Independent Prognostic Factor For Progression Research Articles

The Clinical Significance of Maximum Tumor Diameter on MRI in Men Undergoing Radical Prostatectomy or Definitive Radiotherapy for Locoregional Prostate Cancer

The Clinical Significance of Maximum Tumor Diameter on MRI in Men Undergoing Radical Prostatectomy or Definitive Radiotherapy for Locoregional Prostate Cancer

Risk factors for oral epithelial dysplasias to become malignant: clinical implications

There is a lack of effective clinical management of oral epithelial dysplasias to reduce their risk of malignant transformation and considerable gaps in knowledge regarding the most effective means of treating such lesions. A retrospective cohort of biopsy-confirmed oral epithelial dysplasias consecutively diagnosed in the period 1995–2014 and followed-up until 2017 was identified from pathology department files. Demographic, clinical and follow-up information was collected. Multivariate Cox proportional-hazards models were performed to evaluate sociodemographic, clinical and pathological factors associated with progression to oral squamous cell carcinoma. The study included 144 oral epithelial dysplasias, of which 42% progressed to oral cancer at the end of follow-up (21 years). Clinical aspect of the lesion was described for 77 (53.5%) of the patients. Treatment, age, grade of the lesion and diagnostic period were independent prognostic factors for progression. When considering only patients with described clinical aspect, only treatment and grade of the lesion were independently associated with cancer. The results from this non-selected retrospective cohort of oral epithelial dysplasias underscore the existing limitations of the current standard-of-care of the patients and provide novel insights on the management of these lesions with and without described clinical aspect. Well-designed, robust prospective studies, a homogenized staging system and multidisciplinary treatment guidelines are warranted.

MDM4: A Novel Molecular Target for Treating Idiopathic Pulmonary Fibrosis Associated with Aging

Idiopathic pulmonary fibrosis (IPF) is the end stage of many diffuse parenchymal lung diseases typified by excessive matrix deposition leading to destruction of normal lung architecture and function of unknown etiology. Aging is considered as a strong risk factor and an independent prognostic factor for progression of IPF. However, the exact mechanisms that link the IPF with aging remained unknown, but a number of changes associated with aging revealed in IPF lungs. The p53 gene is a tumour suppressor gene that played a vital role in cancer and it is also known to have activity in fibrosis. MDM2 and MDM4 are the two major inhibitors of p53 .They only differ in their intrinsic E3-ligase activity and promote degradation of p53. MDM4 is a matrix stiffness -regulated negative regulator of p53 highly expressed in fibrotic lesions of IPF. Some of the invitro studies reported that MDM4-p53 pathway promoted lung fibrosis resolution in aged mice, this suggests that MDM4 can be better target against persistent lung fibrosis associated with aging. Also, better knowledge of the pathophysiological mechanisms linking aging to IPF may provide new therapeutic windows to treat this devastating disease.

Vertical Lamina Propria Invasion Diagnosed by En Bloc Transurethral Resection is a Significant Predictor of Progression for pT1 Bladder Cancer.

T1 bladder cancer is characterized by high recurrence and aggressive progression. Muscularis mucosae invasion may be a prognostic factor for progression, but the limitations of conventional transurethral resection of bladder tumors make diagnosis difficult. We correlated degree of invasion with oncologic outcome and evaluated the utility of pathological diagnosis following en bloc resection of bladder tumors. We retrospectively analyzed the records of 123 consecutive patients diagnosed with pT1 bladder cancer between November 2013 and December 2018. Transurethral resection was conducted in 91 patients, and en bloc resection in 32 patients. All specimens were analyzed for invasion depth and pT1 substaging (T1a/b: invasion above or into/beyond muscularis mucosae, pT1m/e: microinvasive or extensively invasive). Primary end points were prognostic values of pT1 substaging and invasion depth. The secondary end point was the pathological diagnostic utility of en bloc resection. Median followup was 23 months. Three-year progression-free survival rate differed significantly depending on muscularis mucosae invasion (pT1a: 97.3%, pT1b: 72.8%; p=0.003) and invasion depth from basal membrane (<2 mm: 90.6%, ≥2 mm: 77.9%; p=0.03). Multivariate analysis showed that sessile tumor and invasion depth from basal membrane ≥2 mm were independent prognostic factors for progression. Diagnostic rates for pT1a/b and invasion depth were 77.6% and 85.9%, respectively, with transurethral resection, but 100% and 100% with en bloc resection (p=0.01 and p=0.03). Vertical lamina propria invasion is predictive of progression in T1 bladder cancer, underlining the importance of accurately diagnosing the degree of vertical lamina propria invasion with en bloc resection.

