Predictors Of Better Overall Survival Research Articles

Prognosis of renal cell carcinoma with bone metastases: Experience in 300 consecutive patients.

463 Background: Bone metastases (BMs) are associated with significant morbidity and shorter survival in metastatic renal cell carcinoma (mRCC). Our purpose was to identify prognostic factors for mRCC patients (pts) with BMs. Methods: Data from mRCC pts with BMs, treated at Gustave Roussy between April 1992 and March 2016, were retrospectively collected. Age, sex, ECOG-Performance Status (PS), Memorial Sloan-Kettering Cancer Center (MSKCC) score, histology, number and site of BMs, concomitant metastases (presence and sites), therapy for BMs (radical resection or palliative surgery, radiotherapy, other local and systemic treatments), time to BMs, and outcome were analyzed. Synchronous solitary bone metastasis (SSBM) was defined as a single bone metastasis without concomitant visceral lesions at the initial diagnosis of RCC. Overall survival (OS) was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan-Maier method and modelled with Cox-regression analysis. Results: Three hundred pts were identified. Median time to BMs was 32.4 months (range 0–324 months). In 64 pts (21%), bone was the only metastatic site and 22 of them (7%) had a SSBM; 236 pts (79%) had concomitant metastases in other sites. Median OS was 23.22 months. SSBM pts had better OS then those with concomitant metastases (40 vs. 20 months; p<0.001). At univariate analysis, number of BMs (p<0.0001), spinal column as site of BMs (p<0.005), concomitant metastases (p<0.0001), Fuhrman grade (p<0.001), non-clear cell histology (p<0.003), and MSKCC score (p<0.001) were significantly associated with poor prognosis. At multivariate analysis, concomitant metastases remained predictor of poor prognosis while good MSKCC, radical resection, and SSBM were predictors of better OS. Conclusions: To our knowledge,this is the largest single-institution experience evaluating prognosis in pts with BMs from RCC. This study suggests that MSKCC score, number of BMs (1 vs. >1) and radical resection are prognostic factors. Additionally, in presence of solitary bone metastasis without other concomitant metastases at the initial diagnosis of RCC, bone surgery should be considered to achieve local tumor control and increase survival.

Parametric response mapping of dynamic CT: enhanced prediction of survival in hepatocellular carcinoma patients treated with transarterial chemoembolization.

The aim of this study was to evaluate the prognostic significance of parametric response mapping (PRM) analysis for hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE). We recruited 65 HCC patients who underwent TACE. These patients underwent longitudinal multiphasic CT before and after TACE. We applied PRM analysis to the baseline CT before TACE and first/second follow-up CTs. The results of PRM analyses were used to stratify patients into responders and non-responders. Overall survival was compared between the two groups. An independent survival analysis using conventional radiological assessments was performed, and the results were compared with PRM results. Univariate and multivariate analyses were performed to identify clinical factors affecting survival. The PRM analyses demonstrated that the responding group had a median survival of 529days, while the non-responding group had a median survival of 263days [hazard ratio (HR) 12.9, p<0.05 for differences in survival]. The manual analyses indicated median survivals of 491 and 329days for the responding and non-responding groups, respectively (HR 2.7, p<0.05). Tumor size, albumin level, and PRM values were found to be significantly related to overall survival after univariate and multivariate analyses. The PRM analysis could be a better predictor of overall survival for patients with HCC undergoing TACE than conventional radiological assessments.

Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a "real world" study.

Ibrutinib has demonstrated significant activity in relapsed/refractory mantle cell lymphoma (MCL) in clinical trials. However, the impact of hematopoietic cell transplantation on the outcomes of ibrutinib and the predictive factors for ibrutinib response has not been well studied. Hence, we conducted a multicenter retrospective study of MCL patients who received ibrutinib to (1) determine the overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of ibrutinib in routine clinical practice, (2) examine characteristics predictive of response to ibrutinib therapy, and (3) describe the outcomes of patients failing ibrutinib. Ninety-seven patients met the eligibility criteria. Overall response rate and median DOR to ibrutinib were 65% and 17months, respectively. Only lack of primary refractory disease was predictive of ibrutinib response on multivariate analysis. Twenty-nine patients received postibrutinib therapies, with an ORR of 48% and a median DOR of 3months. The median OS and PFS for the entire group (n=97) was 22 and 15months, respectively. On multivariate analysis, ibrutinib response, low MCL international prognostic index, and absence of primary refractory disease were predictors of better PFS, while ibrutinib response and Eastern Cooperative Oncology Group performance status ≤1 were predictors of better OS. The median OS postibrutinib failure was 2.5months. Our results confirm the high ORR and DOR of ibrutinib in MCL and that prior hematopoietic cell transplantation does not negatively influence ibrutinib outcomes. Survival following ibrutinib failure is poor with no specific subsequent therapy showing superior activity in this setting. As a result, for select (transplant eligible) patients, allogeneic transplant should be strongly considered soon after ibrutinib response is documented to provide durable responses.

