tbuckley/cabot-search huggingface dataset:
Impact of pelvis irradiation on toxicity of further oxaliplatin-based chemotherapy in rectal cancer.
Authors: Mateusz Spalek, Wojciech Michalski, Krzysztof Bujko, Lucjan Wyrwicz
Journal: Journal of Clinical Oncology (2018)

777 Background: Radiotherapy is used in the neoadjuvant setting in majority of rectal cancer patients, while its effect on overall survival is limited mostly to patients with threatened resection margin. Preoperative pelvic irradiation might damage bone marrow. In consequence, relative dose intensity (RDI) and efficacy of further adjuvant or palliative CT might be reduced. The aim of the study was to assess whether radiation damage to the pelvic bone marrow influences the tolerance of further oxaliplatin-based CT. Methods: We have performed the cohort analysis of patients with adenocarcinoma of rectum or colon receiving FOLFOX-4 chemotherapy in adjuvant or palliative setting between 2011-2016. Oxaliplatin relative-dose intensity (RDI) within 8 weeks from the beginning of CT was calculated for each patient. The major factors, which can reduce oxaliplatin RDI, were analyzed independently (hemathological toxicity, neurological toxicity, occurrence of hypersensitivity reactions to oxaliplatin). The data regarding the first disruption of oxaliplatin dose within all planned courses of FOLFOX-4 was also collected. Results: 220 patients met eligibility criteria. 41 of them received neoadjuvant radio(chemo)therapy (study group), the remaining 179 patients were assigned to control group (n = 179). RDI did not differ significantly between irradiated and non-irradiated patients (p = 0.794). There were no statistically significant differences in observed oxaliplatin-related toxicities. The median time between the start of chemotherapy and the first disruption of oxaliplatin administration was also not statistically different between the two groups (p = 0.156). Conclusions: An impact of preoperative radio(chemo)therapy on RDI or tolerance of FOLFOX was not found in rectal cancer.
RONC-13. OUTCOMES OF RE-IRRADIATION IN PEDIATRIC PATIENTS WITH RECURRENT CNS TUMORS
Authors: Andrew Chang, Jayne Vonbergen, Markus Fitzek, Allan Thornton, Chie-Schin Shih, Kamnesh Pradhan
Journal: Neuro-Oncology (2018)

Pediatric patients with recurrent CNS tumors have limited options. Published data with limited follow-up suggests that patients with >12 months interval after initial radiation may undergo a second course of radiation therapy. Eleven pediatric patients (median age 3.3 years at initial irradiation) with a CNS tumor previously treated with definitive RT to a median dose of 55.8 Gy (50.4 – 59.4 Gy) were re-irradiated to the same area. Second course of definitive RT delivered additional 36.0 – 66.6 Gy after local failure (n = 7), combined local and leptomeningeal metastatic failure (n = 3), or new primary (n=1). Re-irradiation was given in daily fractioned radiotherapy at 1.8 Gy per fraction to focal fields only (n = 7), the craniospinal axis alone (n = 2), or with boost (n =2); one craniospinal patient also had an additional Gamma Knife boost. The median time between courses of irradiation was 44.3 months (12.8 – 267.9 months). The median total combined prescribed dose of radiation to the neural tissues was 109.8 Gy (90.0 – 126 Gy). With a median follow up time for survivors of 97.4 months (84.4 – 98.7 months) after re-irradiation, 5 patients have died from subsequent disease recurrence, 5 patients have no evidence of disease, and one patient has died from likely radiation necrosis. Three of the living patients had radiographic evidence of radiation changes that self-resolved. Re-irradiation in pediatric patients with recurrent CNS tumors can be safely done after a minimum12 month interval between times of irradiation.
Abstract 15635: Creatinine Clearance Was a Superior Predictor for Atherothrombotic Stroke to Estimated Glomerular Filtration Rate
Authors: Satoshi Nishiyama, Tetsu Watanabe, Naoto Hashimoto, Gensai Yamaura, Masahiro Wanezaki, Harutoshi Tamura, Hiroki Takahashi, Takanori Arimoto, Tetsuro Shishido, Tamon Yamanaka, Takuya Miyamoto, Isao Kubota
Journal: Circulation (2016)

