tbuckley/cabot-search huggingface dataset:
First prospective multicenter Italian study on the impact of the 21-Gene Recurrence Score (RS) in adjuvant clinical decisions for ER+/HER2- early breast cancer (BC) patients.
Authors: Maria Vittoria Dieci, Valentina Guarneri, Tommaso Giarratano, Marta Mion, Giampaolo Tortora, Paolo Morandi, Stefania Gori, Laura Merlini, Cristina Oliani, Felice Pasini, Giorgio Bonciarelli, Gaia Griguolo, Enrico Orvieto, Paola Del Bianco, Gian Luca De Salvo, Pier Franco Conte
Journal: Journal of Clinical Oncology (2017)

e12038 Background: The Breast-DX Italy prospective study evaluated the impact of the 21-gene RS on adjuvant treatment decisions for early BC patients. Methods: The study was conducted in 9 centers of the Veneto Region (2 hub and 7 spoke). All consecutive patients with ER+/HER2-, T1 to T3, N0 to N1 early BC who met protocol-defined clinicopathological criteria for “intermediate risk” were included. Pre-RS and post-RS physicians’ treatment recommendations and treatment actually received were collected. Results: From November 2014 to August 2016, n=124 N0 and n=126 N1 patients were enrolled (65% at hub and 35% at spoke centers). The majority had PgR+ (86%), G2 (71%) and pT1c (63%) BC. Median age was 55 yrs, median Ki67 was 20% (range 2-70%). The distribution of RS was: &lt;18 (61%), 18-30 (32%) and &gt;30 (7%). Main factors associated with higher RS were G3 and higher ki67. The addition of chemotherapy (CT) to hormonal therapy (HT) was initially recommended for 48% of the patients (38% of N0 and 57% of N1 patients; 54% and 37% of patients enrolled at hub and spoke centers, respectively). The post-RS recommendation changed from the pre-RS recommendation for 40 patients, mostly from CT+HT to HT (n=30; n=25 with low and n=5 with intermediate RS). Change was more frequent for N1 patients (Table). Of the 72 N1 patients initially recommended to CT+HT, 28% had a post-RS indication to HT alone. The crude number of patients with pre-RS recommendation to CT significantly exceeded the number of patients who finally received it (absolute difference =31; p&lt;0.001). The majority of CT treatments were spared at hub vs spoke centers (n=24 and n=7, respectively). Conclusions: Pre-RS indication to HT alone was frequent, in particular for N0 patients and at spoke centers. The use of the 21-gene RS further contributed in sparing CT administration, more so for N1 patients and at hub centers. The impact of the RS when used at discretion of the clinicians is currently under investigation in the prospective ROXANE study. [Table: see text]
Predictive value of neutrophil-to-lymphocyte ratio on pathological complete response in triple negative breast cancer.
Authors: Daniel Enriquez, Gabriel Antonio De la Cruz Ku, Margiory Fernandez, Eduardo Eyzaguirre, Renato Luque, David Paitan, Maria Luján, Antonella Saavedra, Bryan Valcárcel, Zaida Morante, Hugo Alejandro Fuentes, Silvia P. Neciosup, Henry Leonidas Gomez
Journal: Journal of Clinical Oncology (2017)

e12012 Background: Immune response in Triple Negative Breast Cancer (TNBC) plays a critical role in pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Therefore, neutrophil to lymphocyte ratio (NLR) could be an interesting biomarker to evaluate systemic inflammation in TNBC. Our aim was to evaluate the effect of NLR, also progression free survival (PFS) and overall survival (OS) as secondary objectives. Methods: We reviewed 338 medical records of II-III CS TNBC patients treated with NAC, in the 2000-2014 period, at Instituto Nacional de Enfermedades Neoplasicas. Patients were grouped in NLR &lt; 3 and ≥3. Survival differences were assessed by log-rank test in the univariate analysis and prognostic factors were then investigated by Cox regression analysis. Results: Mean age was 47y [range:24-79], 54% were premenopausal, 90.9% had clinical T3-T4 tumor and 80.5% clinical nodal involvement. There were 44 and 294 pts with II and III CS, respectively. From 338 patients, 259 had NLR &lt; 3 and 79, ≥3. No significant clinical differences were noted between these groups, except a higher mean BMI among patients with NLR &lt; 3 (28 vs 26Kg/m 2 , p = 0.01). pCR rate was higher in NLR &lt; 3 patients (22% vs 15.2%, p &lt; 0.001) and partial response was reached on 70.7% and 62% of pts with NLR &lt; 3 and ≥3, respectively. At 5 year median follow-up, 5-year DFS was higher among patients with NLR &lt; 3 (47 vs 34%, HR = 0.69, 95%CI: 0.50-0.95, p = 0.02) and so was 5-year OS (55 vs 40%, HR: 0.61, CI95%: 0.43-0.85, p = 0.004). At multivariate analysis, premenopausal status, non-pCR and nodal involvement were associated with worse DFS. Otherwise, NLR &lt; 3 (HR: 0.61, 95%CI: 0.43-0.86, p = 0.005) and pCR were predictors of better OS, nonetheless nodal involvement had negative impact on OS. Conclusions: NLR is a valuable predictive biomarker of pCR and OS in TNBC patients. We report less pCR rates due to higher stages among peruvian population.
Review of postmarketing surveillance of molecular targeted anticancer agents in Japan
Authors: Y. Miura, M. Kami, T. Morita, M. Tsubokura, N. Takei, N. Murashige, A. Hori, T. Komatsu
Journal: Journal of Clinical Oncology (2009)