SC01.02 PET-CT for Response Assessment During Induction Therapy of N2 NSCLC

Approximately 30% of patients with non-small cell lung cancer (NSCLC) are found to have locally advanced stage III tumors at initial diagnosis. For these patients the curative therapeutic options include definitive high-dose radiotherapy with concurrent chemotherapy or, alternatively, induction treatment followed by surgery. Preoperative chemotherapy or combined radiochemotherapy protocols followed by resection result in cure rates of 25-35 percent at 3 years for locally advanced NSCLC. However, surgical resection in patients with stage IIIa N2 remains an issue of controversy depending on the extent of lymph node involvement. Neoadjuvant chemo- or radiochemotherapy is being used to reduce disease burden in the mediastinum before surgery since patients who are downstaged via neoadjuvant therapy and then undergo resection experience a significantly longer 5-year survival of 40% to 50% than those who are found to have residual N2 disease at the time of surgery. Thus, identification of patients who are N2 negative after completion of their neoadjuvant therapy is a critical component for patient selection for thoracotomy. However, clinical restaging in these patients often is challenging. Endoscopic ultrasound guided biopsies (EUS/EBUS-FNA) have increasingly become available and are currently preferred procedures for staging and restaging before surgery due to their high diagnostic accuracy.1 Serial PET-CT imaging captures anatomical changes and additionally offers semiquantitative information about morphometric and metabolic tissue changes during induction treatment. Issues of PET-CT performance and quality assurance concerning standardization have been clarified during recent years and the validity of repeated measurements has been approved.2 Successful induction treatment regimens have been frequently found to reduce 18F-FDG uptake and thus PET-CT allows to assess the therapeutic response. Reduction in FDG-uptake of mediastinal lymph nodes after induction therapy has been shown to correlate well with histopathologic response,3 while postinduction PET avidity taken alone was not consistently found to be associated with pathological N2 involvement.4 In the direct comparison of EUS-FNA with PET-CT for restaging after induction chemoradiotherapy, concordance between findings of restaging EUS-FNA and metabolic response of lymph node metastases was observed in 63% patients treated within a prospective study but the diagnostic accuracy of PET-CT was limited.5 Nevertheless, serial FDG-uptake measurements seem to provide prognostic information during induction therapy. Data collected in prospective trials suggest that a decrease in SUVmax between 45% to 60% optimally separates between responders and non-responders.6-9 In a recent large retrospective analysis, a decrease in SUVmax greater than 60% in the involved mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary tumor site.10 An analysis of a randomized trial in potentially resectable stage III NSCLC of induction treatment (including a hyperfractionated accelerated radiotherapy phase) and definitive radiochemotherapy compared with induction treatment followed by surgery confirmed that as early as after two cycles of cisplatin-based induction chemotherapy percentage of SUVmax remaining represents a significant prognostic parameter.9 PET-response was of higher importance than all other clinical factors. Cut-off levels between 0.45 and 0.55 were predictive for freedom from extracerebral progression in all randomized patients. No important differences in the predictive value were observed comparing resection versus definitive radiochemotherapy. PET-response was closely related to extracerebral distant metastases but not to local recurrences, independent of treatment. One might conclude that less PET-responsive tumors are successfully controlled by intensified hyperfractionated accelerated radiochemotherapy or neoadjuvant radiochemotherapy and resection at loco-regional sites so that the highest risk of relapse remains at extracerebral distant sites. Therefore, a selection or intensification of the local therapy according to SUV-decrease is not warranted by these data. Functional imaging has not yet been fully established for treatment guidance but prospective evaluation is underway. In the group of poor-responding patients, treatment intensification by independent systemic options such as targeted therapy or immunomodulating therapy may become emerging new treatment options within clinical trials. 1. De Leyn EJCTS 2014, 2. Young, EJC 1999, 3. Pöttgen CCR 2006, 4. Ripley JTCS 2016, 5. Stigt, Lung Cancer 2009, 6. Hoekstra, JCO 2005, 7. Eschmann, Lung Cancer 2007, 8. Dooms, JCO 2008, 9. Pöttgen, JCO 2016, 10. Barnett ATS 2016. PET-CT; N2; induction, restaging

Beyond breast specific-Graded Prognostic Assessment in patients with brain metastases from breast cancer: treatment impact on outcome.

Brain metastases are a serious relatively common complication of breast cancer. We evaluated prognostic factors for survival after diagnosis of brain metastases from breast cancer in a contemporary cohort of patients. Patients diagnosed with breast cancer brain metastases at our institution between 1999 and March 2016 were evaluated. Overall survival was defined as time from brain metastasis diagnosis to death or last follow-up. Patients were classified according to the Breast cancer-specific Graded Prognostic Assessment (BS-GPA), based on age, Karnofsky performance score and breast cancer phenotype. 181 patients were identified. Tumor phenotype distribution was as follows: triple negative (TN, 18.8%), hormone receptor (HR)-HER2+ (16.6%), HR+HER2+ (23.2%) and HR+HER2- (30.9%), not available (10.5%). Median overall survival from brain metastasis diagnosis was 7.7 mos (95% CI 5.4-10.0 mos). Although TN patients experienced the worse outcome, no significant difference was observed across tumor phenotypes (median 5.1, 7.7, 11.0 and 8.6 months in TN, HR-HER2+, HR+HER2+, HR+HER2-, p = 0.081). The BS-GPA index was significantly associated with overall survival (median 18.8, 8.8, 6.2 and 3.6 months, respectively, for BS-GPA categories 3.5-4, 2.5-3, 1.5-2 and 0-1, p = 0.014). Increased number of local treatments for brain metastasis (radiotherapy or neurosurgery) or the administration of systemic therapy after brain metastasis diagnosis were also significant predictors of better overall survival (p < 0.001) and, when evaluated in multivariate analysis with BS-GPA, both added independent prognostication beyond BS-GPA. Patient-related features, tumor phenotype and multimodal treatments all independently contribute to modulate prognosis of patients diagnosed with breast cancer brain metastases.

