julilili42/papers huggingface dataset:
Prevalence and quantity of circulating tumor cells (CTCs) after adjuvant chemotherapy in patients with HER2-negative early breast cancer (EBC).
2013-05-20

e22075 Background: Prevalence of CTCs after adjuvant chemotherapy in patients with EBC might indicate both treatment response and prognosis. Here we present data on CTC prevalence and quantity assessed after chemotherapy in correlation with tumor characteristics and chemotherapeutic treatment in patients with Her2-negative EBC from the German SUCCESS C study. Methods: The SUCCESS C trial is a randomized, open-label, Phase III study comparing disease free survival (DFS) in patients with HER2-negative EBC treated with either 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC) followed by 3 cycles of Docetaxel(DOC), or 6 cycles of a anthracycline-free regimen with Docetaxel-Cyclophosphamide(DOC-C). The CTC status at chemotherapy cycle 6 was prospectively evaluated using the FDA-approved CellSearch System (Veridex, USA). Results: Valid data on CTC status after chemotherapy were available for 2,336 patients (78% estrogen receptor positive, 6% pT3 or pT4, 12% pN2 or pN3). CTCs were found in 278 (11.9%) patients (median 1, range 1 – 69 CTCs). One CTC was detected in 164 (59%), two CTCs in 57 (21%), three to five CTCs in 45 (16%), and more than five CTCs in 12 (4%) of these patients. CTC prevalence was not significantly associated with tumor size (pT1, pT2, pT3, pT4), nodal stage (pN0, pN+), grading (G1, G2, G3), histological type (invasive ductal, invasive lobular, other), estrogen receptor status, progesterone receptor status, or treatment arm (FEC-DOC, DOC-C), as revealed by both univariate analyses (Chi-square tests, all p &gt; 0.1) and a logistic regression with CTC prevalence as dependent variable. Conclusions: In about 12% of patients with Her2-negative EBC, CTCs in the peripheral blood were detected at the end of adjuvant chemotherapy treatment. However, neither CTC prevalence nor quantity of CTCs were related to tumor characteristics or type of chemotherapeutic regimen. The low rate of CTC-positive patients might be attributed to the negative HER2 status and reflects therefore the relatively low risk of these patients to develop metastatic relaps. Clinical trial information: NCT00847444.
Prognostic impact of changes in circulating tumor cells (CTC) in metastatic breast cancer (MBC).
2013-05-20

11012 Background: To prospectively assess the prognostic value of CTC counts at baseline and after one cycle of therapy and their kinetics for response, progression-free (PFS), and overall survival (OS) in MBC. Methods: MBC patients underwent CTC enumeration (CellSearch, Veridex) at baseline (CTC BL ), after one cycle of a new line of therapy (CTC 1C ), and at progression (CTC PD ). CTC status was classified as negative (neg (−)) or positive (pos (+)) for &lt;5 and ≥5 CTC/7.5 ml peripheral blood, respectively. CTC kinetics (CTC KIN ) from CTC BL to CTC 1C were classified as favorable if CTCs remained neg (neg&gt;neg) or became neg (pos&gt;neg), or as unfavorable (neg&gt;pos or pos&gt;pos). Tumor response was assessed every 2–3 months using RECIST criteria. CTC status and kinetics were associated with outcome using log-rank and Fisher’s exact tests. Results: Of 326 patients enrolled (median age (range) at first diagnosis: 50 (23–81) years), 115/326 (35%) were CTC BL +, 51/162 (31%) were CTC 1C +, and 39/108 (36%) were CTC PD +. Median follow-up was 15.9 months (mos). Median PFS and OS were significantly reduced in CTC BL + compared to CTC BL − patients (PFS, 4.3 vs. 7.1 mos, p = .019; OS, 15.0 mos vs. not reached (nr), p &lt;.001) and for CTC 1C + compared to CTC 1C − patients (p &lt;.001 for PFS and OS). CTC KIN were predictive of progressive disease as best response (neg&gt;neg, 33%; pos&gt;neg, 38%; pos&gt;pos, 60%; neg&gt;pos, 75%; p = .040). PFS and OS for patients with unfavorable CTC KIN were significantly shorter than for favorable CTC KIN (PFS, 3.7 vs. 6.8 mos, p &lt;.001; OS, 7.8 mos vs. nr, p &lt;.001). Conclusions: CTC at baseline, CTC after one cycle and CTC kinetics are highly predictive of outcome in MBC. Serial CTC enumeration could serve as a useful adjunct to standard diagnostic tests in tailoring therapy. Further details of CTC PD will be presented at the meeting. Clinical trial information: S-295/2009.
First-salvage treatment in patients with recurrent or refractory advanced germ-cell cancer after cisplatin-based chemotherapy: A database of the German Testicular Cancer Study Group.
2013-05-20