Measurable Absolute Basophil Count is Associated with Progression to Muscle Invasive Disease in Patients with High-Grade Non-Muscle Invasive Bladder Cancer

Intravesical bacillus Calmette-Guérin (BCG) is the standard adjuvant treatment for high-grade non-muscle invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumor (TURBT). Despite this standard of care - 40% of patients experience a recurrence and - 15% progress to muscle invasive disease. Tumors with Th1-polarized lymphocytic infiltrate in the tumor immune microenvironment may have more favorable response to BCG compared to Th2- polarized tumors. Since basophils have a promoting role in Th2-polarization, we explored the association of blood basophils on the outcome of patients with high-grade NMIBC receiving BCG instillations. Clinical data and pre-operative complete blood count (CBC) results from patients with high-grade NMIBC (Ta, CIS and T1) who received BCG instillations at the Vancouver Prostate Centre (VPC) during years 2011 – 2018 were collected. Absolute basophil count (ABC) was correlated with response to BCG, disease recurrence and progression to muscle invasive disease. A total of 174 patients with primary high grade NMIBC treated with BCG at VPC were identified. Pre-operative complete blood count (CBC) data were available from 161 patients. After the initiation of BCG therapy 40% of patients developed recurrent tumors and 13% progressed to muscle invasive disease. ABC was measurable (³ 0.1 × 103 cells /µl) in the blood of 33 (19%) patients of whom 19 (58%) recurred. A total of 95% of recurrent tumors with measurable ABC were considered BCG-unresponsive. In Kaplan-Meier analysis measurable ABC was associated with tumor recurrence (p = 0.024) and progression to muscle invasive disease (p = 0.00015). In multivariate cox-regression analysis measurable ABC was considered an independent prognostic factor for progression to muscle invasive disease (HR 2.9, 95% CI:1.038 – 8.535, p = 0.042). Measurable blood absolute basophil count may have a prognostic impact for patients with high-grade NMIBC. Further studies with larger patient cohorts are needed to confirm these preliminary results.

Validation of Hyponatremia as a Prognostic Predictor in Multiregional Upper Tract Urothelial Carcinoma.

Hyponatremia has been shown to be associated with prognosis in various cancers, but its role in upper tract urothelial carcinoma (UTUC) is largely unidentified. We created an international multiregional cohort of UTUC, consisting of 524 and 213 patients from Taiwan and the U.S., to validate the significance of hyponatremia. Clinicopathologic characteristics were compared according to the presence of hyponatremia. Univariate and multivariate Cox regression models were used to investigate the association of hyponatremia with disease progression and survival. The impact of hyponatremia in patients from distinct regions was also analyzed. Hyponatremia was found in 143 (19.4%) patients. Hyponatremic patients had significantly worse Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.00001) and higher pT stage (p = 0.002). In multivariate analysis, hyponatremia was an independent prognostic factor for progression (HR 1.585, 95% CI 1.115–2.253, p = 0.010), cancer-specific death (HR 2.225, 95% CI 1.457–3.397, p = 0.0002), and overall mortality (HR 1.819, 95% CI 1.299–2.545, p = 0.0005). Kaplan–Meier analysis showed the consistent adverse effect of hyponatremia on all outcomes in patients from Taiwan and the U.S. (all p < 0.05). Hyponatremia is commonly accessible and can serve as a negative marker for both the general health condition and disease severity of UTUC patients. A similar implication of hyponatremia in progression and survival despite patients’ region of presentation suggests its general applicability across different ethnicities.

Predictive Value of Interim and End-of-Therapy 18F-FDG PET/CT in Patients with Follicular Lymphoma.

