tbuckley/cabot-search huggingface dataset:
Dose-seeking and efficacy study of combination BRAFi and high-dose IFN (HDI) for therapy of advanced melanoma.
Authors: Diwakar Davar, Ahmad A. Tarhini, Hussein Abdul-Hassan Tawbi, Soldano Ferrone, Hassane M. Zarour, John M. Kirkwood
Journal: Journal of Clinical Oncology (2014)

TPS9110 Background: New immunotherapies and BRAF inhibitors (BRAFi) have improved the prognosis of advanced melanoma. Although BRAFi induce regression in ~50% of patients (pts), responses are incomplete and progression typically occurs at 6 months. Intrinsic/acquired resistance mechanisms represent limitations to single agent BRAFi use. Conversely, immunotherapies benefit only 18-30% of patients. In vitro and in vivo studies suggest that treating BRAF mutated melanoma cells with BRAFi increases sensitivity to IFN. We planned a dose-selection and dose-expansion study to evaluate the novel sequential combination of BRAFi followed after 2 weeks by concurrent BRAFi/IFNα. Methods: Study will enroll pts with BRAF V600E recurrent/inoperable stage III/IV melanoma. Primary objectives are to evaluate safety/toxicity, identify a phase II dose (RP2D) of combination, and improve progression free survival (PFS). Secondary objectives include improving response rates and documenting evidence of immune modulation. Pts will initially receive vemurafenib at 960 mg twice daily with a 2 week lead-in to exploit immunomodulatory effects. HDI will commence in week 3 with standard induction (4 weeks) and maintenance (48 weeks) schedules employed for adjuvant therapy. Intravenous IFN will be administered 5 days weekly for 4 weeks at 3 escalating dosage levels - 10, 15, and 20 MU/m2/d. Subcutaneous IFN will be administered thrice weekly for 48 weeks at 3 dose levels - 5, 7.5, and 10 MU/m2/d. As combination has not previously been evaluated, HDI will be escalated in 3 fixed dose levels using Storer’s modified “up and down” scheme to minimize toxicity. Accrual target in the dose expansion phase is 36 patients treated at RP2D. Prior to study and at serial points during, biopsies of accessible lesions will be obtained. We expect that this combination will increase immune recognition of melanoma cells by CD8+ tumor-infiltrating T cells (TILs) through: 1) upregulation of IFN-αR1 and HLA class I APM component expression; 2) inhibition of STAT signaling pathways; and 3) modulation of PD-L1 expression by melanoma cells. Clinical trial information: NCT01943422.
Pharmacodynamic effects of seliciclib (R-roscovitine, CYC202) in patients with undifferentiated nasopharyngeal carcinoma (NPC) using a window trial design.
Authors: W. Hsieh, B.K. Peh, T. Loh, J.H. Chiao, R. Soo, C.Y. Cui, S.R. Green, Y.F. Lai, Manuel Salto-Tellez, B. Mow, B.C. Goh
Journal: Clinical Cancer Research (2005)
Efficacy of AA in patients with metastatic CRPC after progression on DES: Potential cost-efficient treatment paradigm.
Authors: Feras Eleyan, Marc R. Wygoda, Tamar Peretz, Amichay Meirovitz, Hovav Nechushtan, Yakir Rottenberg, Mark Temper, Salah Azzam, Igor Nemirovsky, Eli Sapir, Stephen Jay Frank
Journal: Journal of Clinical Oncology (2014)