6598 Background: Since the safety profile of molecular targeted anticancer agents is different from that of conventional anticancer agents, the safety information is limited. Although postmarketing surveillance (PMS) on safety is important, the appropriate methods of PMS have not been established. Methods: We investigated PMS methods, patients’ performance status (PS), and safety of the eight molecular targeted anticancer agents (imatinib, rituximab, trastuzumab, gefitinib, gemtuzumab ozogamicin [GO], bortezomib, bevacizumab, erlotinib) approved in Japan. We excluded sunitinib and sorafenib as the PMS of these agents were ongoing. Results: Besides PMS of gefitinib, seven PMS enrolled all the patients that received the study agents. The inclusive type of PMS was required at approval of the latest four agents, GO, bortezomib, bevacizumab, and erlotinib. The total number of enrolled patients was 8,776. Seven PMS of imatinib, rituximab, trastuzumab, GO, bortezomib, bevacizumab, and erlotinib enrolled 309, 2,575, 1,142, 316, 666, 2,698, and 1,070 patients, respectively. Data on the frequencies of patients with PS 3–4 were available in five of seven PMS, which were 7%, 7%, 20%, 3%, and 0.1% in PMS of rituximab, trastuzumab, GO, bortezomib, bevacizumab, respectively. Frequencies of severe adverse events were described in four of seven PMS, which were 3–6%, 0.3–4%, 0–45, and 0–2% in PMS of imatinib, rituximab, bortezomib, and bevacizumab, respectively. Interstitial lung disease related to Bevacizumab was unknown in premarketing studies and was observed in 0.4% in PMS. Drug related mortality rates were described in four of seven PMS, which were 1%, 8%, 3%, and 2% in PMS of rituximab, GO, bortezomib, and bevacizumab, respectively. Conclusions: Although PS varied among PMS of different molecular targeted anticancer agents, patients with poor PS were not included in most PMS. Disclosure of PMS results was insufficient. Further investigation on appropriate methods of PMS and its disclosure is warranted. No significant financial relationships to disclose.
Bcl-2 attenuates esculetin-induced apoptosis in human leukemic U937 cells through inactivation of ERK pathway
Authors: Cheol Park, Cheng-Yun Jin, Woo Young Choi, Gi-Young Kim, Yung Hyun Choi, Won Ho Lee
Journal: Clinical Cancer Research (2007)

A8   Esculetin, a coumarin derivative contained in various plants, has been shown to exhibit anti-cancer effects. However, the cellular and molecular mechanism by which esculetin induced apoptosis are poorly understood. In the present study, we determined that esculetin could inhibit the cell growth of U937 cells, which was associated with apoptotic cell death such as increased populations of apoptotic-sub G1 phase, formation of apoptotic bodies, DNA fragmentation and increased the percentage of cells with depolized mitochondrial membrane. Esculetin induced apoptosis through activation of extracellular-regulated kinase (ERK) phosphorylation, up-regulation of death receptor-4 (DR4), cleavaged Bid, induced the proteolytic activation of caspases, and a concomitant degradation and/or down-regulation of poly(ADP-ribose) polymerase (PARP) and phospholipase-γ1 (PLC-γ1). Although esculetin did not alter Bcl-2 expression, overexpression of Bcl-2 were significantly attenuated the change in mitochondrial membrane potential, ERK phosphorylation, up-regulation of DR4 and caspases activation during esculetin-induced apoptosis. Furthermore, Bcl-2 specific inhibitor, HA14-1, restored esculetin-induced apoptosis through activation of ERK phosphorylation in U937/Bcl-2 cells. Thus, our findings imply that some of the biological functions of Bcl-2 may be attributed to their ability to inhibit esculetin-induced apoptosis through inhibition of ERK activation. And esculetin can be used as a new therapeutic approach for the treatment of human monocytic leukemia cells.
Longterm blood cell counts after intraoperative radiotherapy with or without whole breast radiotherapy in breast cancer patients.
Authors: Elena Sperk, Cornelia Wersal, Christel Weiss, Anke Keller, Anette Kipke, Benjamin Tuschy, Marc Suetterlin, Frederik K. Wenz
Journal: Journal of Clinical Oncology (2017)