18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is the standard imaging modality for response evaluation in FDG-avid lymphoma, but the prognostic value is not established in follicular lymphoma (FL). This study investigated the prognostic value of Deauville 5-point scale (D5PS) from paired interim PET/CT (PETInterim) and end-of-induction therapy PET/CT (PETEOI) in patients with FL. FL staging and response assessment PET/CT images from 2013 to 2015 were retrospectively reviewed. PETInterim was performed 3 or 4cycles after chemotherapy and PETEOI after 6 or 8cycles. D5PS scores of 1, 2, and 3 were considered as negative (-), and scores 4 and 5 were considered as positive (+). Statistical analysis was done using Cox regression analysis, Kaplan-Meier survival analysis, and the log-rank test. Thirty-three patients with set of baseline, interim, and end-of-induction therapy PET/CT studies were included. Ten patients (30.3%) had progression. The median progression-free survival (PFS) was 38.8months (range 3.5-72.7months). On PETInterim, 23 patients were negative and 10 were positive. On PETEOI scans, 29 patients were negative, and 4 were positive. On multivariate analysis, PETEOI(-) was associated with longer PFS. PETInterim(+) and PETEOI(+) patients had a significantly shorter PFS than PETInterim(-) patients (39.9months, 95% confidence interval [CI] 23.0-56.9, versus 55.5months, 95% CI 49.7-61.2, p = 0.005) and PETEOI(-) patients (14.2months, 95% CI 8.5-19.8, versus 60.5months, 95% CI 52.1-69.0, p < 0.001). For patients with FL, PETInterim and PETEOI response is predictive of PFS, and PETEOI(+) is an independent prognostic factor for progression of FL.

Adjuvant trans-arterial chemoembolization after hepatectomy significantly improves the prognosis of low-risk patients with R0-stage hepatocellular carcinoma.

Background: Transcatheter arterial chemoembolization (TACE) is one of the local therapies most commonly used to treat intermediate-stage or advanced-stage hepatocellular carcinoma (HCC). However, the clinical benefits of PA-TACE (postoperative adjuvant TACE) for improving prognosis (progress-free survival [PFS] or overall survival [OS]) of low-risk HCC patients with R0-stage HCC after hepatectomy were not very clear.Methods: From January 2005 to December 2012, 180 patients who underwent hepatectomy for HCC treatment were enrolled in this study, and the follow-up of these patients was ended in December 2017. Among these patients, 102 patients were performed PA-TACE 1 month later after R0 hepatectomy and 78 patients without adjuvant TACE after R0 hepatectomy. Survival analysis was calculated using the Kaplan–Meier statistical method. Differences between survival curves of different groups were tested using the univariate log-rank test. Multivariate Cox model was used to search for independent prognostic factors for progression or death and to acquire the adjusted HR.Results: PA-TACE significantly improved the survival of HCC patients received surgical resection. The PFS (progress-free survival) of PA-TACE group (median PFS 52.0 months; 95% CI: 14.0–90.0) was significantly longer than the control group (median PFS 11.1 months; 95% CI: [7.9–14.3]; log-rank P<0.001); and the OS (in PA-TACE group (median OS 90.7 months; 95% CI: 84.4–97.0 months) was also much longer than that of control group (median OS 54.4 months; 95% CI: 38.2–70.6 months; log-rank p<0.001). Moreover, the benefits of PA-TACE are greater for low-risk patients than high-risk patients.Conclusion: In patients with HCC, PA-TACE can significantly prolong progression-free survival and long-term OS. For low-risk patients, the benefits might be greater.

Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine/platinum-treated advanced non-small-cell lung cancer: a prospective validation study

BackgroundCytidine deaminase (CDA) plays a crucial role in the degradation of gemcitabine. In our previous retrospective study, CDA enzymatic activity was the strongest prognostic biomarker of the activity and efficacy of platinum/gemcitabine combinations. The aim of this prospective study was to validate the prognostic role of CDA activity in the first-line treatment of advanced non-small-cell lung cancer.MethodsA total of 124 untreated patients received standard doses of platinum/gemcitabine. CDA activity was baseline measured in plasma samples by spectrophotometric assay.ResultsUsing the median CDA level as cut-off, in the patients with high versus low CDA activity the response rate was 25.0% (95% CI, 14.7–37.8) and 54.1% (95% CI, 40.8–66.9), P = 0.0013; the 6-month progression rate was 34.5% (95% CI, 22.6–46.6) and 54.1% (95% CI, 40.9–65.6), HR = 2.01 (95% CI, 1.32–3.06), P < 0.001; the 1-year survival rate was 23.3% (95% CI, 13.6–34.6) and 57.3% (95% CI, 43.9–68.6), HR = 2.20 (95% CI, 1.46–3.34), P = 0.0002, respectively. CDA activity resulted to be an independent prognostic factor for progression and survival at multivariate analysis.ConclusionsThis study validated prospectively the prognostic role of the CDA activity and should prompt larger and adequately designed randomised prospective studies to establish the predictive impact of this test in improving the outcome of selected patients.

