Predictive Factors For Treatment Outcome Research Articles

Abstract PD15-06: PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NACT) is standard of care for patients with triple-negative breast cancer (TNBC). Treatment response, especially pathologic complete response (pCR), is a strong predictive factor for treatment outcome. In the setting of up-front surgery, retrospective data have suggested improved outcome in patients with early TNBC that received breast-conserving surgery with adjuvant radiotherapy (BCT) as compared to mastectomy. Methods: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were eligible for this project. A total of 1074 patients from 8 prospective NACT trials were analyzed. Endpoints of interest were locoregional recurrence as first site of relapse (LRR, other sites of recurrence were considered competing events), disease-free survival (DFS) and overall survival (OS); analyses were performed using univariate and multivariate Fine-Gray (for LRR) and Cox models including study, age, cT, surgery type and pCR. For the analyses including pCR as covariable, only patients at risk at the landmark time were evaluated. Results: Median age was 48 years, 69.6% of patients had cT2 tumors and 85.3% underwent BCS. Of the 1074 analyzed patients, 48.8% achieved pCR. After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Upon univariate analysis, absence of pCR (hazard ratio [HR]=2.28; 95%CI 1.44-3.61; p< 0.001) and ypT-stage (ypT0/is vs. ypT1-3, HR=0.61; 95%CI 0.40-0.95; p=0.028) were significantly associated with LRR, while type of surgery, age and cT-stage were not. Upon multivariate analysis, absence of pCR was the only factor associated with increased risk of LRR (HR=2.22; 95%CI 1.38-3.58; p=0.001). Patients that underwent mastectomy (N=158) were significantly younger (age ≤ 50 years 72.8% vs. 59.9% for BCT [N=916]; p=0.002) DFS and OS was significantly better in patients who underwent BCT compared to mastectomy (DFS: HR=0.47; 95%CI 0.34-0.66; p< 0.001 and OS: HR=0.40; 95%CI 0.26-0.63; p< 0.001). In multivariate analysis, BCT was associated with a significantly better DFS and OS as compared to mastectomy (DFS: HR=0.51; 95%CI 0.36-0.72; p< 0.001; and OS HR=0.43; 95%CI 0.27-0.68; p< 0.001), whereas absence of pCR was associated with significantly worse DFS and OS (DFS: HR=2.43; 95%CI 1.78-3.31; p< 0.001; and OS: HR=3.15; 95%CI 1.94-5.10; p< 0.001). Conclusions: In this retrospective analysis from the GBG meta-database, treatment response, e.g. pCR, was the main determinant of locoregional recurrence in patients with early stage TNBC treated with NACT. BCT was associated with improved DFS and OS compared to mastectomy, which may at least in part reflect favorable patient selection. Citation Format: David Krug, Valentina Vladimirova, Michael Untch, Thorsten Kühn, Andreas Schneeweiss, Carsten Denkert, Beyhan Ataseven, Christine Solbach, Bernd Gerber, Hans Tesch, Michael Golatta, Sabine Seiler, Jörg Heil, Valentina Nekljudova, Sibylle Loibl. PD15-06 Pathologic complete response and breast-conserving surgery are associated with improved prognosis in patients with early-stage triple-negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-06.

High grade breast ductal carcinomas have high density of tumor-associated macrophages.

The role of tumor-associated macrophages (TAMs) is double-natured and still controversial. Depending on different settings, macrophages may suppress or promote tumor growth. TAM density may be one of the predictive factors of treatment outcome in cancer patients. To evaluate the density of tumor-associated macrophages in breast cancer and its relationship with various histopathologic findings. 55patients with invasive ductal carcinoma of breast who underwent mastectomy were enrolled. Sections of tumor samples were stained and the density of CD68+ cells was evaluated. There was anassociation between estrogen receptor (ER) expression and CD68density (p = 0.010) as the higher densities of CD68were seen inER negative tumors. Moreover, there was a significant relationship between histological grade and CD68density (p =0.006). The higher TAM density is associated with higher tumor grade and negative ER expression in breast cancer tissues. These findings revealed that inflammation could have an important role in malignancies.

Adipose tissue stromal vascular fraction and adipose tissue stromal vascular fraction plus platelet-rich plasma grafting: New regenerative perspectives in genital lichen sclerosus.