Introduction:  Kidney dysfunction is a risk factor for cardiovascular diseases as well as end stage renal disease. Estimated glomerular filtration rate (eGFR) is a well-established marker for kidney function. However, eGFR is often inaccurate since it is affected by several factors such as age, gender, and muscle mass. Therefore, creatinine clearance (CCr) estimated by Cockcroft-Gault Equation is sometimes recommended especially for elderly patients.   Hypothesis:  We hypothesized that kidney dysfunction evaluated by CCr is more closely associated with formation of aortic arch plaque compared to eGFR.   Methods:  We enrolled 644 patients (447 males, 64.4 ± 12.3 years) who underwent transesophageal echocardiography and carotid ultrasonography, and measured eGFR and CCr. We defined aortic arch plaque as wall thickness 4 mm or more and/or the presence of ulceration or mobile plaque in aortic arch. We determined the patients with aortic arch plaque and/or atherothrombotic stroke as high-risk patients for atherothrombotic stroke.   Results:  There were 139 patients with aortic arch plaque and 102 patients with history of atherothrombotic stroke. As a result, there were 158 high-risk patients. The high-risk patients were older and had higher prevalence of hypertension, diabetes, dyslipidemia, and smoking history and lower prevalence of atrial fibrillation compared with low-risk patients. CCr and eGFR were significantly lower in high-risk patients than in low-risk patients. Arch wall thickness and carotid plaque score were higher in high-risk patients compared with low-risk patients. CCr showed a greater correlation with arch wall thickness compared with eGFR. The prevalence of aortic arch plaque and/or atherothrombotic stroke was increased with advancing kidney dysfunction. In multivariate analysis, CCr was an independent predictor for high risk atherothrombotic plaque. In receiver operating characteristic analysis, the area under the curve of CCR was larger than eGFR (AUC 0.759 vs. 0.688).   Conclusions:  Aortic arch plaque was deteriorated with advancing kidney dysfunction. CCr was a superior predictor for atherothrombotic stroke to eGFR.
David Oliver: At last, some political honesty?
Authors: David Oliver
Journal: BMJ (2018)

BerkshireI've repeatedly criticised the government and its arm's length bodies for selective use of data on NHS performance, staffing, and funding. 1 2 Spin is futile when there are frequent independent reports on the true picture.In May and June 2018, for instance, we've seen a King's Fund report on NHS funding performance and international comparators, 3 the Centre for Progressive Policy's Diagnosis Critical paper, 4 the House of Commons Library's own hard hitting, data rich report on NHS performance, 5 and the Institute for Fiscal Studies' reports on health 6 and social care 7 funding.There's no hiding place from such scrutiny for politicians.The NHS has among the fewest acute beds and clinicians per 1000 among OECD nations; it faces major funding shortfalls, workforce gaps, declining staff morale, recruitment, and retention, and worsening operational performance.Reductions in social care funding have left that sector on the brink of collapse, with people and their families increasingly denied services that were already rationed and restricted.
Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies
Authors: Justin Taylor, Dean Pavlick, Akihide Yoshimi, Christina Marcelus, Stephen S. Chung, Jaclyn F. Hechtman, Ryma Benayed, Emiliano Cocco, Benjamin H. Durham, Lillian Bitner, Daichi Inoue, Young Rock Chung, Kerry Mullaney, Justin M. Watts, Eli L. Diamond, Lee A. Albacker, Tariq I. Mughal, Kevin Ebata, Brian B. Tuch, Nora Ku, Maurizio Scaltriti, Mikhail Roshal, Maria Arcila, Siraj Ali, David M. Hyman, Jae H. Park, Omar Abdel-Wahab
Journal: Journal of Clinical Investigation (2018)

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.
CRAN-06. CHILDREN WITH PINEOBLASTOMA. A SINGLE-INSTITUTION SERIES
Authors: Iwona Filipek, Monika Drogosiewicz, Marta Perek-Polnik, Ewa Swieszkowska, Wieslawa Grajkowska, Elzbieta Jurkiewicz, Pawel Kowalczyk, Bozenna Dembowska-Baginska
Journal: Neuro-Oncology (2018)