Genomic Copy Number Complexity Correlates With Overall Survival in Glioblastoma Patients

Whole genome copy number analysis is increasingly available and now routinely performed for high-grade glial neoplasms at our institution. The purpose of this study is to determine if overall genomic complexity or specific gene copy number variations correlate with survival outcomes in patients with glioblastoma (GBM). Twenty-seven patients, diagnosed with GBM prior to February 2015 and analyzed using the Affymetrix OncoScan FFPE Assay for gene copy number variations, were identified and their charts reviewed. All patients received standard therapy consisting of focal radiation therapy and temozolomide. Actuarial overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method and subgroups compared by the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. Standard demographic and tumor-related variables were evaluated. In addition, based on OncoScan data, tumors were classified as “complex” when whole genome copy number patterns exhibited multiple segmental gains and losses requiring multiple double strand breaks and “simple, or non-complex” when changes involved whole arm or chromosome losses or gains. Finally, exact copy numbers were determined for thirteen specific gene loci (CCNE1, CDK4, CDK6, EGFR, FGFR3, INSR, IRS1, IRS2, MDM2, MDM4, PDGFRA, PTEN, and SOX2) and each evaluated as individual variables. Statistical analyses were performed on the SPSS Statistics software, v23. Our cohort consisted of 11 women and 16 men. Median age was 63.2 years (range: 39.0-86.2 years). Median KPS was 80 (range: 60-90). Tumors were hypermethylated at MGMT in 13/27 (48.1%) and harbored mutant IDH1 in 2/27 (7.4%). When classifying by genomic complexity, distribution of simple:complex GBMs was 11:16. Median follow-up times for all and living patients were 14.7 and 15.8 months, respectively. Median PFS and OS were 9.4 and 20.2 months, respectively. OS was significantly better in the complex (median = 20.2 mos) versus simple (median = 14.7 mos) subgroup by log-rank test (P value = 0.034). Younger age, complex genomic organization and lower IRS2 (insulin receptor substrate 2) copy number were significant predictors of better OS by univariate analyses with P values of 0.036, 0.049, and 0.049, respectively. Complex genomic organization and lower IRS2 copy number retained prognostic significance for OS in multivariate analysis with P values of 0.026 and 0.011, respectively. Increased genomic complexity and lower IRS2 copy number were significantly correlated with longer OS. Both factors may serve as potential markers for increased sensitivity to therapy. Our findings are hypothesis generating and will require validation in a larger cohort.

Abstract 3423: Overweight and obesity predict better overall survival rates in cancer patients with distant metastases

Abstract Background: Recent studies conducted in patients with chronic diseases have reported an inverse association between body mass index (BMI) and mortality. However, the question as to whether BMI may predict prognosis in patients with metastatic cancer remains open. We therefore designed the current retrospective study to investigate the potential association between BMI and overall survival (OS) in patients with distant metastases (DM) and a favorable performance status. Methods: Between 2000 and 2012, a total of 4,010 cancer patients with DM who required radiotherapy (RT) and had their BMI measured at the initiation of RT were identified. The relation between BMI and OS was examined by univariate and multivariable analysis. Results: The median OS time was 3.23 months (range: 0.1−122.17) for underweight patients, 6.08 months (range: 0.03−149.46) for normal-weight patients, 7.99 months (range: 0.07−158.01) for overweight patients, and 12.49 months (range, 0.2−164.1) for obese patients (log-rank: P &amp;lt; 0.001). Compared with normal-weight patients, both obese (HR = 0.676; 95% P &amp;lt; 0.001) and overweight individuals (HR = 0.84; P &amp;lt; 0.001) had a reduced risk of all-cause mortality in multivariable analysis. Conversely, underweight patients had a significantly higher risk of death from all causes (HR = 1.41; P &amp;lt; 0.001). Conclusions: Overweight and obesity are independent predictors of better OS in metastatic patients with a good performance status. Increased BMI may play a role to identify metastatic patients with superior survival outcome and exhibit a potential to encourage aggressive management in those patients even with metastases. Citation Format: Ngan M. Tsang. Overweight and obesity predict better overall survival rates in cancer patients with distant metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3423.

A Novel System for the Surgical Staging of Primary High-grade Osteosarcoma: The Birmingham Classification.

Chemotherapy response and surgical margins have been shown to be associated with the risk of local recurrence in patients with osteosarcoma. However, existing surgical staging systems fail to reflect the response to chemotherapy or define an appropriate safe metric distance from the tumor that will allow complete excision and closely predict the chance of disease recurrence. We therefore sought to review a group of patients with primary high-grade osteosarcoma treated with neoadjuvant chemotherapy and surgical resection and analyzed margins and chemotherapy response in terms of local recurrence. (1) What predictor or combination of predictors available to the clinician can be assessed that more reliably predict the likelihood of local recurrence? (2) Can we determine a better predictor of local recurrence-free survival than the currently applied system of surgical margins? (3) Can we determine a better predictor of overall survival than the currently applied system of surgical margins? This retrospective study included all patients with high-grade conventional osteosarcomas without metastasis at diagnosis treated at one center between 1997 and 2012 with preoperative chemotherapy followed by resection or amputation of the primary tumor who were younger than age 50 years with minimum 24-month followup for those still alive. A total of 389 participants matched the inclusion criteria. Univariate log-rank test and multivariate Cox analyses were undertaken to identify predictors of local recurrence-free survival (LRFS). The Birmingham classification was devised on the basis of two stems: the response to chemotherapy (good response = ≥ 90% necrosis; poor response = < 90% necrosis) and margins (< 2 mm or ≥ 2 mm). The 5-year overall survival rate was 67% (95% confidence interval [CI], 61%-71%) and 47 patients developed local recurrence (12%). Intralesional margins (hazard ratio [HR], 9.9; 95% CI, 1.2-82; p = 0.03 versus radical margin HR, 1) and a poor response to neoadjuvant chemotherapy (HR, 3.8; 95% CI, 1.7-8.4; p = 0.001 versus good response HR, 1) were independent risk factors for local recurrence (LR). The best predictor of LR, however, was a combination of margins ≤ 2 mm and a less than 90% necrosis response to chemotherapy (Birmingham 2b HR, 19.6; 95% CI, 2.6-144; p = 0.003 versus Birmingham 1a; margin >2 mm and more than 90% necrosis HR, 1). Two-stage Cox regression model and higher Harrell's C statistic demonstrate that the Birmingham classification was superior to the Musculoskeletal Tumor Society (MSTS) margin classification for predicting LR (Harrell's C statistic Birmingham classification 0.68, MSTS criteria 0.59). A difference in overall survival was seen between groups of the Birmingham classification (log-rank test p < 0.0001), whereas the MSTS margin system was not discriminatory (log-rank test p = 0.14). Based on these observations, we believe that a combination of the recording of surgical margins in millimeters and the response to neoadjuvant chemotherapy can more accurately predict the risk of local recurrence than the current MSTS system. A multicenter collaboration study initiated by the International Society of Limb Salvage is recommended to test the validity of the proposed classification and if these findings are confirmed, this classification system might be considered the standard practice in oncology centers treating patients with osteosarcomas and allow more effective communication of margin status for research. Level IV, prognostic study.