Lichen sclerosus (LS) is a chronic relapsing, inflammatory skin disorder usually involving the anogenital region of both sexes lacking a resolutive therapy. This study compared adipose tissue derived-stromal vascular fraction (AD-SVF) and AD-SVF-enriched platelet-rich plasma (PRP) therapy in the management of genital LS patients. Additionally, in vitro evaluation of cells and growth factors contained in the injected SVF has been evaluated as possible predictive factors for treatment outcome. The study population was 40 patients diagnosed with LS who were symptomatic despite medical treatment. Patients (age 43-78 years) randomized into two groups using a 1:1 allocation ratio, were evaluated clinically and assessing dermatology life quality index (DLQI) before and 6 months after treatment. Both procedures demonstrated a strong safety profile with no complications linked to the therapy. After 6 months, both treatments allowed for a significant improvement respect to baseline. Combinatory therapy demonstrated decreased efficacy in late stage patients. No correlations have been found between clinical and biological findings. AD-SVF and AD-SVF plus PRP are safe and effective regenerative approaches for genital LS patients. Clinical results support the preferential use of combinatory therapy for early stage patients confirming a synergic effect of AD-SVF and PRP. In contrast, AD-SVF plus PRP is discouraged for late stage patients.

Childhood sexual abuse predicts treatment outcome in conversion disorder/functional neurological disorder. An observational longitudinal study.

ObjectiveExplore trauma, stress, and other predictive factors for treatment outcome in conversion disorder/functional neurological disorder (CD/FND).MethodsProspective observational design. Clinical cohort study among consecutive outpatients with DSM‐IV CD/FND in a specialized mental health institution for somatic symptom disorders and related disorders (SSRD), presented between 1 February 2010 and 31 December 2017. Patient files were assessed for early childhood trauma, childhood sexual abuse, current stress, and other predictive factors. Patient‐related routine outcome monitoring (PROM) data were evaluated for treatment outcome at physical (Patient Health Questionnaire [PHQ15], Physical Symptoms Questionnaire [PSQ]) level as primary outcome, and depression (Patient Health Questionnaire [PHQ9]), anxiety (General Anxiety Disorder [GAD7]), general functioning (Short Form 36 Health Survey [SF36]), and pain (Brief Pain Inventory [BPI]) as secondary outcome.ResultsA total of 64 outpatients were included in the study. 70.3% of the sample reported childhood trauma and 64.1% a recent life event. Mean scores of patients proceeding to treatment improved. Sexual abuse in childhood (F(1, 28) = 30.068, β = 0.608 p < .001) was significantly associated with worse physical (PHQ15, PSQ) treatment outcome. 42.2% reported comorbid depression, and this was significantly associated with worse concomitant depressive (PHQ9) (F[1, 39] = 11.526, β = 0.478, p = .002) and anxiety (GAD7) (F[1,34] = 7.950, β = 0.435, p = .008) outcome.ConclusionChildhood sexual abuse is significantly associated with poor treatment outcome in CD/FND. Randomized clinical trials evaluating treatment models addressing childhood sexual abuse in CD are needed.

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer.

Neuropilin-2 (NRP2) is a prognostic indicator for reduced survival in bladder cancer (BCa) patients. Together with its major ligand, vascular endothelial growth factor (VEGF)-C, NRP2 expression is a predictive factor for treatment outcome in response to radiochemotherapy in BCa patients who underwent transurethral resection. Therefore, we investigated the benefit of combining cisplatin-based chemotherapy with irradiation treatment in the BCa cell line RT112 exhibiting or lacking endogenous NRP2 expression in order to evaluate NRP2 as potential therapeutic target. We have identified a high correlation of NRP2 and the glioma-associated oncogene family zinc finger 2 (GLI2) transcripts in the cancer genome atlas (TCGA) cohort of BCa patients and a panel of 15 human BCa cell lines. Furthermore, we used in vitro BCa models to show the transforming growth factor-beta 1 (TGFβ1)-dependent regulation of NRP2 and GLI2 expression levels. Since NRP2 was shown to bind TGFβ1, associate with TGFβ receptors, and enhance TGFβ1 signaling, we evaluated downstream signaling pathways using an epithelial-to-mesenchymal transition (EMT)-assay in combination with a PCR profiling array containing 84 genes related to EMT. Subsequent target validation in NRP2 knockout and knockdown models revealed secreted phosphoprotein 1 (SPP1/OPN/Osteopontin) as a downstream target positively regulated by NRP2.

