Predictive Factors For Progression Research Articles

Progression of non-anemic macrocytosis to anemia in HIV-positive persons receiving zidovudine-containing regimens in a resource-limited setting.

Non-anemic macrocytosis is frequently observed among HIV-positive persons treated with zidovudine in resource-limited settings. Although zidovudine-associated anemia is well recognized, the probability and predictors of progression from non-anemic macrocytosis to anemia are still unknown. A retrospective cohort study was conducted among HIV-positive persons receiving zidovudine-containing antiretroviral therapy (ART) with non-anemic macrocytosis. Kaplan-Meier and Cox regression analyses were used to determine the probability and predictive factors of progression from non-anemic macrocytosis to anemia, respectively. Of 318 HIV-positive persons, 59.4% were male; mean age was 44.3years. The median follow-up duration was 5.8years. The probabilities of progression to anemia at 1, 3 and 4years were estimated at 9.4, 17.3 and 21.3%, respectively. Almost all anemia was mild asymptomatic. Duration of zidovudine use [hazard ratio (HR) = 1.141; 95% confidence interval (CI),1.036-1.256; p = .007], CD4 count prior to start zidovudine [HR = 0.991; 95%CI,0.982-0.999; p = .038], and hematocrit level at development of macrocytosis [HR = 0.683; 95%CI,0.541-0.861; p = .001] were significant factors to predict progression to anemia. Non-anemic macrocytosis in HIV-positive persons receiving zidovudine-containing ART can progress to anemia. Longer duration of zidovudine use, lower CD4 cell counts at ART initiation, and lower hematocrit level at development of macrocytosis are predictive factors for progression to anemia.

Clinical and histological predictive factors of reclassification of prostate cancer patients on active surveillance

Introduction and objectiveActive surveillance (AS) has been established as a therapeutic strategy in patients with low-risk prostate cancer. Demographic and anatomopathological factors that increase the probability of reclassifying patients have been identified. Materials and methodsLaboratory and histopathological data were collected from 116 patients included on AS since 2014. Univariate analysis was performed with Chi-square, t-student and Kendall's Tau, multivariate analysis according to logistic regression and Kaplan-Meier curves were calculated. ResultsOf the 116 patients in AS, the median age at diagnosis was 66 years and the median follow-up was 13 months (2–72). Of these, 61 (52.6%) are still on surveillance, while 55 (47.4%) have left the program, mostly due to histological progression (52 patients (45.2%)); radical prostatectomy was performed in 27 (49.1%). Prostate volume (PV)≤60cc and the number of positive cylinders >1 in diagnostic biopsy (P=.05) were associated with higher reclassification rate in univariate analysis (P<.05). Multivariate analysis showed that these two variables significantly correlated with higher reclassification rate (PV 60 cc: OR 4.39, P=.04; >1 positive cylinder at diagnostic biopsy: OR 2.48, P=.03). ConclusionsIt has been shown that initial ultrasound volume and the number of positive cylinders in the diagnostic biopsy are independent risk factors for reclassification. Initial PSA, laterality of the affected cylinders and PSA density were not predictive factors of progression in our series.

Factores clínicos e histológicos predictores de reclasificación en pacientes incluidos en programa de vigilancia activa de cáncer de próstata

Introduction and ObjectiveActive surveillance (AS) has been established as a therapeutic strategy in patients with low-risk prostate cancer. Demographic and anatomopathological factors that increase the probability of reclassifying patients have been identified. Materials and MethodsLaboratory and histopathological data were collected from 116 patients included on AS since 2014. Univariate analysis was performed with Chi-square, t-student and Kendall's Tau, multivariate analysis according to logistic regression and Kaplan-Meier curves were calculated. ResultsOf the 116 patients in AS, the median age at diagnosis was 66 years and the median follow-up was 13 months (2-72). Of these, 61 (52.6%) are still on surveillance, while 55 (47.4%) have left the program, mostly due to histological progression (52 patients (45.2%)); radical prostatectomy was performed in 27 (49.1%). Prostate volume (PV) ≤ 60cc and the number of positive cylinders > 1 in diagnostic biopsy (p = 0.05) were associated with higher reclassification rate in univariate analysis (p < 0.05). Multivariate analysis showed that these two variables significantly correlated with higher reclassification rate (PV 60 cc: OR 4.39, p = 0.04; > 1 positive cylinder at diagnostic biopsy: OR 2.48, p = 0.03). ConclusionsIt has been shown that initial ultrasound volume and the number of positive cylinders in the diagnostic biopsy are independent risk factors for reclassification. Initial PSA, laterality of the affected cylinders and PSA density were not predictive factors of progression in our series.

