tbuckley/cabot-search huggingface dataset:
Effect of epitopes derived from the mutated region of cytoplasmatic nucleophosmine 1 (NPM1) on CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia.
Authors: Jochen Greiner, Yoko Ono, Susanne Hofmann, Vanessa Schneider, Anita Schmitt, Lu Zhang, Elmar Mehring, Marlies Goetz, Konstanze Dohner, Joannis Mytilineos, Markus Wiesneth, Hartmut Dohner, Michael Schmitt
Journal: Journal of Clinical Oncology (2012)

6567 Background: Mutations of the nucleophosmin gene (NPM1mut) are one of the most frequent molecular alterations in AML and constitute an important prognostic marker. The impact of NPM1mut on leukemogenesis and progression remains to be elucidated. Immune responses against NPM1mut might contribute to the favourable prognosis of AML patients with NPM1mut. Therefore, we examined T cell responses against NPM1mut. Methods: NPM1 wildtype as well as NPM1mut were screened for HLA-A*0201 binding T cell epitopes with the help of different algorithm programs. Ten peptides with most favourable characteristics were tested with ELISpot analysis for interferon-γ and granzyme B in 33 healthy volunteers and 30 AML patients. Tetramer assays against most interesting epitopes were performed and chromium release assays were used to show the cytotoxicity of peptide-specific CD8+ T cells. Moreover, HLA-DR-binding epitopes were used to test the role of CD4+ T cells in NPM1 immunogenicity. Results: Two epitopes (#1 and #3) derived from NPM1mut induced CD8+ T cell responses in a high frequency. In healthy volunteers, immune responses were detected in 39%/18% against #1 and #3, and in 33%/44% of NPM1mut AML patients against #1 and #3. NPM1-peptide primed effector T cells showed specific lysis of pulsed T2 cells as well as leukemic blasts in chromium release assays. In tetramer assays a significant CD8+ T cell population could be detected. To obtain a robust and continuous T cell reaction, the help of CD4+ T cells is indispensable. Therefore, we investigated the increase of CD8+ T cell responses by the activation of CD4+ T cells stimulated with longer peptides called overlapping peptides (OL). Potent HLA-DR epitopes were predicted and several favourable peptides (OL 1 to 8) were synthesized. OL8 showed favourable results to activate both CD8+ and CD4+ T cells. Conclusions: Taken together, NPM1mut represents a candidate for immunotherapeutic approaches and we hypothesize that it is also potentially involved in immunogenic rejection of NPM1mut leukemic blasts. Therefore, NPM1mut is a promising target structure for specific immunotherapies in AML patients.
Erratum to “Sleeping Beauty-Mediated Transposition and Long-Term Expression in Vivo: Use of the LoxP/Cre Recombinase System to Distinguish Transposition-Specific Expression”
Authors: Paul R. Score, Lalitha R. Belur, Joel L. Frandsen, Jennifer L. Geurts, Tomoyuki Yamaguchi, Nikunj V. Somia, Perry B. Hackett, David A. Largaespada, R. Scott McIvor
Journal: Molecular Therapy (2006)

The publisher regrets the following error: On page 617, in the author line, the name of Jennifer L. Geurts was listed incorrectly as Jennifer L. Guerts. The correct author line appears above. Sleeping Beauty-Mediated Transposition and Long-Term Expression in Vivo: Use of the LoxP/Cre Recombinase System to Distinguish Transposition-Specific ExpressionScore et al.Molecular TherapyMarch, 2006In BriefThe Sleeping Beauty transposon system (SB) has been shown to mediate nonviral integration of expression constructs resulting in long-term gene expression in several mammalian targets. Often, however, it is difficult to discern long-term expression resulting from transposition vs nonhomologous chromosomal recombination or maintenance of plasmid DNA in an extrachromosomal form. We have designed a system to silence expression from nontransposed sequences, making it possible to determine more specifically the amount of expression resulting from transposition. Full-Text PDF Open Archive
HPV and survival in patients with oropharyngeal squamous cell cancer of the head and neck (OPC) treated with induction chemotherapy followed by chemoradiotherapy (ST) versus chemoradiotherapy alone (CRT): The Dana-Farber experience.