Outcomes and complications of Hyperthermic IntraVesical Chemotherapy using mitomycin C or epirubicin for patients with non-muscle invasive bladder cancer after bacillus Calmette-Guérin treatment failure.

IntroductionChemohyperthermia is a feasible option in BCG (bacillus Calmette-Guérin) failure patients who desire bladder preservation. We aimed to assess outcomes and complications of chemohyperthermia using mitomycin C (MMC) or epirubicin (EPI).Material and methodsFrom March 2017 to February 2020, 103 BCG failure or intolerance patients with high-risk NMIBC (non-muscle invasive bladder cancer) underwent a hyperthermic intravesical chemotherapy (HIVEC) regimen. Five patients did not complete at least 5 instillations and were excluded from analysis. MMC was used in 72 out of 98 patients (Group A) while EPI was used in 26 patients (Group B). Response to HIVEC, predictive factors for treatment outcome and the disease-free survival (DFS) were defined as primary endpoints. The complications of chemohyperthermia were assessed as a secondary endpoint.ResultsNo significant differences were found in recurrence and progression after induction course between Groups A and B. Kaplan-Meier disease-free survival was 22.61 months in Group A and 21.93 in Group B. The log-rank test showed no statistically significant difference between the two curves (p = .627). In the multivariate analysis, patients with tumor size ≥3 cm (p = .029), recurrence rate >1/year (p = .034), concomitant carcinoma in situ (CIS) during transurethral resection of bladder (TURB) (p = .039) and BCG-unresponsive status (p = .048) were associated with a worse response to chemohyperthermia. The use of MMC or EPI did not influence the response to treatment (p = .157). A slightly significant higher rate of overall complications (p = .0488) was observed in Group B. A significantly higher rate of Grade 3 frequency/urgency (p = .0064) contributed to this difference. The use of EPI was the only independent factor associated with severe urinary frequency/urgency (p = .017). No patients experienced Grade 4/5 adverse events.ConclusionsHIVEC can be considered a feasible option in BCG failure/intolerant NMIBC patients, avoiding or postponing radical cystectomy in some particular subclasses of patients.

Clinical significance of periosteal reaction as a predictive factor for treatment outcome of medication-related osteonecrosis of the jaw.

Regarding treatment strategies for medication-related osteonecrosis of the jaw (MRONJ), surgical therapy has recently been reported to be more effective than conservative therapy. However, some patients did not achieve complete healing, even when extensive surgery was performed. Periosteal reaction in MRONJ patients is often observed by the CT examination. Tssshe purpose of this study was to investigate the relationship between periosteal reaction and treatment outcome of MRONJ. A total of 164 surgeries in 136 patients with MRONJ at two hospitals were included in the study. Correlations between various clinical and radiographic factors and treatment outcome were examined with Cox regression analysis. The results showed that the presence of periosteal reaction, as well as primary disease involving malignant tumor, were independent risk factors related to poor outcome. Furthermore, we examined factors related to the occurrence of the periosteal reaction and found that 4 variables were significantly correlated with periosteal reaction by multivariate analysis: gender (female), site (lower jaw), primary disease (malignant tumor), and osteosclerosis (severe). The present study clarified that the cure rate after surgical treatment decreased in cases with periosteal reaction, suggesting that it is necessary to review the treatment method.

Predictive factors for brace treatment outcome in adolescent idiopathic scoliosis: a best-evidence synthesis.

To evaluate predictive factors for brace treatment outcome in adolescent idiopathic scoliosis (AIS) by a systematic review of the literature. Eligible studies evaluating one or more predictive factors for brace treatment outcome were included following a systematic search in PubMed and EMBASE on October 23, 2017. Inclusion criteria were: (1) subjects diagnosed with AIS, (2) age ≤ 18years, (3) treated with a thoraco-lumbo-sacral orthosis (TLSO), and (4) evaluated one or more predictive factors of treatment outcome (failure and/or success). The methodological quality of included studies was independently assessed by two authors. Pooling was not possible due to heterogeneity in statistical analysis. Predictive factors were presented according to a best-evidence synthesis. The literature search identified 26 studies that met the inclusion criteria, and multiple types of TLSO braces were identified (Boston, Wilmington, Chêneau, Osaka Medical College, Dresdner Scoliosis Orthosis and SPoRT). A total of 19 radiographic and 8 clinical predictive factors were reported. Strong evidence was found that lack of initial in-brace correction is associated with treatment failure. Moderate evidence suggests that brace wear time is associated with failure and success, whereas initial curve magnitude and curve type are not. The results of this review suggest that lack of initial in-brace correction is strongly associated with brace treatment failure. Future studies on the threshold for minimal immediate in-brace correction, as a potential indication for brace treatment, are recommended. These slides can be retrieved under Electronic Supplementary Material.