e12014 Background: After radiotherapy changes in blood cell counts (BCC) can be seen. Leukocytopenia may have a negative impact on the immune system, outcome and quality of life of breast cancer survivors. No reports on changes of the three blood cell lines (leukocytes=WBC, erythrocytes=RBC, thrombocytes=PLT) after IORT w/o whole breast radiotherapy (WBRT) in breast cancer patients have been reported. Methods: 256 patients had IORT during breast conserving surgery. In 198 patients WBRT (46-50Gy/2Gy) + IORT (20Gy) and in 58 patients IORT as accelerated partial breast irradiation=APBI (20Gy) was given. Preoperative BCC were used as baseline. In 214 patients BCC were available after 1-90 days, in 139 during the 1st year, in 86 in the 2nd, in 66 in the 3rd, in 51 in the 4th and in 34 in the 5th year of follow-up. Dunnett-tests were used to calculate adjusted p-values (p&lt;0.05=significant). Results: After IORT/WBRT a decrease of WBC was seen during the 1st year. Afterwards no changes were seen. After IORT APBI no changes were seen during 5 years follow-up. RBC was decreased at all time points after IORT/WBRT, and through the 1st year after IORT APBI. PLT decreased during the 1st year and stayed low during 5 years after IORT/WBRT. No changes in PLT were seen after IORT APBI. Hemoglobin (HGB) decreased after 3 months, during the 1st and 5th year after IORT/WBRT. After IORT APBI, HGB decreased only during the 1st year and stayed stable during follow-up. Conclusions: Decreases of all blood cell lines were seen at least transiently after IORT/WBRT. PLT and RBC stayed decreased. After IORT APBI, HGB and RBC decreased only during the 1st year and WBC and PLT remained stable during the whole follow-up. [Table: see text]
ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC).
Authors: Debu Tripathy, Sara M. Tolaney, Andrew David Seidman, Carey K. Anders, Nuhad K. Ibrahim, Hope S. Rugo, Chris Twelves, Veronique Dieras, Volkmar Müller, Alison Hannah, Mary Tagliaferri, Javier Cortés
Journal: Journal of Clinical Oncology (2017)

TPS1120 Background: EP is a next generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival (OS) at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). A Phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of OS (HR 0.087; p = 0.08); a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86]; p &lt; 0.01) (Perez Lancet Oncol 2015). The current Phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP vs TPC in an open-label, randomized Phase 3 study. Eligibility includes ECOG PS 0 or 1; adequate organ function who received prior ATC (in neo/adjuvant or locally advanced/MBC setting); pts must have had ≥1 prior cytotoxic regimen for MBC (triple negative BC); ≥2 prior cytotoxic regimens and either 1 prior hormone therapy (HR+ BC) or 1 prior HER2 targeted therapy (HER2+ BC). Pts must have undergone definitive local therapy of BM (whole brain radiation [RT]; stereotactic RT or surgical resection as single-agent or combination); signs/symptoms of BM must be stable with steroids unchanged or decreasing for ≥7 days prior to randomization. Primary endpoint is OS. Key secondary endpoints: ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV cytotoxic agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR = 0.67); 1 interim analysis at 50% of deaths (130 events) will be performed. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment will begin early 2017. Clinical trial information: NCT02915744.
Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter–Deficit Prodromal Cohort
Authors: Danna Jennings, Andrew Siderowf, Matthew Stern, John Seibyl, Shirley Eberly, David Oakes, Kenneth Marek
Journal: JAMA Neurology (2017)

