tbuckley/cabot-search huggingface dataset:
Association between <i>EGFR</i> gene mutations and clinical and pathological characteristics of lung adenocarcinoma in patients of the South of Russia.
Authors: Dmitry I. Vodolazhsky, Liubov Yu Vladimirova, Konstantin Vladimirovich Dvadnenko, Elena N. Gudueva, Yaroslav S. Enin, Denis D. Olejnikov, Igor A. Leyman, Yury N. Lazutin
Journal: Journal of Clinical Oncology (2015)

e18534 Background: EGFR gene mutations are an effective marker for targeted therapy of lung cancer. EGFR plays an important role in proliferation of epithelial cells. EGFR overexpression is detected in many tumors, including 60-70% of small cell lung cancer (SCLC) cases. EGFR mutations are observed in approximately 10% of the European population and in 30-50% of the Asian population. The purpose of this study was to analyze polymorphism of 29 somatic mutations of EGFR (including T790M, exon 19 deletions, L858R, L861Q, G719X, S768I, exon 20 insertions) in tissues of lung adenocarcinoma in patients of the South of Russia, as well as to detect the connection between the found mutations and clinical and pathological characteristics of patients. Methods: We analyzed distribution of mutations depending on sex, age, smoking status, tumor differentiation and stage, clinical picture of the disease and treatment of patients with lung adenocarcinoma in the South of Russia. 278 patients (174 men, 104 women) aged 29-77 years with lung adenocarcinoma were examined. 29 somatic mutations were identified using the EGFR RGQ PCR Kit (QIAGENE, Germany) and Rotor-Gene Q thermocycler (QIAGENE, Germany). Results: EGFR mutations were found in 21.5% of patients; 46.6% of all mutations were 19 exon deletions, 45% - L858R; 1.6% – L861Q, 5% - G719X, 1.6% - exon 20 insertions. Mutant EGFR in G1 and G3 tumors was observed almost 2 times less often than in patients with G2 tumors (р = 0.0266). EGFR mutations were more often (almost by 1.5 times, р = 0,2160) observed in stage I-II of the disease in comparison with stage III-IV. Conclusions: The detected patterns of mutations allow to conclude that patients of the South of Russia belong to intermediate group between Asian and the European population. Potential risk groups have been formed according to the data on regularities of mutation distribution.
Results of multicenter phase II WSG Neo-Predict trial: Predictive markers for evaluation of response to neoadjuvant paclitaxel+trastuzumab+lapatinib in HER2-positive early breast cancer.
Authors: Christian Eichler, Oleg Gluz, Ulrike Nitz, Matthias Christgen, Petra Krabisch, Reinhard Hackenberg, Markus Skrobol, Volker Möbus, Ronald Kates, Johannes Schumacher, Hans Heinrich Kreipe, Nadia Harbeck, Mathias Warm
Journal: Journal of Clinical Oncology (2017)

582 Background: Trastuzumab (T) and Lapatinib (L) containing neoadjuvant chemotherapy (NACT) increases pathological complete response (pCR) (vs. T or nihil) in HER2+ early breast cancer (EBC). Early clinical response markers (e.g. Ki67) in a 3-week biopsy or in residual tumor correlate with therapy efficacy and risk of relapse. This WSG Neo-Predict trial aimed to define early predictive markers for therapy response in a dual blockade (T+L) NACT setting. Methods: Patients with cT1c-cT4c HER2+ EBC were treated by paclitaxel (P) (80 mg/m 2 weekly) with L (750 mg p.o. daily) + T (2 mg/kg) weekly for 12 weeks. Adjuvant treatment with 4 cycles of Epirubicin/Cyclophosphamide (omission allowed in patients with pCR) and T for an additional 40 weeks was recommended. Primary objectives were pCR (ypT0/is/ypN0) and identification of a dynamic predictive test for pCR using a re-biopsy after three weeks of NACT (early response defined as central Ki67 decrease &gt;30% (vs. baseline) and/or low cellularity (&lt;500 invasive tumor cells)). Results: From 2013-2015, 64 patients (n=80 planned) were recruited. Overall pCR was 41% (41% for HER2+/HR+ (n=34) and 45.5% for HER2+//HR- (n=22)). A 0% pCR in the “non-responder” (n=7) group (vs. 50% in the “responder” (n=34) and 42% in the “missing response” (n=20) groups) is intriguing despite methodological limitations. Missing data for early response assessment in a substantial number of patients and negative DFS data from the ALTTO trial did not justify trial continuation. 