Childhood ADHD and treatment outcome: the role of maternal functioning

BackgroundRelatively little is known about the role of maternal functioning in terms of attention deficit hyperactivity disorder (ADHD) symptoms, attachment style and resilience as predictive factors for treatment outcome when offspring are diagnosed with ADHD.ObjectiveTo investigate whether maternal functioning is associated with treatment outcome in children with ADHD.MethodsThe study formed part of a larger naturalistic observational study of children with ADHD. A battery of self-report measures was used to assess selected factors in maternal functioning at the point of referral (baseline data); adult ADHD-symptoms, adult attachment style and adult resilience. Associations between these domains and child treatment response were subsequently examined in a 1-year follow up.ResultsMaternal ADHD-symptoms and degree of resilience were significantly correlated to symptom reduction in offspring diagnosed with ADHD. However, the association between maternal attachment style and child treatment response as measured by the ADHD-RS did not reach statistical significance.ConclusionTo our knowledge, this is the first study to consider potential protective factors along with risk factors in maternal functioning and the impact on child treatment outcome. The study contributes to our knowledge of the potential role of maternal functioning in treatment outcome for children with ADHD.

Short- and long-term results of endoscopic ultrasound-guided transmural drainage for pancreatic pseudocysts and walled-off necrosis.

AIMTo evaluate the short- and long-term results of endoscopic ultrasound-guided transmural drainage (EUS-GTD) for pancreatic fluid collection (PFC) and identify the predictive factors of treatment outcome for walled-off necrosis (WON) managed by EUS-GTD alone.METHODSWe investigated 103 consecutive patients with PFC who underwent EUS-GTD between September 1999 and August 2015. Patients were divided into four groups as follows: WON (n = 40), pancreatic pseudocyst (PPC; n = 11), chronic pseudocyst (n = 33), and others (n = 19). We evaluated the short- and long-term outcomes of the treatment. In cases of WON, multiple logistic regression analyses were performed to identify the predictor variables associated with the treatment success. In addition, PFC recurrence was examined in patients followed up for more than 6 mo and internal stent removal after successful EUS-GTD was confirmed.RESULTSIn this study, the total technical success rate was 96.1%. The treatment success rate of WON, PPC, chronic pseudocyst, and others was 57.5%, 90.9%, 91.0%, and 89.5%, respectively. Contrast-enhanced computed tomography using the multivariate logistic regression analysis revealed that the treatment success rate of WON was significantly lower in patients with more than 50% pancreatic parenchymal necrosis (OR = 17.0; 95%CI: 1.9-150.7; P = 0.011) and in patients with more than 150 mm of PFC (OR = 27.9; 95%CI: 3.4-227.7; P = 0.002).The recurrence of PFC in the long term was 13.3% (median observation time, 38.8 mo). Mean amylase level in the cavity was significantly higher in the recurrence group than in the no recurrence group (P = 0.02).CONCLUSIONThe reduction of WON by EUS-GTD alone was associated with the proportion of necrotic tissue and extent of the cavity. The amylase level in the cavity may be a predictive factor for recurrence of PFC.

Abstract 1134: Tissue transglutaminase is a new therapeutic target to overcome steroid resistance in T cell acute lymphoblastic leukemia

