tbuckley/cabot-search huggingface dataset:
Genetic landscape of resistance to CDK4/6 inhibition in circulating tumor DNA (ctDNA) analysis of the PALOMA3 trial of palbociclib and fulvestrant versus placebo and fulvestrant.
Authors: Nicholas C. Turner, Ben O'Leary, Ros Cutts, Yuan Liu, Sarah Hrebien, Xin Huang, Matthew Beaney, Kerry Fenwick, Fabrice Andre, Sibylle Loibl, Sherene Loi, Isaac Garcia-Murillas, Cynthia Huang Bartlett, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2018)

1001 Background: CDK4/6 inhibition combined with endocrine therapy is now a standard of care for advanced estrogen receptor (ER) positive breast cancer. Mechanisms of resistance to CDK4/6 inhibitors have been described in pre-clinical models, although there is limited evidence from clinical samples. We investigated the mechanisms of resistance to CDK4/6 inhibitor in the PALOMA3 trial using ctDNA analysis. Methods: The PALOMA3 phase III trial randomized 521 patients with endocrine pre-treated disease to palbociclib and fulvestrant (P+F) versus placebo and fulvestrant (F). Using driver mutation targeted sequencing we conducted a longitudinal ctDNA analysis in 193 pairs of baseline and end of treatment (EOT) plasma samples, supplemented with exome ctDNA sequencing in 16 paired samples of high tumor purity from patients treated with P + F. Results: Paired ctDNA analysis was performed on P+F (n = 125) and F alone (n = 68), with the ctDNA cohort representative of the overall study. RB1 mutations emerged at EOT on P+F in a small minority of patients (6/125, 4.8%, p = 0.041), with no RB1 mutations emerging at EOT on F alone. New driver mutations emerged in both PIK3CA (p = 0.00018) and ESR1 at EOT, in particular the ESR1 Y537S mutation (p = 0.006), with no difference in frequency between P+F and F groups. Evolution of driver gene mutations was uncommon in patients progressing early on P+F, but common in patients progressing late on treatment. Paired exome analysis in 16 patients on P+F demonstrated that clonal evolution was frequent during P+F therapy, with copy number profiles remaining consistent before and after treatment. Conclusions: Breast cancer driver mutation landscapes are largely similar after treatment with P+F and with F alone, with acquired PIK3CA and ESR1 Y537S mutations that likely contribute to fulvestrant resistance. Acquired RB1 mutations are selected infrequently by P + F. These findings may inform future treatment strategies to address resistance to palbociclib and fulvestrant.
HSP110 sustains chronic NF-κB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization
Authors: Christophe Boudesco, Els Verhoeyen, Laurent Martin, Catherine Chassagne-Clement, Leila Salmi, Rana Mhaidly, Céline Pangault, Thierry Fest, Selim Ramla, Fabrice Jardin, Olaf-Oliver Wolz, Alexander N. R. Weber, Carmen Garrido, Gaetan Jego
Journal: Blood (2018)
Report on breast cancer care (BRECC) registry at the Kenyatta National Hospital, Nairobi, Kenya.
Authors: Nicolas Anthony Othieno-Abinya, Alice Musibi, Catherine Nyongesa, Raymond Omollo, Benjamin Njihia, Beatrice Nyawira, Ochieng' Noel Onyango, Andrew Gachii
Journal: Journal of Clinical Oncology (2018)