Authors: Jochen H. Lorch, Glenn Hanna, Wei Dai, Vijaya Thotakura, Vidya Nair, Zachary Jaffa, Marshall R. Posner, Sewanti Atul Limaye, Guilherme Rabinowits, Roy B. Tishler, David J Sher, Robert I. Haddad
Journal: Journal of Clinical Oncology (2012)

5582 Background: HPV status is a major prognostic marker for survival in patients with OPC. We examined overall survival (OS) and progression free survival (PFS) in patients with OPC and known HPV status treated at Dana-Farber Cancer Institute with ST and CRT between 2002 and 2011. Methods: 280 patients with OPC and known HPV status were identified retrospectively and clinical information was recorded. Results: 174 patients were treated with CRT (124 HPV positive, 50 HPV negative) and 106 patients were treated with ST (77 HPV positive, 29 HPV negative). For all 280 patients, OS and PFS were significantly better for patients who were HPV positive compared to those who were HPV negative. 3 year OS was 89.1% for HPV positive (95% CI, 83.8-94.7) and 70.5% for HPV negative patients (95%CI, 59.9-83%, HR 0.37, p=0.0007). Among HPV positive patients treated with CRT, 13/124 had died at 3 years (OS 88.5%, 95%CI 81.7-95.9) while 13 deaths were recorded among 50 HPV negative patients (OS 72.2%, 95% CI 59.1-88.2, HR 0.38, p=0.011). PFS at 3 years was also significantly better for HPV positive versus HPV negative patients(81.7% vs 58.8%, HR 0.42, p=0.006). In the group treated with ST, outcomes were similar despite a higher rate of stage IV versus stage III disease compared to the group treated with CRT (100% stage IV in ST versus 77% stage IV and 23% stage III disease in CRT group). Three year OS was 89.7% for HPV positive and 68.2% in the HPV negative group (8/77 HPV pos vs 10/29 HPV neg, HR 0.33, p=0.015). PFS was borderline better for HPV positive patients (81% vs 61.7%, HR 0.48, p= 0.058). Conclusions: We present the DFCI experience treating OPC with ST and CRT for patients with known HPV status over one decade.OS and PFS were superior for HPV positive versus HPV negative patients. Outcomes were virtually identical for patients treated with CRT versus ST despite a higher rate of stage IV disease in the ST group. Outcomes for the HPV negative patients in particular were superior compared to the published literature.
Ex-vivo sensitivity-directed combination chemotherapy compared to DTIC monochemotherapy in chemo-naive advanced metastastic melanoma (ChemoSensMM): A multicenter randomized phase-3 DeCOG trial.
Authors: Selma Ugurel, Carmen Loquai, Patrick Terheyden, Dirk Schadendorf, Erika Richtig, Jochen Utikal, Ralf Gutzmer, Knuth Rass, Cord Sunderkötter, Annette Stein, Michael Fluck, Martin Kaatz, Uwe Trefzer, Axel Hauschild, Rudolf Stadler, Carola Berking, Hubert E. Pehamberger, Annette Kopp-Schneider, Jürgen C. Becker
Journal: Journal of Clinical Oncology (2015)

e20080 Background: The ex-vivo chemosensitivity profile derived from viable tumor cells showed to predict the outcome of anti-melanoma chemotherapy in a phase-2 trial. This multicenter randomized phase-3 trial was aimed to test for superiority of a sensitivity-directed chemotherapy compared to a standard chemotherapy regimen, and to confirm the ex-vivo determined chemosensitivity index (CSI) as a predictor of chemotherapy outcome. Methods: Tumor cells obtained from metastatic lesions were tested for sensitivity to chemotherapeutic drug combinations using an ATP-based viability assay. Chemo-naive patients with advanced metastatic melanoma were randomly assigned to receive either sensitivity-directed combination chemotherapy (paclitaxel+cisplatin or treosulfan+gemcitabine) or monochemotherapy with dacarbazine (DTIC). The primary study endpoint was disease-specific survival (overall, OS; progression-free, PFS). Secondary study endpoints were response and toxicity. Results: After enrollment of 287 patients and a median follow-up of 9.2 months, the PP population (n = 244) showed no survival difference between the two treatment arms (n = 122 each), sensitivity-directed chemotherapy vs DTIC (median PFS 2.5 vs 2.3 months, HR = 0.91, 95% CI 0.70-1.18, p = 0.48; median OS 9.2 vs 9.0 months, HR = 1.07, 95% CI 0.80-1.44, p = 0.64). Patients tested chemosensitive (CSI ≤ 100) showed no survival difference compared to patients tested chemoresistant (CSI > 100). Disease control rate (CR+PR+SD) tended to be higher in patients treated with sensitivity-directed chemotherapy compared to patients treated with DTIC (34.5% vs 23.5%, p = 0.064); objective response rates (CR+PR) showed no difference between both groups (11.2% vs 12.6%, p = 0.74). Severe toxicities (CTC grade 3-4) were more frequently observed in patients treated with sensitivity-directed chemotherapy compared to patients treated with DTIC (45.1 vs 14.1, p < 0.0001). Conclusions: Combination chemotherapy directed by ex-vivo sensitivity profiling did not result in a survival advantage compared to DTIC monochemotherapy in advanced metastatic melanoma. Clinical trial information: NCT00779714.