Abstract Background: The treatment response to steroid is the most important predictive factor for treatment outcome of T-cell acute lymphoblastic leukemia (T-ALL). To improve survival for steroid-resistant T-ALL patients, it is necessary to develop innovative therapeutic strategies to overcome steroid resistance. This study attempts to determine new therapeutic strategies to overcome steroid resistance for patients with T-ALL. Tissue transglutaminase (TG2) is a intracellular calcium-dependent protein cross-linking enzyme reported to be highly expressed in various metastatic or drug-resistant cancer cells, and chronic expression of TG2 constitutively activates nuclear factor kappa B (NF-kappaB). Methods: We used biochemical and molecular methodologies to demonstrate that TG2 modulation leaded to overcome the steroid resistance in T-ALL. Results: We generated the steroid-adapted subclones of T-ALL cell lines that were extremely less sensitive to steroid than their parent T-ALL cells. We found that steroid-resistant subclones of T-ALL cells expressed much higher levels of TG2 than their parent cells and the modulation of TG2 activities altered NF-kappaB expression in this steroid-resistant cells. Inhibition of TG2 suppressed steroid resistance and improved the cytotoxicity of leukemia cells in steroid-adapted subclones of T-ALL. Conclusion: This study shows that TG2 expression is elevated with steroid resistance in T-ALL and the modulation of TG2 induces the cytotoxicity of steroid-adapted T-ALL. TG2 could be a new therapeutic target to overcome steroid resistance in T-ALL. Furthermore, change of TG2 expression could serve as markers of induced steroid resistance in T-ALL. Citation Format: Hyun Joo Jung. Tissue transglutaminase is a new therapeutic target to overcome steroid resistance in T cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2017-1134

Treatment success in neck pain: The added predictive value of psychosocial variables in addition to clinical variables

Background and aimsIdentification of psychosocial variables may influence treatment outcome. The objective of this study was to prospectively examine whether psychosocial variables, in addition to clinical variables (pain, functioning, general health, previous neck pain, comorbidity), are predictive factors for treatment outcome (i.e. global perceived effect, functioning and pain) in patients with sub-acute and chronic non-specific neck pain undergoing physical therapy or manual therapy. Psychosocial factors included treatment outcome expectancy and treatment credibility, health locus of control, and fear avoidance beliefs. MethodsThis study reports a secondary analysis of a primary care-based pragmatic randomized controlled trial. Potential predictors were measured at baseline and outcomes, in 181 patients, at 7 weeks and 26 weeks. ResultsHierarchical logistic regression models showed that treatment outcome expectancy predicted outcome success, in addition to clinical and demographic variables. Expectancy explained additional variance, ranging from 6% (pain) to 17% (functioning) at 7 weeks, and 8% (pain) to 16% (functioning) at 26 weeks.Locus of control and fear avoidance beliefs did not add significantly to predicting outcome. ConclusionsBased on the results of this study we conclude that outcome expectancy, in patients with non-specific sub-acute and chronic neck pain, has additional predictive value for treatment success above and beyond clinical and demographic variables. ImplicationsPsychological processes, health perceptions and how these factors relate to clinical variables may be important for treatment decision making regarding therapeutic options for individual patients.

Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study.

BackgroundAccording to EULAR recommendations, biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitor, tocilizumab (TCZ), and abatacept (ABT) are in parallel when prescribing to rheumatoid arthritis (RA) patients who have shown insufficient response to conventional synthetic DMARDs. However, most prediction studies of therapeutic response to bDMARDs using gene expression profiles were focused on a single bDMARD, and consideration of the results from the perspective of RA pathophysiology was insufficient. The aim of this study was to identify the specific molecular biological features predicting the therapeutic outcomes of three bDMARDs (infliximab [IFX], TCZ, and ABT) by studying blood gene expression signatures of patients before biologic treatment in a unified test platform.MethodsRA patients who responded inadequately to methotrexate and were later commenced on any one of IFX (n = 140), TCZ (n = 38), or ABT (n = 31) as their first biologic between May 2007 and November 2011 were enrolled. Whole-blood gene expression data were obtained before biologic administration. Patients were categorized into remission (REM) and nonremission (NON-REM) groups according to CDAI at 6 months of biologic therapy. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets differentially expressed between these two groups for each biologic. Then, we compiled “signature scores” for these gene sets, and the prediction performances were assessed.ResultsGSEA showed that inflammasome genes were significantly upregulated with IFX in the NON-REM group compared with the REM group. With TCZ in the REM group, B-cell-specifically expressed genes were upregulated. RNA elongation, apoptosis-related, and NK-cell-specifically expressed genes were upregulated with ABT in the NON-REM group. Logistic regression analyses showed that “signature scores” of inflammasomes, B-cell-specifically expressed, and NK-cell-specifically expressed genes were significant, independently predictive factors for treatment outcome with IFX, TCZ, and ABT, respectively. The AUCs of ROC curves of these signature scores were 0.637, 0.796, and 0.768 for IFX, TCZ, and ABT, respectively.ConclusionsWe have identified original gene expression predictive signatures uniquely underlying the therapeutic effects of IFX, TCZ, and ABT. This is, to our knowledge, the first attempt to predict therapeutic effects of three drugs concomitantly using a unified gene expression test platform.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1052-8) contains supplementary material, which is available to authorized users.