Pineoblastoma is a rare, highly aggressive supratentorial tumour, more frequently diagnosed in young children. The prognosis remains poor. AIM: To present own experience with children with pineoblastoma. PATIENTS AND 14 pts: 8 girls and 6 boys treated between 1998 and 2017 were analyzed. 5 pts (36%) were under 3 years of age. 7 pts underwent complete tumour resection, 2-partial resection and 5- biopsy. At the onset of treatment six patients had disseminated disease. 9 pts were treated according to protocol for MB HR group (with radiotherapy), 5 pts according to own baby protocol. 9 pts (64%) achieved good response to treatment (CCR-4 pts, CR-4 or PR-1). Four patients experienced tumour progression. 7 out of 14 patients are alive 3 ms to 17years from diagnosis (median 3years 4ms). Seven patients died (10ms to 8years from diagnosis). 1 pt died of long term post- radiotherapy sequelae. 5 yr EFS was 23 %, OS- 57%. 10 yr EFS and OS were 23 and 30,1% consecutively. 10 out of 14 pts relapsed 7ms to 4 years 3ms from diagnosis. 9 pts received second line treatment- 4 are alive. Children younger than 3 years of age treated without radiotherapy had worse outcome with 5 yrs OS estimated at 0% vs 74,1% in older children treated with chemotherapy and radiotherapy (p=0,014). Pineoblastoma is highly malignant CNS neoplasm of childhood with dismal prognosis. In our series children below 3 years of age treated without radiotherapy had poorer responses and worse outcome.
EMBR-08. CHOROID PLEXUS TUMORS IN 2018: THE CPT-SIOP EXPERIENCE AND LONG-TERM OUTCOME
Authors: Uwe R Kordes, Stefan Hartung, Ulrike Löbel, Ann-Kathrin Ozga, Heidi Traunecker, Jenny Adamski, Iwona Filipek, Miklos Garami, Guirish Solanki, Martin Hasselblatt, Torsten Pietsch, Rolf-Dieter Kortmann, Ricken Christoph, Beate Timmermann, Johannes Wolff
Journal: Neuro-Oncology (2018)

Choroid plexus tumors (CPT) comprise choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (aCPP, WHO grade II), and choroid plexus carcinoma (CPC, WHO grade III). CPT from 20 nations were prospectively recruited into the CPT-SIOP-2000 study (01/2000–03/2010, n=129, median follow-up 7.4 years) and the CPT-SIOP registry (04/2010-01/2018, n=119). Non-surgical risk-stratified treatment consisted of i) chemotherapy for all CPC, all metastatic CPT and incompletely resected aCPP regardless of metastases ii) focal radiotherapy in non-metastatic CPC >3y, iii) craniospinal radiotherapy in non-metastatic CPC >3y during the registry phase. Non-metastatic CPP and aCPP R0 were followed by surveillance. CPT-SIOP-2000 randomized six cycles of carboplatin/VP16/VCR vs. cyclophosphamide/VP16/VCR. Alternating combination of these cycles were given to registry patients with CPC (n=16). WHO grading was the most significant prognostic variable for OS and EFS in CPT patients, five-year OS/EFS accounting for 100/96% in CPP (n=84), 97/79% in aCPP (n=88) and 58/35% in CPC (n=76). Of note, 5y OS/EFS was 100/92% for aCPP patients <2y (n=59) as compared to 85/39% for aCPP patients >2y (n=22). CPCs opting for postop surveillance only progressed with dissemination. Carboplatin based chemotherapy trended superiorly. Clinical staging had minor impact on survival in the primary treatment groups. Radiotherapy for CPC without Li-Fraumeni syndrome had a survival advantage in the first five years of follow-up, craniospinal field did not improve survival for non-metastatic CPC. Delayed radiotherapy for young patients with CPC that progressed on chemotherapy achieved meaningful responses (n=8). In conclusion: adjuvant therapy improves outcome for high risk CPT.
Nemorubicin: A doxorubicin-like structure with a novel mechanism of action different from anthracyclines
Authors: Cristina Geroni, Maria Antonietta Sabatino, Dario Ballinari, Marina Ciomei, Aurelio Marsiglio, Luigi Quintieri, Maura Floreani, Massimo Broggini
Journal: Cancer Research (2006)