e12546 Background: Breast cancer is the most common cancer among women in Kenya. Kenyatta National Hospital (KNH) is the only public institution offering comprehensive cancer care in Kenya. Methods: To determine the pathology, clinical care pattern and outcome of breast cancer at the KNH. Patients with histologically or cytologically confirmed breast cancer, and able to provide written, informed consent, with no prior interventional therapy were enrolled after approval by the institutional regulatory board. Surgery, radiotherapy and systemic therapy were applied in line with Kenyan guidelines, adopted from ESMO,ASCO and NCCN. Primary endpoints were overall survival (OS) and progression-free survival (PFS) at a median follow-up of 5 years. Results: Between 08/08 2011 and 02/07/2014, 400 patients, 396 women (99%) and 4 men (1%) were included. Age range 21 to 84 years, median 48.5. Those aged < 40 years were 87 (21.8%), 175 (43.8%) aged ≥ 50 years, and 72 (18%) were > 60 years. Breast lump commonest presentation in 308 of 388 (79.4%), breast pain in 104 (26.8%). Eighteen out of 396 (4%) had history of breast cancer in first-degree relatives, 23 (5.8%) in second-degree, and 23 (5.8%) other relative. Pathology were DCIS in 32 of 386 (8.3%), LCIS in 4(1%), invasive ductal NOS in 340 (88.1%), and invasive lobular in 10 (2.6%). ER + in 185 of 312 cases (59.3%), ER- in 111 (36.6%). PR+ in 172 (55.1%), and PR- in 123 (39.4%). ER+/PR+ were 159 (51%), ER-/PR+ 13 (4.2%), ER+/PR- were 42 (13.5%), ER-/PR- were 98 (24.5%). Her2/Neu was + in 74 of 313 cases (23.6%), - in 206(65.8%), equivocal in 30 (9.6%). Hormone-receptor (HR)+/Her2+ were 172 (55.1%), HR+/Her2- were 25 (8%), HR-/Her2- cases (triple-) were 79 (25.2%). Tumour stage I was diagnosed in 26 of 353 patients (7.4%), stage II in 119(33.7%), stage III in 105(29.7%), and stage IV in 74 (21%). At 60 months follow-up, 100 patients (25%) had died. Those < 50 years had a significantly poorer overall survival than those ≥ 50 (p = 0.018). Conclusions: Close to two-thirds of patients were in stages II and III. Young age was associated with earlier death. Clinical trial information: NCT01484483.
Therapeutic innovation in adult-onset Still’s disease (and other rare inflammatory disorders): how to secure evidence-based medicine?
Authors: Philippe Guilpain, Alain Le Quellec, Alexandre Thibault Jacques Maria
Journal: Annals of the Rheumatic Diseases (2018)

Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder with heterogeneous clinical presentation and unspecific features (spiking fever, pharyngitis, arthritis, skin rash with elevated acute phase reactants).1 Its diagnosis is one of exclusion, and necessitates ruling out many other conditions, notably neoplastic and infectious ones. Based on clinical experience and literature, a ‘dichotomous view’ of AOSD is emerging, with two distinct AOSD clinical subtypes, potentially requiring distinct treatments1 2: a non-Mendelian autoinflammatory disease with pre-eminent systemic symptoms and intense inflammatory state, sometimes associated with life-threatening complications such as reactive haemophagocytic lymphohistiocytosis, and a rheumatic disease with pre-eminent chronic polyarthritis and possibly destructive polyarthritis with lower inflammatory state. Currently, this ‘dichotomous view’ is not only supported by clinical observations, but also by findings on cytokine profiles and responses to biotherapies in some refractory patients.2 Indeed, interleukin (IL)-1β, IL-6 and IL-18 would be associated with ‘systemic AOSD’, whereas tumour necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) and IL-8 would be of greater involvement in ‘rheumatic AOSD’.3–6 Of note, this dichotomous approach remains controversial and the choice of biologics (targeting ‘appropriate’ cytokines) is still empirical in refractory patients. One could hope that cytokine monitoring provides information towards a personalised approach. However, such immunobiological tools are technically difficult to develop for daily practice and remains phantasmagorias even though they would be very useful at the time when several biotherapies are already successfully used or are under evaluation in clinical trials (https://clinicaltrials.gov/).

In Annals of the Rheumatic Diseases , Gabay et al report the results of a multicentre, open-label study evaluating the safety and efficacy of the recombinant IL-18-binding protein (IL-18BP), tadekinig alfa, in patients with difficult-to-treat AOSD.7 IL-18 was indeed reported increased in patients with AOSD and systemic onset juvenile idiopathic arthritis. This work provides the first demonstration of the therapeutic …
Invasive Methicillin-Resistant<i>Staphylococcus aureus</i>Infections Among Persons Who Inject Drugs — Six Sites, 2005–2016
Authors: Kelly A. Jackson, Michele K. Bohm, John T. Brooks, Alice Asher, Joelle Nadle, Wendy M. Bamberg, Sue Petit, Susan M. Ray, Lee H. Harrison, Ruth Lynfield, Ghinwa Dumyati, William Schaffner, John M. Townes, Isaac See
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In the United States, age-adjusted opioid overdose death rates increased by >200% during 1999-2015, and heroin overdose death rates increased nearly 300% during 2011-2015 (1). During 2011-2013, the rate of heroin use within the past year among U.S. residents aged ≥12 years increased 62.5% overall and 114.3% among non-Hispanic whites, compared with 2002-2004 (2). Increases in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections related to increases in injection drug use have been recently highlighted (3,4); likewise, invasive bacterial infections, including endocarditis, osteomyelitis, and skin and soft tissue infections, have increased in areas where the opioid epidemic is expanding (5-7). To assess the effects of the opioid epidemic on invasive methicillin-resistant Staphylococcus aureus (MRSA) infections during 2005-2016, surveillance data from CDC's Emerging Infections Program (EIP) were analyzed (8). Persons who inject drugs were estimated to be 16.3 times more likely to develop invasive MRSA infections than others. The proportion of invasive MRSA cases that occurred among persons who inject drugs increased from 4.1% in 2011 to 9.2% in 2016. Infection types were frequently those associated with nonsterile injection drug use. Continued increases in nonsterile injection drug use are likely to result in increases in invasive MRSA infections, underscoring the importance of public health measures to curb the opioid epidemic.
Tumor-infiltrating lymphocytes and serum anti-p53 autoantibody in HER2-positive breast cancer treated with neoadjuvant chemotherapy.
Authors: Eriko Tokunaga, Katsumi Takizawa, Takanobu Masuda, Hideki Ijichi, Chinami Koga, Wakako Tajiri, Junko Tanaka, Yoshiaki Nakamura, Kenichi Taguchi, Mayumi Ishida
Journal: Journal of Clinical Oncology (2018)