Bendamustine Improves Clinical Outcome in Chronic Lymphocytic Leukemia (CLL) According to Different Clinical and Biological Prognostic Factors
Authors: Giovanni Del Poeta, Maria Ilaria Del Principe, Dario Ragusa, Pietro Bulian, Francesco Buccisano, Francesca Maria Rossi, Alessio Pio Perrotti, Luca Maurillo, Paolo de Fabritiis, Valter Gattei, Sergio Amadori
Journal: Blood (2014)
High FGF21 levels are associated with altered bone homeostasis in HIV-1-infected patients
Authors: José M. Gallego-Escuredo, Maria Karuna Lamarca, Joan Villarroya, Joan C. Domingo, Ma Gracia Mateo, Ma del Mar Gutierrez, Francesc Vidal, Francesc Villarroya, Pere Domingo, Marta Giralt
Journal: Metabolism (2017)
The acute toxicity results of the GETUG-AFU 22 study: A multicenter randomized phase II trial comparing the efficacy of a short hormone therapy in combination with radiotherapy to radiotherapy alone as a salvage treatment for patients with detectable PSA after radical prostatectomy.
Authors: Stephane Gilles Guerif, Igor Latorzeff, Lise Roca, Djelila Allouache, Stephane Supiot, Edouard Lagneau, Pierre Richaud, Deniaud-Alexandre Elisabeth, Philippe Ronchin, Benyoucef Ahmed, Lysian Cartier, Hadji Hamidou, Ali Hasbini, Gilles Crehange, Pascal Pommier, Guy De Laroche, Muriel Habibian, Emmanuel Gross, Philippe Fourneret, Laurent Salomon
Journal: Journal of Clinical Oncology (2017)

16 Background: Radical prostatectomy (RP) is recommended as a standard treatment for localized prostate cancer. However no recommendations exist for pts with detectable PSA after RP. Methods: Pts with localized prostate cancer, treated by RP (R0 or R1), with a PSA level post-RP ≥ 0.2 ng/mL and ≤ 2 ng/mL at randomization and N0 M0 on imaging were included. Pts were randomized (1:1) to radiotherapy (RT) alone (RT arm) or 6 months degarelix hormone therapy (HT) with RT (RT+HT arm). RT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint is the event-free survival (EFS). Secondary endpoints are: 5-yr EFS and metastases-free survival, 5 and 10-yr OS, acute and late toxicity (CTCAE V4.0), and QOL. With 122 patients, the probability of selecting the most effective arm is over 80% for a 20% reduction in the HR = 0.80. Results: From Dec-2012 to Sept-2015, 125 pts were included (RT arm: 64 pts; RT+HT arm: 61). Median follow up is 14.7 months (6.2; 33.5). The baseline characteristics are well-balanced: median age was 66 yrs (50-77), all men having an ECOG ≤ 1 (ECOG 0 in 92%), a median Gleason score of 7 (3-9), a median PSA of 0.3 ng/mL (0.09-1.82) post-RP and 0.6 ng/mL (0.12-3.65) at randomization. All pts received 33 Fr of RT. In the RT+HT arm 98.4% of pts received the 6 months of HT planned. All pts were eligible for safety analysis. No grade 4 toxicity or toxic death was reported. Grade 3 acute toxicity, occurring within 6 months of RT, were reported for 11/125 pts (9%): 3/64 pts (5%) in the RT arm and 8/61 pts (13%) in RT+HT arm (NS). Regarding grade 3 toxicities, the following occurred only in the RT+HT arm: erectile dysfunction (3 pts) and urinary incontinence (2 pts); in contrast, dysuria/pollakiuria (2 pts) occurred only in the RT arm. In the RT+HT arm, grade 2 toxicities included hot flushes (8 pts) and decreased libido (7 pts). Conclusions: In terms of acute toxicities the RT+HT arm is well tolerated with the observed toxicities usually expected with concomitant HT. The primary endpoint analysis is expected for 2018. Clinical trial information: NCT01994239.