Oncologic outcomes and predictive factors for progression in pT3a renal cell carcinoma

We aimed to evaluate oncologic outcomes of pT3a renal cell carcinoma (RCC) patients that treated with radical or partial nephrectomy and identify clinical or pathological factors that predict local recurrence or metastasis.In this single center, retrospective study, we evaluated medical records of 856 patients who underwent radical or partial nephrectomy for RCC. Patients who had pT3aN0M0 RCC in final pathology and at least 6 months of follow-up included in the study. Patients' demographic characteristics, laboratory parameters, tumor characteristics and oncological outcomes were recorded. Cancer specific and overall survivals were our primary outcomes. Multivariate analysis was performed to identify factors affecting oncologic outcomes.A total of 86 pT3aN0M0 RCC patients were included final analysis of our study. During the mean 60.75 months follow up, 3 patients (3.5%) had experienced local recurrence and 19 patients (22.1%) had experienced metastasis. Total of 24 patients (27.9%) had died during the follow up. In this population 10-year OS was 70.8%, 10-year PFS was 61.3% and 10-year CSS was 78.4%. In multivariate analysis, chronic renal failure (CRF) was an independent worse prognostic factor for overall survival (p=0.03). Besides this sarcomatoid differentiation was an independent prognostic factor for PFS, CSS and OS (p=<0.001).Our study investigated the predictive factors for worse oncologic outcomes in pT3aN0M0 RCC patients. Although many factors have predictive value in univariate analysis, only sarcomatoid differentiation have independent predictive value for worse CSS, PFS and OS. Besides sarcomatoid differentiation, CRF is an independent prognostic factor for poor OS.

Similar Survival and Genetic Features between Clonal Cytopenia of Undetermined Significance and Lower-Risk Myelodysplastic Syndrome

BackgroundIdiopathic cytopenia of undetermined significance (ICUS) is characterized by a persistent and clinically significant cytopenias which does not meet the diagnostic criteria for myelodysplastic syndrome (MDS). In some patients with ICUS, disease evolution to MDS or acute myeloid leukemia after variable periods of time was observed in several studies. However, the incidence and predictive factors of progression as well as management guidelines for ICUS patients are not well established. We aimed to identify the clinical and genetic characteristics of ICUS in comparison with lower-risk MDS for understanding the pathophysiologic features and providing guidance for treating physicians.MethodsWe performed targeted deep sequencing including 61 myeloid neoplasm-related genes with a MiSeqDx sequencer (Illumina) using bone marrow (BM) samples obtained from the patients with ICUS (n=139) and MDS (n=226) between May 2009 and December 2019. The cut-off level of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Cloncal cytopenia of undetermined significance (CCUS) was defined as ICUS with ≥ 2% VAF of mutations and lower-risk MDS was defined as MDS with revised international prognostic scoring system ≤3.5.ResultsWhen we compared the overall survival (OS) of the patients according to the disease subtypes, OS of CCUS (77.0% at 5-year) was significantly better than that of higher-risk MDS (41.0%, P<.001) and worse than non-clonal ICUS (94.1%, P=.050), but it was similar to the OS of lower-risk MDS (67.9%, P=.363). Next, we compared the clinical and mutational features between CCUS (n=78) and lower-risk MDS (n=99). As shown in Table, there was no significant difference of patient characteristics between two groups except for higher hemoglobin level (10.5 vs. 9.0 g/dL, P=.008) in CCUS than lower-risk MDS, and the rate of red blood cell transfusion dependency was not different (P=.738). The median number of mutated genes of CCUS and lower-risk MDS were 1 (range, 0-4) and 1 (range, 0-6) (P=.651), and the median mutation numbers were 1 (range, 0-5) in CCUS and 2 (range, 0-7) in lower-risk MDS, respectively (P=.711). The mutational profiles of 61 genes were also similar between CCUS and lower-risk MDS except for SF3B1 (2.6% in CCUS and 18.2% in lower-risk MDS; P=.001) and STAT3 (5.1% in CCUS and 0% in lower-risk MDS; P=.023). Overall, 11 of 78 CCUS and 24 of 99 MDS died, and the causes of death were not different between two groups (P=.861).ConclusionIn our study, CCUS and lower-risk MDS showed similar OS which was significantly better than higher-risk MDS and worse than non-clonal ICUS. The clinical and mutational characteristics were also similar except for the degree of anemia and the SF3B1 and STAT3 mutation. Our findings suggest that the patients with CCUS may be regarded and treated as the lower-risk MDS despite a lack of significant dysplasia or MDS-associated definitive chromosomal abnormality. DisclosuresChoi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Other: Advisory board; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board.