e12648 Background: Neoadjuvant chemotherapy (NAC) is one of the standard therapeutic strategies for HER2-positive early breast cancer. Tumor-infiltrating lymphocytes (TILs) have been shown to predict response to NAC. Serum p53 autoantibody (Ab) has been shown to be correlated with aggressiveness of breast cancer, and the association between serum HER2 and the sensitivity to anti-HER2 therapy has been reported. In this study, the relationships between TILs, serum p53 Ab and serum HER2 and the efficacy of NAC in HER2-positive primary breast cancer were investigated. Methods: Eighty patients with HER2 positive breast cancer (HER2+ BC) at clinical stage I-IIIB, who were treated with NAC, were included in this study. Anthracycrin (A) and taxane (T) (A/T) were used for 39, A and T+anti-HER2 therapy (A/T+anti-HER2) were used for 41 patients. TILs were evaluated using the sections obtained by core needle biopsy before NAC on hematoxylin and eosin (HE)- stained sections, and reported for the stromal compartment within the borders of the invasive tumor. Serum p53 Ab and serum HER2 were evaluated by ELISA, using blood samples obtained before NAC. Results: Pathological complete response (pCR) was obtained in 22 patients (27.5%). The pCR rate was significantly higher in the patients treated with A/T+anti-HER2 than those treated with A/T alone (p = 0.0032). High serum p53 Ab was associated with high TILs (p = 0.0173). High TILs and high p53 Ab were significantly correlated with pCR (p = 0.0007 and 0 = 0.0241). Serum HER2 was associated with neither TILs nor pCR rate. High TILs were significantly correlated with the better prognosis in terms of relapse-free survival (p = 0.0136) and distant metastasis-free survival (p = 0.0094). High serum p53 Ab and low serum HER2 was related to the better prognosis, although they were not statistically significant. Conclusions: High TILs and high serum p53Ab were significantly associated with high pCR rate and better prognosis in the patients with HER2+ BC treated with NAC.
Reciprocal Regulation of DUSP9 and DUSP16 Expression by HIF1 Controls ERK and p38 MAP Kinase Activity and Mediates Chemotherapy-Induced Breast Cancer Stem Cell Enrichment
Authors: Haiquan Lu, Linh Tran, Youngrok Park, Ivan Chen, Jie Lan, Yangyiran Xie, Gregg L. Semenza
Journal: Cancer Research (2018)

Triple-negative breast cancer (TNBC) has a poor prognosis due to its aggressive characteristics and lack of targeted therapies. Cytotoxic chemotherapy may reduce tumor bulk, but leaves residual disease due to the persistence of chemotherapy-resistant breast cancer stem cells (BCSC), which are critical for tumor recurrence and metastasis. Here, we demonstrate that hypoxia-inducible factor (HIF)-1-dependent regulation of mitogen-activated protein kinase (MAPK) signaling pathways contributes to chemotherapy-induced BCSC enrichment. Chemotherapy increased DUSP9 expression and decreased DUSP16 expression in a HIF1-dependent manner, leading to inhibition of ERK and activation of p38 signaling pathways, respectively. Inhibition of ERK caused transcriptional induction of the pluripotency factor Nanog through decreased inactivating phosphorylation of FoxO3, while activation of p38 stabilized Nanog and Klf4 mRNA through increased inactivating phosphorylation of RNA-binding protein ZFP36L1, both of which promoted specification of the BCSC phenotype. Inhibition of HIF1 or p38 signaling blocked chemotherapy-induced pluripotency factor expression and BCSC enrichment. These surprising results delineate a mechanism by which a transcription factor switches cells from ERK to p38 signaling in response to chemotherapy and suggest that therapeutic targeting of HIF1 or the p38 pathway in combination with chemotherapy will block BCSC enrichment and improve outcome in TNBC.Significance: These findings provide a molecular mechanism that may account for the increased relapse rate of women with TNBC who are treated with cytotoxic chemotherapy and suggest that combining chemotherapy with an inhibitor of HIF1 or p38 activity may increase patient survival. Cancer Res; 78(15); 4191-202. ©2018 AACR.
Long-term adalimumab efficacy in patients with moderate-to-severe hidradenitis suppurativa/acne inversa: 3-year results of a phase 3 open-label extension study
Authors: Christos C. Zouboulis, Martin M. Okun, Errol P. Prens, Robert Gniadecki, Peter A. Foley, Charles Lynde, Jamie Weisman, Yihua Gu, David A. Williams, Gregor B.E. Jemec
Journal: Journal of the American Academy of Dermatology (2018)
Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers
Authors: Yu Chen, Ping Chi
Journal: Journal of Hematology & Oncology (2018)