4559 Background: About 20-30% of patients (pts) with advanced germ-cell cancer (GCC) relapse after cisplatin-based chemotherapy. This database evaluates first salvage treatment and the prognostic categories at first relapse according to the International Prognostic Factors Study Group (= IPFSG; JCO 2010). Methods: A total of 144 pts (78% nonseminoma) with relapsed or refractory GCC undergoing 1 st salvage treatment with either conventional (CD-CX) or high-dose chemotherapy with autologous stem cell support (HD-CX) from 16 German centers were retrospectively analysed. Results: Subgroups according to the IPFSG prognostic categories, were: very low risk in 9/144 (6%), low risk in 26/144 (18%), intermediate risk in 78/144 (54%), high risk in 27/144 (19%), and very high risk in 4/144 pts (3%). 1 st salvage treatment consisted of HD-CX in 96 (67%) and CD-CX in 48 pts (33%). Treatment response was CR/PR- in 60%, PR+/SD in 33%, and PD in 7%. After a median follow-up (mFU) of 21 months (mos) (range, 0 – 193), 53% of all pts had relapsed and 30% had died resulting in a median progression-free survival (PFS) of 7 mos ( 95% CI 0-16) and overall survival (OS) of 47 mos ( 95% CI 21-73). At subsequent relapses, 25/48 pts (52%) received HD-CX as &gt; 2 nd -salvage treatment. For the total cohort, PFS rate after 2 years was 35%, and OS rate after 5 years was 53%. Stratification according to IPFSG prognostic categories significantly correlated with PFS (p=0.001) and OS (p=0.004) after 1 st salvage treatment. Even among high-risk and very high risk (n=31, mFU 12 mos) a PFS of 37 % at 2 years and an OS of 60 % at 2 years was observed, after 1 st or 2 nd salvage treatment, which might be due to patient selection and short follow-up. Conclusions: IPFSG prognostic categories highly correlated with observed PFS and OS after first salvage treatment in this cohort of pts with refractory or relapsed GCC. First salvage treatment with CD- or HD-CX resulted in overall 5 year-OS rates of about 50% across all prognostic categories. Even pts with high and very high risk achieved 2 year-OS rates of about 60% with salvage HD-CX at first or subsequent relapses.
The association of objective response and overall survival in patients with inoperable or metastatic gastric and esophagogastric junction (EGJ) cancer: A pooled analysis of individual patient data from first-line clinical trials.
2013-05-20

