julilili42/papers huggingface dataset:
Resection margin and locoregional control in vulvar cancer: A subset analysis of the AGO CARE-1 multicenter study.
2014-05-20

5608 Background: Recently, the standard of minimal pathological resection margin distance of 8mm in surgery for primary vulvar cancer has been challenged since several single center analyses failed to show impact of smaller margins for disease control. Methods: The AGO CaRE-1 study is a retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Patients with primary squamous-cell vulvar cancer FIGO stage 1B and higher (UICC-TNM version 6) treated at 29 gynecologic cancer centers in Germany 1998-2008 were included in a centralized database. While a total of 1,618 patients were documented, this subgroup analysis focuses only on surgically staged node-negative patients with complete tumor resection and known margin distance without radio/chemotherapy (n=289). Results: Median age of the 289 analyzed patients was 66 years (22-94); 141 (48.8%) had pT1b, 140 (48.4%) pT2 and 8 (2.8%) pT3 tumors. 125 (43.3%) underwent complete, 127 (43.9%) partial vulvectomy and 37 (12.8%) radical local excision. The median minimal resection margin was 5 mm (1mm–33mm); median follow-up was 38.8 months. 46 patients (15.9%) developed disease recurrence, thereof 34 (11.8%) at the vulva, after a median of 18.3 months. Vulvar recurrence rates were 12.6% in the group of patients with a resection margin <8mm and 10.2% in patients with a margin ≥8mm. Other sites of recurrent disease were groins (8 cases; 2.8%), pelvis (1 case; 0.3%) and distant (3 cases; 1.0%). When analyzed as a continuous variable, margin distance had no significant impact on disease-free survival (HR per mm increase 0.945, 95% CI 0.886 – 1.009, p=0.090). Similarly, neither uni- nor multivariate analysis adjusted for age, tumor stage, tumor grade, depth of invasion and tumor diameter could reveal a significant difference in disease-free survival between the subgroup of patients with a margin ≥8 or <8mm (multivariate HR 0.642, 95% CI 0.355 – 1.162, p=0.143). Results were consistent when looking at vulvar recurrences only. Conclusions: Tumor-free resection margins are crucial for loco-regional control in vulvar cancer. The need for a minimal margin of 8mm could, however, not be observed in the large cohort of the AGO-CaRE database.
Surgical staging and its prognostic impact on patients with borderline ovarian tumors (BOT): A subanalysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study.
2014-05-20

5562 Background: Incomplete surgical staging was shown to be a negative prognostic factor for patients with borderline ovarian tumors (BOT). However, little is known about the prognostic impact of each individual staging procedure. Methods: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 in 24 German AGO centers were analyzed. Staging quality was evaluated following German guidelines. In patients with adequate surgery regarding their reproductive organs (bilateral salpingo-oophorectomy or intended fertility preserving surgery in patients ≤55 years), other recommended staging procedures (omentectomy, peritoneal biopsies, cytology, and, for mucinous histology, appendectomy) were evaluated applying uni- and multivariate regression models with respect to progression-free survival (PFS), separately for serous and mucinous histology. Results: A total of 559 serous BOT (64.1%) were opposed to 268 mucinous BOT (30.7%). For patients with serous histology, each additionally skipped staging procedure raised the risk for recurrence by at least 25% (HR 1.25; 1.95; 2.37 respectively) becoming statistically significant in case of two or more missing steps. The most crucial procedures were omentectomy in serous and appendectomy in mucinous BOT with HR of 2.00 (p=0.004) and HR of 4.86 (p=0.012) in univariate analyses. Together with established prognostic factors as FIGO stage, tumor residuals, and fertility preservation, omentectomy (HR 1.91; 95%CI 1.15, 3.19; p=0.01) retained a statistically significant impact on PFS in multivariate analysis for serous BOT as did appendectomy in case of mucinous histology (HR 4.60; 95%CI 1.33, 15.86; p=0.02). Conclusions: Individual surgical staging procedures appear to have prognostic importance for BOT patients. Despite excellent overall prognosis, the risk for recurrence rises with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.
Quantitative assessment of melanoma spread in sentinel and non-sentinel lymph nodes and survival.
2014-05-20