Abstract 89: A TGF-beta Pathway-SREBP1 axis controls liver diseases from nonalcoholic steatohepatitis to hepatocellular carcinoma

Abstract Background/Aims: The global epidemic of obesity has led to an alarming rise in nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC). In addition to abnormal fat accumulation and liver injury, fibrosis is a key predictive factor for progression and transformation. Yet, our understanding of how a major fibrosis pathway, transforming growth factor β (TGF-β), and how members, SMAD3 with its adaptor SPTBN 1 -contribute to the progression of NASH-driven HCC remains unclear. Here, we sought to better understand the role of TGF-β1/SMAD3/SPTBN1 in regulating the switch between NASH and HCC. Methods: We generated liver-specific SPTBN1 knockout mice (Albumin Cre+Sptbn1loxp/loxp, LKO). LKO and controls were given a high-fat diet (HFD) or DEN; Phenotypic analyses and mechanistic insight were obtained through RNA-seq, mass spectrometry, structure modeling, cell fractionation, and imaging-immunofluorescence, immunohistochemistry, and interactions studies were performed in human HCC cell lines (Huh7, Hep3B). Results: Strikingly, LKO did not develop HFD induced obesity, NASH, and cancer, that occurred in wild type, Flox control, NASH, and DEN/HCC models. Compared to controls, LKO liver tissues displayed 2-7-fold decreases in NASH associated pro-fibrotic genes (Col1a1, Col1a2) and lipid metabolism genes (CD36, Slc27a1, Plin4, Plin2) (p&amp;lt;0.05), and over 4-fold increases in Fgf21 mRNA levels (LKO vs control: 3.67±1.9 vs 0.84±0.16). Analysis of key regulators of lipogenesis revealed decreased SREBP1 (0.33±0.11 VS 1.35±0.22, p=0.006) and targets as well as PPARG (3.15±1.24 VS 19.03±4.98, p=0.02) in LKO compared to controls. Functionally, Sptbn1 MEF cells show marked reduction in SREBP1 reporter activity compared to WT MEFs (LDLR-luc: 0.25±0.04 vs 1.0±0.08, p&amp;lt;0.05) with decreased nuclear SREBP1 labeling in LKO tissues. Depletion of Sptbn1 leads to impaired TGF-β1/SMAD3 signaling and decreased TNF-α induced ER stress/caspase-3 activated SREBP1. N-terminal SPTBN1 (D50-T975) binds SREBP1 (Q295-K374) and induces its nuclear translocation. HFD -driven caspase-3 activation and SREBP1-SPTBN1 cleavage and binding occur independently of insulin induced gene (INSIG) and SREBP cleavage-activating protein (SCAP). We observe raised levels of SPTBN1 together with Caspase-3, and lipogenic pathways (e.g., FASN, SCD1) in human NASH/HCC progression. Additional human HCC TCGA analysis revealed poor prognosis in patients with high SREBP1 activity. Finally, siRNA targeting Sptbn1 in vivo protects mice from HFD-induced NASH and reduces NASH-associated transcriptional changes in a human 3D-culture NASH model. Conclusions: We uncovered a surprising and promising role of SPTBN1 siRNA in inhibiting NASH and HCC, through modulation of its binding partners, SMAD3 and SREBP1. These data provide new insights into the switch in obesity driven liver cancer as well as new therapeutic targets. Citation Format: Shuyun Rao, Zhanhuai Wang, Kazufumi Ohshiro, Sobia Zaidi, Xiaochun Yang, Patricia Latham, Wilma Jogunoori, Xianyan Xiang, Inhee Chung, Kirti Shetty, Michele Vacca, Antonio Vidal-Puig, Lopa Mishra. A TGF-beta Pathway-SREBP1 axis controls liver diseases from nonalcoholic steatohepatitis to hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 89.

P0507ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE. ABOUT 32 CASES

Abstract Background and Aims Anti-Glomerular basement membrane disease « anti-GBM » is a rare autoimmune disease. It most often results in a rapidly progressive glomerulonephritis syndrome associated with intra-alveolar hemorrhage. The diagnostic confirmation is histological, by the demonstration of linear deposits of immunoglobulins (IgG) along the glomerular basement membrane. The aim of our study was to describe its epidemiological, clinical, biological, immunological, histological, and evolutionary characteristics and to identify the different prognostic factors for predicting patient survival and renal survival. Method It was a retrospective, descriptive and analytical study including patients over 16 years old with anti-GBM disease proved by kidney biopsy and followed up over a period of 32 years (January 1985 to July 2017), in Internal Medicine Department of Charles Nicolle Hospital of Tunis. Results We collected 32 patients with a sex ratio H/F = 1.13. The mean age at diagnosis was 42 years old with extremes of 18 to 81 years old. The most frequent extra-renal manifestations were pulmonary (53%), neurological (12.5%) and ocular (6%) manifestations. Hematuria associated with proteinuria was constantly found. The latter was nephritic in 31% of patients. All patients had renal insufficiency on admission, oligo-anuric in 60% of cases. The use of extra-renal treatment at admission was necessary in 75% of patients. On the immunological level, the search for anti-MBG antibodies, performed in 20 patients, was positive in 65% of cases. All our patients had undergone a renal biopsy puncture with direct immunofluorescence study. Diffuse extra-capillary glomerulonephritis was observed in 93% of patients. Corticotherapy was initiated in 27 cases, associated with plasma exchange in 21 cases and cyclophosphamide in 17 cases. Nine of our patients died in the first year. Renal outcome was marked by partial remission in 2 cases and end-stage renal failure in 19 cases. In univariate analysis, an age greater than 60 years and the occurrence of respiratory distress were predictors of death. Oligo-anuria and need dialysis on admission were predictive factors for progression to end-stage renal failure. Conclusion Anti-GBM disease is a serious illness. Current therapeutic modalities have significantly improved patient survival. These must be intensive and rapid in order to hope for a favorable renal evolution whose prognosis remains reserved.