27% of patients experienced severe adverse events (AE). 11.5% had &gt; grade 3 AEs (including diarrhea, septic shock, leukopenia, and pneumonia). Conclusions: We observed a clinically meaningful pCR with moderate toxicity with only 12 weeks of paclitaxel weekly with dual HER2 blockade (T+L). Effect of additional chemotherapy in patients with pCR after 12 weeks of monochemotherapy remains questionable due to a strong prognostic effect of pCR in HER2+ EBC. In view of 0% pCR (by hypothesis-generating explorative analysis), a different treatment approach should be investigated in patients without “early response” by further prospective trials. Clinical trial information: 2012-003679-21.
Clinical outcomes in ER+ HER2-negative breast cancer (BC) where treatment decisions incorporated the 21-gene recurrence score (RS): Elderly (≥70 yrs) vs younger patients (Pts).
Authors: Salomon M. Stemmer, Mariana Steiner, Shulamith Rizel, Noa Ben Baruch, Lior Soussan-Gutman, Avital Bareket-Samish, Bella Nisenbaum, Kevin Isaacs, Georgeta Fried, Ora Rosengarten, Tamar Peretz, Christer Svedman, Debbie McCullough, Shmuel Klang, Jamal Zidan, Larisa Ryvo, Bella Kaufman, Steven Shak, Nicky Liebermann, David B Geffen
Journal: Journal of Clinical Oncology (2017)

543 Background: Elderly BC pts are generally undertreated, despite evidence suggesting that they may benefit from adjuvant chemotherapy (CT). We compared treatments/clinical outcomes in elderly vs younger Clalit Health Services (CHS) pts undergoing RS testing. Methods: This exploratory analysis of the CHS registry included BC pts with N0/N1mi/N1 disease who were RS-tested from 1/2006 (CHS approval of the test) through 12/2010 (N0) or 12/2011 (N1mi/N1). Medical records were reviewed to verify treatments/recurrences/survival. Results: The analysis included 458 elderly and 2052 younger pts, with a median (range) follow-up of 5.7 (0.9-9.6) and 6.1 (0.1-10.3) yrs, respectively. In the elderly/younger pts, median age was 73/58 yrs, 48%/52% had grade 2 tumors, median tumor size was 1.6/1.5 cm, 70%/72% were N0 and 30%/28% were N1mi/N1. RS distribution (&lt;18, 18-30, ≥31) among elderly pts was 56%, 33%, and 11%, respectively, compared to 49%, 41%, and 10%, respectively, in younger pts. In pts with RS 18-30 and RS≥31, CT use was significantly lower in the elderly ( P&lt;.001). Kaplan-Meier estimates for 5-yr distant recurrence and BC death risk are presented (Table). Conclusions: In elderly pts, the proportion of those with RS≥31 was very similar to younger pts; however, overall CT use was significantly lower. Within each RS group, there was no statistically significant difference in clinical outcomes between the age groups; though, numerically, in RS 18-30 pts, outcomes were worse in the elderly. In pts with RS&lt;18, outcomes were excellent regardless of age and despite very low rates of CT use. [Table: see text]
Glioblastoma-derived factors induce STAT3 phosphorylation and hamper human dendritic cell and Langerhans cell differentiation
Authors: Hester van Cruijsen, Dinja Oosterhoff, Jelle Lindenberg, Robert van Boerdonk, Cynthia Fehres, Karin Weijers, Giuseppe Giaccone, Rik Scheper, Klaas Hoekman, Tanja de Gruijl
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1031 