FRI-128 - Tenofovir versus Tenofovir plus Entecavir for Chronic Hepatitis B with Lamivudine-Resistance and Entecavir-Resistance

Summary We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy (TDF group) and TDF plus entecavir (ETV) combination-rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.

Combined external and intracavitary irradiation in treatment of advanced cervical carcinomas: predictive factors for treatment outcome and early and late radiation reactions.

The objective of this study was to find out predictive factors of tumor control as well as acute and late radiation reactions in treatment of advanced cervical carcinomas. In a series of 134 primary cervical carcinomas in International Federation of Gynecology and Obstetrics stages I to IV treated with combined external pelvic and intraluminal cervical-vaginal brachytherapy, predictive and prognostic factors were analyzed with regard to tumor control, recurrences, survival data, and adverse effects. Concomitant chemotherapy was given to 48 patients (35.8%). The external beam therapy was given with a 4-field technique (50-60 Gy) and brachytherapy was given with a high-dose rate (iridium-192) afterloading technique using a ring applicator set. A computed tomographically based 3-dimensional dose-planning system was used for the external beam therapy and for the brachytherapy planning. The mean age of the patients was 65 years. A total of 110 tumors were squamous cell carcinomas and 24 were adenocarcinomas or adenosquamous carcinomas. A total of 111 tumors were in International Federation of Gynecology and Obstetrics stages I to II; 23 tumors, in stages III to IV. The primary control rate of the complete series was 92.5%. Tumor size, the brachytherapy dose, the combined external and brachytherapy dose, as well as the number of days of interruption (delay) of irradiation were all significant predictive factors for local tumor control. Forty recurrences (30%) were recorded. Early radiation reactions were recorded in 67% (mostly grade 1) and were associated with the widths of the anterior-posterior and lateral pelvic fields. Serious late radiations reactions (grade 3-4) were noted in 11%. The width of the lateral pelvic fields, left point A and B doses, dose to the rectal reference point, as well as asymmetry of the dose distribution were associated with late severe reactions. Prior abdominal and pelvic surgery was also a high-risk factor for late tissue reactions. Concomitant chemotherapy did not increase the risk for acute or late toxicity.

Expression Of Tissue Transglutaminase Is Associated With Glucocorticoid Resistance In T-Cell Acute Lymphoblastic Leukemia

Glucocorticoids are core drugs in the treatment of T-cell acute lymphoblastic leukemias (T-ALL) because they induce apoptosis and cell-cycle arrest in leukemia lymphoblasts. The treatment response to glucocorticoid is the most important predictive factor for treatment outcome of T-ALL. Development of secondary glucocorticoid resistance is lethal to the patients at relapse. To improve survival for glucocorticoid-resistant T-ALL patients, it is necessary to develop new therapeutic strategies to overcome glucocorticoid resistance. In the present study, we used biochemical and molecular methodologies to demonstrate that tissue transglutaminase (TG2) confers glucocorticoid resistance in T-ALL. TG2 is a calcium-dependent protein crosslinking enzyme reported to be overexpressed in various metastatic or chemotherapy-resistant cancer cells including lymphoma cells. We found that T-ALL cells expressed elevated levels of TG2. We generated a model of glucocorticoid-adapted subclones of T-ALL cell lines that were extremely less sensitive to glucocorticoid than the parent cells. Glucocorticoid-adapted subclones not only showed the change of ABC transporters activity but also increased TG2 expression and activity than the parent cells in T-ALL. Inhibition of TG2 suppressed glucocorticoid resistance and improved the cytotoxicity of glucocorticoid in glucocorticoid-adapted subclones of T-ALL. Our study is the first to show the expression of TG2 and the contribution of TG2 to glucocorticoid resistance in T-ALL. The modulation of TG2 expression could be a new therapeutic target to overcome glucocorticoid resistance in T-ALL. Furthermore, change of TG2 expression could serve as markers of secondary glucocorticoid resistance in T-ALL. Disclosures:No relevant conflicts of interest to declare.