Programmed cell death-ligand 1 expression is associated with a favourable immune microenvironment and better overall survival in stage I pulmonary squamous cell carcinoma

BackgroundProgrammed cell death-ligand 1 (PD-L1) is expressed in a subgroup of lung cancer that may benefit from immunotherapy. The interaction between PD-L1 expression and tumour infiltrating lymphocytes (TIL) remains poorly understood. This study investigated the expression of PD-L1 in surgically resected stage I pulmonary squamous cell carcinoma (SqCC) and correlated it with TILs in tumour microenvironments, common driver mutations, and clinical outcomes. Materials and methodsOne hundred and five patients with surgically resected stage I squamous cell carcinoma were examined. Paraffin-embedded tumour sections were stained with PD-L1 antibody. Tumours with moderate-to-strong membrane staining in ≥5% of tumour cells were scored as positive for PD-L1 expression. The driver mutation epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B (BRAF) were examined by direct sequencing, while anaplastic lymphoma kinase (ALK), phosphoinositide 3-kinase catalytic alpha (PI3KCA), and fibroblast growth factor receptor 1 (FGFR1) were analysed by immunohistochemistry. The correlations of PD-L1 expression with each subtype of TIL, driver mutations, clinicopathologic parameters, and clinical outcomes were analysed. ResultsThere was positive PD-L1 expression in 56.2% (59/105) of patients. PD-L1 expression was not associated with the common clinicopathologic features and mutations of EGFR, KRAS, BRAF, ALK, PI3KCA, and FGFR1. As regards TILs composition, tumour PD-L1 expression was significantly associated with increased tumour epithelial CD8+ T cells and stromal CD4+ T cells. Otherwise, PD-L1 (+) tumour cells were negatively correlated with PD-L1 (+) immune cells within tumour stroma. By multivariate analysis, tumour PD-L1 expression and increased CD4+ T cell infiltrations in the tumour stroma were independent predictors of better overall survival and had a trend of better disease-free survival. ConclusionsPD-L1 expression is associated with a favourable immune microenvironment in stage I pulmonary SqCC and correlates with better clinical outcome.

The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism.

Although testosterone suppression during androgen-deprivation therapy (ADT) and obesity have been reported to affect ADT efficacy, there are few comprehensive analyses on the impact on ADT outcome. Recently, we demonstrated that the SRD5A2 polymorphism was associated with metastatic prostate cancer prognosis. Therefore, in this study, we investigated the relationship between ADT serum testosterone levels or body mass index (BMI) and the prognosis among men treated with primary ADT for metastatic prostate cancer. In addition, we examined the association of serum testosterone levels during ADT with the SRD5A2 polymorphism. This study included 96 Japanese patients with metastatic prostate cancer. The relationship between clinicopathological parameters, including serum testosterone levels during ADT and BMI, and progression-free survival, overall survival and survival from progression following primary ADT treatment for metastatic prostate cancer was examined. Additionally, the association between the SRD5A2 gene polymorphism (rs523349) and serum testosterone levels during ADT was examined in 86 cases. Among clinicopathological parameters, the lowest quartile of serum testosterone levels during ADT was a significant predictor of better overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. The CC allele in the SRD5A2 gene (rs523349), encoding the less active 5α-reductase, was associated with lower serum testosterone levels during ADT. Taken together, these findings revealed a dramatic suppression of serum testosterone by ADT was associated with better survival among men with metastatic prostate cancer that have undergone primary ADT, which may be affected by the SRD5A2 gene polymorphism.