Glioblastoma can systemically affect T cell and monocyte functions, but little is known about its direct effect on dendritic cell (DC) differentiation. Identification of glioblastoma derived immune suppressive factors and abrogation of their effects might make the tumor environment more susceptible to anti-tumor effector functions and increase the efficacy of vaccination strategies. CD34+ or CD14+ precursor cells were differentiated into interstitial DCs or Langerhans Cells (LCs) in the presence of conditioned medium of the human glioblastoma cell lines U251 and U373. Glioblastoma-conditioned medium inhibited DC and LC differentiation, resulting in maintained CD14 and reduced CD1a expression. Simultaneously, CD14+ HLA-DR- cells were induced displaying a phenotype consistent with myeloid suppressor cells (MSC). This phenotypic inhibition coincided with functional DC impairment as determined by allogeneic mixed leukocyte reaction and cytokine production profiles. Furthermore, western blot analysis showed that glioblastoma-conditioned medium induced phosphorylation of STAT3 in both DCs and LCs. Addition of cucurbitacin-I, a JAK2/STAT3 phosphorylation inhibitor, or neutralizing antibodies against interleukin (IL)-6 or transforming growth factor (TGF)-β during DC or LC differentiation reduced the levels of activated STAT3 and partially reversed the glioblastoma-induced suppression of DC or LC differentiation. In line with these data, high levels of IL-6 and TGF-β were found in the glioblastoma-conditioned media. In conclusion, the glioblastoma-derived soluble factors IL-6 and TGFβ hamper DC and LC differentiation. Targeting these factors or downstream signaling events (e.g. STAT3) may reverse their immune suppressive effects and potentially facilitate the efficacy of immunotherapies.
Bone morphogenetic protein signaling governs biliary‐driven liver regeneration in zebrafish through tbx2b and id2a
Authors: Tae‐Young Choi, Mehwish Khaliq, Shinya Tsurusaki, Nikolay Ninov, Didier Y.R. Stainier, Minoru Tanaka, Donghun Shin
Journal: Hepatology (2017)

Upon mild liver injury, new hepatocytes originate from preexisting hepatocytes. However, if hepatocyte proliferation is impaired, a manifestation of severe liver injury, biliary epithelial cells (BECs) contribute to new hepatocytes through BEC dedifferentiation into liver progenitor cells (LPCs), also termed oval cells or hepatoblast-like cells (HB-LCs), and subsequent differentiation into hepatocytes. Despite the identification of several factors regulating BEC dedifferentiation and activation, little is known about factors involved in the regulation of LPC differentiation into hepatocytes during liver regeneration. Using a zebrafish model of near-complete hepatocyte ablation, we show that bone morphogenetic protein (Bmp) signaling is required for BEC conversion to hepatocytes, particularly for LPC differentiation into hepatocytes. We found that severe liver injury led to the up-regulation of genes involved in Bmp signaling, including smad5, tbx2b, and id2a, in the liver. Bmp suppression did not block BEC dedifferentiation into HB-LCs; however, the differentiation of HB-LCs into hepatocytes was impaired due to the maintenance of HB-LCs in an undifferentiated state. Later Bmp suppression did not affect HB-LC differentiation but increased BEC number through proliferation. Notably, smad5, tbx2b, and id2a mutants exhibited similar liver regeneration defects as those observed in Bmp-suppressed livers. Moreover, BMP2 addition promoted the differentiation of a murine LPC line into hepatocytes in vitro.Bmp signaling regulates BEC-driven liver regeneration through smad5, tbx2b, and id2a: it regulates HB-LC differentiation into hepatocytes through tbx2b and BEC proliferation through id2a; our findings provide insights into promoting innate liver regeneration as a novel therapy. (Hepatology 2017;66:1616-1630).