<h3>Importance</h3> Detecting individuals at risk for Parkinson disease (PD) during the prodromal phase could clarify disease mechanisms and allow for treatment earlier in the disease process to possibly slow or prevent the onset of motor PD. <h3>Objective</h3> To determine if the combination of smell identification testing followed by dopamine transporter (DAT) imaging can accurately and efficiently identify individuals from the general population at risk for conversion to a clinical diagnosis of PD. <h3>Design, Setting, and Participants</h3> Participants were identified from the community by olfactory testing assessed longitudinally with DAT imaging 2 and 4 years after baseline and by annual clinical follow-up to determine whether they had clinical evidence to establish a PD diagnosis. Participants were contacted by mail and completed olfactory testing at home. Longitudinal follow-up of clinical measures and DAT imaging occurred at specialty centers. There were 203 hyposmic and 100 normosmic participants. A total of 185 hyposmic and 95 normosmic individuals had at least 1 follow-up visit, and 152 hyposmic participants (82.2%) were either observed for 4 years or converted to PD during follow-up. <h3>Main Outcomes and Measures</h3> Percentage of individuals with hyposmia and a DAT deficit that converted to PD and the change in PD clinical scale scores (Unified Parkinson’s Disease Rating Scale) and DAT imaging during 4-year follow-up. <h3>Results</h3> Of 280 total participants, 140 (50.0%) were male, and the mean (SD) age of the cohort was 63 (8.7) years. Among 21 participants with hyposmia and a DAT deficit (65% or less of age-expected lowest putamen binding ratio) at baseline, 14 (67%) converted to PD at 4 years compared with 2 of 22 participants (9%) with a DAT in an indeterminate range (greater than 65%-80%) and 3 of 109 participants (2.8%) with no DAT deficit (greater than 80%) at baseline. Individuals with a baseline DAT deficit experienced a 4-year decline in DAT binding of 20.23% (SD, 15.04%) compared with 3.68% (SD, 18.36%) and 5.45% (SD, 13.58%) for participants with an indeterminate and no DAT deficit, respectively (<i>P</i> = .002). The relative risk of conversion to a diagnosis of PD in hyposmic individuals with a DAT deficit was 17.47 (95% CI, 7.02-43.45) compared with individuals with either indeterminate or no DAT deficit. <h3>Conclusions and Relevance</h3> The combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. Individuals with hyposmia and a DAT deficit had a 5% reduction in DAT binding annually, similar to early PD. These results provide a framework for planning disease prevention studies in PD.
Study of the therapeutic management of gastric carcinoid tumors from data of the French national cohort of neuroendocrine tumors: CARGAS study.
Authors: Sylvain Manfredi, Bérengère Leconte, Thomas Uguen, Samuel le Sourd, Charlotte Cernon, Jeff Morcet, Fabrice Laine, Eric Baudin, Guillaume Cadiot
Journal: Journal of Clinical Oncology (2015)

4094 Background: 4 types of gastric NETs are described: type 1 developed on atrophic gastritis (70-80% of cases), type 2 (5-6% of cases) as part of MEN 1, sporadic type 3 (14-25% of cases), and Type 4 corresponding to poorly differentiated NETs (6-8%) (1). The natural history of types 1 and 2 is usually benign, while type 3 and 4 are more aggressive. Treatments of these four types are different and based on European guidelines (2). Those recommendations are based on data of small series. Methods: The objective of this study was to study of the treatment and monitoring of gastric NETs registred prospectively in a national cohort. Secondary objectives: epidemiology, overall survival. The National Register of GTE records all TNE via e-crf. Results: At the end-point of the study 197 gastric NETs were recorded (2.5% of all the NETs registred, 11th frequency tumor). A study of each case, on site, was conducted. 181 (91.9%) complete records were analyzed. The characteristics of these tumors are presented in the table below. Gastrin was measured in 31% of patients and chromogranin A in 36.9%. A somatostatin analogue was administered to 16 patients (8.8%). Conclusions: This cohort represents the largest cohort known to date. It provides us important data on epidemiology of these tumors and their management. There are very likely over-reporting of type 3 and 4 in this register. 181 gastric NETs Type1 (84) Type 2 (5) Type 3 (49) Type 4 (43) p % 46.4% 2.8% 27.1% 23.8% Male 35.7% 60% 65.3% 72.1% < 0.0001 Age at diagnosis 53.3 49.7 59.0 60.3 0.02 Size < 1cm 47.6% 20.0% 16.3% 2.3% < 0.0001 Median size mm 11.3 29.8 35.3 39.4 < 0.0001 n tumor < 6 52.4% 40.0% 71.4% 81.4% < 0.0001 Stage at diagnosis - local - locoregional - metastasis - 94.1% 6.0% - - 100% - - - 28.6% 16.3% 55.1% - 14.0% 18.6% 65.1% - < 0.0001 Differenciation - benign - well differenciated - poor differenciated - 47.6% 46.4% 3.6% - 40.0% 60.0% - 2.0% 58.7% - 11.6% 88.4% - < 0.0001 Treatment - endoscopic - surgery - chemotherapy - 92.7% - 60.0% 40.0% - 43.7% 41.2%% 5.9% - 6.0% 42.4% 39.4% - < 0.0001 5 years survival 98.3% 100% 60.6% 39.6% < 0.0001
Psychiatrist who kicked back at patient is suspended for six months
Authors: Clare Dyer
Journal: BMJ (2017)