Unlike many conventional cancers with preferential patterns of oncogenic genetic alterations, TRK fusions resulting from NTRK1/2/3 genetic alterations drive oncogenic transformations in more than 20 different malignancies over diverse tissue/cell lineages, in both children and adults. A recent "basket" study of larotrectinib, a TRK inhibitor, has demonstrated significant efficacy in TRK fusion-positive tumors of all types from infants to the elderly. Here, we discuss the larotrectinib study and perspectives and challenges in developing "tumor-agnostic" targeted therapies in rare tumors.
Contrast-enhanced intra-operative ultrasound as a clinical decision making tool during surgery for colorectal liver metastases: The ULIIS study.
Authors: Serge Evrard, Grégoire Désolneux, Milene Isambert, Simone Mathoulin-Pélissier, Aurélien Dupré, Michel Rivoire, Vittorio Catena, Jean Palussière, Derek Dinart, Carine A. Bellera
Journal: Journal of Clinical Oncology (2018)

422 Background: In the era of parenchymal sparing surgery, detecting more colorectal liver metastases (CRLM) is essential to optimize the treatment. We evaluated the added-value of contrast enhanced intraoperative ultrasound (CE-IOUS) with a prospective design. Methods: We used an optimal 2-stage Simon’s design for this two-center study open for patients with operable CRLMs. Primary objective was the justified clinical utility of contrast-enhanced IOUS. Secondary objectives included detection rate of CRLMs, characterization rate of focal liver lesions, specific toxicity and detection of missing CRLMs. Results: Among the 58 eligible patients, 54 were eligible and assessable. Of these 54 patients, 36 were men (66.7%), median age was 63.6 years (range, 37-81), and 43 patients underwent pre-operative chemotherapy. The median number of CRLMs was 2 (range, 1-11). Pre-operative staging was performed using MRI in all 58 eligible patients, CT scan in 41 (70%) and PET-scan in 21 (36%). Compared to pre-operative staging, IOUS allowed identification of 40 new CRLMs in 11 (20.4%) patients. Furthermore, compared to IOUS, CE-IOUS allowed identification of 9 additional CRLMs in 8 (14.8%) patients. The correct detection rate based on pathological exams was 0.94. No additional missing CRLM was diagnosed. The surgical procedure was altered in 5 (9.26%) patients but was justified only in 4 patients (one lesion was ablated without previous biopsy), leading to a clinical utility rate of 7.70% (95 CI, [3.2, 18.6]). There was no specific toxicity reported. Conclusions: Despite the primary endpoint not met for one protocol violation,the Uliis study demonstrates an added-value for CE-IOUS for surgeons treating CRLMs, especially for advanced cases pre-treated by chemotherapy. Clinical trial information: NCT01880554.
IPATunity130: A pivotal randomized phase III trial evaluating ipatasertib (IPAT) + paclitaxel (PAC) for <i>PIK3CA/AKT1/PTEN</i>-altered advanced triple-negative (TN) or hormone receptor-positive HER2-negative (HR+/HER2–) breast cancer (BC).
Authors: Rebecca Dent, Sung-Bae Kim, Mafalda Oliveira, Steven J. Isakoff, Carlos H. Barrios, Joyce O'Shaughnessy, Xuyang Lu, Matthew Wongchenko, Denise Bradley, Aruna Mani, Jose Baselga, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2018)

