tbuckley/cabot-search huggingface dataset:
SMAD4 promotes TGF-β–independent NK cell homeostasis and maturation and antitumor immunity
Authors: Youwei Wang, Jianhong Chu, Ping Yi, Wejuan Dong, Jennifer Saultz, Yufeng Wang, Hongwei Wang, Steven Scoville, Jianying Zhang, Lai-Chu Wu, Youcai Deng, Xiaoming He, Bethany Mundy-Bosse, Aharon G. Freud, Li-Shu Wang, Michael A. Caligiuri, Jianhua Yu
Journal: Journal of Clinical Investigation (2018)

SMAD4 is the only common SMAD in TGF-β signaling that usually impedes immune cell activation in the tumor microenvironment. However, we demonstrated here that selective deletion of Smad4 in NK cells actually led to dramatically reduced tumor cell rejection and augmented tumor cell metastases, reduced murine CMV clearance, as well as impeded NK cell homeostasis and maturation. This was associated with a downregulation of granzyme B (Gzmb), Kit, and Prdm1 in Smad4-deficient NK cells. We further unveiled the mechanism by which SMAD4 promotes Gzmb expression. Gzmb was identified as a direct target of a transcriptional complex formed by SMAD4 and JUNB. A JUNB binding site distinct from that for SMAD4 in the proximal Gzmb promoter was required for transcriptional activation by the SMAD4-JUNB complex. In a Tgfbr2 and Smad4 NK cell–specific double–conditional KO model, SMAD4-mediated events were found to be independent of canonical TGF-β signaling. Our study identifies and mechanistically characterizes unusual functions and pathways for SMAD4 in governing innate immune responses to cancer and viral infection, as well as NK cell development.
Prevalence of urinary symptoms in women with early-stage breast cancer and treatment with (neo)adjuvant chemotherapy.
Authors: Joanne E. Mortimer, Louise Wong, Sarah Flores, Carolyn E. Behrendt, Christopher Chung
Journal: Journal of Clinical Oncology (2018)

e22098 Background: Studies in breast cancer survivors suggest a high prevalence of urinary symptoms, often attributed to cancer therapy. The current observational study assessed urinary incontinence (UI) before and after (neo)adjuvant treatment of early-stage breast cancer. Methods: Women with Stage I-III breast cancer were eligible for study participation if they were to receive (neo)adjuvant chemotherapy or endocrine therapy and consented to complete the urogenital distress inventory (UDI-6) and incontinence impact questionnaire (IIQ-7) prior to and 3 months after initiation of (neo)adjuvant therapy. Results: ±±6.8) completed the pre-treatment survey. Participants were non-Hispanic White (55.2%), Hispanic (18.7%), Asian (15.3%), African American (5.4%), or not stated (5.4%). At baseline, most (79.8%) participants reported symptoms of overactive bladder (OAB, 29.1%), stress incontinence (SI, 10.8%), or mixed incontinence (MI, 39.9%). Adjusted for subjective retention, being at least 50 years old and/or post-menopausal was associated with pre-treatment MI (p = 0.01) and SI (p = 0.07) but not OAB (p = 0.22). Parity, obesity, and history of smoking were not associated with any type of UI pre-treatment. Among the163 cases who completed 3-month questionnaires, 22 (13.6%) reported major impact on QoL, independently associated with subjective retention (p < 0.01), MI (p = 0.01), maximal distress from symptoms (p < 0.01), and additional unit of BMI (p = 0.01). Of participants no more than moderately bothered by UI pre-treatment (n = 137), 39 (28.5%) reported new (12/32) or more bothersome UI (27/105) following cancer treatment. Neither type of chemotherapy nor patient characteristics predicted new or worsened UI after treatment. Of these treatment-associated UI cases, few (5/39, 12.8%) reported major impact on QoL. Conclusions: Urinary incontinence associated with age/menopausal status is highly prevalent in women newly diagnosed with breast cancer. Moreover, at least a quarter of patients who undergo (neo)adjuvant therapy develop new or worsened UI within 3 months. Patients should be screened for UI before as well as after treatment for breast cancer.