e16100 Background: , Sequential hormonal deprivation therapy incorporating old inexpensive pharmaceuticals may still have a role in the treatment of castrate resistant metastatic prostate carcinoma(CRPC). Abiraterone Acetate(AA), a CYP 17 inhibitor, initially approved by the FDA for CRPC in the post chemotherapy setting after showing improvement in OS, PFS, PSA and clinical response attained approval in the chemotherapy naïve patient essentially resulting in the majority of patients receiving this agent earlier in their disease course. Diethylstilbestrol(DES) is a nonsteroidal estrogen, first used for CRPC in 1941 . The effectiveness of orchiectomy, LHRH agonists, and the cardiovascular toxicity associated with DES has relegated it to a minor role in the treatment of CRPC. One month supply AA costs $6,285 compared to one month DES $114. Methods: Patient records at a single large academic center were reviewed if they had been treated for metastatic CRPC first with DES and at time of progression later had received in their disease course treatment with AA. We report a series of 18 patients with Mean Age 70(62-83), Gleason 7(4-10), all received LHRH treatment with 8/18 receiving second line bicalutamide to which 3/8 responded. Results: Clinical response to DES occurred in 9/18 patients for Mean 8.5 months (2-12). At time of initiation of AA, Median PSA 104(1.07-1,000), 11/18 had prior docetaxol, all had bone involvement. PSA decline greater 30% occurred 8/18. Clinical benefit with decrease in pain was achieved in 8/18 patients. Conclusions: There is potential utility for a strategy of sequential testosterone ablative therapies to achieve the desired postponement toxic interventions, chemotherapy. Patients responded to AA after progression on DES, showing absence of cross- resistence. Our patient cohort suggests that there may still be a role for old and inexpensive agents including DES and similar to the incremental improvement in outcome seen in the treatment paradigm of other metastatic diseases such as breast and colon cancer where new therapeutics are given sequentially without discarding older more cheaper therapies may be a model to explore for castrate resistant metastatic prostate patients.
Avoiding Unnecessary Prostate Biopsies With MRI
Authors: Anita Slomski
Journal: JAMA (2017)

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Diagnostic accuracy of ultrasonography, breast MRI, and 18F-FDG PET/CT for axillary lymph node metastasis in breast cancer patients.
Authors: Hee-Chul Shin, Hee Sung Kim, Sung Jun Park
Journal: Journal of Clinical Oncology (2014)

e12023 Background: The aim of this study was to evaluate the diagnostic performance of ultrasonography (US), breast magnetic resonance imaging (MRI), and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for axillary lymph node metastasis in breast cancer patients. Methods: Between 2012 and 2013, 180 breast cancer patients received curative breast cancer surgery. Preoperative ultrasonography, breast MRI, and 18F-FDG PET/CT were performed. Complete axillary lymph node dissection was performed when a metastatic lymph node was detected preoperatively or intra-operatively. Results: Among 180 patients, 53 patients (31.1%) had axillary metastatic lymph node. The sensitivity of US, MRI, and PET/CT for the detection of axillary lymph node metastasis was 55% for US, 72% for MRI, and 44%, respectively. The specificity of US, MRI, and PET/CT for the detection of axillary lymph node metastasis was 88%, 78%, and 92%, respectively. The positive predictive value and negative predictive value of US, MRI, and PET/CT for the detection of axillary lymph node metastasis were 67%, 60%, and 71%, respectively, and 81%, 86%, and 79%, respectively. In multivariate logistic regression analysis, pathologic lymph node metastasis was associated with positive finding for axillary metastasis of US, MRI, and PET/CT, independently (P = 0.028, P = 0.03, and P = 0.017, respectively). With the combining three modalities, scoring system for detecting axillary lymph node metastasis was developed and the AUC for positive lymph node metastasis was 0.811 (95% CI, 0.737 - 0.886). Conclusions: The diagnostic accuracy of US, MRI, and 18F-FDG PET/CT were similar. However, combining three imaging modalities could increase the diagnostic accuracy of axillary lymph node metastasis, preoperatively.
First-line capecitabine (X) monotherapy versus capecitabine plus oxaliplatin (XELOX) in elderly patients with advanced gastric cancer (AGC): results from the first interim analysis.
Authors: In Gyu Hwang, Hyo Rak Lee, Hui Young Lee, Jun Ho Ji, Jung Hun Kang, Soon Il Lee, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Won Ki Kang
Journal: Journal of Clinical Oncology (2015)