A national survey of general internists' preferences and knowledge gaps regarding the care of childhood cancer survivors.
Authors: Tara O. Henderson, Paul C. Nathan, Kenneth Rasinski, Eugene Suh, Mackenzie Kigin, Kristen Wroblewski, Jennifer Ford, Emily S. Tonorezos, Kevin C. Oeffinger, Christopher Daugherty
Journal: Journal of Clinical Oncology (2012)

9586 Background: Although most childhood cancer survivors (CCS) report obtaining health care in the community, primary care physicians’ views and knowledge regarding the long-term follow-up (LTFU) care of CCS are largely unknown. Methods: Surveys were mailed to a random sample of 1,907 general internists under age 65 years from the American Medical Association Physician Masterfile in November 2011. A second mailing to non-responders is ongoing. Results: 892 (47%) physicians have responded. Respondents have practiced a median of 10 years (range: 3-20), and see a median of 70 patients/week (range: 40-100). 46% are in solo/group practice, 17% in multi-specialty practice, and 14% in academic practice. In the last five years, 53% have seen at least one CCS, 71% of whom have never received a treatment summary. 85% prefer to care for CCS in consultation with a cancer center based physician. A vignette of a 29-year-old female treated for Hodgkin lymphoma with mantle radiation at age 16 was provided and participants were asked a series of questions regarding monitoring for late effects. The percentage of responses that were concordant with available LTFU Surveillance Guidelines were: breast cancer, 29%; cardiac, 15%; thyroid, 77%; and all three recommendations, only 5%. By logistic regression, greater likelihood of concordance with at least one surveillance recommendation was associated with being female (OR=2.0 95% CI 1.3-3.1), seeing more patients/week (OR=1.4 per SD increase, 95% CI 1.1-1.7) and more years in practice (OR=1.3 per SD increase, 95% CI 1.0-1.6). The two modalities felt to be most useful for independent care of CCS by internists were access to LTFU guidelines and receiving a patient-specific care plan from the cancer center. Conclusions: Although the majority of internists are willing to follow CCS, they appear unfamiliar with the available LTFU guidelines and prefer to care for patients in collaboration with a cancer center based physician.
Thymic carcinoma: A cohort study of prognostic factors after surgical resection from the European Society of Thoracic Surgeons database.