The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets
Authors: Sameer Zaman, Saman S. Zaman, Timothy Scholtes, Matthew J. Shun‐Shin, Carla M. Plymen, Darrel P. Francis, Graham D. Cole
Journal: European Journal of Heart Failure (2017)

Abstract Aims The prescription of optimal medical therapy for heart failure is often delayed despite compelling evidence of a reduction in mortality. We calculated the absolute risk resulting from delayed prescription of therapy. For comparison, we established the threshold applied by clinicians when discussing the risk for death associated with an intervention, and the threshold used in official patient information leaflets. Methods and results We undertook a meta‐analysis of randomized controlled trials to calculate the excess mortality caused by deferral of medical therapy for 1 year. Risk ratios for angiotensin‐converting enzyme inhibitors, beta‐blockers and aldosterone antagonists were 0.80, 0.73 and 0.77, respectively. In patients who might achieve a 1‐year survival rate of 90% if treated, a 1‐year deferral of treatment reduced survival to 78% (i.e. an annual absolute increase in mortality of 12 in 100 patients). This corresponds to an additional absolute mortality risk per month of 1%. A survey of clinicians carried out to establish the risk threshold at which they would obtain written consent showed the majority (85%) sought written consent for interventions associated with a 12‐fold lower mortality risk: one in 100 patients. A systematic review of UK patient information leaflets to establish the magnitude of risk considered sufficient to be stated explicitly showed that leaflets begin to mention death at a ∼18 000‐fold lower mortality risk of just 0.0007 in 100 patients. Conclusions Deferring heart failure treatment for 1 year carries far greater risk than the level at which most doctors seek written consent, and 18 000 times more risk than the level at which patient information leaflets begin to mention death.
Abstract 387: Role of Glycolysis in Cardiac Adaptation to Exercise
Authors: Andrew Gibb, Aruni Bhatnagar, Bradford Hill
Journal: Circulation Research (2015)

Cardiac stressors affect the function and structure of the heart with prominent effects on metabolism. While the heart typically derives most (~80%) of its energy from fatty acids, the exercised heart is associated with an enhanced capacity to utilize a variety of carbon sources to sustain energy demands that would be advantageous during increased workloads and ischemic events. Due to the central role of glycolysis in glucose metabolism, it is likely that changes in the glycolytic rate regulate cell growth, homeostasis and stress responses. In this study, we assessed how exercise affects glucose metabolism in the myocardium and whether genetically decreasing glycolysis in the heart - using a validated, cardiac-specific, dominant negative form of phosphofructokinase 2 (kd-PFK2) - affects cardiac adaptation to exercise. Adult male FVB/NJ mice were subjected to forced treadmill running for 30 days. Exercise performance was measured and echocardiographic analysis was used to assess changes in cardiac function. Immunoblotting was performed to quantify the abundance of key enzymes involved in glucose metabolism. Exercise training increased exercise capacity by 70% (p &lt; 0.01) and work performed by 69% (p &lt; 0.01). Exercise training also induced cardiac hypertrophy (15%; p &lt; 0.01) associated with a 1.4 fold increase in mitochondrial content (p &lt; 0.05). Cardiac function remained largely unchanged with a significant reduction of 5% in ejection fraction (p &lt; 0.01) and an increase in the left ventricle chamber dimensions (p &lt; 0.05). Relative myocardial abundance of thirteen glycolytic and glucose metabolism enzymes remained unchanged. The kd-PFK2 mice showed that low levels of glycolysis in the heart promote cardiac hypertrophy (15%; p &lt; 0.01) and prevent physiological hypertrophy due to exercise. In comparison with WT mice, the kd-PFK2 mice had a 20% lower exercise capacity (p &lt; 0.05). These findings suggest that the glycolytic rate regulates cardiac adaptations to exercise and may mediate some of the beneficial effects of exercise training on exercise capacity.