Depth of Invasion Alone is Not an Independent Prognostic Factor in Early-Stage Node-Negative Oral Cavity Carcinoma

The use of depth of invasion (DOI) as a prognostic factor and criterion for neck dissection (ND) in patients with oral cavity carcinoma (OCC) has been the topic of multiple clinical analyses. However, these studies are heterogeneous, frequently including patients of any stage and with multiple other histologic risk factors for recurrence. In addition, patients often received adjuvant treatment in the form of chemotherapy and/or radiation. Thus, it is difficult to draw conclusions on the importance of DOI as a true prognostic factor. We created a unique population of patients with DOI as the sole risk factor for recurrence to accurately evaluate whether it is an independent prognostic factor for progression in patients with early-stage node-negative OCC. All patients were drawn from an institutional review-board approved database of OCC patients treated at a single academic institution between 2003 and 2013. A total of 560 patients were retrospectively reviewed. Patients were included in the final analysis if they had pathologic T1-2N0 OCC treated with surgical resection with or without neck dissection (ND). Pathology specimens were independently reviewed by 2 board-certified pathologists to confirm proper evaluation of DOI and other histologic parameters. Patients were excluded if they received adjuvant treatment, chemotherapy for other cancer diagnoses in the follow up period, or if other high-risk pathologic features were present, including: perineural invasion, lymphovascular invasion, positive lymph nodes, and close or positive margins. Kaplan-Meier and Cox proportional hazards regression analyses were performed to identify factors predictive for local (LR) and regional recurrence (RR), as well as progression free survival (PFS). A total of 126 patients with T1-2 N0 OCC were analyzed. Median follow up for the entire cohort was 42.5 months and median overall survival (OS) was 46 months. Median DOI for all sites was 4 mm, with 60 (47.6%) patients with DOI <4 mm and 66 (52.4%) patients with DOI ≥4 mm. There was no significant difference in local (p=0.95), regional (p=0.81), or distant (p=0.96) recurrence between patients with DOI <4 mm and ≥4 mm. In total, 50 (42.9%) patients underwent ND. There was no significant difference in LR among patients with DOI <4 mm and ≥4 mm (p=0.95). In patients with DOI <4 mm, 5-year RR was 0% if ND was performed and 22% if ND was omitted. In the subset of patients with oral tongue carcinoma and DOI <4mm (n=36), there were no regional or distant recurrences in those patients who underwent ND compared to 20% and 4% in patients who did not undergo ND. On multivariate analysis including T stage, gender, age, DOI, and multiple head and neck primaries, the only factor significant for PFS was ND (HR 0.25, p=0.006). In this study, we show that DOI ≥4 mm alone does not predict for worse local, regional, or distant recurrence. ND appeared to improve the RR for even those with DOI <4mm.

Prognostic value of metabolic variables of [18F]FDG PET/CT in surgically resected stage I lung adenocarcinoma.

The objective of this study was to assess the prognostic value of metabolic tumor burden measured by positron emission tomography/computed tomography (PET/CT) in patients with stage I lung adenocarcinoma.We reviewed 127 consecutive patients with pathologically proven stage I lung adenocarcinoma who underwent pretreatment [18F]FDG PET/CT scans in our hospital from 2005 June to 2012 June. The maximum, mean, and peak standardized uptake value (SUVmax, SUVmean, and SUVpeak), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and computed tomography volume (CTV) were measured. The Kaplan–Meier and Cox proportional hazards model were used with age, gender, TNM stage, clinical stage, histological grade, nodule type, tumor size, and metabolic parameters to predict progression-free survival (PFS). The cut-off point was determined through receiver-operating characteristic curve.In univariate analysis, the histological grade, nodule type, diameter (cut-off value of 2.0 cm), CTV (6.56 cm3), SUVmax (3.25 g/mL), SUVmean (1.58 g/mL), SUVpeak (1.84 g/mL), MTV (4.80 cm3), and TLG (10.40) were significantly associated with PFS (all P value < .05). Patients with poorly differentiated adenocarcinoma, solid nodule type, large size, and high metabolic tumor burden were associated with poor prognosis. In multivariate analysis, only histological grade was independent prognostic factors for progression with a P value of .005 (RR, 0.355; 95% CI, 0.173–0.728). Among 5 PET/CT metabolic parameters, only MTV was independent prognostic factors for progression with a P value of .031 (RR, 1.118; 95% CI, 1.010–1.237).Histological grade was an independent predictor for progression in patients with stage I lung adenocarcinoma. Among 5 PET/CT metabolic parameters, only MTV was an independent predictor for progression.