Loss of CHEK2 Predicts Progression in Stage pT1 Non-Muscle-Invasive Bladder Cancer (NMIBC).

Downregulation of checkpoint protein kinase 2 (CHEK2), which is involved in DNA repair, is associated with poorer outcome in various tumors. Little is known about the role of CHEK2 in urothelial carcinoma of the bladder (UCB). In the present study, we investigated the prognostic impact of CHEK2 protein expression in stage pT1 UCB. This retrospective, single-center analysis was carried out in a cohort of patients initially diagnosed with a pT1 UCB between 2007 and 2015. Immunohistochemical (IHC) staining of CHEK2 was performed. CHEK2 expression was correlated with recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) using Kaplan-Meier analysis and multivariable Cox regression analysis. The analysis included 126 patients (86% male, median age 71years). Loss of immunohistochemical protein expression of CHEK2 (<10%) was associated with significantly worse PFS (p = 0.041). Likewise, CHEK2 loss identified a subgroup of patients with worse PFS in the high-risk groups with concomitant CIS (p = 0.044), multifocal tumors (p < 0.001) and tumor grading G3 according to WHO1973 (p = 0.009). Multivariable Cox regression analysis revealed both loss of CHEK2 expression (HR: 4.18, 95%-CI: 1.35-12.93; p = 0.013) and multifocal tumors (HR: 4.53, 95%-CI:1.29-15.92; p = 0.018) as the only predictive factors for progression. Loss of IHC expression of CHEK2 in pT1 UCB is an independent predictor for progression to muscle-invasive disease and is also associated with worse PFS. This could help to identify high-risk patients who would benefit from early cystectomy.

1505-P: Plasma Glucose Level at 1h Post 75g OGTT Is the Best Predictor of the Development of Glucose Intolerance in Subjects with Normal Glucose Tolerance—The Toon Health Study

Background: Although glucose intolerance (GI) is diagnosed by fasting and 2h plasma glucose (PG) levels during a 75g OGTT, the upper limit of 1h PG level remains to be undefined in subjects with NGT. Previous report focusing on changes from NGT + IGT to diabetes has reported that 1h PG with ≥155 mg/dl is the risk for future diabetes in the world. However, IGT is well known as a risk factor for cardiovascular disease, few studies have focused on changes from NGT to GI. We therefore conducted a 5-year prospective study intended for NGT subjects to clarify the best predictor of the development of GI. Methods: To diagnose GI, we performed a 75gOGTT. We enrolled 1383 NGT subjects from The Toon Health Study. Finally, we analyzed 981 individuals with NGT who had a repeat health checkup. To investigate valuable predictive factors of progression of GI, we performed ROC curve analyses and compared fasting PG, 1h post OGTT, 2h post OGTT, and HbA1c. Results: ROC curve analyses revealed that 1h post OGTT was the best predictor of the development of GI in NGT (sensitivity 66%, specificity 74%, at a cutoff value of 149 mg/dl). In NGT with 1h PG&amp;gt;149mg/dl, odd ratio for the development of GI was 4.7 (95% CI: 3.25-6.80) compared to the reference after adjustment for age, sex, and BMI (p&amp;lt;0.0001). Conclusions: PG level at 1h post 75g OGTT was the best predictor of the development of GI in NGT. Disclosure M. Takakado: None. Y. Takata: None. T. Hadate: None. Y. Matsushita: None. R. Kawamura: None. K. Maruyama: None. I. Saito: None. H. Osawa: None.

Response to Transforaminal Epidural Block as a Useful Predictive Factor of Postherpetic Neuralgia.

Despite the high frequency of nerve blocks in the acute phase of herpes zoster, factors associated with intervention, such as response to epidural block, have not been analyzed as predictive factors of postherpetic neuralgia (PHN). To determine the predictive factors of progression to PHN in the presence of interventions, we analyzed the medical records of 145 patients who underwent transforaminal epidural injection (TFEI) in the acute phase of herpes zoster. A total volume of 5 mL (a mixture of 0.5% lidocaine and 5 mg dexamethasone) was injected during TFEI. Corticosteroid was used only for the first TFEI. Clinical data of age, sex, involved dermatome, presence of comorbidity, time from zoster onset to first TFEI, numerical rating scale (NRS) before TFEI, NRS at 1 week and 1, 3, and 6 months after the first TFEI, and number of TFEI were collected and analyzed. Through multivariate logistic regression analysis, pain improvement less than 50% at 1 week after the first TFEI was a strong predictive factor of progression of PHN at all time points. Response to TFEI appears to be a stronger predictive factor of progression to PHN than patient factors of sex, age, degree of initial pain, and presence of co-morbidity.