A consultant psychiatrist who was convicted of assault for kicking a patient who had kicked her has been suspended from practice for six months by a medical practitioners tribunal.

Temitope Ademola was working in a learning disability service for NHS Grampian in Aberdeen when the incident occurred in January 2014. Ademola also placed her hand over the female patient’s mouth, restricting her breathing, her conviction stated. She was sentenced to 200 hours of community service.

Ademola, who qualified in Nigeria in 1997, was a new consultant at the time of the incident. …
Mobilization of peripheral blood progenitor cells by sequential administration of interleukin-3 and granulocyte-macrophage colony- stimulating factor following polychemotherapy with etoposide, ifosfamide, and cisplatin [see comments]
Authors: W Brugger, K Bross, J Frisch, P Dern, B Weber, R Mertelsmann, L Kanz
Journal: Blood (1992)
Investigating tumoral and temporal heterogeneity through comprehensive -omics profiling in patients with metastatic triple negative breast cancer.
Authors: Christopher Szeto, Rahul Parulkar, AJ Sedgewick, Stephen Charles Benz, Fabiola Cecchi, Todd A. Hembrough, Charles Joseph Vaske, Zack Sanborn, Shahrooz Rabizadeh, Elisabeth Mahen, Kimberly Burton, Patrick Soon-Shiong, Nicole Maria Kuderer, Francis Mark Senecal, Sibel Blau, C. Anthony Blau
Journal: Journal of Clinical Oncology (2017)

1093 Background: The “Intensive Trial of OMics in Cancer”-001 (ITOMIC-001; Clinicaltrials.gov ID: NCT01957514) enrolls patients with metastatic triple negative breast cancer (TNBC) who are platinum-naive and scheduled to receive cisplatin. Multiple biopsies (up to 7 metastatic sites) are performed under carefully controlled conditions prior to and upon completion of cisplatin treatment and following any subsequent therapies. Samples are chosen for DNA sequencing, RNA sequencing, and quantitative proteomics (GPS Cancer). Here we describe the -omic alterations acquired during treatment. Methods: We analyzed 74 biopsies from 17 patients taken at various clinical timepoints (e.g. initial diagnosis, initial trial recruitment, following cisplatin treatment, etc.) spanning 2 years on trial and over 8 years before recruitment. This dataset includes 64 whole genomes (with matched-normal blood samples), 44 RNAseq expression profiles, and 23 proteomic sets. GPS Cancer, which comprises whole genome sequencing, whole transcriptome sequencing, and targeted quantitative proteomics was used to detect somatic alterations, measure mutational burdens, and estimate expression profiles of both transcripts and proteins. PARADIGM pathway analysis was used to identify network-level changes through integration of all available data types. Results: While mutational profiles within patients were largely stable over time, we observed up to a 10-fold difference in the magnitude of mutational burden between patients. Following cisplatin treatment, the expression of over 300 genes were significantly perturbed, and an average of 270 mutations per patient were introduced. PARADIGM integrated pathway analysis shows differential activity in the MYC/MAX and ETS1 pathways during tumor progression. Conclusions: Using GPS Cancer we provide detailed characterizations of the molecular profiles of metastatic TNBC across space and over time. We demonstrate the potential for using this information to discover mechanisms underlying treatment resistance and disease progression. Our findings form the basis for molecularly informed QUILT trials for combination therapy.
That's life—and death
Authors: Theodore Dalrymple
Journal: BMJ (2007)

What fails to happen is sometimes as important as what does happen. This is most famously (and felicitously) expressed in Dr Conan Doyle's story Silver Blaze :

“Is there anything to which you would like to draw my attention?”

“To the curious incident of the dog in the night-time.”

“The dog did nothing in the night-time.”

“That was the curious incident,” remarked Sherlock Holmes.

Likewise, as every married couple knows, what is unsaid is often as important as what is said. And what historians omit from, or do not emphasise in, their accounts of the past tells us much about the mentality of their own times.

In the philosopher David Hume's The History of England from the Invasion of Julius …