Real world health and economic outcomes in patients with non-stem cell transplant (NSCT) multiple myeloma initially treated with lenalidomide and/or bortezomib-based regimens.
Authors: Kejal Parikh, Safiya Abouzaid, Chi-Chang Chen, Catherine Balderston McGuiness, Rolin L. Wade
Journal: Journal of Clinical Oncology (2016)

8038 Background: Our objective was to evaluatereal world health and economic outcomes in patients (pts) with newly treated multiple myeloma (MM) receiving common first line (1L) treatments (Tx). Methods: Data from PharMetrics Plus was used to identify pts with a lenalidomide (R) or bortezomib (V) claim (index date), between 1/1/2009 and 3/31/2014 with ≥ 2 MM diagnosis codes (ICD-9 203.0x) 12 months pre- or 3 months post-index. Regimens were defined as all MM Tx observed within 60 days of index. Pts were followed to progression within the limits of the data. Time to next treatment (TTNT), a progression proxy, was defined as addition of a new agent > 60 days from index, or Tx restart following a > 90 day therapy gap. Chi-square was used to compare categorical variables, T-tests for means, and Wilcoxon rank-sum tests for medians. Results: A total of 1,128 NSCT MM pts were indexed to first line (1L) Tx of R (n = 435) or V (n = 367) +dexamethasone (d) based doublet (Rd or Vd), RVd (n = 195), or other V-based triplet (V3, n = 131). Mean 1L Tx duration was longer in Rd versus Vd (14.6 vs. 9.9 months, p < .0001). In pts where progression could be followed to second line (2L) Tx (n for Rd = 203; Vd = 179; RVd = 89; V3 = 67), mean time to 2L Tx was longer with Rd versus Vd (12.7 vs. 9.8 months, p = 0.0055). In RVd and V3 patients progressing to 2L, mean 1L Tx duration and TTNT were similar, although RVd pts had significantly more pathologic fracture at index, a marker of more severe disease. In patients progressing to 2L, median monthly-proportioned 1L costs were lower with Rd versus Vd ($14,705 vs. $16,547, p = 0.0147). Monthly costs in 1L decreased to $1,432-$9,311 across 1L groups at month 9, but escalated with progression, where total median costs in the first 3 months were $15,125 per month. Conclusions: This retrospective analysis of NSCT MM pts initially treated with R and/or V-based Tx found a significantly longer TTNT and lower costs with 1L Rd versus Vd. TTNT was similar between RVd and V3 Tx pts. Tx progression was associated with escalating costs.
Comparison of clinical outcome and safety after minimally invasive esophagectomy: Ivor Lewis versus McKeown—A real-world multicenter observational study from China.
Authors: Yang Liu, Yin Li, Xiangning Fu, Lunxu Liu, Lin Xu, Xiaofei Li, Jian Hu, Heng Zhao, Xun Zhang, Deruo Liu, Haiying Yang, Tong Zhang
Journal: Journal of Clinical Oncology (2018)

4052 Background: Ivor Lewis (Iv) and McKeown (Mc) are two commonly used minimally invasive esophagectomy. Currently, there are limited data to compare effectiveness and safety between Iv and Mc in China. Methods: We conduct the study based on a national collaborative prospective esophageal cancer (EC) database (designed by LinkDoc Technology Co, Ltd.).EC patients who underwent Iv or Mc esophagectomy from Jan.2010 to Jun.2017 and pathologically confirmed stage Ⅰ~Ⅲ with middle thoracic and lower thoracic esophagus were enrolled. Log-rank test was used in the comparison of the two surgery groups. And Cox’s proportional hazard models and logistic regression were used in the factors analyses. Results: Total 1862 patients (1447 males and 415 females) were enrolled, mean age of 61.4.8±7.9. Among the patients, there were 97.2% squamous cell carcinoma, 1% adenocarcinoma and 1.8% others. 