Predictive factors for progression through the difficulty levels of Pilates exercises in patients with low back pain: a secondary analysis of a randomized controlled trial

BackgroundThe progression through the difficulty levels of Pilates exercises is a subjective criterion, that depends on the therapist's experience and ability to identify the best moment to progress to the next level. ObjectiveTo identify the factors that interfere in the progression through the difficulty levels of the Pilates exercises in patients with chronic nonspecific low back pain. MethodsData from 139 patients with chronic nonspecific low back pain from a randomized controlled trial were used for statistical analysis using binary logistic regression. The dependent variable was the progression through the difficulty levels, and the independent variables were age, gender, educational level, low back pain duration, pain intensity, general disability, kinesiophobia, previous physical activity, and number of absences. ResultsThe factors that interfered in the progression through the difficulty levels were previous physical inactivity (odds ratio [OR]=5.14, 95% confidence interval [CI]: 1.53–17.31), low educational level (OR=2.62, 95% CI: 1.12–6.10), more advanced age (OR=0.95, 95% CI: 0.92–0.98) and more absences (OR=0.63, 95% CI: 0.50–0.79). These variables explain 41% of the non-progression through the difficulty level of the exercises. ConclusionPhysical inactivity, low educational level, more advanced age and greater number of absences can be interfering factors in the progression through the difficulty levels of the Pilates exercises in patients with chronic nonspecific low back pain.

Circulating cell free tumor DNA detection as novel biomarkers to monitor desmoid tumors evolution.

11063 Background: Since desmoid tumors (DT) exhibit an unpredictable clinical course, with stabilization and/or spontaneous regression, an initial “wait-and-see” policy is the new standard of care to select best indications of active treatments in case of significant evolution. Therefore, translational research is crucial to identify predictive factors of progression. Most DT are characterized by CTNNB1 mutation (CM) in exon 3 (T41A, S45F, S45P). Circulating cell-free tumoral DNA (ctDNA), named "liquid biopsy", has emerged as a new promising non-invasive tool to detect biomarker in several cancers. Methods: We present a method of detection of DT-specific CM using a targeted strategy digital droplet PCR (ddPCR) on cell-free DNA (cfDNA) extracted from blood samples of 31 DT patients (pts). T41A, S45P, S45F and their respective CTNNB1 wild-type probe were designed for ddPCR. Furthermore, we analyzed the correlation of cfDNA levels (CTNNB1 wt/ml plasma) and evolution of the tumor. Results: Initial DT CM statuswas known for 28 pts and unknown for 3 pts. 24 pts presented a CM (17 pts T41A, 6 pts S45F and 1 pt S45P), 2 pts a mutation of APC, 2 pts were wild-type, and 3 pts were undetermined. Among pts with a CM, CTNNB1 mutants were detected in the cfDNA of 6 patients (19.4%). CM detection was not correlated with the quantity of cfDNA analyzed (p = 0,7263–Mann-Whitney (MW)). Absolute quantification of cfDNA (CTNNB1 wt) normalized by mL of plasma displayed higher levels for patients with progressive DT (p = 0,0009 - MW), this difference of cfDNA quantity was also present between progressive, stable and self-regressive DT (p = 0,0012 - MW). A threshold of 875 CTNNB1 copies/mL predicted DT progression with a sensibility of 100% (CI95%: 59-100) and a specificity of 76.5% (CI95%: 50.1-93.2). Absolute cfDNA quantity was also higher in patients harboring multiple desmoids (p = 0.0292 - MW). Conclusions: The absolute quantification of normalized cfDNA is correlated with evolution of the disease, independently of the initial tumor type of CM. This study opens the perspective of using cfDNA as a genomic biomarker to assess the tumor dynamics at initial diagnosis, and to monitor treatment strategy in case of tumor evolution.

Long-term single-institute experience with trimodal bladder-preserving therapy with proton beam therapy for muscle-invasive bladder cancer.

We retrospectively elucidated the oncological outcomes, prognostic factors and toxicities of proton beam therapy in trimodal bladder-preserving therapy for muscle-invasive bladder cancer at our institution. From 1990 to 2015, 70 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal transurethral resection of the bladder tumor, small pelvis photon irradiation, intra-arterial chemotherapy and proton beam therapy. The overall survival rate, progression-free survival rate, time to progression, predictive factors for progression and toxicities were analyzed. Progression was defined as when muscle-invasive recurrence, distant metastasis or upper urinary tract recurrence was observed. The patients' median age was 65 (range 36-85) years. The median follow-up period was 3.4 (range 0.6-19.5) years. The 5-year cumulative overall survival rate, progression-free survival rate and time to progression rate were 82%, 77%, and 82%, respectively. In univariate and multivariate analyses, tumor multiplicity and tumor size (≥5 cm) were significant and independent factors associated with progression (hazard ratio 3.5, 95% confidence interval 1.1-12; hazard ratio 5.0, 95% confidence interval 1.3-17; P <0.05 for all). As for toxicity, 26 (18%) patients had grade 3-4 acute hematologic toxicities and 2 (3%) patients had grade 3 late genitourinary toxicity. No patient had to discontinue the treatment due to acute toxicity. Our bladder-preserving therapy with proton beam therapy was well tolerated and achieved a favorable mortality rate. Tumor multiplicity and tumor size were important risk factors for progression. Our findings indicate that this therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients.