TPS1117 Background: In the LOTUS trial in advanced TNBC, adding IPAT to first-line PAC improved progression-free survival (PFS; primary endpoint), particularly in patients (pts) with PIK3CA/AKT1/PTEN-altered tumors [Kim, Lancet Oncol 2017]. The pivotal double-blind placebo (PBO)-controlled randomized phase III IPATunity130 trial (NCT03337724) aims to confirm and build on findings from LOTUS. Methods: Eligible pts have ECOG performance status 0/1 and RECIST-measurable locally advanced/metastatic BC not amenable to resection with curative intent. Pts are allocated to either cohort A (TNBC; n≈249) or cohort B (HR+/HER2– not suitable for endocrine therapy; n≈201) according to their most recent locally assessed receptor status (in recurrent/metastatic tumor if available). In cohort A, any prior systemic therapy for advanced TNBC is prohibited, whereas cohort B pts may have received prior systemic therapy except chemotherapy for advanced BC. Tumor PIK3CA/AKT1/PTEN eligibility is tested centrally by next-generation sequencing (Foundation Medicine). Stratification factors are prior (neo)adjuvant chemotherapy, geographic region, and either tumor PIK3CA/AKT1-activating mutation status (cohort A) or prior PI3K/mTOR inhibitor therapy (cohort B). Pts in both cohorts are randomized 2:1 to 28-day cycles of PAC 80 mg/m2 (d1, 8, & 15) combined with either oral IPAT 400 mg/day (d1–21) or PBO until disease progression, intolerable toxicity, or withdrawal. Crossover to IPAT after progression on PAC + PBO is prohibited. The primary endpoint is investigator-assessed PFS by RECIST v1.1. Secondary endpoints include overall survival (key secondary), objective response rate (RECIST v1.1), duration of response, clinical benefit rate, EORTC QLQ-C30 global health status/health-related quality of life, and safety. Cohorts A and B will be analyzed separately. For each cohort, PFS will be compared between treatment arms using a stratified log-rank test. The trial is actively accruing pts. Clinical trial information: NCT03337724.
The macaque anterior cingulate cortex translates counterfactual choice value into actual behavioral change
Authors: Elsa F. Fouragnan, Bolton K. H. Chau, Davide Folloni, Nils Kolling, Lennart Verhagen, Miriam Klein-Flügge, Lev Tankelevitch, Georgios K. Papageorgiou, Jean-Francois Aubry, Jerome Sallet, Matthew F. S. Rushworth
Journal: Nature Neuroscience (2019)
Clinical characteristics of triple-negative breast cancer in the African American population: A retrospective cohort analysis.
Authors: Tejas Modi, Hamid Shaaban, Yashpal Modi, Gunwant K. Guron
Journal: Journal of Clinical Oncology (2012)

e12025 Background: Triple-negative breast cancer (TNBC) is defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. It is a very heterogeneous group of which a subset is clinically associated with an aggressive behavior and poor prognosis. They typically have a high relapse rate despite standard therapy. This study aimed to characterize the clinicopathologic findings and outcomes of these patients in an urban, predominantly African American (AA) population. Methods: Patients diagnosed with TNBC at the Regional Cancer Center at St Michael’s Medical Center in Newark, NJ between 2000 and 2008 were identified from the tumor registry databases. The clinical data was reviewed as a retrospective cohort for demographic information, clinical stage at presentation, recurrence rates and outcomes. Results: 42 pts were identified (median age 56) of which 28 (67%) were AA, 7 (16.7%) Hispanic (H) and 7 (16.7%) Caucasian. 22 patients (52.4%) presented with advanced disease (Stage 3, 4) and 18 of these patients were AA. At mean follow-up of 28 months, 12 (28.5%) pts had progressive disease with pulmonary metastases most common followed by brain metastases. The AA group displayed a trend towards shorter time to progression (TTP) (AA: 10.7 months vs. others: 14.7 months) and the younger patients less than 50 had a shorter TTP (12.3 months vs. 14.1 months). Tumor size was described &gt; than 2 cm in 60%, &lt; than 2 cm in 40%. Lymph nodes were positive in 43% and negative in 57%. Nuclear grade was 1 in 7%, 2 in 8.5% and 3 in 84.5%, respectively. A total of 8 (19%) patients died during the follow-up period. Conclusions: In the cohort we studied, we observed a trend that patients with TNBC in our urban city cancer center were more likely to be AA. These patients were more likely to present with advanced disease. AA and younger patients (less than 50) were more likely to have a more aggressive disease. Whether this could be attributed to non-compliance with mammogram screenings and healthcare disparities in the underserved AA inner city population is not clear but more research is needed to identify germline markers associated with TNBC which could potentiate effective therapies for women with TNBC.