667 were performed with Iv esophagectomy and 1195 patients with Mc esophagectomy. Number of lymph nodes examined,mean was 14.4 ±9.02 in Iv group, compared with 21.5±11.57 in Mc group, p< 0.05. Recurrence rate was 12.3% in Iv group and 7.6% in Mc group, p< 0.05. The 5 years overall survival (OS) was 51% in Iv group and 59% in Mc group, p< 0.05. Multivariate analysis showed that risk factors for EC recurrence after esophagectomy include operation type (Iv vs Mc, odds ratio 1.70, CI 1.187-2.430), N stage and T stage, p< 0.05. Operation type (Ic vs Mc, HR 1.49, CI 1.153-1.928), N stage and T stage were hazard factors for OS in analysis of multivariate cox’s proportional hazard models, p< 0.05. Especially, for the subgroup diagnosed as stage T3 at middle thoracic esophagus, Recurrence and OS were significantly different according to surgery type. Median blood loss was 300 mL in Iv group compared with 200 mL in Mc group, p< 0.05. Post-operative complications was significantly less in Iv group, p< 0.05. Conclusions: Our data showed that Mc is preferred with better lymphadenectomy, lower recurrence and improved survival compared with Iv, especially for patients diagnosed as stage T3 at middle thoracic esophagus. And Lv showed significantly less severe post-operative complications than Mc. Clinical trial information: ChiCTR1800014802.
A phase I/II trial of cabozantinib (C) with or without panitumumab (P) in patients (pts) with RAS wild-type (WT) metastatic colorectal cancer (mCRC): Clinical outcomes in pts with <i>MET</i> amplification (amp) detected in blood.
Authors: Jingquan Jia, Donna Niedzwiecki, Hope Elizabeth Uronis, Michael Morse, Yousuf Zafar, Shiaowen David Hsu, Emily Bolch, Rebecca J Nagy, Richard B. Lanman, AmirAli Talasaz, Sherri Haley, Andrew B. Nixon, John H. Strickler
Journal: Journal of Clinical Oncology (2018)

3555 Background: MET amp is a well described driver of acquired EGFR antibody (Ab) resistance. Blood-based genomic profiling of cell free (cf)DNA is a safe and efficient means to identify pts with acquired MET amp. To determine whether a MET targeting strategy is feasible and clinically active in pts with MET amp RAS WT mCRC, we studied pts treated with an anti-c-MET multi-kinase inhibitor (C) combined with an anti-EGFR Ab (P) or (C) alone. Methods: Pts with RAS WT mCRC were enrolled in 2 cohorts: 1) C+P combination (C+P); or 2) C monotherapy (C) (NCT02008383). Peripheral blood was sequenced for up to 73 single nucleotide variants, insertions/deletions, fusions, and amps, including MET amp (Guardant360, Guardant Health). Pts enrolled in the C+P cohort received retrospective cfDNA profiling for MET amp. Pts enrolled in the C cohort were prospectively screened for MET amp; only those pts with MET amp in blood were treated in the C cohort. Results: 64/65 pts (98%) had detectable cfDNA (C+P = 13; C = 51). MET amp was identified in 12 pts (18%) (C+P = 4; C = 8). Among pts with MET amp detected in blood the median copy number was 2.6 (range 2.3-6.4). 8 pts with MET amp received treatment (C+P = 4; C = 4); 7 pts were evaluable for efficacy (C+P = 4; C = 3). 1 pt (C+P cohort) had a RECIST PR, and this pt had low grade EGFR and MET co-amp (MET= 2.3 copies; EGFR= 2.2 copies). 4/7 pts (57%) had a reduction of measurable RECIST target lesions, 3 of whom received C+P (PR = 1; SD = 1; PD = 1) and 1 (SD; 27% reduction) received C. 3/4 pts in the C+P cohort had EGFR and MET co-amp, 2 of these pts had a reduction in RECIST lesions (PR = 1; PD = 1). No evaluable pts in the C cohort had EGFR and MET co-amp. Conclusions: This study demonstrates the feasibility of utilizing cfDNA to identify MET amp in pts with RAS WT mCRC. Although there are signals of clinical activity for the C+P combination and C alone in this limited sample, further study is needed. The ideal MET amp copy number threshold, the role of EGFR co-amp, and the additive value of combined EGFR blockade remain to be determined. Clinical trials utilizing cfDNA to identify and treat MET amp mCRC are ongoing. Clinical trial information: NCT02008383.