9082 Background: We have recently shown that quantification of cancer dissemination from melanoma to sentinel nodes is feasible and can be combined with other characteristics of the primary tumor to improve outcome prediction. Here we asked whether quantitative assessment of cancer spread to non-sentinel nodes could further improve outcome prediction. Methods: The study includes 128 melanoma patients with microscopic positive sentinel nodes who underwent complete lymph node dissection at the University of Tübingen. We analyzed 267 sentinel nodes and 1129 non-sentinel nodes from these patients by pathology and by quantitative immunocytology. For immunocytology half of the node was disaggregated mechanically, single cell suspensions were dispensed onto slides, stained with the melanoma specific antibody gp100. For each node we recorded the disseminated cancer cell (DCC) density, defined as the number of gp100 positive cells per million lymph node cells examined. Results: Quantitative immunocytology showed melanoma spread in non-sentinel nodes in 101 of 128 patients (79%), pathology was positive in 23 of 128 patients (18%). At a median follow-up of 67 months (range 3 to 136 months) 45 patients (35%) had died from melanoma. DCC densities in the sentinel node predicted outcome by univariable and multivariable analyses. Additional quantitative assessment of DCC densities in non-sentinel nodes did not significantly improve outcome prediction. A model based on DCC density in the sentinel node and thickness of melanoma predicted outcome even more precisely than a model based on the current AJCC staging system that includes information about the total number of histopathologically positive nodes. Conclusions: Quantitative reporting of the sentinel node status allows accurate prediction of melanoma outcome without knowledge of the status of non-sentinel nodes. Routine measurement of DCC densities in sentinel nodes may improve patient stratification for clinical trials and facilitate treatment decisions at the time of sentinel node biopsy when the complete nodal status is unknown.
NY-ESO-1 specific CD4+ Thelper1 cells for immunotherapy of cancer.
2014-05-20

3071 Background: NY-ESO-1 is an attractive target for adoptive T cell transfer (ACT) as it is expressed on a variety of tumors, but not in normal tissue except germline cells. Immune attack against cancer is mediated by cell lysis or induction of growth arrest through paralysis directly in tumor cells. The latter can be achieved by CD4+, IFN-γ-producing Thelper1 (Th1) cells. Translation of this immune mediated mechanisms into clinical application has been limited by complex in vitro protocols and regulatory hurdles. Methods: We established a short protocol according to good manufacturing practice (GMP) to generate NY-ESO-1 specific T cells with focus on Th1 cells. After presensitization with overlapping NY-ESO-1-peptides, IL-2 and IL-7, T cells were enriched based on IFN-γ capture technique. Cells were expanded using autologous feeder cells and IL-2, IL-7 and IL-15 and T-cell specificity and function was analyzed. Results: Large numbers of specific NY-ESO-1 CD4+ T cells with a Th1 cytokine profile and lower numbers of cytokine secreting CD8+ T cells could be generated with a sustained expansion potential. Manufactured CD4+ T cells show strong specific responses with IFN-γ+, TNF-α+ and IL-2+ and induce growth arrest and apoptosis in tumor cells. The T-cell products did not include alloreactive or regulatory T cells. Specificity was confirmed with a new identified MHC class II matched NY-ESO-1 derived peptide and recognition of processed NY-ESO-1 Protein was demonstrated. Conclusions: Adoptive T-cell transfer by a novel cancer treatment-approach with tumor-antigen specific CD4+ Th1 lymphocytes can be performed to boost anti-cancer immunity and is feasible with T cells from healthy allogeneic donors as well as with autologous T cells from cancer patients. The T-cell generation process was approved by the regulatory authorities. Due to the frequent expression of NY-ESO-1 in tumors the therapy is applicable to a large patient collective in different cancer entities.
Centralized analysis of phase II ECG dataset of resminostat, an orally available histone-deacetylase inhibitor (HDACi).
2014-05-20