A recall program for the outcome of conventional root canal treatment performed in a teaching hospital

Objectives: This study investigated the long-term survival and the prognostic factors of endodontic treatments performed in a dental teaching hospital. The aim was to calculate the probabilities of success or failure according to the follow-up extent and to assess the time allowed for a complete periapical healing. Materials and methods. A cohort of 185 teeth were re-examined 1–4 years after treatment. The outcome was assessed on the basis of radiographic and clinical criteria as success, uncertain or failure. A survival analysis using the Cox model was used (i) to explore tooth survival and periapical healing over the time and (ii) to highlight the predictive factors of treatment outcome. Results. After 2 years, the appearance of an apical periodontitis remained lower than 3.5%, whereas only 22.8% of periapical healed cases were notified. The prognosis factors are: (i) for teeth with initial healthy periapical conditions, coronal leakage (p = 0.002) with the higher risk of failure (RR = 19.77), absence of correspondence filling length/shaping = 0.026), type of teeth (p = 0.041) and (ii) for teeth with apical periodontitis, number of root canals (p = 0.000,91), correspondence filling length/shaping length (p = 0.017) and over-filling (p = 0.09). New periapical lesions or tooth loss were recorded after 2 years. Half of the successful cases of periapical healing were observed during the follow-up from 2–4 years. Conclusions. This longitudinal study shows that coronal leakage is responsible for late failure and that periapical healing is long to achieve. Therefore, endodontic treatments may require a follow-up of over 2 years.

Late nodal metastasis in early-stage node-negative oral cavity cancers after successful sole interstitial brachytherapy: An institutional experience of 42 cases in India

Purposes Brachytherapy, either alone or in combination with external irradiation, is a useful organ-preserving approach in the treatment of primary head and neck cancers. Treatment of regional nodal drainage area is not warranted in early-stage oral cavity cancers because T1N0 oral cavity cancers have less than 20% likelihood of nodal spread. We reviewed the records of interstitial brachytherapy cases of oral cavity cancers in our brachytherapy unit to assess the clinical outcome of the patients treated. Methods and Materials We tried to correlate the clinical outcome of the disease with different predictive factors for treatment outcome and to analyze statistically the role of these factors. Results Cases treated with combined external irradiation with interstitial brachytherapy included higher T stage, with greater risk for nodal spread, though initially node negative. As these were treated with microscopic dose for nodal clinical target volume, nodal recurrence was fewer (18.5%). On the contrary, although the early-stage (T1N0) oral cavity cancers that were treated with brachytherapy alone had initially a less than 20% chance of nodal metastasis, there was an increased risk up to 80% for late nodal metastasis after treatment. Tumor thickness >6 mm ( p = 0.044) and need for a multiplanar implant ( p = 0.008) were found to be statistically significant risk factors for nodal recurrence. Other factors like high-grade tumors, ulcero-infiltrative lesions, implant of mobile tongue, and low hemoglobin, though relevant, were not found to be statistically significant. Conclusions We recommend prophylactic nodal irradiation in addition to brachytherapy even for early-stage oral cancers treated with interstitial brachytherapy. Furthermore, the invasive procedure of interstitial brachytherapy causing a disruption of body’s physiologic barrier to localize the disease is itself a probable risk factor for late nodal recurrence. Whether this, apart from the poor prognostic factors, causes increased chance of spread of a localized disease needs to be evaluated by a large prospective randomized study. This is needed to find out exactly the scenario where exclusive brachytherapy will be appropriate for treatment of early-stage oral cavity cancers.

Genetic Alterations Detected by High-Resolution Array Comparative Genomic Hybridization in Microdissected HRS Cells Correlate with Treatment Outcome in Classical Hodgkin Lymphoma