Bone Marrow DKK-1 Levels in Smoldering Multiple Myeloma Patients: A New Independent Risk Factor for Progression

The presence of bone disease is the hallmark to differentiate patients with active multiple myeloma (MM) from those with smoldering MM (SMM). The diagnostic criteria for active MM have been recently updated; including patients previously defined high-risk SMM among those with active MM in the presence of biomarkers of malignity. Actually SMM patients can be stratified for the risk of progression to active MM based on several factors but new parameters to identify patients with a high risk of progression need to be defined. Particularly there are not any molecular factors able to differentiate the new high-risk SMM patients. Recently, we analyzed bone marrow (BM) levels of several cytokines and chemokines involved in the MM-induced alterations of the bone remodeling finding that BM levels of Activin A, C-C motif chemokine ligand 20 (CCL20), Dickkopf 1 (DKK-1) and osteoprotegerin (OPG) were significantly different among patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), SMM and MM (Dalla Palma B et al. Leukemia 2016). Thus, in this study we focused on those soluble factors in order to evaluate their possible role as new markers of risk progression in SMM patients.We analyzed a total cohort of 87 patients with SMM as defined by the International Myeloma Working Group updated diagnostic criteria for MM and related disorders (serum monoclonal protein (IgG or IgA) ≥ 3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal BM plasma cells 10%-60%, and absence of myeloma defining events or amyloidosis) admitted to our Myeloma Unit between 2007 and 2015 and who underwent to BM aspirate. The median age of the patients was 65 years (range 38-92); 50 were males and 37 were females; light chain was kappa in 68% of patients and lambda in 32%, whereas heavy chain was IgG in 76%, IgA in 23% and IgD in 1%. Standard risk factors evaluated were size of serum M protein (≥ 3 g/dL in 14% of patients), percentage of BM plasma cells and immunoparesis (present in 66% of patients). Free Light Chain (FLC) ratio was not available in all patients. DKK-1, Activin A, CCL20, and OPG BM plasma levels were measured by ELISA assay. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher’s exact test. P value of <0.05 was considered significant. The influence of BM cytokine and chemokine levels on the progression to active MM in SMM patients was examined by Kaplan-Meier and Cox regression analysis.With a median follow-up time of 42 months, 21 patients progressed to active MM; median time to progression was 16 months. BM Activin A, CCL20 and OPG median levels were not significantly different between progressed and not SMM patients (median levels: Activin A 401.97 pg/mL vs 402.93 pg/ml, p=0.70; CCL20 68.68 pg/mL vs 62.08 pg/mL, p=0.80; OPG 101.94 pg/mL vs 118.74 pg/mL, p=0.86). Conversely SMM patients progressed to active MM showed significantly higher DKK-1 BM levels as compared to patients who had not progressed (median levels: 1777.50 pg/mL vs 782.77 pg/mL, p=0.007). The progression-free survival was significantly worse in patients with BM DKK-1 above the median (DKK-1 median level: 971 pg/mL; p=0.021 by log rank test). In multivariate analysis, adjusted for standard risk factors such as the size of serum M protein, the percentage of BM plasma cells, the presence of the immunoparesis, we found that BM DKK-1 levels remained an independent prognostic factor for progression to active MM (p=0.001).In conclusion, our study indicates that BM median levels of DKK-1 are able to identify the SMM patients with higher risk of progression to active MM, and may represent a new independent risk factor for progression in SMM patients. DisclosuresGiuliani:Celgene: Research Funding; Janssen: Research Funding.

Serum tryptase concentration and progression to end-stage renal disease.