Patterns of metastatic disease progression after treatment with first-line enzalutamide or abiraterone in castration-resistant prostate cancer (CRPC).
Authors: Elizabeth K Lee, Benjamin A. Teply, Benjamin Louis Maughan, Michael Anthony Carducci, Emmanuel S. Antonarakis, Samuel R. Denmeade
Journal: Journal of Clinical Oncology (2016)

e16539 Background: Abiraterone (A) and enzalutamide (E) are life-prolonging treatments for metastatic CRPC, yet their potent activity against the androgen receptor (AR) axis often yields tumors that have undergone transformation to a more clinically resistant state, making these tumors refractory to further androgen-directed therapies at the time of progression. Potential mechanisms for such transformation include neuroendocrine differentiation, expression of splice variants, and a shift to alternative non-AR signaling pathways. Based on accumulating clinical observations, we hypothesized that men treated with first-line A or E may have increased visceral metastasis at the time of disease progression compared to their baseline. Methods: We retrospectively examined patterns of metastatic disease in patients with CRPC who were docetaxel-naïve and treated with first-line A or E at our institution from 2012-2015. Baseline clinical and disease characteristics were compared using descriptive statistics and t-tests. Pre- and post-treatment proportions of site-specific metastases were compared using McNemar’s test of paired proportions. Preliminary comparisons between A- and E-treated patients were made. Results: 83 consecutive men were included; 26 received first-line E over a median of 8.6 months, and 57 received first-line A over a median of 7.6 months. At baseline, 77% of patients had bone, 43% had lymph node, 10.8% had lung, and 2.4% had liver metastasis. Of the 83 patients, 78 have experienced radiographic progression to date. Increased proportions of post-treatment lymph node metastases (43% pre vs 58% post, p = 0.004) and bone metastases (77% pre vs 88% post, p = 0.012) were seen. The percent of men with liver metastases increased 4-fold after progression on A or E (2.4% pre vs 9.6% post, p = 0.031). Conclusions: Increased proportion of liver metastasis after progression on first-line A or E raise the possibility that CRPC is being driven to clinically aggressive disease in some patients. Future work will attempt to link these clinical outcomes with biomarkers (such as AR-V7 expression or neuroendocrine phenotypes). Updated information will be presented.
Adjuvant radiation “sandwiched” between 6 cycles of carboplatin and paclitaxel for FIGO stage III endometrioid adenocarcinoma.
Authors: Nicola Joseph Nasser, Keyur J. Mehta, Aneesh Pirlamarla, Jennifer Jorgensen, Dennis Yi-Shin Kuo, Shalom Kalnicki
Journal: Journal of Clinical Oncology (2018)

e17567 Background: Locally advanced endometrioid adenocarcinoma (EAC) is an aggressive disease with the potential of metastatic spread and local recurrence after initial surgical resection. Adjuvant treatment often includes a combination of chemotherapy (CTx) and/or radiation therapy (RT). GOG 122 showed that adjuvant chemotherapy was important in preventing recurrence for locally advanced EAC. Other studies for carcinosarcoma and serous papillary tumors of the uterus showed improved outcomes using an adjuvant ”sandwich” chemoradiation (CRT) regimen, splitting CTx before and after RT. We retrospectively review patients treated postoperatively with the ”sandwich” regimen for FIGO stage III endometrioid adenocarcinoma. Methods: Thirty-four patients with FIGO stage III EAC were treated between 2008-2016 with the “sandwich” regimen: 1) 3 cycles of carboplatin (AUC 6)and paclitaxel 175 mg/m2; 2) RT (45Gy in 25 fractions) to the pelvis and, when