4051 Background: While doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in AGC, there has been a price to pay in terms of toxicity. Since the main goal of AGC treatment remains palliation, this multi-center randomized phase III trial compared efficacy and safety of X monotherapy with those of XELOX combination in elderly patients with AGC. Methods: Patients with chemotherapy-naïve, measurable AGC, aged 70 years or older were randomized 1:1 to receive X (capecitabine 1,000 mg/m2 bid po on D1-D14) or XELOX (X plus oxaliplatin 110 mg/m2 iv on D1). Treatment was repeated every 21 days until disease progression, unacceptable toxicity, or withdrawal. Primary end point was overall survival (OS). The present report contains the results from the first interim analysis conducted at Dec 2014. Results: As of Oct 2014, 50 patients with a median age of 77 (range, 70 to 84) were enrolled (X, n = 26; XELOX, n = 24). The two treatment arms were well balanced with respect to baseline characteristics. No treatment-related serious adverse events or unexpected toxicities were observed. The most frequently observed toxicities were nausea and hand-foot syndrome, with fatigue and peripheral neuropathy more common in XELOX than in X patients. Median PFS was significantly longer in XELOX arm than in X arm (7 v 3 months, respectively; HR 0.33, 95% CI 0.17-0.64). OS was also longer with XELOX (14 v 6 months; HR 0.60; 95% CI 0.29-1.23). Conclusions: XELOX combination chemotherapy results in improved efficacy but does not increase toxicities compared with X monotherapy in elderly patients with AGC. Although HR for OS did not achieve predefined margin, an independent data monitoring committee recommended early stopping of the trial based on the evidence of superiority with XELOX. Clinical trial information: NCT01470742.
Understanding of early-phase clinical trials among a cohort of advanced cancer patients with limited standard treatment options.
Authors: Daniel Paul Dohan, Laura Trupin, Christopher Koenig, Fay J. Hlubocky, Christopher Daugherty
Journal: Journal of Clinical Oncology (2014)

9651 Background: Early phase (EP) trials are typically offered to ACP once they exhaust standard treatment options. Limited knowledge exists about what patients understand regarding EP trials as they approach the end of standard treatments. Methods: ACP were recruited from five clinics at an academic medical center with an EP trials program. Patients were eligible if treating oncologists deemed them likely to exhaust standard treatment in 6-12 months. Eligible patients completed a 60 minute qualitative interview. Clinical research was only discussed if patients raised it during the interview. Interviews were audio recorded and transcribed; Atlas.ti was used for thematic coding. Results: 82 patients were recruited; 60 mentioned clinical research. Thematic analysis showed that understanding of clinical research differed along two dimensions: Accuracy and Specificity. Some ACP accurately described research; others had inaccurate understandings. Patients described the research process with different degrees of specificity (see Table). Conclusions: ACP with limited standard treatment options had mixed understandings of clinical research. Improving ACP understanding before EP trials are discussed may be appropriate. Accurate Inaccurate Specific It is randomized in the fact that there are three different levels to it. So you have somebody that’s going to get the highest dosage of both drugs, you’re going to have a group that’s going to get the lowest dosage and then you’re going to have a third group that’s going to take the [study drug]. The [study drug] appears to have put a second roadblock to cell division and I think it was January that they started this phase. So it may be just a carry-on from the first one or it may be a new phase [I] of a new study . . . to determine the efficacy of the drug and how it affects the patients. General One of them’s about ready to be whatever the last phase is. I think that’s the one we’re going with. It’s about ready to be approved, FDA approved, so it must be on the later phases. I am still in a double-blind study so nobody knows if I’m getting the drug, which is a bummer. If I was in a Phase III, I would know I’m getting it.
Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC) from the phase III PREVAIL clinical trial.
Authors: Andrew J. Armstrong, Ping Lin, Celestia S. Higano, Cora N. Sternberg, Guru Sonpavde, Bertrand F. Tombal, Arnoud J. Templeton, Karim Fizazi, De Phung, Elaine Karol Wong, Andrew Krivoshik, Tomasz M. Beer
Journal: Journal of Clinical Oncology (2017)