Mast cell activation can lead to nonclassical activation of the Renin-Angiotensin-Aldosterone System. However, the relevance of this to human chronic kidney disease is unknown. We assessed the association between serum tryptase, a product of mast cell activation, and progression to end-stage renal disease or mortality in patients with advanced chronic kidney disease. We stratified patients by use of angiotensin-converting enzyme inhibitors/angiotensin receptor II blockers (ACEi/ARB). This was a prospective cohort study of 446 participants recruited into the Renal Impairment in Secondary Care study. Serum tryptase was measured at recruitment by sandwich immunoassay. Cox regression analysis was undertaken to determine variables associated with progression to end-stage renal disease or death. Serum tryptase concentration was independently associated with progression to end-stage renal disease but not with death. In patients treated with ACEi or ARB, there was a strong independent association between higher tryptase concentrations and progression to end-stage renal disease; when compared to the lowest tertile, tryptase concentrations in the middle and highest tertiles had hazard ratios [HR] of 5·78 (95% confidence interval [CI] 1·19-28·03, P = 0·029) and 6·19 (95% CI 1·49-25·69, P = 0·012), respectively. The other independent risk factors for progression to end-stage renal disease were lower age, male gender, lower estimated glomerular filtration rate and higher urinary albumin creatinine ratio. Elevated serum tryptase concentration is an independent prognostic factor for progression to end-stage renal disease in patients with chronic kidney disease who are receiving treatment with an ACEi or ARB.

Second transurethral resection and prognosis of high-grade non-muscle invasive bladder cancer in patients not receiving Bacillus Calmette-Guérin

Abstract Objective To define the natural history of T1G3 bladder tumor not receiving intravesical Bacillus Calmette-Guerin (BCG) and to assess the diagnostic and therapeutic value of a second transurethral resection (Re-TUR) in these patients. Patients and methods Retrospective study on the natural history of 210 patients treated at two institutions for T1G3 bladder carcinoma without associated CIS. In no case was BCG administered; 79 (37.6%) received TUR alone, and 131 (62.4%) Re-TUR 4–6 weeks later; 23 (12.4%) underwent cystectomy for tumor progression. Results Median follow-up was 55 (78 IQR) months, male/female ratio 8/1, and mean age 70.6 ± 11.8 (range 37–93). 19.5% were free of recurrence at 10 years, and 61.9% free of progression. Independent prognostic factors for progression were solid pattern (HR: 2.71; p = .0004), multiplicity (HR: 2.26; p = 0.003), and recurrence at 3 months (HR: 3.4; p = 0.003). Cancer-specific survival was 81.5% at 5 and 69% at 10 years. Independent predictors of survival were: progression during the first year (HR: 17.9; p p = 0.02), multiplicity (HR: 2.05; p = 0.03), and age > 65 years (HR: 2.9; p = 0.03). Re-TUR avoided under-staging (7.4%), detected T1G3 residual disease (10.7%), reduced recurrence rate at 3 months (11.4–4.6%; p = 0.06), and rate of progression on the 1st year (13.9–3.8%; p = .0075). However, in these patients the risk remains and no differences were detected in the long term in terms of recurrence (log-rank, p = 0.14), progression ( p = 0.91), or cancer death ( p = 0.21) in patients treated with Re-TUR. Conclusion The recurrence in the first 3 months of a T1G3 tumor not receiving BCG is the main risk factor for progression, and progression of this type of tumors within the first year is the main factor of cancer death. The Re-TUR improves both variables but it does not change the long-term prognosis.

Segunda resección transuretral y pronóstico del cáncer de vejiga no músculo-invasivo de alto grado en pacientes que no reciben bacilo de Calmette-Guérin

ObjectiveTo define the natural history of T1G3 bladder tumor not receiving intravesical Bacillus Calmette-Guerin (BCG) and assess the diagnostic and therapeutic value of a second transurethral resection (Re-TUR) in these patients. Patients and methodsRetrospective study on the natural history of 210 patients treated at two institutions for T1G3 bladder carcinoma without associated CIS. In no case was BCG administered; 79 (37.6%) received TUR alone, and 131 (62.4%) Re-TUR 4 to 6 weeks later; 23 (12.4%) underwent cystectomy for tumor progression. ResultsMedian follow-up was 55 (78 IQR) months, male/female ratio 8/1, and mean age 70.6+11.8 (range 37-93). 19.5% were free of recurrence at 10 years, and 61.9% free of progression. Independent prognostic factors for progression were solid pattern (HR: 2.71; P=.0004), multiplicity (HR: 2.26; P=.003), and recurrence at 3 months (HR: 3.4; P=.003). Cancer-specific survival was 81.5% at 5 and 69% at 10 years. Independent predictors of survival were: progression during the first year (HR: 17.9; P<.0001), solid pattern (HR: 2.13; P=.02), multiplicity (HR: 2.05; P=.03), and age>65 years (HR: 2.9; P=.03). Re-TUR avoided under-staging (7.4%), detected T1G3 residual disease (10.7%), reduced recurrence rate at 3 months (11.4 to 4.6%; P=.06), and rate of progression on the 1st year (13.9 to 3.8%; P=.0075). However, in these patients the risk remains and no differences were detected in the long term in terms of recurrence (log-rank, P=.14), progression (P=.91), or cancer death (P=.21) in patients treated with Re-TUR. ConclusionThe recurrence in the first 3 months of a T1G3 tumor not receiving BCG is the main risk factor for progression, and progression of this type of tumors within the first year is the main factor of cancer death. The Re-TUR improves both variables but it does not change the long-term prognosis.