Lessons from surgical outcome for intracranial meningioma involving major venous sinus.

Intracranial meningiomas involving the major venous sinus (MVS) pose several complication risks upon performing radical resection. Some surgeons consider MVS invasion a contraindication for a complete resection of meningioma, and others suggest total resection followed by venous reconstruction. The aim of the study was to analyze our surgical results and discuss management strategy for intracranial meningiomas involving the MVS. Between 1993 and 2011, 107 patients with intracranial meningiomas involving MVS underwent surgery in our institution. Clinicoradiological features including pathological features and operative findings were retrospectively analyzed. Median follow-up duration was 60.2 months (range, 6.2–218.2 months). Distributions of tumor cases according to the involved sinus were as follows: 86% parasagittal, 10.3% tentorial, and 3.7% peritorcular. Simpson Grade I/II removal was achieved in 93 of 107 patients (87%). Partially or totally occluded MVS by their meningiomas (Sindou classification IV and V) was found in 39 patients (36%). Progression rate was 12% (13/107) and progression-free survival rates were 89%, 86%, and 80% at 5, 7, and 10 years, respectively. Sindou classification (IV/V) and Karnofsky performance status (KPS) score 6 month after the surgery (KPS < 90) were predictive factors for progression in our study (P = 0.044 and P = 0.001, respectively). The resection degree did not reach statistical significance (P = 0.484). Interestingly, there was no progression in patients that underwent radiation therapy or gamma knife radiosurgery for residual tumor. There were no perioperative deaths. Complication rate was 21% with brain swelling being the most common complication. There was no predictive factor for occurrence of postoperative complication in this study. In conclusion, complete tumor resection with sinus reconstruction did not significantly prevent tumor recurrence in intracranial meningioma involving MVS. Considering the complications from this procedure as it has possibly related with reduced postoperative KPS score, the tumor should be removed as much as possible while leaving remnant portion with significant invasion of sinus or drainage vein. Following radiation therapy or gamma knife radiosurgery for a remnant or recurred meningioma might then be justified.

Abstract P5-08-24: Evaluation of single nucleotide polymorphisms (SNPs) as predictive factors of progression (PFS) and metastatic (MFS) free survival in adjuvant breast cancer (BC)

Abstract Background: Adjuvant chemotherapy (ACT) using anthracyclines and taxanes is a standard treatment for BC. Usual criteria as age, SBR grade, HER2 or hormonal status (HS), estrogen receptor (ER), triple negative BC, histological type, lymphovascular invasion (LVI), Ki67, tumor size and lymph node involvement are not yet sufficient for ACT decision. As SNPs located in genes involved in metabolism or transport of cytotoxic drugs may affect efficacy of ACT, we investigated the potential of 49 SNPs to predict response to ACT in BC. Methods: From 01/2008 to 01/2012, 418 patients (pts) with BC treated with ACT were included. 309 pts received FEC100-Docetaxel regimen (cohort 1), and 109 pts with HER2 overexpression FEC100-Docetaxel-Trastuzumab regimen (cohort 2). Genotyping of 49 SNPs was performed on germline DNA using real time PCR with SNPType (Fluidigm) or Taqman probes (Life technologies) on BioMark Platform (Fluidigm). PFS, MFS and overall survival (OS) were estimated by Kaplan-Meier method. Association of clinicopathologic features (CPF) with PFS/MFS was evaluated by log-Rank test. After ensuring Hardy-Weinberg equilibrium was respected, PFS/MFS were correlated to CPF and genotypes, using univariate and multivariate Cox logistic regression. A prognostic score was established. Results: PFS, MFS and OS rates were respectively 81.8%, 83.4% and 87.3% in cohort 1 (3.4 years of median follow up (FU)) and 90.1%, 90% and 93.8% in cohort 2 (4 years of FU). In cohort 1, univariate analysis revealed that 5 SNPs, SLCO1B3 (rs11045585), NOS3 (rs1799983), CYB2B6 (rs2279345), BRCA1 (rs799917) and CYP2D6 (rs3892097) were associated with MFS. Genotypes, HR, 95%CI and p value are as follows: SLCO1B3 GG 7.73 (1.83-32.7) p=0.001, NOS3 GT 0.32 (0.14-0.76) p=0.006, CYB2B6 TT 2.29 (1.02-5.13) p=0.04, BRCA1 CT 0.41 (0.19-0.89) p=0.02, and CYP2D6 AG 2.14 (1.05-4.36) p=0.03. Multivariate analysis revealed that 4 SNPs remained associated with metastatic risk: CYB2B6; TT 2.38 (1.05-5.41) p=0.038, NOS3; GG-TT 3.11 (1.33-7.27) p=0.009, BRCA1; CC-TT 2.21 (1.01-4.85) p=0.047, CYP2D6; AG 2.14(1.04-4.40) p=0.039. No CPF was associated with survival. Prognostic model revealed a metastatic risk of 10.25 (1.29-81.31) if these four adverse genotypes coexist. In cohort 2, subject to limited number of events, age (p=0.03), HS (p=0.06), ER (p=0.05), LVI (p=0.02) tumor size (p=0.003) and 2 SNPs were associated in univariate with PFS: CYB2B6 (rs2279345); CT 5.73 (1.22-27) p=0.01, MTHFR (rs1801133); CT 4.61 (0.98-21.7) p=0.03. Multivariate analysis showed unfavorable PFS for heterozygous patients for CYB2B6 or for MTHFR: 9.67 (1.82-51.28) p=0.008 and 5.62(1.19-26.59) p=0.03 respectively and if tumor size was ≥T2 10.78 (2.12-54.90) p=0.004. Conclusion: SNPs of genes involved in oxidative stress (NOS3 rs1799983; GG-TT), docetaxel transport (SLCO1B3 rs11045585; GG) cyclophosphamide (CYB2B6 rs2279345; TT in cohort 1 ou CT in cohort 2) and 5FU metabolism (MTHFR rs1801133; CT), or DNA repair (BRCA1rs799917; CC-TT) are associated with survival in pts treated with ACT. BRCA1, CYB2B6 and SLCO1B3 represent potential attractive tools for guiding ACT indication. Citation Format: Ducoulombier A, Dumont A, Revillion F, Bonneterre J, Peyrat J-P. Evaluation of single nucleotide polymorphisms (SNPs) as predictive factors of progression (PFS) and metastatic (MFS) free survival in adjuvant breast cancer (BC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-24.