e13526 Background: Resminostat (4SC-201) is an orally available pan-HDAC inhibitor that revealed substantial clinical activity and was well tolerated by patients with advanced malignancies when administered as single agent or in combination with anti-cancer compounds. Cardiac safety of resminostat was evaluated across patients of 3 clinical Phase II studies. Methods: Resminostat was administered in a dose range of 100 mg up to 800 mg once-daily in repeated 14-day cycles consisting of 5 consecutive treatment days followed by a 9-day rest period to 111 patients with advanced cancer (hepatocellular ca., Hodgkin lymphoma or colorectal ca.). Standard 12-lead rest ECGs were conducted frequently for determination of potential effects on QT interval prolongation. An intensive profile of >10 single ECGs was performed from Day 1 to 5 during Cycle 1, and less frequent in following cycles if no clinically relevant findings occurred. Subsequent to on-site clinical assessment, ECGs were analysed by a trained cardiologist. ECG parameters were measured in lead II across 3 consecutive beats using markers for the respective ECG intervals. In sum, 3792 ECGs from 108 evaluable patients were available for analysis. Results: QTc interval increased in a range from 0-10 ms during treatment days. A HR increase of 0-10 bpm was detected which was frequently accompanied with corresponding shortening of PR and QT intervals. HR correction with Fridericia’s formula did not reveal consistent QTc changes. Incidence of QTcF outliers was very small. The results suggest that resminostat does not affect the duration of myocardial repolarisation in a consistent manner. At daily doses ≥ 400 mg, unspecific flattening of the T-wave and slight depression of the ST-segment were frequently observed. However, in most cases such findings were already present at baseline. No severe arrhythmias were observed under treatment. Conclusions: Centralised analysis of Phase II ECG data did not reveal a consistent, drug-induced prolongation of the QTc interval. At doses levels ≥ 400 mg, unspecific changes in T-wave morphology and slight ST-segment depression were observed. Administration of resminostat was associated with moderate increases in HR.
Validation of a nomogram predicting nonsentinel lymphnode metastases among patients with breast cancer after neoadjuvant chemotherapy (NACT): A transSENTINA substudy.
2014-05-20

e12022 Background: The optimal timing for sentinel lymph node biopsy (SLNB) in the setting of NACT is still unclear. Recent studies such as SENTINA suggest that performing SLNB in patients with a cN1 status before but converting to a cN0 status through NACT may result in an unacceptable false-negative rate. There is a need to predict non-SLN status and tailor axillary surgery after NACT. We validated the Jeruss-Nomogramm to predict non-SLN lymph node metastases after primary surgery in patients after NACT. Methods: The SENTINA trial was described in length last year. The Jeruss-nomogram includes lymphovascular invasion after NACT , detection method, multicentricity after NACT, clinical initial nodal involvement, and pathologic tumor size after NACT. It was applied to patients converting froom cN1 to cN0 status through NACT (arm C) but with histologically positive SLN (ypN+). The performance of the nomograms was evaluated by the area under the receiver operator curve (AUC). Results: This subgroup comprised 592 patients with 153 patients having a positive SLN after NACT and had all available data to run the nomogram. Our calculations result in an AUC-value of 0.659 (CI: 0.571 – 0.746, p=0.001) showing a significantly better performance than by random choice (AUC=0.5). For this analysis, we selected a cutpoint of 90% showing reasonable sensitivity (0.81) but low specificity (0.438). A subgroup of 75 patients from SENTINA having complete data for all nomograms shows a better performance of the Jeruss nomogram (0.709, CI: 0.587-0.832) which was still lower compared to e.g. the MSKCC nomogram with the best predictive value among the established nomograms (AUC=0.821, CI: 0.724-0.917). Conclusions: Validation of the Jeruss nomogram in the post-neoadjuvant setting yielded AUC values lower than in the original validation cohort lower than those of nomograms from patients with primary surgery (MSKCC) suggesting predictive inferiority of the prior nomogram compared to others. Our results show that nomograms predicting non-SLN status need to be optimized to avoid full axillary dissection in patients after NACT.
Effect of the BRAF inhibitor LGX818 on endoplasmic reticulum stress and sensitivity of NRAS-mutant melanoma cells to the MEK inhibitor binimetinib.
2014-05-20