Abstract 165: Platelet Derived Growth Factor (pdgf) is Associated With Progression of Symptomatic Intracranial Large Artery Atherosclerosis

Background and Purpose: Studies on the molecular pathways involved in the progression of intracranial large artery atherosclerosis are rare. We aimed to study the relationship between biomarkers and the risk of progression of symptomatic intracranial large artery atherosclerosis. Methods: Of 409 patients in Trial of cilostazol in symptomatic intracranial stenosis-2 (TOSS-2) study, 52 patients showed progression of symptomatic intracranial large artery atherosclerosis on MRA after 7 months. We selected 20 patients with progression and 40 age- and sex- matched control patients. We collected blood sample initially, one month and 7 month after infarction, and multiplex analysis of biomarkers including interleukin-1,2,6,8,10, soluble CD40ligand, TNF alpha, PDGF, soluble ICAM, E-selectin and VCAM , MMP-2,3,9, SOD1,2,3 and adipokines, were performed. Results: Demographic features such as age, sex, hypertension, diabetes and smoking history were not different between both groups. On univariate analysis, 7 month PDGF-AA (3053 ± 2896 pg/ml, vs 1444±1548 pg/ml), PDGF-AB/BB (15304.0±15634 pg/ml vs 5627±8656 pg/ml) level and MPO(25.7±33.9vs 9.9±8.7ng/ml) were higher in progression group. On multivariate analysis using logistic model, 7 month PDGF AA is independent prognostic factor for progression of intracranial large artery atherosclerosis (p=0.012). Conclusion: PDGF-AB/BB level is associated with progression of symptomatic intracranial large artery atherosclerosis.

Isolated limb perfusion for in‐transit melanoma metastases: Melphalan or TNF‐melphalan perfusion?

Indications for treatment of melanoma in-transit metastases (ITMs) confined to the limb with isolated limb perfusion (ILP) are not well defined. This study reports the Groningen regional therapeutic perfusion experience with melphalan (M-ILP) and TNF-melphalan (TM-ILP) for ITMs, and reviews of the melanoma TNF-melphalan ILP literature. Between 1991 and 2012, 60 patients were treated with ILP. Patients with "small" ITMs received M-ILP (10-13 mg melphalan/L limb volume) and patients with "bulky" disease TM-ILP (1-4 mg TNF); 19 M-ILPs and 41 TM-ILPs were performed, 26 Stage IIIB, 31 Stage IIIB and 1 stage IV disease. Overall response after 57 ILPs was 90%; CR 27 (45%), PR 27 (45%), no response 3 (5%); after 9 M-ILPs CR 6 (32%) and 41 TM-ILPs CR 21 (51%, P = 0.124). For younger patients (<65 years) CR was 69% and for elderly patients 29% (P = 0.003). For low volume disease (<5 ITMs) CR was 75% and for high volume disease (≥5 ITMs) 41% (P = 0.038). After median follow-up of 15 months (range, 1-144) there was local recurrence or disease progression in 36 patients (60%). Positive lymph node status was associated with local progression, absence of CR and Stage IIIC disease; these were independent prognostic factors for progression to systemic disease. M-ILP is an effective regional treatment for melanoma ITMs, whereas for bulky disease TM-ILP should be the first choice. In-field progression-free survival after ILP is determined by the biological behavior of the ITMs and the patient's immune system.