indicated, to the para-aortic lymph nodes, and vaginal brachytherapy (15 Gy in 3 fractions prescribed to 0.5 cm vaginal depth); 3) 3 more cycles of carboplatin (AUC 5) and paclitaxel. Patients who received less than 4 cycles of CTx were excluded. Intensity modulated radiation therapy (IMRT) was used to reduce normal tissue toxicity. Results: Median follow-up was 3.1 years. All patients completed the prescribed RT. Twenty-nine patients completed 6 cycles of chemotherapy, 3 finished 5 cycles, and 2 finished 4 cycles due to toxicity. Grade 3-4 hematologic toxicity was seen in 19 (56%) patients. Acute gastrointestinal toxicity of grade ≥ 2 was reported in 4 (12%) patients. There was no reported acute genitourinary toxicity of grade ≥ 2. Grade 2 vaginal stenosis was seen in 5 (15%) patients. Actuarial progression-free survival at 3 and 5 years was 84.1% and 59.8%, respectively. Actuarial overall survival at 3 and 5 years was 88% and 77%, respectively. Conclusions: Adjuvant IMRT “sandwiched” between carboplatin/paclitaxel CTx for FIGO stage III EAC is well tolerated, with the worst toxicity being hematologic. This regimen also provides a good overall survival at 5 years, though lower PFS shows that there are patients living with evidence of disease.
TCT-411 Comparison of the strategies for side branch intervention according to Fractional Flow reserve in coronary bifurcation lesions
Authors: Sang-Cheol Cho, Osung Kwon, Kyusup Lee, Hanbit Park, Minsoo Kim, Sang Yong Om, Yong-Hoon Yoon, Tae oh Kim, Sun Hack Lee, Do-yoon Kang, Pil Hyung Lee, Jung-Min Ahn, Seung-Whan Lee, Duk-Woo Park, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
Importance of β-Catenin for cancer stem cell generation and tumorigenic activity in nasopharyngeal carcinoma.
Authors: Rui Jiang
Journal: Journal of Clinical Oncology (2016)

e17532 Background: Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors with poor prognosis and recurrence in South China. The hard eradication of NPC in clinic is predominantly due to cancer stem cells (CSCs). Increasing evidence revealed that the aberrant activation of Wnt/β-catenin was positively correlated with the produce of CSCs. Methods: To further investigate the effect of β-catenin on CSCs and tumorigenesis in NPC, a CNE2 cell line (pLKO.1-sh-β-catenin-CNE2) with stably suppressed expression of β-catenin was used in this study. The expressions of biomarkers in CSCs including c-myc, Nanog, Oct3/4, Sox2, EpCAM, as well as adhesion-related proteins like E-cadherin and vimentin were analyzed by western blot analysis and immunofluorescent staining. The proliferation and migration abilities were investigated by MTT assay and transwell assay, respectively. Cell cycle was analyzed by flow cytometry. Finally, xenograft was performed to determine the effect of β-catenin on oncogenesis in vivo. Results: Results showed that the expressions of c-myc, Nanog, Oct3/4, Sox2, and EpCAM were all decreased in pLKO.1-sh-β-catenin-CNE2 cells. It was also found that vimentin was down-regulated, while E-cadherin was upregulated. Results of MTT and transwell assays suggested that the proliferation and migration abilities were impaired by silencing of β-catenin, and more cells were arrested in G1 phase when compared with the control. In vivo study indicated that the tumor growth was markedly suppressed in experimental group. Conclusions: Based on current findings, β-catenin may function as an essential protein for the maintenance of migration and proliferation abilities of NPC cells, and a complicated network consisting of c-myc, Nanog, Oct3/4, Sox2, EpCAM, E-cadherin, vimentin and β-catenin may be involved in the inherent regulation mechanisms.
Clinical lymph node staging by imaging in colorectal cancer: A flip of the coin?