9062 Background: The BRAF inhibitors vemurafenib and dabrafenib have demonstrated antitumor activity in patients with metastatic BRAFV600-mutant melanoma. However, patients with BRAF wild-type, in particular patients with aggressive NRAS-mutant melanoma, do not benefit. In a phase 2 trial, the MEK inhibitor binimetinib showed activity in patients with NRAS-mutant melanoma with overall response rates of >20%. In a previous study, we showed that the BRAF inhibitor vemurafenib induces apoptosis in BRAFV600-mutant melanoma cells through a mechanism involving induction of endoplasmic reticulum (ER) stress. ER stress induction appeared to be an off-target effect of vemurafenib that remarkably enhances its pro-apoptotic activity in BRAFV600-mutant melanoma. Methods: In this study, we investigated whether it is possible to take advantage of ER stress induction to establish effective combination therapies for patients with NRAS-mutant melanoma. Results: BRAF-mutant and NRAS-mutant metastatic melanoma cell lines were treated with the BRAF inhibitors vemurafenib, dabrafenib and LGX818, and the classical ER stress inducer thapsigargin, and were subjected to electron microscopy. Of note, LGX818 induced morphological features of ER stress, including a significant dilation of the ER in both BRAF-mutant and NRAS-mutant melanoma cell lines. As expected, LGX818 inhibited phosphorylation of ERK and growth and induced apoptosis in BRAF-mutant but not in NRAS-mutant melanoma cells. However, LGX818 significantly enhanced growth inhibition and apoptosis induced by the MEK inhibitor binimetinib in NRAS-mutant melanoma cells. Moreover, LGX818 in combination with binimetinib induced the expression of the ER stress-related factors p8, ATF4, ATF3, CHOP and TRB3 in NRAS-mutant melanoma cells. siRNA inhibition of ATF4 reduced melanoma cell apoptosis induced by LGX818 combined with binimetinib. Conclusions: These data suggest that the BRAF inhibitor LGX818 induces endoplasmic reticulum stress and potentiates the antitumor activity of MEK inhibitors in NRAS-mutant melanoma.
Senescence induction in human melanoma by the combined action of type II interferon and tumor necrosis factor.
2014-05-20

e22213 Background: Adoptive T-cell transfer is a promising therapeutic option for patients with metastatic malignant melanoma. Recent evidence suggests that CD4+ T helper (Th1) lymphocytes are of great importance for those therapeutic strategies as they orchestrate the response of cytotoxic T lymphocytes and can impair tumor growth through cytokine signaling. The secretion of interferon-γ (IFN-γ) and tumor necrosis factor (TNF) by Th1 lymphocytes seems to be crucial for efficient tumor control. Methods: We treated a panel of melanoma cell lines with IFN-γ and TNF. Analysis of cell cycle arrest was performed by FACS. To generate tumor-antigen specific Th1 lymphocytes, we primed peripheral blood mononuclear cells with peptide pools from different tumor-antigens. After stimulation with IL-2 und IL-7, we enriched IFN-γ producing cells with the IFN-γ capture technique. Subsequently we expanded the Th1 cells over 2 weeks. Results: Here we show first that IFN-γ and TNF induce various types of cell cycle arrest, including a predominant G0/G1 arrest. In some melanomas the cell cycle arrest remained stable over 7 passages after withdrawal of IFN-γ and TNF, while it was of shorter duration in others. As this suggested that the G0/G1 growth arrest may be reverted in melanomas, we repeatedly pulsed the cancer cells every 3 weeks. This treatment induced in human melanoma cells senescence, as defined by stable growth arrest and induction of the senescence associated secretory phenotype. Moreover, we established a culture method that allows to generate melanoma-antigen specific Th1 lymphocytes with a GMP conform protocol. The supernatants of such tumor-specific Th1 cells also induced a G0/G1 cell cycle arrest and senescence, like the combined action of IFN-γ and TNF. Conclusions: The Th1 cytokines IFN-γ and TNF induce senescence in a large spectrum of human melanomas. In order to establish a therapeutically applicable treatment approach, we are currently developing devices for the GMP-conform generation of tumor-antigen specific Th1 lymphocytes.
Bisphosphonate treatment of primary breast cancer patients with disseminated tumor cells in the bone marrow.
2014-05-20