Solitary plasmocytoma: 19-year retrospective study and review of the literature

Solitary Plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by localized plasma cell infiltration. Radiotherapy is recommended as the treatment of choice. Epidemiological data is important to evaluate the effectiveness of treatment and the progression to Multiple Myeloma (MM). We described the clinical features and follow-up of 32 patients with SP treated with radiotherapy as primary treatment at our Department of Radiotherapy and we reviewed the literature on prognostic factors of progression to MM. Ninety percent of patients (71% complete response and 19% partial response) responded to treatment. Fourteen patients progressed to MM with a median time of progression of 16, 9 months. With a median follow-up of 40 months, the 5 and 10-year estimated Overall Survey (OS) was 62, 6% and 47, 7% respectively. Predictive factors of progression are still controversial. New factors are emerging in the fields of pathology, imagiology and immunology and thus we wait longer follow-up to confirm their predictive value. SP is highly radiosensitive and radiotherapy combines excellent control rates with minimal toxicity. However, it is a heterogeneous disease and approximately half of the patients will progress to MM. Identifying the patients more likely to progress would allow us to treat them in a different way.

Glomerular tip adhesions predict the progression of IgA nephropathy

BackgroundFocal segmental glomerulosclerosis-like lesions have been proposed to be predictive factors for IgA nephropathy. This single center, retrospective cohort study was designed to clarify which clinical and pathological factors are predictive of decreased estimated glomerular filtration rate (eGFR) at 5 and 10 years in IgA nephropathy patients.MethodsOf the 229 patients with IgA nephropathy who were admitted to Aichi Medical University Hospital between 1986 and 2010, 57 were included in this study during the 5 to 10 years after renal biopsy. Clinical, laboratory, and pathological parameters were analyzed by multiple linear regression analysis with backward elimination to determine independent risk factors. After identifying such factors, we compared patients with and without each factor using the Student’s t test, Wilcoxon test, or Mann–Whitney U test.ResultsFour variables were identified as predictive factors for progression of IgA nephropathy: initial eGFR (p = 0.0002), glomerular tip adhesion (p = 0.004), global sclerosis (p = 0.019), and diastolic blood pressure (p = 0.024). The annual decrease in eGFR of patients with (n = 9) or without glomerular tip adhesions (n = 48) was 4.13 ± 3.58 and 1.49 ± 2.89 ml/min/1.73 m2, respectively (p = 0.015). Serum total cholesterol levels were 231 ± 45 mg/dl and 196 ± 42 mg/dl, respectively (two-sided p = 0.064; one-sided p = 0.032).ConclusionsThe presence of glomerular tip adhesions predicts the progression of IgA nephropathy. High levels of serum total cholesterol may affect glomerular tip adhesions.