Overweight and obesity predict better overall survival rates in cancer patients with distant metastases

Recent studies conducted in patients with chronic diseases have reported an inverse association between body mass index (BMI) and mortality. However, the question as to whether BMI may predict prognosis in patients with metastatic cancer remains open. We therefore designed the current retrospective study to investigate the potential association between BMI and overall survival (OS) in patients with distant metastases (DM) and a favorable performance status. Between 2000 and 2012, a total of 4010 cancer patients with DM who required radiotherapy (RT) and had their BMI measured at the initiation of RT were identified. The relation between BMI and OS was examined by univariate and multivariable analysis. The median OS time was 3.23 months (range: 0.1–122.17) for underweight patients, 6.08 months (range: 0.03–149.46) for normal‐weight patients, 7.99 months (range: 0.07–158.01) for overweight patients, and 12.49 months (range, 0.2–164.1) for obese patients (log‐rank: P < 0.001). Compared with normal‐weight patients, both obese (HR = 0.676; 95% P < 0.001) and overweight individuals (HR = 0.84; P < 0.001) had a reduced risk of all‐cause mortality in multivariable analysis. Conversely, underweight patients had a significantly higher risk of death from all causes (HR = 1.41; P < 0.001). Overweight and obesity are independent predictors of better OS in metastatic patients with a good performance status. Increased BMI may play a role to identify metastatic patients with superior survival outcome and exhibit a potential to encourage aggressive management in those patients even with metastases.

Abstract A61: Detection of ovarian cancer micrometastasis using nanoparticle-delivered probe targeted towards tumor-associated neovasculature.

Abstract Background: Ovarian cancer causes more death than all other gynecologic malignancies combined. In patients, the best predictor of overall survival is the amount of residual disease following surgical debulking. Indeed, studies have shown that patients have the best prognosis when maximal surgical effort is accomplished. However, despite numerous technological advances, surgery still primarily relies on white-light reflectance and the surgeon's vision. As such, micrometastasis are usually missed and most patients clinically classified as a complete responder carry residual tumor burden, eventually recur, and succumb to the disease. We hypothesize that we can utilize the specific phenotype of tumor-associated neovasculature to target optical enhancers to locate and delineate micrometastasis. Specific targeting is achieved by encapsulating deep infrared dye (DIR) in FDA-approved PLGA-based nanoparticle (NP) coated with the peptide sequence arginine-glycine-aspartate (RGD). RGD binds with high affinity to αVβ3 integrins, which are minimally expressed in quiescent blood vessels and normal cells but overexpressed in tumor-associated neovasculature and cancer cells of various origins, including ovarian cancer. Thus our objective is to develop specific tumor-targeting optical enhancers that can aid surgeons in the performance of microscopic tumor debulking with the goal of minimizing residual disease. Materials and methods: Intra- peritoneal (i.p.) tumors are established in nude mice using ovarian cancer cells that stably express mCherry fluorescent protein, which allows the colocalization of DIR signal and mCherry+ micrometastatic lesions. Using this model we compared the ability of soluble DIR, DIR encapsulated in naked NP (DIR-NP), and DIR encapsulated in RGD-coated NP (DIR-RGD-NP) to detect ovarian cancer micrometastasis. Formulations were delivered i.p. and fluorescence signal were measured ex vivo following necropsy. More importantly, the ability of the probe to locate and delineate micrometastatic lesions was determined using fluorescent dissection microscope. Results: Colocalization analysis of DIR and mCherry fluorescent images obtained at necropsy demonstrated the sensitivity of DIR-RGD-NP. In these animals, we observed 75% colocalization of DIR and mCherry signals compared to 26% in animals administered DIR-NP and 0% in those given soluble DIR. Ex vivo analysis of mean DIR intensity in tumors less than 2 mm showed mean fluorescent intensity (MFI) of 1209 in animals administered DIR-RGD-NP versus 155 MFI in animals administered DIR-NP. Morphological examination under the dissection microscope show that in animals administered DIR-RGD-NP, we can locate 81% of the mCherry+ micrometastasis based on DIR staining. In these animals, tumors less than 1 mm were detectable due to a halo of DIR staining around each micrometastatic lesion. In these foci, DIR signal was observed to stain the vasculature surrounding the small tumor implants especially those in the mesentery and diaphragm. In contrast, we were able to detect only 18% of the mCherry+ micrometastasis in animals administered DIR-NP. Conclusion: We demonstrate that we can visualize micrometastasis by using RGD as a tool to target the unique phenotype of ovarian cancer-associated neovasculature. RGD-coated nanoparticles are able to carry probes to the tumor microenvironment leading to optimal staining of micrometastasis. Our results highlight the use of this nanotechnology platform in microscopic surgical debulking to assure maximal surgical effort, minimize residual disease, and improve patient survival. Furthermore, delineation of tumor borders will also reduce inadvertent injury to vital structures and decrease surgery-associated morbidities. Citation Format: Ayesha Alvero, Eydis Lima, Dongin Kim, Sean Orton, Mary Pitruzzello, Yang Yang-Hartwich, Dan-Arin Silasi. Detection of ovarian cancer micrometastasis using nanoparticle-delivered probe targeted towards tumor-associated neovasculature. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A61.

Utility of Routine PET Imaging to Predict Response and Survival After Induction Therapy for Non-Small Cell Lung Cancer

Data from clinical trials suggest that changes in the glucose avidity of the primary site of lung cancer during induction therapy, measured by changes in (18)F-fluorodeoxyglucose positron emission tomography, correlate with tumor response. Little information about the utility of changes in positron emission tomography imaging of involved lymph nodes during induction chemotherapy is available. The utility of positron emission tomography imaging of either the primary site or nodal metastases, obtained during routine clinical care outside of a clinical trial setting, to predict response has also not been examined. A retrospective review of all surgical patients with non-small cell lung cancer at a single institution imaged between 2000 and 2006 with (18)F-fluorodeoxyglucose positron emission tomography before or after induction therapy was performed. An increase in standardized uptake value in the primary site of disease during induction therapy was associated with reduced overall survival after resection. Neither pretreatment standardized uptake value nor percentage change in the primary site was associated with overall survival after resection. A decrease in standardized uptake value of greater than 60% in the involved N2 mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary site of disease. An increase in glucose avidity of non-small cell lung cancers during induction therapy was associated with a worse prognosis compared with stable or any decrease in standardized uptake value. Changes in the glucose avidity of mediastinal nodal metastases may be a stronger predictor of survival than changes in the primary site of disease.

Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant Transformation: An International Collaboration

We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used toconstruct an optimal model. Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer priorchemotherapy regimens (p <0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy.

Gemtuzumab-Ozogamicin Containing Regimens As Induction Therapy Give the Highest Complete Remission Rate and the Longest Overall Survival Compared with Other Induction Regimens in Patients with Newly Diagnosed Acute Myeloid Leukemia

Introduction. Conventional induction treatment in young non APL-Acute Myeloid Leukemia (AML) patients is still represented by the association of an antracycline and Cytarabine, which offers a complete remission (CR) rate not inferior to 60%. The addition of Gemtuzumab Ozogamicin (GO) as a third or fourth drug, already demonstrated to improve clinical outcome, in terms of CR rates.Aims of the study. We retrospectively evaluated and compared the efficacy of different induction schedules, in terms of CR rates and Overall Survival (OS), administered to two groups of AML patients. Group 1 (n=139) was treated with a GO containing course (MyFLAI or MyAIE schedules); Group 2 (n=270) received a non-GO based regimen including or not Fludarabine (FLAI, FLAN, FLAG, 3+7 or DAE).Patients and Methods. From 1997 to 2014,409 newly diagnosed AML patients were treated in 3 Italian Institutions. Their median age was 53 (range 19-74) and 52 (range 17-75) years, respectively.According to karyotype (performed in 392/409 patients), FLT3 (available for 244/409 patients), and NPM1 mutational status (available for 157/409 patients), based on the NCCN-2013 risk stratification criteria, 35.2% of the patients were considered at High Risk (HR) (31.6% and 36.4% in the two groups, respectively) and 7.6% at low risk (LR) (7.8% and 7.0%, respectively).Results. The complete remission (CR) rate after induction was 81.4% and 70.4% for Group 1 and 2, respectively (p=0.01). Deaths during induction (DDI), occurring in the first 50 days from 1st line therapy, were 4/139 (2.9%) in Group 1 and 22/270 (8.1%) in Group 2 (p=0.003).Patients treated with GO showed a better OS than patients of Group 2 (Figure 1); the 5-years OS in the two groups was 54.01% and 34.9%, respectively, and different according to age (54.0% and 34.9% respectively (p=0.0003) in patients <60 years, 30.2% and 13.5% respectively (p=0.001) in patients ³60 years). The 5-years Event Free Survival (EFS) in the two groups was 45.6% and 30.8% respectively (p=0.0003) (Figure 2).Then, with a logistic univariate regression analysis.,we explored the impact of GO therapy in terms of CR rate. The use of GO was identified as a strong predictor of the achievement of a 1st CR (p=0.008). Moreover, a logistic multivariate regression analysis (risk and age) confirmed the role of the compound as a predictor of higher CR rate (p=0.013).We also performed a Cox Regression analysis, to investigate the impact of GO therapy, age and risk on OS: the use of GO was confirmed to be an independent predictor of better OS (p<0.0001) with a Hazard Ratio of 1.966 (p<0.0001).In a sub-analysis performed on HR patients, we observed a significantly better outcome in Group 1 than in Group 2 in terms of OS (p=0.0074, 5-year OS 47.7%; in group 2 OS 21.0% respectively, Figure 3) and EFS (p=0.001). However, there was no difference in terms of CR rate (p=ns). In particular, HR patients with adverse karyotype, may benefit from GO induction therapy in terms of OS (5-years OS 42.9% and 12.8% in Group 1 and 2, respectively, p=0.02); nevertheless FLT3 mutations negative impact canÕt be overcome by the drug administration (5-years OS 66.6% and 61.3% in Group 1 and 2, respectively).In SR AML, GO offered a better OS (p=0.036, 5-years OS 51.4% and 41.9% respectively).Comparing with Fisher's exact test the rate of increment in 5-years OS between Group1 and Group2 in HR and SR AML, we demonstrate that treatment with GO gave the higher benefit in HR AML (p=0.0005).Conclusions. These data showed that a four-drugs intensified induction therapy is a feasible approach in AML patients: adding GO at any induction regimen is an independent and strong predictor of better OS and higher CR rates. In our population, GO was not associated with a higher incidence of DDI.This approach, could be strongly recommended in SR and HR AML patients, due to karyotype abnormalities, in which showed an advantage in term of OS if compared with other standard regimens. On the contrary, we donÕt suggest the same schedule in FLT3 mutated patients, in which no benefits have been observed.Acknowledgments Work supported by ELN, AIL, AIRC, Progetto Regione-Universitˆ 2010-12 (L.Bolondi), FP7 NGS-PTL project. [Display omitted] [Display omitted] [Display omitted] DisclosuresSoverini:Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Fanin:Novartis Farma: Speakers Bureau. Cavo:BMS: Honoraria; Millenium Pharmaceuticals: Honoraria; Jansenn: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Onyx: Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Martinelli:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; ROCHE: Consultancy; MSD: Consultancy; AMGEN: Consultancy; Ariad: Consultancy.