11044 Background: The role of the addition of bisphosphonates (BPs) to adjuvant breast cancer treatment is unclear. Recent trials have reported different results in terms of survival. In a large meta-analysis, menopausal status was found to predict efficacy of BPs. As BPs primarily target the skeletal system to modify disease progression, we aimed to investigate whether primary breast cancer (PBC) patients that harbor disseminated tumor cells (DTCs) in their bone marrow (BM) might benefit from adjuvant BPs. Methods: BM aspirates were collected from patients that underwent surgery for PBC at Tuebingen University Hospital, Germany between 01/2001 and 01/2013. DTCs were identified by immunocytochemistry (pancytokeratin antibody A45/B3) and cytomorphology. Patients with a DTC-positive BM were included into this retrospective analysis. The influence of BP therapy on disease free (DFS) and overall survival (OS) was analyzed in an univariate (log-rank test) and multivariate analysis (cox regression). Results: 794 patients were available for this retrospective analysis. In 329 (41%) of these patients, BPs were added to conventional adjuvant therapy. Univariate analysis revealed that there was a significant risk reduction in terms of DFS (hazard ratio (HR)=0.42 [95% confidence interval (CI): 0.25-0.69], p<0.001) and OS (HR=0.49 [95% CI: 0.30-0.82], p=0.006) in patients treated with BPs. In a subgroup analysis, BPs significantly enhanced DFS (p=0.018) but not OS (p= 0.235) in premenopausal patients; in postmenopausal patients BPs improved DFS (p=0.014) and OS (p=0.009). In a multivariate analysis, independent predictors of reduced DFS were BP treatment and nodal status and independent predictors of reduced OS were BP treatment, nodal status and PR status. Conclusions: Adjuvant BP therapy can improve survival in primary breast cancer patients that harbor DTCs in the BM. Whether the DTC status is predictive for BP treatment efficacy must be evaluated in prospective trials.
The GERMELATOX DeCOG-trial: German melanoma patients and their attitude toward toxicity during adjuvant interferon treatment.
2014-05-20

TPS9113^ Background: Although trials of adjuvant interferon alfa-2b (IFN alpha-2b) in high-risk melanoma patients suggest improvement in disease-free survival (DFS), a metaanalysis could only show a marginal OS survival benefit (OS). Widespread use of adjuvant IFN alpha-2b has been decreased by its significant toxicity.In 2001 Kilbridge et al. (J Clin Oncol 2001) asked US-patients about the degree of improvement in 5-year DFS they would expect to tolerate IFN. At least half of the patients were willing to tolerate mild to moderate and severe IFNa-2b toxicity for 4% and 10% improvements of DFS. On average, patients rated quality of life (QoL) with melanoma recurrence much lower than even severe IFNa-2b toxicity.To date, no data exist on willingness of German melanoma patients to be treated with IFNa-2b. In Germany, melanoma patients are managed by specialized skin cancer units mainly located in certified skin cancer centers and core university hospitals. The willingness of dermatologists to use IFN depends strongly on their experience and capacity to manage IFN-related side effects.A comparison between a German cohort and the US-cohort of Kilbridge would allow new insights into country specific treatment differences. So far no direct comparison has been made between willingness of patients compared to their physicians. Methods: In this multicenter non-interventional trial (“GERMELATOX trial”) of the Dermatologic Cooperative Oncology Group we assessed preferences and utilities for health outcomes associated with adjuvant IFN among 200 melanoma patients not eligible for IFN due to the low-risk features of their melanoma and 100 dermatooncologists from 10 different melanoma units using the standard gamble technique supported by the willingness to pay mode. The trial described four typical IFN alpha-2b toxicity scenarios and the following three posttreatment outcomes: disease-free health and melanoma recurrence (with or without IFN alpha-2b) leading to cancer death. We also asked patients the improvement in 5-year disease-free survival they would require to tolerate IFN toxicities.The recruitment of the study will be completed in mid 2014.