRI, with further T2* imaging at 24 hours after USPIO (ferumoxytol, 4 mg/kg) infusion, at baseline and 3 months. Myocardial oedema and USPIO enhancement were determined within areas of LGE as well as throughout the myocardium.
Myocarditis was confirmed in nine of the 14 suspected cases of myocarditis. There was greater myocardial oedema in regions of LGE in patients with myocarditis when compared with healthy volunteer myocardium (T2 value, 57.1±5.3 vs 46.7±1.6 ms, p<0.0001). There was no demonstrable difference in USPIO enhancement between patients and volunteers even within regions displaying LGE (change in R2*, 35.0±15.0 vs 37.2±9.6 s
, p>0.05). Imaging after 3 months in patients with myocarditis revealed a reduction in volume of LGE, a reduction in oedema measures within regions displaying LGE and improvement in ejection fraction (mean -19.7 mL, 95% CI (-0.5 to -40.0)), -5.8 ms (-0.9 to -10.7) and +6% (0.5% to 11.5%), respectively, p<0.05 for all).
In patients with acute myocarditis, USPIO-enhanced MRI does not provide additional clinically relevant information to LGE and T2 mapping MRI. This suggests that tissue-resident macrophages do not provide a substantial contribution to the myocardial inflammation in this condition.Clinical trial registration NCT02319278; Results.
Sera from 16 patients suffering from active psoriasis without arthropathy (2 guttate, 10 nummular, and 4 mixed type) were examined for the presence of circulating immune complexes. Five routine ...laboratory assay systems were used, based on C1q-binding or detection of IgG-coupled C1q and C3-breakdown products. In 14 patients, no elevated levels of circulating immune complexes were detected. One patient, who additionally suffered from late-phase HIV-1 infection, showed C1q-binding activities as well as levels of IgG-coupled C1q and C3-breakdown products in four of the assay systems, which indicated the presence of immune complexes in his serum. In another patient, with nummular psoriasis, slightly elevated levels of circulating immune complexes were measured by two of the assay systems. These results question the hypothesis of an essential pathogenic role of circulating immune complexes in psoriasis.
Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with ...overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/International Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. χ
-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2.
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