The Functional Distance Between Mismatched HLA-DPB1 Increases Risks of Relapse and Mortality after Unrelated Donor Hematopoietic Cell Transplantation for AML, ALL and MDS: A Refinement of the T Cell Epitope Group Algorithm for Permissive Mismatches

Background: We and others have previously shown that non-permissive T cell epitope (TCE) group mismatches at HLA-DPB1 are associated with the risks of mortality after hematopoietic cell transplantation (HCT) from 10/10 HLA-matched unrelated donors (Fleischhauer et al, Lancet Oncol 2012; Pidala et al, Blood 2014). Moreover, we recently reported that TCE groups are reflected by a numerical score assignable to each HLA-DPB1 allele based on the combined median impact of 12 naturally occurring amino acid substitutions (AAS) on allorecognition of HLA-DPB1*09:01 as reference, termed functional distance (FD) (Crivello et al, Biol Blood Marrow Transplant 2015). Here we studied the association between the Delta in FD scores of HLA-DPB1 alleles present in the patient and in the donor (Delta-FD), and the clinical outcome of unrelated HCT.Methods: 417 consecutive adult patients transplanted from a 10/10 HLA-matched unrelated donor AML (n=302 [72%]), ALL (n=58 [8%]), or MDS (n=57 [14%]) at the University Hospital Essen between the years 2005 and 2014 were included in the analysis. 37 pairs were matched for both HLA-DPB1 alleles (12/12 HLA matches) while the remaining 380 pairs were HLA-DPB1 mismatched. Among the latter, Delta-FD scores were calculated as the absolute number of [FDpatient-FDdonor] on the basis of previously described FD scores for each HLA-DPB1 allele (Crivello et al, Biol Blood Marrow Transplant 2015).Results: The median Delta-FD score of HLA-DPB1 mismatched pairs was 1.64 (0.01-7.46). Receiver Operator Curves indicated stratification into 2 subgroups with Delta-FD scores <=2.665 (n=253 [66%]) and >2.665 (n=127 [34%]) as the best predictor of overall survival (OS). The 2 subgroups showed no significant differences for the distribution of major variables including diagnosis, disease status at transplant, immune prophylaxis and conditioning regimen, except for the percentage of permissive HLA-DPB1 TCE mismatches which was significantly higher in the subgroup with Delta-FD scores <=2.665 (p<0.0001).With a median follow-up of 4 yrs for surviving pts, the 5-yrs OS in the entire HLA-DPB1 mismatched cohort was 48%. In the 2 Delta-FD subgroups, the Kaplan-Meier (KM) probabilities of OS were 52% for Delta-FD <=2.665 and 38% for Delta-FD >2.665 (p<0.008), compared to 50% and 44% (p=0.31) for permissive and non-permissive TCE mismatches, respectively. In multivariate analysis, independent predictors of OS were time-dependent acute GvHD (HR 3.41, p<0.0001) and chronic GvHD (HR 0.41, p<0.0001), the use of anti-thymocyte globulin (HR 0.58, p=0.0006), disease status at transplant (HR 1.27, p<0.007), patient age (HR 1.63 p<0.007), and the stratified Delta-FD score (HR 1.51, p<0.007). Moreover, Delta-FD scores >2.665 were associated with lower probability of event-free survival (HR 1.48, p<0.007), due to significantly higher risks of disease relapse (HR 1.52, p<0.03) and NRM (HR 1.50, p<0.045), but not of acute or chronic GvHD. No significant differences were observed for any of the endpoints between 12/12 HLA-matched and 10/10 HLA-matched pairs with Delta-FD <=2.665.Conclusion: Stratification of HLA-DPB1 mismatches according to Delta-FD scores between donor and recipient represents a refinement of our previously published TCE algorithm of non-permissive mismatches with significant overlaps. In comparison to the latter, Delta-FD scores showed improved associations with the risks of mortality and relapse after 10/10 HLA-matched unrelated HCT in the patient cohort analyzed. If confirmed, these findings could provide a refined tool for donor-recipient matching for HLA-DPB1, and suggest that the combined impact of key AAS on T-cell alloreactivity, rather than AAS at individual positions, are relevant parameters for risk prediction in HLA-DPB1 mismatched HCT. DisclosuresNo relevant conflicts of interest to declare.

Checkpoint Blockade with Neoantigen Cancer Vaccines for Personalized Immunotherapy

Methods for harnessing the exquisite specificity of the immune system to eliminate tumors have been under development since the start of the 20th century, with numerous studies in animal models and trials in humans. Despite accumulating evidence, there has been widespread skepticism in the cancer community about whether tumors could be controlled by spontaneous immunity, and whether effective immunotherapy would be feasible to develop. However, the field has now passed an inflection point as new results have quelled these doubts, including: (i) several large clinical studies that have identified infiltrating CD8+ T cells as one of the best predictors of overall survival in human cancers, with strong validation in a large study of colorectal cancers; (ii) adoptive T cell therapy that effectively eradicates some types of B cell leukemias and (iii) novel checkpoint blockade (CPB) therapies inducing unprecedented long-term cures for patients with solid tumors, and more recently with blood malignancies. With the availability of these novel immunologic agents, the priority has shifted to understanding the mechanisms of and predicting responses to each treatment. Fundamental to this endeavor is the understanding of the crosstalk between tumor cells and immune cell populations within the tumor microenvironment and the selective pressure they mutually exert on each other. At the heart of cancer and host immune cell coevolution is the tumor antigen and host antigen-specific T cell interaction. The cytotoxic T cell-cognate antigen interaction forms the mechanistic basis for immune-mediated recognition and the killing of malignant cells, and provides selective pressure on the cancer cell to evolve. While the search for immunogenic tumor antigens has been the subject of decades-long studies, multiple lines of evidence have convincingly demonstrated tumor neoantigens as an important class of immunogenic tumor antigens. Neoantigens arise from amino acid changes encoded by somatic mutations in the tumor cell and have the potential to bind to and be presented by personal HLA molecules. With the recent availability of next-generation sequencing, systematic approaches to identify mutations leading to amino acid changes have become feasible. This development, together with the improved sensitivity of well-validated neural network/machine learning-based algorithms that predict binding to class I MHC, has enabled the implementation of neoantigen discovery pipelines. Recent studies by us and others in humans and mice have leveraged these tools to demonstrate evidence of protective immunity when targeting tumor neoantigens. We have further incorporated this approach to discover antigen targets to generate a multi-epitope personalized therapeutic cancer vaccine, that we are now testing in phase I clinical trials. Altogether, effective targeting of tumor neoantigens occurs spontaneously and during CPB, and offers prospects of a powerful, new immunotherapy. Disclosures No relevant conflicts of interest to declare.