Progression of carotid atherosclerosis in patients with systemic lupus erythematosus

The progression of carotid atherosclerosis in lupus patients is frequently encountered, and it is determined by both traditional and nontraditional risk factors. Of the 181 patients initially included in the study, 157 patients were reevaluated after 39(37-42) months. The progression of atherosclerosis was defined as the increase in the intima-media thickness (IMT) >0.15mm and/or an increase of the plaque score. The predictive factors of progression were identified using the Poisson regression model. The median of the cohort age at baseline was 38years (range 29-46years; 96.2% female, 75.8% nonwhite). Carotid atherosclerosis progression was observed in 43 patients (27.4%), an increased plaque score was observed in nine patients (5.7%), an increase of IMT >0.15mm was observed in 31 (19.7%), and both issues were present in three patients (1.9%). The univariate determinants of atherosclerosis progression were age, systemic lupus erythematosus (SLE) duration, and higher serum level of triglycerides (p < 0.05). The presence of nephrotic proteinuria (p = 0.063), stage 3 or greater chronic kidney disease (p = 0.091), and longer duration of prednisone use (p = 0.056) showed a tendency towards association with progression of atherosclerosis. The independent risk factors for progression were the SLE duration (p = 0.008, RR = 1.06, 95% CI = 1.03-1.10) and the presence of nephrotic proteinuria (p = 0.022, RR = 4.22, 95% CI = 2.18-8.15). The progression of atherosclerosis occurred in a substantial number of young SLE patients during a short-term follow-up. The independent factors associated with this progression emphasize the importance of SLE in determining atherosclerosis in these individuals.

The impact of treatment with hylan G-F 20 on progression to total hip arthroplasty in patients with symptomatic hip OA: a retrospective study

Introduction:There is scarce data available on intra-articular hyaluronan’s ability to modify the progression of osteoarthritis (OA).Objective:The purpose of this retrospective pilot study was to assess the impact of treatment with hylan G-F 20 on progression to total hip replacement (THR) in patients with symptomatic hip OA.Research design and methods:The records of patients presenting with symptomatic hip OA and treated with hylan G-F 20 were analysed. Endpoints were the number of THRs performed and the survival time (in months) between commencement of treatment and THR, if performed. Endpoints were evaluated for the entire study population and for those sub-groups of patients which were, or were not, defined as candidates for THR prior to intra-articular treatment. Predictive factors of progression to THR were also assessed.Results:A total of 850 patients’ records were evaluated and 224 patients’ data were included in the study and evaluated. Eighty-four patients (37.5%) progressed to THR, 206 patients (92.0%) achieved 12 months survival, 170 patients (75.9%) achieved 24 months survival, and 69 patients (30.8%) achieved 5 years survival. Mean survival time was 36 months. Classification as a THR candidate, Lequesne score, ultrasound pattern and the presence of diabetes were predictive factors for progression to THR.Conclusions:These results suggest that hylan G-F 20 could be included in the management of symptomatic hip OA before recommendation for THR, particularly in patients presenting with milder symptoms, or in patients where, due to comorbidities or personal choice, THR is not a feasible option. Limitations of this study include the retrospective study design and the lack of a control group to determine any placebo effect of hylan G-F 20. Further prospective studies are therefore needed to corroborate these results.

Factors Affecting Response to Bacillus Calmette-Guérin Plus Interferon for Urothelial Carcinoma in Situ

The unpredictable behavior of carcinoma in situ and its high potential for recurrence and progression make identifying patient characteristics predicting a poor prognosis a priority. We assessed which factors affect the response to bacillus Calmette-Guérin plus interferon-α therapy in patients with urothelial carcinoma in situ. We analyzed data on a subset of 231 patients with carcinoma in situ enrolled in a multicenter, phase II trial of bacillus Calmette-Guérin plus interferon-α therapy for nonmuscle invasive bladder cancer. Analysis included patients who were bacillus Calmette-Guérin naïve and those with previous exposure to failed bacillus Calmette-Guérin therapy. We evaluated factors potentially affecting the bacillus Calmette-Guérin plus interferon-α response, including patient age, gender, tumor stage, multifocality, prior tumor stage, the previous bacillus Calmette-Guérin failure pattern, courses and maintenance, and prior chemotherapy. The complete response rate at 3 and 6 months in naïve vs previously failed bacillus Calmette-Guérin cases was 76% and 70% vs 76% and 66%, respectively. The 24-month disease-free rate was decreased in the 53 patients with a history of 2 or more failed bacillus Calmette-Guérin courses vs that in the 71 with a history of 1 failed course and bacillus Calmette-Guérin naïve patients (23% vs 57% and 60%, respectively). The 22 patients with refractory carcinoma in situ had the worst outcome of a 23% disease-free rate at 24 months while the 59 with relapse within 1 year had an intermediate outcome of 42% vs 59% in the 33 with relapse after 1 year. Patients with a history of papillary disease did better than those without such a history (p=0.019). Factors associated with a poor response to bacillus Calmette-Guérin plus interferon-α therapy in patients with carcinoma in situ are prior tumor stage, 2 or more prior bacillus Calmette-Guérin failures and a bacillus Calmette-Guérin failure pattern.