4095 Background: The aim of the study is to determine whether the achievement of an objective response to first-line chemotherapy is prognostic of patient’s outcome in gastric/EGJ adenocarcinoma. Methods: Individual patient (pts) data from prospective first-line trials conducted by a single study group were used. Patients received platin/5-FU based chemotherapy with or without docetaxel. Responses were evaluated according to WHO criteria in all trials. Response data, patients’ characteristics (age, sex, entity, histological type, primary location, ECOG PS, and type and number of metastatic sites), type of chemotherapy, and overall survival data were analyzed. Results: 612 pts were included. Median age was 66 yrs; 31.5% had ECOG status 0, 58.3% ECOG 1, and 9.8% ECOG 2 &amp; 3. Gastric primaries were found in 44.4% and EGJ in 35.8% of pts (19.7% were overlapping/not evaluable). According to Lauren classification, 36.8% had intestinal, 32.4% diffuse, and 8.5% mixed types (22.4% were not classifiable). 64.5% had positive non-regional lymph nodes (LN) involvement, 14.1% LN involvement without other metastases, 33.3% had peritoneal carcinomatosis, 44.0% liver and 16.7% lung metastases. Response rates were complete (CR) in 3.1%, partial (PR) in 36.4%, stable disease (SD) in 34.5%, and progressive disease (PD) in 15.0% pts (10.9% were not evaluable). Overall response rate (OR; CR + PR) was 39.5%. Median overall survival times in pts with CR vs PR vs SD vs PD were 37.9 vs 14.7 vs 10.9 vs 5.2 months, respectively; p=1.26 x 10 -33 ). OR (CR or PR) also strongly predicted OS (16.7 vs 8.1 months in pts with vs no OR, p=1.08 x 10 -17 ). OR remained the strongest predictor of OS in the multivariate analysis (p=6.55 x 10 -7 ) including all baseline criteria mentioned above followed by ECOG PS (p=0.048) and the presence of non-regional LN as the only site of metastasis (p=0.034). Conclusions: The achievement of an objective response is the strongest predictor of survival in pts with gastric and EGJ cancer and could serve as a surrogate marker if validated.
A new molecular diagnostic tool for pneumocystis jirovecii-pneumonia (PjP) detection: Results from European multicenter clinical study CS-2011.
2013-05-20

e20652 Background: Pneumocystis pneumonia (PCP) is a frequent and serious infectious complication in tumor patients. PCP is caused by Pneumocystis jirovecii, a fungal pathogen which is uncultivable in vitro. Highly-sensitive and time-efficient diagnostic tools are needed for early PCP treatment, especially in patients with impaired immune status. Methods: We evaluated a prototype of a new non-invasive molecular diagnostic tool (Unyvero System) using polymerase chain reaction (PCR) for P. jirovecii detection in respiratory samples (bronchoalveolar lavage fluid, tracheal aspirates, sputum) of hospitalized patients suffering from pneumonia. Results were obtained in an open-label, multicentric, non-randomized clinical study (CS-2011) conducted in 5 European hospitals. Unyvero system test results were compared to study site specific PCR results for P. jirovecii detection. Discrepant results were analysed for clinical relevance of molecular diagnostic tool results. Results: P. jirovecii was detected in 11 patients (1.49 %) out of 739 evaluable study patients: Of these, 8 cases (1.08 %) were detected only with the Unyvero System, 2 cases only with site-established techniques and 1 case with both methods. An independent academic cross-check of these 8 Unyvero System -positive cases showed that 5 cases were false positives due to signal reading failure. The remaining 3 cases could be confirmed as true positives by control PCP-PCR, indicating Unyvero P. jiroveciidetection results of 2 false negatives, 4 true positives and 5 false positives. Conclusions: The overall detection rate for P. jirovecii was low (11 out of 739) in this study population. Although more positive cases were found using the Unyvero System, it remains unclear if this was of clinical significance, especially as two clinically confirmed PCP cases could not be detected. The Unyvero System prototypes had a rate of 0.7% false positive results (5 out of 739 samples) which might have led to an overtreatment under real conditions. However, the correct detection of 4 positive cases within 3 hours might render the Unyvero System a valuable diagnostic future tool.
Biomarq: A novel approach to automated HER2-analysis of circulating tumor cells (CTCs).
2013-05-20