Effect of preoperative chemotherapy on survival of patients with upper urinary tract urothelial carcinoma clinically involving regional lymph nodes.

To determine the effect of preoperative chemotherapy on survival in patients with upper urinary tract urothelial carcinoma clinically involving regional lymph nodes. We retrospectively analyzed 55 consecutive patients who received radical nephroureterectomy with or without preoperative chemotherapy for upper urinary tract urothelial carcinoma clinically involving regional lymph nodes at a single institution between January 1991 and December 2013. Median follow up was 18 months (range 2-193). Of 55 patients, 24 (43.6%) received preoperative chemotherapy (study group) and 31 (56.4%) underwent primary surgery (control group). Preoperative chemotherapy consisted of two to four cycles (median 3) of cisplatin-containing regimens. The fraction of patients with lower pathological T stage and N stage than clinical T stage and N stage was higher in the study group (29.2% and 54.2%) compared with the control group (3.2% and 16.1%; P = 0.013 and 0.010, respectively). The 5-year overall survival rate was significantly higher in the study group than in the control group (44.0% vs 12.9%, log-rank, P = 0.003). In multivariate analysis incorporating age at diagnosis, Eastern Cooperative Oncology Group Performance Status, clinical N stage and the number of removed lymph nodes, preoperative chemotherapy was a predictor of better overall survival (P = 0.047, HR 0.47, 95% CI 0.22-0.99). Preoperative chemotherapy might provide better survival outcomes in patients with upper urinary tract urothelial carcinoma clinically involving regional lymph nodes.

BMET-12SURVIVAL IN BREAST CANCER PATIENTS WITH BRAIN METASTASES AFTER GAMMA KNIFE STEREOTACTIC RADIOSURGERY

BACKGROUND: Recent studies have suggested a difference in outcome for breast cancer patients with brain metastases based on breast cancer subtype. These subtypes are defined as ER/PR+ and HER2- (luminal A), ER/PR+ and HER2+ (luminal B), ER/PR- and HER2- (triple-negative), and ER/PR- and HER2+ (HER2). The recently published modified Graded Prognostic Analysis (GPA) score for predicting overall survival (OS) in these patients includes subtype, number of CNS metastases, age, and performance status. We investigated whether this model was predictive of outcomes in these patients treated with Gamma Knife Stereotactic Radiosurgery (GKRS) at our institution and if any additional factors were predictive. METHODS: We reviewed all patients treated by GKRS for brain metastases from breast cancer at our institution from 2000 to 2014. Characteristics included subtype, age at breast cancer diagnosis, clinical stage, chemotherapy, age at diagnosis of brain metastases, Karnofsky Performance Status, years between breast cancer diagnosis and brain metastases, number of brain metastases, extracranial metastases, controlled primary tumor, type of treatment, and GPA score. OS was calculated using the Kaplan-Meier method and Cox regression analysis was performed to identify predictors. RESULTS: 61 patients were included. The majority of patients had luminal type. These patients were more likely to present with multiple metastases (p = 0.024). The median survival after treatment for the entire cohort was 16 months. We found no significant difference in survival based on subtype. According to GPA score, patients with the highest score had the best OS (p = 0.112). Multivariate analysis showed that stage II or III breast cancer at diagnosis, more than three brain metastases, and treatment with surgery and whole brain radiation for brain metastases were predictors for worse OS. CONCLUSION: In our cohort, breast cancer subtype is not a significant predictor for survival in these patients. The breast-cancer specific GPA was a good predictor of OS.

Optimal Threshold and Time of Absolute Lymphocyte Count Assessment for Outcome Prediction after Bone Marrow Transplantation

The recovery pace of absolute lymphocyte count (ALC) is prognostic after hematopoietic stem cell transplantation. Previous studies have evaluated a wide range of ALC cutoffs and time points for predicting outcomes. We aimed to determine the optimal ALC value for outcome prediction after bone marrow transplantation (BMT). A total of 518 patients who underwent BMT for acute leukemia or myelodysplastic syndrome between 1999 and 2010 were divided into a training set and a test set to assess the prognostic value of ALC on days 30, 60, 90, 120, 180, as well as the first post-transplantation day of an ALC of 100, 200, 300, 400, 500, and 1000/μL. In the training set, the best predictor of overall survival (OS), relapse-free survival (RFS), and nonrelapse mortality (NRM) was ALC on day 60. In the entire patient cohort, multivariable analyses demonstrated significantly better OS, RFS, and NRM and lower incidence of graft-versus-host disease (GVHD) in patients with an ALC >300/μL on day 60 post-BMT, both including and excluding patients who developed GVHD before day 60. Among the patient-, disease-, and transplant-related factors assessed, only busulfan-based conditioning was significantly associated with higher ALC values on day 60 in both cohorts. The optimal ALC cutoff for predicting outcomes after BMT is 300/μL on day 60 post-transplantation.