3845  Nemorubicin is a potent antitumor agent currently in Phase II clinical studies for the treatment of primary hepatocellular carcinoma. Preclinical data showed that nemorubicin, although structurally related to doxorubicin, is not cardiotoxic, overcomes anthracyclines resistance and has a novel mechanism of action. We previously demonstrated that nemorubicin induces DNA strand breaks primarily through topoisomerase-I cleavage. As expected, nemorubicin is active in cells resistant to topoisomerase II inhibitors, whereas it is inactive against camptotecins resistant cells. In addition, we found that in vitro human hepatocytes or microsomes generate a nemorubicin metabolite (PNU-159682) that is hundred times more cytotoxic than the parent compound and that binds covalently to DNA. To further characterize the mechanism of action of nemorubicin, we generated a L1210 cell line resistant to nemorubicin. Since resistant L1210 cells were more sensitive than the parental cell line to UV irradiation and to platinum derivatives and alkylating agents, we reasoned that the nucleotide excision repair (NER) system might be involved in mediating the cytotoxic activity of nemorubicin. To test this hypothesis we used CHO cell lines proficient or deficient in excision repair cross-complementing (ERCC) genes, namely ERCC1 and ERCC6 genes. We found that nemorubicin is more cytotoxic in NER proficient than in deficient cells, suggesting that the NER system is involved in the induction of nemorubicin cytotoxicity. Comparable results were obtained testing PNU-159682 on NER proficient or deficient cells. In summary, nemorubicin, although structurally related to doxorubicin, has a novel mechanism of action that involves the NER system, providing the rationale for clinical combination studies of nemorubicin with platinum derivatives or alkylating agents.
Response to Comment on Stiermaier et al. Prevalence and Prognostic Impact of Diabetes in Takotsubo Syndrome: Insights From the International, Multicenter GEIST Registry. Diabetes Care 2018;41:1084–1088
Authors: Thomas Stiermaier, Francesco Santoro, Ibrahim El-Battrawy, Natale Daniele Brunetti, Ibrahim Akin, Ingo Eitel
Journal: Diabetes Care (2018)

We thank Del Buono et al. (1) for their interest in our study about diabetes in Takotsubo syndrome (TTS) (2), and we are pleased that our work was inspiring for their analysis.

The potential causal association between diabetes and the occurrence of TTS is obviously an extremely controversially discussed issue. Previously, the observation of a low diabetes prevalence in some TTS populations led to the assumption that diabetes is protective for the emergence of the disease (3). Diabetic cardiovascular autonomic neuropathy leading to catecholamine hyposecretion and amelioration of adrenergic effects to …
Prospective evaluation of the frequency of genital lichen sclerosus in 79 patients with systemic sclerosis
Authors: R. Goussot, C. Francès, K. Cury, D. Bessis, T. Martin, E. Chatelus, A. Mahé, L. Messer, F. Séverac, N. Meyer, D. Lipsker
Journal: British Journal of Dermatology (2018)
ATRT-01. SYNCHRONOUS CENTRAL NERVOUS SYSTEM (CNS) ATYPICAL TERATOID/ RHABDOID TUMOR (AT/RT) AND MALIGNANT RHABDOID TUMOR OF THE KIDNEY - REVIEW OF THE LITERATURE
Authors: Mohammad H Abu Arja, Priyal Patel, Summit Shah, Jeffery Auletta, Erin Meyer, Suzanne E Conley, Jennifer Aldrink, Jonathan Pindrik, Mohamed S AbdelBaki
Journal: Neuro-Oncology (2018)

CNS AT/RTs with synchronous/ metachronous extra-CNS primary tumors are a rare entity with a dismal prognosis. A literature review was conducted on patients diagnosed with CNS AT/RT and synchronous/ metachronous extra-CNS primary tumors. Our review yielded information on 32 children diagnosed with CNS AT/RT with additional extra-CNS primary tumors. The median age at diagnosis was four months. Male: female ratio was 2:1. Twenty-three patients presented within the age of six months. The most common extra-CNS site was the kidney (69%). Germline SMARCB1 mutation was found in all of the tested patients. The median overall survival was 5.8 months post-diagnosis. Only four patients were found to be alive with no evidence of relapse. All of the survivors receive high-dose chemotherapy (HDCT) followed by autologous peripheral blood stem cell transplant (PBSCT). Three of them had gross-total resection of the intracranial tumor and one did not receive any intracranial surgical resection. Two of the survivors did not receive any radiotherapy. One child received upfront focal radiotherapy, while the remaining patient received focal radiotherapy only after the progression of the intracranial tumor. Three of the surviving patients received intrathecal chemotherapy; two of them included methotrexate. The rarity of patients with CNS AT/RT with additional extra-CNS manifestations and the lack of a standard treatment protocol have contributed to the reported dismal prognosis. A multimodal treatment approach including maximal surgical resection, intrathecal chemotherapy, and HDCT with peripheral PBSCT may improve the outcomes for this patient population, without the need for upfront radiotherapy.
TLR4<sup>+</sup>CXCR4<sup>+</sup> plasma cells drive nephritis development in systemic lupus erythematosus
Authors: Kongyang Ma, Jingyi Li, Xiaohui Wang, Xiang Lin, Wenhan Du, Xi Yang, Fangxiang Mou, Yongfei Fang, Yanbin Zhao, Xiaoping Hong, Kwok Wah Chan, Xiaoming Zhang, Dongzhou Liu, Lingyun Sun, Liwei Lu
Journal: Annals of the Rheumatic Diseases (2018)