Authors: Nelleke Pietronella Maria Brouwer, Rutger Carel Hubert Stijns, Lemmens Valery, Iris D. Nagtegaal, Regina GH Beets-Tan, Jurgen FÃ¼tterer, Rob H.A. Verhoeven, Johannes H.W. de Wilt
Journal: Journal of Clinical Oncology (2017)

e15160 Background: Clinical lymph node staging by MRI and CT is important in stratification for neoadjuvant therapy in colorectal cancer. Overstaging may result in unnecessary neoadjuvant therapy, but understaging may refrain patients from adequate preoperative treatment. This study aims to provide insight in current daily practice in clinical lymph node staging in CRC in the Netherlands. Methods: All patients with primary CRC, diagnosed between 2003-2014, who underwent lymph node dissection were selected from the nationwide population-based Netherlands Cancer Registry (n=100,211). Trends in patient- and tumor-characteristics, and lymph node staging were analyzed. For the years 2011-2014, sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated for clinical lymph node staging, with histology as the gold standard. Only patients without preoperative treatment were analyzed. Since prospective studies have shown that 5x5 Gy radiotherapy (RT) followed by total mesorectal excision within 10 days does not lead to nodal downstaging, an additional analysis was performed in this group. Results: The proportion clinically positive lymph nodes increased significantly between 2003-2014; from 7% to 22% for colon cancer and from 7% to 53% for rectal cancer. The proportion histological positive lymph nodes remained fairly stable over time (±35% colon, ±33% rectum). During 2011-2014, clinical lymph node staging was available in the registry in 86% of colon cancer patients, 92% of rectal cancer patients without neoadjuvant treatment and 95% of rectal cancer patients with 5x5 Gy RT. The parameters based on data from this period are presented in table 1. Conclusions: With a sensitivity and PPV of approximately 50%, clinical lymph node staging is about as accurate as flipping a coin. This leads to overtreatment in patients with rectal cancer with neoadjuvant RT. Acceptable specificity and NPV limit the risk of undertreatment. [Table: see text]
Evaluation of serum Cystatin-C as a prognostic and predictive factor in patients with newly diagnosed multiple myeloma.
Authors: Rakesh Reddy, Ritu Gupta, Nitin Mathur, Lata Rani, Atul Sharma, Lalit Kumar
Journal: Journal of Clinical Oncology (2016)

8044 Background: Cystatin-C is recently gaining significance as a marker for disease activity in multiple myeloma. We aimed to study whether serum Cystatin-C is prognostic of disease severity and predicted response to treatment. Methods: Serum samples were collected from patients of multiple myeloma at the time of diagnosis and after 4 cycles of therapy. Serum Cystatin-C was measured by Quantitative sandwich ELISA (Quantikine immunoassay kit, R&D systems). To correlate serum Cystatin-C with myeloma severity as per International Staging System (ISS) stages, 13 patients were required in each stage (5% α error, 80% power). Results: Of 41 patients recruited, 15 patients were ISS 3 and 13 each were ISS 1 and 2. ISS 3 patients had increased mean (± SD) serum Cystatin-C (1931 ng/ml± 766) compared to ISS 2 (1071ng/ml± 510, p = 0.001) and ISS 1 (771ng/ml±142, p < 0.001). Serum Cystatin-C has shown positive correlation with β2microglobulin (r = 0.78, p < 0.001), bone marrow plasma cell percentage (r = 0.41, p = 0.009), serum lactate dehydrogenase (r = 0.36, p = 0.03) and inverse correlation with Hemoglobin (r = -0.51, p < 0.001) and serum albumin (r = -0.35, p 0.02). Cystatin-C level decreased from baseline (mean±SD 1291±754 ng/ml) to post 4 cycles of treatment (1041±792 ng/ml; p = 0.002). Baseline level of serum Cystatin-C was higher in treatment non-responders (mean±SD 1894±824 ng/ml) compared to treatment responders (1188±703 ng/ml; p = 0.03). On ROC analysis, a baseline Cystatin-C level of > 1283ng/ml predicted treatment failure with 84% sensitivity and 77% specificity (Area under ROC 0.75). Conclusions: Serum Cystatin-C correlated well with markers of disease severity and is predictive of response to treatment in patients with newly diagnosed multiple myeloma.