Authors: Enrico Ruffini, Frank C. Detterbeck, Dirk Van Raemdonck, Gaetano Rocco, Pascal Alexandre Thomas, Walter Weder, Alessandro Brunelli, Francesco Guerrera, Shaf Keshavjee, Nasser K. Altorki, Jan Schutzner, Alper Toker, Lorenzo Spaggiari, Alex Arame, Eric Kian Saik Lim, Federico Venuta
Journal: Journal of Clinical Oncology (2013)

7602 Background: Thymic carcinomas are rare tumors which have recently been separated from thymomas due to their different histologic/clinical characteristics. Most of the current literature is composed of small series spanned over extended time periods Methods: The European Society of Thoracic Surgeons (ESTS) developed a retrospective database collecting data on patients with thymic tumors submitted to surgery (1990-2011). Out of 2,265 incident cases, there were 229 thymic carcinomas. Clinical-pathologic characteristics were analyzed including age, gender, stage (Masaoka), histologic subtypes (squamous cell/others), type of resection (complete/incomplete), tumor size, induction and adjuvant therapy (chemotherapy-ChT/radiotherapy-RT), recurrence. Primary outcome was overall survival (OS); secondary outcomes were disease-free survival (DFS) and the cumulative incidence of recurrence. Survival analysis was performed using univariate and multivariate (Cox-shared frailty) competing-risk models. Missing data were analysed using multiple-imputation techniques Results: A multidisciplinary approach (surgery, ChT and RT) was used in most patients. Induction therapy was employed in 78 patients (ChT, 53; ChT/RT 23; RT, 2). Adjuvant therapy was employed in 150 patients (ChT, 19; ChT/RT, 72; RT, 59). Complete resection (R0) was achieved in 71% of the patients. Five and 10-year OS were 60% and 35%. Five and 10-year DFS were 62% and 43%. Cumulative incidence of recurrence was 0.25, 0.32 and 0.40 at 3, 5, and 10 years. Independent OS predictors (multivariate analysis) were young age (p=0.006), stage I/II (vs. III/IV, p=0.02), R0 resection (p&lt;0.001), adjuvant therapy (ChT, RT or both) (p=0.02). Independent predictor of recurrence (univariate analysis) was tumor size (p=0.05). Conclusions: In thymic carcinomas submitted to surgical resection, increased age,Masaoka stages III-IV and incomplete resection had a significant impact in worsening survival. Larger tumors had an increased risk of recurrence. The administration of adjuvant ChT or RT was associated with improved overall survival. A multidisciplinary approach to these rare tumors remains essential.
Effectiveness and safety of clofazimine in multidrug-resistant tuberculosis: a nationwide report from Brazil
Authors: Margareth Dalcolmo, Regina Gayoso, Giovanni Sotgiu, Lia D'Ambrosio, Jorge L. Rocha, Liamar Borga, Fatima Fandinho, Jose U. Braga, Vera M.N. Galesi, Draurio Barreira, Denise A. Sanchez, Fernanda Dockhorn, Rosella Centis, Jose A. Caminero, Giovanni B. Migliori
Journal: European Respiratory Journal (2017)

Although clofazimine is used to treat multidrug-resistant tuberculosis (MDR-TB), there is scant information on its effectiveness and safety. The aim of this retrospective, observational study was to evaluate these factors as well as the tolerability of clofazimine in populations in Brazil, where it was administered at a daily dose of 100 mg·day −1 (body weight ≥45 kg) as part of a standardised MDR-TB treatment regimen until 2006 (thereafter pyrazinamide was used). All MDR-TB patients included in the Sistema de Informação de Tratamentos Especiais da Tuberculose (SITETB) individual electronic register were analysed. The effectiveness of clofazimine was assessed by comparing the treatment outcomes of patients undergoing clofazimine-containing regimens against those undergoing clofazimine-free regimens and its safety by describing clofazimine-attributed adverse events. A total of 1446 patients were treated with clofazimine-containing regimens and 1096 with pyrazinamide-containing regimens. Although success rates were similar in patients treated with clofazimine versus those treated with pyrazinamide (880 out of 1446, 60.9%, versus 708 out of 1096, 64.6%; p=0.054), clofazimine-treated cases exhibited higher death rates due to tuberculosis than pyrazinamide-treated ones (314 out of 1446, 21.7%, versus 120 out of 1096, 10.9%) but fewer failures (78 out of 1446, 5.4%, versus 95 out of 1096, 8.7%) and less loss to follow-up (144 out of 1446, 10.0%, versus 151 out of 1096, 13.8%). No relevant differences were detected when comparing adverse events in patients treated with clofazimine-containing regimens to those treated with clofazimine-free regimens. However, the incidence of side-effects was less than previously reported (gastro-intestinal complaints: 10.5%; hyper-pigmentation: 50.2%; neurological disturbances: 9–13%).