In patients with systemic lupus erythematosus (SLE), immune tolerance breakdown leads to autoantibody production and immune-complex glomerulonephritis. This study aimed to identify pathogenic plasma cells (PC) in the development of lupus nephritis.PC subsets in peripheral blood and renal tissue of patients with SLE and lupus mice were examined by flow cytometry and confocal microscopy, respectively. Sorting-purified PCs from lupus mice were adoptively transferred into Rag2-deficient recipients, in which immune-complex deposition and renal pathology were investigated. In culture, PCs from lupus mice and patients with SLE were treated with a TLR4 inhibitor and examined for autoantibody secretion by enzyme-linked immunospot assay (ELISPOT). Moreover, lupus mice were treated with a TLR4 inhibitor, followed by the assessment of serum autoantibody levels and glomerulonephritis activity.The frequencies of TLR4+CXCR4+ PCs in peripheral blood and renal tissue were found significantly increased with the potent production of anti-dsDNA IgG, which were associated with severe renal damages in patients with SLE and mice with experimental lupus. Adoptive transfer of TLR4+CXCR4+ PCs from lupus mice led to autoantibody production and glomerulonephritis development in Rag2-deficient recipients. In culture, TLR4+CXCR4+ PCs from both lupus mice and patients with SLE showed markedly reduced anti-dsDNA IgG secretion on TLR4 blockade. Moreover, in vivo treatment with TLR4 inhibitor significantly attenuated autoantibody production and renal damages in lupus mice.These findings demonstrate a pathogenic role of TLR4+CXCR4+ PCs in the development of lupus nephritis and may provide new therapeutic strategies for the treatment of SLE.
QOL-45. PROFILES OF EXECUTIVE FUNCTIONS IN SURVIVORS OF PEDIATRIC BRAIN TUMOR. A COMPREHENSIVE APPROACH
Authors: Jeanne Roche, Mathilde Chevignard, Didier Le Gall, Didier Frappaz, Jean-Luc Roulin, Arnaud Roy
Journal: Neuro-Oncology (2018)

Executive functions (EF) are a collection of distinct but related high-level processes, of major importance during development. They are frequently impaired following childhood brain tumors, with negative consequences on academic achievement and overall independence. This study aimed at performing a comprehensive assessment of EF domains, using a combination of performance-based tasks and a daily life questionnaire. We developed a novel test battery (FEE), based on Diamonds’ developmental framework of EF (2013), comprised of 10 subtests assessing flexibility, inhibition, working memory, and planning, controlling for lower level processes (i.e. language, visual-spatial skills). Outcome measures include different performance indicators (e.g. number of errors, time...). Twenty-seven children treated for various brain tumors and 27 matched healthy controls, performed the FEE battery, as well as the parent- and teacher-ratings of the Behavior Rating Inventory of Executive Functions (BRIEF) questionnaire. The association between performance-based and rating measures of EF was also examined. Patients performed significantly worse than controls on some, but not all subtests. The main finding was that overall, patients performed tasks slower than controls, without significantly more errors. Correlations between performance-based tasks and the BRIEF questionnaire were weak and not significant, as most often reported in the literature. This study allowed identification of a specific dysexecutive profile that should be confirmed in a larger sample of pediatric brain tumor survivors. These findings could lead to improvements in EF assessment, to better understanding of EF deficits basis (i.e. the cognitive cost of slow information processing) and their consequences, and development of targeted interventions.
Revisiting NPH Insulin for Type 2 Diabetes
Authors: Matthew J. Crowley, Matthew L. Maciejewski
Journal: JAMA (2018)

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