INTRODUCTION: Clinical decision making in Hodgkin lymphoma (HL) is primarily based on clinical variables in part because the scarcity of the malignant Hodgkin Reed Sternberg cells (HRS cells) hampers their molecular characterization. However, more recently investigation using laser capture microdissection has allowed a more detailed analysis of these cells. The objective of this study was to detect genomic alterations in HRS cells and correlate these changes with treatment outcome.PATIENTS AND METHODS: We studied 53 patients with classical HL who were primarily treated at the BC Cancer Agency in Vancouver between 1984 and 2006. All received at least 4 cycles of polychemotherapy and stage-dependent radiotherapy if indicated. The cohort included 43 pretreatment samples and 10 biopsies taken at relapse. Treatment failure was defined as disease progression or relapse at any time (n=23), treatment success as absence of progression (n=30). Whole genome amplification (GenomePlex, Sigma) of pools from 500–1000 individually picked, microdissected HRS cells (Molecular Machines & Industries Cellcut with Nikon Eclipse TE2000-S microscope) was performed. 200 ng of amplified DNA was hybridized to 32k submegabase resolution BAC tiling arrays (SMRT) against sex-matched control-DNA. Scoring of array CGH data was performed by computational analysis using CNA-HMMer v0.1 (available at http://www.cs.ubc.ca/~sshah/acgh/) based on a Hidden Markov Model (HMM). Clustering of the 53 cases was performed using the K-medoids algorithm. Areas of amplification bias and known copy number polymorphisms were excluded.RESULTS: On average whole genome amplification generated 500-fold amplification of genomic DNA. The most frequent copy number alterations (>20% of cases) included gains of 2p14–24.3, 9p12–24.3, 12p11.21–13.33, 16p11.2–13.3, 17p11.2–13.3, 17q11.1–25.1, 19p12–13.3, 19q12–13.43, 20q11.21–13.32, 21q22.11–22.2 and losses of 1p36.31–36.33, 6q11.1–27, 7q22.1–36.3, 8p23.1–23.3, 11q22.3–25, 13q33.3–34 and Xq11.2–28. We also identified several small changes (<5 Mbs) such as loss of 1p36.32, 5q31.1 or 6q23.3 and amplification of 1q32.1, 8q24.21, 17q21.31 or 20q13.2. When comparing the different outcome groups we more frequently identified gains of chromosomal regions 12p13.31–13.33 and 16p12.1–13.3 in treatment failures (39% vs. 13%, Fisher exact p=0.05 and 43% vs. 10%, p=0.009), and losses of chromosomal regions 16q12.1–12.2 and 17p13.1–13.2 (17% vs. 0%, p=0.061 and 27% vs. 4%, p=0.061) were more frequently observed in treatment successes. We did not find significant differences of these changes between pretreatment (n=13) and relapse biopsies (n=10) of patients failing treatment. Using unsupervised analysis we identified a sample cluster of eight cases characterized by simultaneous occurrence of gains of 2p, 16p, 17p, 19q and losses of 6q. Notably, treatment failed in six of these cases.DISCUSSION: The combination of laser microdissection with subsequent WGA and high resolution array CGH provides a robust and sensitive platform for detecting chromosomal imbalances in microdissected HRS cells. We identified at high-resolution new and recurrent changes defining chromosomal regions that potentially harbor oncogenes and tumor suppressor genes crucial to the pathogenesis of HL. Furthermore, we found copy number alterations that are significantly associated with disease progression which, therefore, could serve as predictive factors for treatment outcome.

Graves' disease and radioiodine therapy

This study was performed to determine the results of ablative radioiodine therapy (RIT) when the achieved dose in the thyroid was above 200 Gy and to characterize predictive factors for treatment outcome. A total of 571 consecutive patients were observed for 12 months between July 2001 and June 2004. Inclusion criteria were a confirmed diagnosis Graves' disease, compensation of hyperthyroidism and withdrawal of antithyroid drugs two days before preliminary radioiodine-testing and RIT. The intended dose was 250 Gy and the therapeutically achieved dose was calculated from serial uptake measurements. The end-point measure was thyroid function 12 months after RIT; success was defined as elimination of hyperthyroidism. The relation between success rate and the achieved dose, thyroid volume, age and sex of patients, TSH- and TRAb-values and presence of ophthalmopathy was analysed. Relief from hyperthyroidism was achieved in 96% of patients who received more than 200 Gy, even for thyroid volumes >40 ml. The success of ablative RIT was not influenced by age or sex of patients, or by TSH- or TRAb values or concomitant ophthalmopathy. The mean achieved dose in the thyroid was 298 Gy with a standard deviation of 74.6 Gy. To achieve a dose of over 200 Gy with the above standard deviation, we recommend calculating an intended dose of 250 Gy and using a dosimetric approach with early and late uptake values in the radioiodine test, to allow early therapeutic intervention should the posttherapeutic thyroid dose fall unexpectedly below 200 Gy.