138 Background: Prognostic models require updating to reflect contemporary medical practice. In a post hoc analysis of the phase 3 PREVAIL trial (enzalutamide vs placebo), we identified prognostic factors for overall survival (OS) in chemotherapy-naïve men with mCRPC. Methods: Patients were randomly divided 2:1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined candidate prognostic factors (including treatment) were analyzed in a multivariable Cox model with stepwise procedures and in a penalized Cox proportional hazards model using the adaptive least absolute shrinkage and selection operator (LASSO) penalty (data cutoff June 1, 2014). A multivariable model predicting OS was developed using the training set; the predictive accuracy was assessed in the testing set using time-dependent area under the curve (tAUC). The testing set was stratified based on risk score tertiles (low, intermediate, high), and OS was analyzed using Kaplan-Meier methodology. Results: Demographics, disease characteristics, and OS were balanced between the training and testing sets; median OS was 32.7 months for both datasets. There were no enzalutamide treatment-prognostic factor interactions (predictors). The final multivariable model included 11 prognostic factors: prostate-specific antigen, treatment, hemoglobin, neutrophil-lymphocyte ratio, liver metastases, time from diagnosis to randomization, lactate dehydrogenase, ≥ 10 bone metastases, pain, albumin, and alkaline phosphatase. The tAUC was 0.74 in the testing set. Median (95% confidence interval [CI]) OS for the low-, intermediate-, and high-risk groups (testing set) were not yet reached (NYR) (NYR–NYR), 34.2 months (31.5–NYR), and 21.1 months (17.5–25.0). The hazard ratios (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.20 (0.14–0.29) and 0.40 (0.30–0.53), respectively. Conclusions: Our validated prognostic model incorporates factors routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide and identifies subsets of men with widely differing survival times.
Ultrasound evaluation of diaphragm function in mechanically ventilated patients: comparison to phrenic stimulation and prognostic implications
Authors: Bruno-Pierre Dubé, Martin Dres, Julien Mayaux, Suela Demiri, Thomas Similowski, Alexandre Demoule
Journal: Thorax (2017)

<h3>Rationale</h3> In intensive care unit (ICU) patients, diaphragm dysfunction is associated with adverse clinical outcomes. Ultrasound measurements of diaphragm thickness, excursion (EXdi) and thickening fraction (TFdi) are putative estimators of diaphragm function, but have never been compared with phrenic nerve stimulation. Our aim was to describe the relationship between these variables and diaphragm function evaluated using the change in endotracheal pressure after phrenic nerve stimulation (Ptr,stim), and to compare their prognostic value. <h3>Methods</h3> Between November 2014 and June 2015, Ptr,stim and ultrasound variables were measured in mechanically ventilated patients &lt;24 hours after intubation ('initiation of mechanical ventilation (MV)', under assist-control ventilation, ACV) and at the time of switch to pressure support ventilation ('switch to PSV'), and compared using Spearman9s correlation and receiver operating characteristic curve analysis. Diaphragm dysfunction was defined as Ptr,stim &lt;11 cm H<sub>2</sub>O. <h3>Results</h3> 112 patients were included. At initiation of MV, Ptr,stim was not correlated to diaphragm thickness (p=0.28), EXdi (p=0.66) or TFdi (p=0.80). At switch to PSV, TFdi and EXdi were respectively very strongly and moderately correlated to Ptr,stim, (r=0.87, p&lt;0.001 and 0.45, p=0.001), but diaphragm thickness was not (p=0.45). A TFdi &lt;29% could reliably identify diaphragm dysfunction (sensitivity and specificity of 85% and 88%), but diaphragm thickness and EXdi could not. This value was associated with increased duration of ICU stay and MV, and mortality. <h3>Conclusions</h3> Under ACV, diaphragm thickness, EXdi and TFdi were uncorrelated to Ptr,stim. Under PSV, TFdi was strongly correlated to diaphragm strength and both were predictors of remaining length of MV and ICU and hospital death.
The effect of demographics and socio-economic factors on survival in unresectable intrahepatic cholangiocarcinoma: A Surveillance, Epidemiology and End Results (SEER) population study.
Authors: Johannes Maximilian Ludwig, Minzhi Xing, Hyun Sik Kim
Journal: Journal of Clinical Oncology (2015)