Cutoff value of time to prostate-specific antigen nadir is inversely correlated with disease progression in advanced prostate cancer

To identify the early predictor of progression to castration-resistant prostate cancer (CRPC) for different stage of advanced PC patients, we focused on time to prostate-specific antigen (PSA) nadir following primary androgen deprivation therapy (PADT). We reviewed 184 advanced (locally advanced and metastatic) PC patients (101 patients with bone metastasis (BM) and 83 patients without BM at presentation) who had received PADT at our institution. We evaluated laboratory data, pathological results, and the influence of PSA kinetics impact on disease progression. The progression rates were analyzed with reference to the nadir PSA level and time to PSA nadir (TTN) following PADT by Kaplan-Meier method. In all, 103 patients (56%) progressed to CRPC. Nadir PSA lower than 0.2 ng/ml (nadir ≤0.2) during PADT was observed in 114 patients (62%). Median TTN was 8.5 months in patients with BM and 11.5 months in patients without BM. Multivariate analysis revealed that nadir ≤0.2 following PADT (P<0.001), longer TTN (>8 months) (P<0.001), extent of disease on bone scan grade (P=0.02), and T stage (P=0.04) in BM group and nadir ≤0.2 following PADT (P<0.001), longer TTN (>11 months) (P<0.001), and T stage (P=0.03) in without BM group were independent prognostic factors for progression. In both groups, longer TTN identified patients with prolonged progression-free survival in both nadir ≤0.2 and >0.2 nadir levels. Longer TTN is strongly associated with a low risk of disease progression, and the cutoff value of TTN could be inversely correlated with disease progression.

Prognostic Significance of Substaging according to the Depth of Lamina Propria Invasion in Primary T1 Transitional Cell Carcinoma of the Bladder

PurposeTo evaluate the prognostic significance of the depth of lamina propria invasion in primary T1 transitional cell carcinoma (TCC) of the bladder.Materials and MethodsWe retrospectively reviewed the medical records of 183 patients with primary T1 TCC of the bladder who had undergone transurethral resection (TUR) at our institution. Substaging was defined according to the depth of lamina propria invasion as follows: T1a, superficial invasion of lamina propria; T1b, invasion into the muscularis mucosa (MM); T1c, invasion beyond the MM but not to the muscularis propria. The prognostic significance of various clinicopathological variables for recurrence and progression was analyzed.ResultsOf the 183 patients, substaging was T1a in 119, T1b in 57, and T1c in 7 patients. The recurrence rate was 32.8% for T1a and 40.6% for T1b/c, but there was no significant difference between the two groups. The progression rate was significantly different between the two groups: 5.8% in T1a and 21.9% in T1b/c (p=0.003). The cancer-specific mortality rate was also significantly different: 4.2% in T1a and 14.0% in T1b/c (p=0.036). In the univariate analysis, microscopic tumor architecture was the only significant prognostic factor for recurrence. In the univariate and multivariate analysis concerning progression, depth of lamina propria invasion and concomitant carcinoma in situ were significant prognostic factors.ConclusionsSubstaging according to the depth of lamina propria invasion in primary T1 TCC of the bladder was an independent prognostic factor for progression. This suggests that substaging would be helpful for guiding decisions about adjuvant therapies and follow-up strategies.

Prognostic Value of Loss of Heterozygosity at Chromosome 9p in Non–muscle-invasive Bladder Cancer

To investigate the prognostic value of loss of heterozygosity (LOH) at chromosome 9p in patients with non-muscle-invasive bladder cancer (NMI-BC). Between 2000 and 2006, we included in the study 84 patients with NMI-BC. LOH analyses were performed on tumor tissue using 3 microsatellite markers at chromosome 9p. Associations of LOH with recurrence and progression of the tumors were evaluated. Frequency of LOH at 9p was 11.1%, 29.0%, and 31.6% in pTaG1, pTaG2, and pT1G3 tumors, respectively. Recurrence occurred in 27 patients. None of the markers was able to predict recurrence. Progression occurred in 9.5% of the cases, with progression to muscle-invasive bladder cancer (MI-BC) in 4.8% of the cases. LOH at IFN-alpha was significantly associated with progression to MI-BC (P = .006). In the case of LOH at IFN-alpha, 2-year progression-free survival and progression-free survival to MI-BC were both 59.3%, compared with 97.1% and 98.6%, respectively, in case of conservation of LOH in multivariable analysis, LOH at IFN-alpha remained statistically associated with progression and progression to MI-BC. LOH at IFN-alpha was a significant and independent predicting factor of progression and progression to MI-BC, with P = .05 and 0.01 (HR 4.8 for progression; HR 24.2 for muscle invasion). Our study suggests that LOH at IFN-alpha is an independent prognostic factor for progression to MI-BC. LOH analysis of bladder tumors may help in the management of NMI-BC. Specifically, it could be of use in selecting patients for early aggressive treatment and/or in planning close follow-up schedule.