638 Background: Targeted treatment approaches directed against CTCs might improve the outcome of metastatic breast cancer patients. Accurate and reproducible assessment of the CTC phenotype is a requirement to use CTCs as treatment targets. The aim of this study was to test the suitability of the automated BioMarQ System (Veridex, USA) – an enhancement of the FDA-approved CellSearch System (Veridex USA) for CTC detection– for assessing the Her2-status of CTCs based on fluorescence and cell-morphology data. Methods: Data on classification of the Her2-status into four groups (0, +, ++, +++) obtained by visual inspection of CTCs after immunocytochemical staining with the CellSearch System, and of BioMarQ-generated automatic measures on fluorescence and cell morphology via image clips generated from raw images were available for 329 CTCs from 17 metastatic breast cancer patients. A discriminant analysis was performed to test whether linear combinations of the fluorescence and/or cell morphology measures allow a separation of CTCs into four groups according to the visual classification of their Her2-status. Results: The highest concordance with the visual classification was obtained by a set of three discriminant functions based on the five variables mean-, maximum- and integrated fluorescence intensity, cell area (μm 2 ), and coefficient of variation for the pixel fluorescence values within a cell. All five variables differed significantly among the 17 patients (Kruskal-Wallis-test, all p &lt; 0.001). Based on the three discriminant functions, 74.5% of all cases were correctly assigned to the four visually obtained categories (6 out of 8 CTCs classified as +++; 57 out of 80 as ++; 17 out of 65 as +, 165 out of 176 classified as 0). Conclusions: Our preliminary analysis shows that discriminant functions derived from measures on fluorescence and cell morphology generated by BioMarQ correctly assigned the Her2-status of CTCs to the four visually obtained categories in 75% of all cases. Further analysis based on a larger number of Her2-positive CTCs, and cross validation by FISH-analysis will provide deeper insight into the suitability of BioMarQ for objectively assessing the Her2-status of CTCs.
Update on pilot study on antitumor efficacy of intravenously applied synergistic combinations of diflunisal, PAS, and aspirin in patients with advanced solid tumors.
2013-05-20

e22114 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of Diflunisal, Paraaminosalicylic acid (PAS) and Aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance and its update is presented. Methods: A total of 65 patients (n=65) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of Diflunisal and Aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response and tumor marker where available. Results: Out of 65 patients treated 8 patients suffered from colorectal cancer, 17 from breast cancer, 6 from ovarian cancer, 3 from lung cancer, 3 from gastric cancer, 3 from glioblastoma, 3 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 2 from pancreatic cancer, 1 from choledochus cancer, 3 from prostate cancer, 5 from sarcomas, 2 from head and neck cancer, 1 from melanoma, 1 from cervical cancer, and 1 from thyroid cancer, respectively. Side effects related to the therapy have been fatigue grade I (30%), nausea grade I (13,3%), tinnitus (25%), hypertension (2,5%), dyspnea (3,3%) and burning sensation in tumor areas (65%). 33 patients were evaluable for metric response, 20 for metabolic and 19 for tumor marker response assessment. For tumor marker follow up 11 % had a CR, 53 % a PR, 26 % a SD of &gt; 3 month and 11 % a PD. For metric follow up 3 % had a CR, 33 % a PR, 39 % a SD of &gt; 3 month and 24 % a PD. For metabolic follow up 10 % had a CR, 35 % a PR, 35 % a SD of &gt; 3 month and 20 % a PD. Conclusions: This continuing pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous Diflunisal, PAS and Aspirin in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study should be performed.
Disseminated tumor cells in bone marrow of patients with endometrial and cervical cancer.
2013-05-20

5598 Background: The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients is associated with poor prognosis. Several studies demonstrated that tumor cell dissemination may occur in gynecologic cancer and affect clinical outcome. The aim of our study was to evaluate the incidence of DTC and to assess their prognostic significance in patients with gynecologic malignancies. Methods: Bone marrow aspirates from 623 patients with primary endometrial (331), cervical (228), and vulvar cancer (64) undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between November 2001 and May 2012, were included into the study. Disseminated tumor cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. Results: Disseminated tumor cells were detected in 18% of BM aspirates from patients with gynecological malignancies. Incidences of DTC in endometrial, cervical, and vulvar cancer were 21%, 16% and 16%, respectively. The presence of DTC was associated with a lower tumor grade in endometrial cancer For patients with vulvar cancer, no correlation with established clinicopathological factors was observed. In case of cervical cancer, BM positivity was correlated with International Federation of Gynecology and Obstetrics stage, nodal involvement and the presence of lymphangiosis carcinomatosa. For all analyzed tumor entities, no association between BM status and clinical outcome could be observed. Conclusions: Disseminated tumor cells are a common phenomenon in solid tumors. However, only in cervical cancer DTC postivity was associated with advanced disease. The consequences for DTC positive patients have to be determined.
An Fc-optimized NKG2D-Ig fusion protein for induction of NK cell reactivity against breast cancer.
2013-05-20