Granulocyte and monocyte apheresis can control juvenile generalized pustular psoriasis with mutation of<i>IL36RN</i>
Authors: Y. Koike, M. Okubo, T. Kiyohara, R. Fukuchi, Y. Sato, S. Kuwatsuka, T. Takeichi, M. Akiyama, K. Sugiura, A. Utani
Journal: British Journal of Dermatology (2017)

Patients with deficiency of interleukin‐36 receptor antagonist (DITRA), due to mutation of IL36RN, exhibit psoriatic phenotypes, typically generalized pustular psoriasis (GPP). We report a paediatric patient with DITRA, whose cutaneous lesions varied from psoriasis vulgaris in infancy to annular pustular psoriasis with acute exacerbation to GPP at 13 years of age. Conventional systemic treatments for GPP, which include oral retinoids, ciclosporin and methotrexate, are controversial in paediatric cases, because of their adverse effects and uncertain long‐term consequences. Granulocyte monocyte apheresis, a process associated with few adverse events, promptly controlled the GPP of our paediatric patient, and has potential as a suitable alternative treatment for paediatric patients with DITRA.
Association of changes in circulating cell-free plasma DNA (cfDNA) and circulating tumor cells (CTC) during treatment with clinical outcome from olaparib in castration-resistant prostate cancer (CRPC): Exploratory analyses from the TOPARP-A trial.
Authors: Joaquin Mateo, Helen Mossop, Jane Goodall, David Lorente, Nuria Porta, Suzanne Carreira, Susana Miranda, Zafeiris Zafeiriou, Christy Ralph, Suneil Jain, Robert J. Jones, Syed A. Hussain, Tony Elliott, Andrew Protheroe, Berni Ebbs, Lorna Leonard, Diletta Bianchini, Penelope Flohr, Emma Hall, Johann S. De Bono
Journal: Journal of Clinical Oncology (2017)

141 Background: Response biomarkers are needed to optimize treatment switch decisions in CRPC patients. CTC and cfDNA may have clinical utility as response biomarkers; we studied them during olaparib treatment in a phase II trial in CRCP (Mateo et al NEJM 2015). Methods: CTC were enumerated using CellSearch (Jannsen Diagnostics) and cfDNA was extracted with the QIASymphony circulating DNA kit (Qiagen) from blood samples taken at baseline, 4- and 8-weeks (wk) of therapy. Radiological progression-free survival (rPFS) was defined as time from starting treatment to progression by RECIST 1.1, bone scan (PCWG2) or death. Overall survival (OS) was defined as time from starting treatment to death. CTC changes were categorized based on conversion from ≥ 5 to &lt; 5 CTC/7.5ml blood and on ≥ 30% decline (Lorente et al Eur Urol 2016). cfDNA changes were evaluated as percentage change from baseline (continuous and binary). The prognostic value of CTC and cfDNA changes were assessed by Landmark analysis and Cox models with time-varying covariates; p-value &lt; 0.01 were considered significant to account for multiple tests. Results: Overall, 13/47 (28%) and 16/42 (38%) evaluable patients had a CTC conversion at 4- and 8-wk respectively. A CTC conversion after 4-wk of olaparib associated with longer rPFS (median 8.9 vs 2.7 months [m], p = 0.001); a similar association was found at 8-wk. A 30% CTC decline at 4-wk also associated with longer rPFS (median 4.4 vs 2.6 m, p = 0.004). CTC conversion as a time-varying covariate associated with longer OS (HR 0.26, 95%CI 0.14-0.50, p &lt; 0.001). Median baseline cfDNA was 31.6 ng/ml (IQR 19.4-57.1); 46 and 42 patients were evaluable for cfDNA changes at 4- and 8-wk. Percentage changes in cfDNA at 4- and 8- wk associated with rPFS (HR 1.01 and 1.005; p = 0.005 and 0.002 respectively) but association with OS was not significant. cfDNA declines ≥ 50% at 8- wk associated with longer rPFS (median 8.9 vs 2.7 m, p = 0.007) and OS (17.0 vs 10.1 m, p = 0.004). Conclusions: Decreases in CTC counts and cfDNA concentration associate with improved outcome from olaparib (rPFS, OS) in the TOPARP-A trial. Clinical trial information: NCT01682772.