e15117 Background: To investigate long-term survival in patients with unresectable ICC based on socio-demographic factors in a large-scale population study. Methods: The US Surveillance, Epidemiology and End Results (SEER) database was queried for patients with ICC not amenable to cancer-directed surgery/radiation diagnosed from 2000-2010. Mean overall survival (OS) was stratified according to patient characteristics including gender, age at diagnosis, ethnicity, geographic location, income, education, and urbanization. Kaplan-Meier estimation and Cox proportional hazard models were used for survival analysis and to assess independent prognostic factors for OS. Results: Of 63,434 newly diagnosed liver cancer patients, 5,409 had ICC, median age 71 yrs, 50% male. OS was significantly correlated with age at diagnosis (< 70 vs. ≥ 70 yrs, 24.0 vs. 17.5 months, p < .001), ethnicity (white, black, American Indian, Asian/Pacific Islander; 20.6, 18.6, 18.2, 18.3 months; p < .001), geographic location (East, Northern Plains, Southwest, Pacific Coast, Alaska; 20.5, 23.4, 17.5, 20.7, 30.5 months; p = .03), income (median household income ≥ $45k vs. < $45k/year, 17.6 vs. 21.5 months, p < .001), education (% bachelor degree or above, ≥ 25% vs. < 25%, 19.2 vs. 21.9 months, p < .001) and degree of urbanization (county population ≥ 50k vs. < 50k, 21.4 vs. 14.3 months, p = .007). Conclusions: In unresectable ICC, socio-demographic factors including age <70, white ethnicity, those from Alaska, urban settings, and higher income & education levels were significantly correlated with prolonged OS in a population-based study. Demographic Factors Mean OS P-value Age at Diagnosis < 70 yrs* 24.0 ± 1.0 < 0.001 ≥ 70 yrs 17.5 ± 1.0 Ethnicity White* 20.8 ± 0.8 < 0.001 Black 18.6 ± 1.4 American Indian 18.2 ± 0.9 Asian/Pacific Islander 18.3 ± 1.8 Region East 20.5 ± 1.3 0.03 Northern Plains 23.4 ± 2.7 Southwest 17.5 ± 2.6 Pacific Coast 20.7 ± 0.9 Alaska* 30.5 ± 4.1 Urbanization Urban* 21.4 ± 0.8 0.007 Rural 14.3 ± 2.2 Median Household Income < $45k/year 17.6 ± 1.7 < 0.001 ≥ $45k/year* 21.5 ± 0.8 % Bachelor degree or higher < 25% 19.2 ± 0.6 < 0.001 ≥ 25%* 21.9 ± 1.0 *Stat. Significance
Downregulation of Let-7i to promote stem-like properties of head and neck cancer cells through activating ARID3B-Oct4 axis.
Authors: Tsai-Tsen Liao, Muh-Hwa Yang
Journal: Journal of Clinical Oncology (2013)

e13584 Background: Head and neck squamous cell carcinoma (HNSCC) is one of the major male cancers worldwide, and the main therapeutic strategies include surgery, radiotherapy and chemotherapy. Cancer stem cells are a small population of tumor cells that are responsible for tumorigenesis, tumor recurrence and treatment resistance. let-7 family microRNAs have been shown to function as a tumor suppressor. Here we aim to investigate the role of let-7i in regulating stem cell properties in HNSCC. Methods: Luciferase reporter assay were used to identify the targets of let-7i; Western blot to analysis the correlation between ARID3B and Oct4; ChIP assay confirm the binding of ARID3B to Oct4 proximal promoter; Quantitative RT-PCR to analyzed the level of ARID3B, Oct4, and let-7i in the 52 pairs of samples containing primary tumor tissues and adjacent normal epithelium from head and neck cancer patients with different stage receiving surgery. Results: ARID3B, a member of the AT-rich interaction domain family proteins which plays an essential role during embryogenesis, is a bona fide target of let-7i. ARID3B promotes stem-like properties of HNSCC cells and upregulates a panel of stemness genes, and Oct4 is one of the most prominent ones to be upregulated. ARID3B direct binds to the AT-rich region of Oct4 promoter to activate its transcription. Downregulation of let-7i in HNSCC samples correlates with a corresponding upregulation of Oct4 and ARID3B. Conclusions: We propose a mechanism of let-7i repression-mediated stem-like properties through releasing the suppression of a novel let-7i target ARID3B, which leads to transcriptional activation of stemness genes. The results provide useful information in elucidating the mechanism of HNSCC progression and also provide potential targets in developing HNSCC-specific treatment.