3054 Background: The anti-tumor activity and clinical success of the monoclonal antibody trastuzumab, approved for treatment of HER2/neu-overexpressing breast cancer, is at least partially mediated by induction of antibody dependent cellular cytotoxicity (ADCC). However, only about 20% of patients show HER2/neu overexpression, and trastuzumab treatment is associated with side effects. The ligands of the activating immunoreceptor NKG2D (NKG2DL) are widely expressed on malignant cells, but generally absent on healthy tissue. We aimed to take advantage of this tumor-restricted expression by using NKG2DL as target-antigens on breast cancer cells. To this end we generated NKG2D-Ig fusion proteins with modified Fc moieties and studied their ability to induce NK cell anti-tumor reactivity. Methods: The Fc parts within the constructs were modified by amino acid exchange as previously described (Lazar 2006; Armour 1999). Direct effects on tumor cell viability as well as induction of NK cell activation, degranulation, cytotoxicity and IFN-γ release in cultures with breast cancer cell lines expressing different HER2/neu levels were determined. Results: Compared to NKG2D-Fc containing a wildtype Fc part (NKG2D-Fc-WT) or trastuzumab, our mutants (S239D/I332E and E233P/L234V/L235A/ΔG236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell Fc receptor, respectively. In contrast to trastuzumab, no direct effect of the constructs on tumor cell viability was observed. In cultures of NK cells and breast cancer cells, NKG2D-Fc-KO significantly reduced NK reactivity due to blocking immunostimulatory NKG2D-NKG2DL interaction. NKG2D-Fc-WT substantially enhanced NK reactivity by induction of ADCC, while the effects of NKG2D-Fc-ADCC by far exceeded that of NKG2D-Fc-WT and, in case of HER2/neu-low targets also that of Herceptin. Conclusions: Fc-engineered NKG2D-Ig fusion protein effectively target breast cancer cells for NK anti-tumor reactivity. Due to the tumor-restricted expression of NKG2DL, NKG2D-Fc-ADCC may constitute an attractive means for immunotherapy especially of HER2/neu-low or -negative breast cancer.
antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers
2013-05-21

Microbial secondary metabolites are a potent source of antibiotics and other pharmaceuticals. Genome mining of their biosynthetic gene clusters has become a key method to accelerate their identification and characterization. In 2011, we developed antiSMASH, a web-based analysis platform that automates this process. Here, we present the highly improved antiSMASH 2.0 release, available at http://antismash.secondarymetabolites.org/. For the new version, antiSMASH was entirely re-designed using a plug-and-play concept that allows easy integration of novel predictor or output modules. antiSMASH 2.0 now supports input of multiple related sequences simultaneously (multi-FASTA/GenBank/EMBL), which allows the analysis of draft genomes comprising multiple contigs. Moreover, direct analysis of protein sequences is now possible. antiSMASH 2.0 has also been equipped with the capacity to detect additional classes of secondary metabolites, including oligosaccharide antibiotics, phenazines, thiopeptides, homo-serine lactones, phosphonates and furans. The algorithm for predicting the core structure of the cluster end product is now also covering lantipeptides, in addition to polyketides and non-ribosomal peptides. The antiSMASH ClusterBlast functionality has been extended to identify sub-clusters involved in the biosynthesis of specific chemical building blocks. The new features currently make antiSMASH 2.0 the most comprehensive resource for identifying and analyzing novel secondary metabolite biosynthetic pathways in microorganisms.
The rise and fall of the Phytophthora infestans lineage that triggered the Irish potato famine
2013-05-21

Phytophthora infestans, the cause of potato late blight, is infamous for having triggered the Irish Great Famine in the 1840s. Until the late 1970s, P. infestans diversity outside of its Mexican center of origin was low, and one scenario held that a single strain, US-1, had dominated the global population for 150 years; this was later challenged based on DNA analysis of historical herbarium specimens. We have compared the genomes of 11 herbarium and 15 modern strains. We conclude that the 19th century epidemic was caused by a unique genotype, HERB-1, that persisted for over 50 years. HERB-1 is distinct from all examined modern strains, but it is a close relative of US-1, which replaced it outside of Mexico in the 20th century. We propose that HERB-1 and US-1 emerged from a metapopulation that was established in the early 1800s outside of the species' center of diversity.