Phase II trial of pembrolizumab in combination with nab-paclitaxel in patients with metastatic HER2-negative breast cancer.
Authors: Maryann J. Kwa, Alyssa Iwano, Francisco J. Esteva, Yelena Novik, James L. Speyer, Ruth Oratz, Marleen Iva Meyers, Deborah M. Axelrod, Rebecca Hogan, Sandra Mendoza, Judith D. Goldberg, Franco Muggia, Sylvia Adams
Journal: Journal of Clinical Oncology (2017)

TPS1124 Background: Immunotherapy has shown therapeutic promise in several cancers, including breast cancer. Monotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated durable responses in patients with metastatic triple-negative breast cancer (mTNBC) (Nanda et al, JCO 2016) and metastatic estrogen receptor-positive (mER+)/HER2-negative breast cancer (Rugo et al, SABCS 2015). Furthermore, response rates have been increased with combination approaches with chemotherapy (Adams et al, ASCO 2016). Based on these results, we seek to study the anti-tumor efficacy and safety of pembrolizumab (anti-PD-1 antibody) and nab-paclitaxel, the impact of therapy on the tumor microenvironment, and predictive markers of response. Methods: This is an ongoing single-arm open-label multi-cohort phase II study of pembrolizumab and nab-paclitaxel in patients treated with ≤2 prior lines of therapy for metastatic HER2-negative breast cancer (n = 50) (ClinicalTrials.gov: NCT02752685). Thirty patients with mTNBC and 20 patients with mER+/HER2-negative breast cancer will be enrolled. Enrollment of patients with metaplastic breast cancer is encouraged. Patients will receive pembrolizumab 200 mg IV on day 1 plus nab-paclitaxel 100 mg/m 2 IV on day 1 and 8 (21-day cycle). Prior taxane therapy given &gt; 3 months before cycle 1 is allowed. Primary objective is treatment efficacy, as determined by overall response rate (RECIST 1.1). Secondary objectives include safety, progression-free survival, overall survival, and duration of response. Serial tumor biopsies will be performed to assess changes in the tumor microenvironment from baseline with chemotherapy alone (cycle 1) and then with chemoimmunotherapy (cycle 2 and subsequent cycles). Mutational and neoantigen load, TILs by histopathological assessment, TCR by immunosequencing, and immune gene profiles in tumors will be evaluated. PD-L1 expression in tumor tissue is not required for enrollment but will be assessed as a predictive marker. The potential role of the gut microbiome in modulating the immune response will also be evaluated by 16S rRNA. An initial safety run-in with 12 subjects has been completed with no unexpected toxicity. Clinical trial information: NCT02752685.
Cerebellar metastases as the only brain metastatic site and correlation with molecular characteristics of primary breast cancer.
Authors: Zorica Tomasevic, Zoran Tomasevic, Danica Grujicic, Zeljko Kovac, Zorka Milovanovic, Ivana Minic, Daniela Kolarevic
Journal: Journal of Clinical Oncology (2017)

e12509 Background: Contrary to well recognized higher incidence of brain metastases (BM) in HER2 3+ and triple negative (TN) BC, correlation with BC molecular subtypes and cerebellar metastases is not well explored. Methods: From January 2007 to Jun 2016, 269 patients with BCBM have been prospectively registered at the Institute for Oncology and Radiology of Serbia. We analyzed metastases localization within brain, and identified 28 patients with cerebellar metastases. Correlation with molecular subtype of primary BC, median time to cerebellar metastases development, treatment and survival were also analyzed Results: 28 patients (10.4%) of median 47 years (29-63) had cerebellar metastases as the only brain metastatic site confirmed by CT/MRI. Median time to cerebellar BM was 21 months (range 0-141). Cerebellum was the first distant metastatic site in 20/28 patients (71.4%), and 8 (28. 5%) patients had inoperable BC and/or distant metastases before cerebellar metastases development. Molecular subtype of primary BC was known for 27/28 pts (96.4%): 21 pts (77.7%) had HER2 3+BC; 14 (52%) had ER/PR negative BC and there were no TNBC. Fifteen patients (53.5%) were treated with brain surgery + postoperative WBRT, 4 (14%) with gamma knife, while remaining 9 pts (32%) underwent WBRT only. Patients with good performance (PS 0-2) also received various systemic treatments +/- trastuzumab/ lapatinib. Mean survival upon cerebellar metastases was 19.2 months (median 9, range 2-123+ months); 39% patients were alive after 12 months; 21% after 24 months; 14% after 36 months. One patient (3.6%) is alive without relapse/progression 123 months+ after cerebellar metastases extirpation; trastuzumab is ongoing through all that period. Conclusions: Majority of analyzed patients with cerebellar metastases had HER2 3+ BC (77.7%). It is also interesting that none of patients within this group had TNBC Therefore, it seems reasonable to speculate that some still unrecognized BC and/or cerebellar soil characteristic, contribute to HER2 3+ BC predilection to cerebellum in this rare patient subgroup.
APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC).
Authors: Gunter Von Minckwitz, Marion Jennifer Procter, Evandro De Azambuja, Dimitrios Zardavas, Adam Knott, Giuseppe Viale, Thomas M. Suter, Amal Arahmani, Nathalie Rouchet, Emma Clark, Mark Benyunes, Istvan Lang, Christelle Levy, Denise A. Yardley, Jose Bines, Richard D. Gelber, Martine J. Piccart-Gebhart, Jose Baselga
Journal: Journal of Clinical Oncology (2017)

LBA500 Background: In previous trials P significantly prolonged progression free and overall survival and increased pCR rates when added to T+C in pts with HER2-positive breast cancer (BC). The APHINITY trial was designed to test whether the addition of P to adjuvant T+C improves pt outcomes. Methods: Pts with adequately excised HER2-positive, pT1-3 EBC were randomly assigned to receive standard adjuvant C plus one year of either T + P or T + Pla. Eligible pts had either node-positive disease, or node-negative disease (pN0) and a tumor size of &gt; 1.0 cm. Pts with pN0, T1b tumors with high risk features were initially eligible. The primary efficacy endpoint was invasive disease-free survival (IDFS); we assumed a 3-year IDFS of 91.8% with P and 89,.2% with Pla. Results: 4805 pts were randomized to C and T plus either P (n = 2400) or Pla (n = 2405). Baseline demographics and tumor characteristics between the arms were well balanced, with 63% and 36% of pts having node-positive and hormone receptor negative EBC respectively. P and Pla treatments were completed in 84.5% and 87.4% of patients, respectively. IDFS events occurred in 171 (7.1%) P pts and 210 (8.7%) Pla pts (hazard ratio (HR) 0.81 (95% CI 0.68-1.00), P = 0.045). Estimates of IDFS at 3 years were 94.1% and 93.2% in the P and Pla arms, respectively. The node-positive cohort had a 3-year IDFS rate of 92.0% for P compared with 90.2% for Pla (HR 0.77 (95% CI 0.62-0.96), P = 0.019). The pN0 cohort had a 3-year IDFS rate of 97.5% for P and 98.4% for Pla; HR = 1.13 (95% CI 0.68-1.86). The safety profile of P was consistent with previous trials. For the primary cardiac endpoint (heart failure or cardiac death) and secondary cardiac endpoint (asymptomatic or mildly symptomatic LVEF decline) rates were low, 0.7% vs 0.3% and 2.7% vs 2.8%, in the P and Pla arms, respectively. Diarrhea grade ≥3 was more frequent with P (9.9% vs 3.7%). Conclusions: The APHINITY trial met its primary endpoint: P significantly improved IDFS in patients with HER2-positive EBC when added to T+C. No new safety signals were identified. Clinical trial information: NCT01358877.