tbuckley/cabot-search huggingface dataset:
On-demand Gamma Knife combined with BRAF inhibitors for the treatment of melanoma brain metastases.
Authors: Caroline Gaudy-Marqueste, Romain Carron, Christine Delsanti, Anderson Loundou, Sandrine Monestier, Elodie Archier, Marie-Aleth Richard, Jean Regis, Jean-Jacques Grob
Journal: Journal of Clinical Oncology (2014)

9083 Background: Both Gamma-Knife radiosurgery (GKRS) and BRAF-inhibitors (BRAF-I) have been shown to be useful in melanoma patients with brain metastases (BM), thus suggesting that it could be interesting to combine their respective advantages. However cases of radiosensitization following conventional radiation therapy in BRAF-I treated patients have raised serious concerns about the real feasibility and risk/benefit ratio of this combination. Methods: Blind review by 2 independent observers of brain MRI follow-up pictures and survival assessment in all patients who had been treated by GKRS and BRAF-I at a single institution. Results: Among53 GKRS performed in 30 patients who ever received BRAF-I and GKRS, 33 GKRS were performed in 24 patients while under BRAF-I treatment, from which only 4 with an interruption of BRAF-I. The 20 other GKRS were performed in 15 patients (including 9 of the 24) before initiation of BRAF-I treatment. Out of the 263 BM treated, only 3 edemas and 3 hemorrhages were detected within 2 months after GKRS and 4 edemas and 7 hemorrhages were detected later. No case of BM radiation necrosis and no scalp radiation dermatitis occurred. Neither the MRI features nor the incidence of the rare adverse events were deemed unexpected in such a population of melanoma BM. Median survival from first GKRS and first dose of BRAF-I was 24.7, and 48.8 weeks, respectively. Conclusions: This series does not show immediate radiotoxicity nor radiation-recall, in melanoma patients with BRAF-I whose BM are treated by GKRS. Interrupting BRAF-I for stereotactic radiosurgery of BM seems useless, although it is still advised for other radiation therapies. Overall very favorable survival figures suggest to test the potential benefit of combining stereotactic radiosurgery and BRAF-I.
Comparison of Sales Income and Research and Development Costs for FDA-Approved Cancer Drugs Sold by Originator Drug Companies
Authors: Kiu Tay-Teo, André Ilbawi, Suzanne R. Hill
Journal: JAMA Network Open (2019)

<h3>Importance</h3> High costs and risks of research and development (R&amp;D) have been used to justify the high prices of cancer drugs. However, what the return on R&amp;D investment is, and by extension what a justifiable price might be, is unclear. <h3>Objective</h3> To compare incomes from the sales of cancer drugs with the estimated R&amp;D costs. <h3>Design, Setting, and Participants</h3> This observational study used global pharmaceutical industry sales data to quantify the cumulative incomes generated from the sales of cancer drugs for companies that have held patents or marketing rights (originator companies). All cancer drugs approved by the US Food and Drug Administration from 1989 to 2017 were identified from the United States Food and Drug Administration's website and literature. Itemized product sales data were extracted from the originator companies' consolidated financial reports. For drugs with data missing in specific years, additional data was sought from other public sources, or where necessary, estimated values from known reported values. Drugs were excluded if there were missing data for half or more of the years since approval. Data analysis was conducted from May 2018 to October 2018. <h3>Main Outcomes and Measures</h3> Sales data were expressed in 2017 US dollars with adjustments for inflation. Cumulative incomes from the sales of these drugs were compared against the R&amp;D costs estimated in the literature, which had been adjusted for the costs of capital and trial failure (risk adjusted). <h3>Results</h3> Of the 156 US Food and Drug Administration–approved cancer drugs identified, 99 drugs (63.5%) had data for more than half of the years since approval and were included in the analysis. There was a median of 10 years (range, 1-28 years) of sales data with 1040 data points, 79 (7.6%) of which were estimated. Compared with the total risk-adjusted R&amp;D cost of $794 million (range, $2827-$219 million) per medicine estimated in the literature, by the end of 2017, the median cumulative sales income was $14.50 (range, $3.30-$55.10) per dollar invested for R&amp;D. Median time to fully recover the maximum possible risk-adjusted cost of R&amp;D ($2827 million) was 5 years (range, 2-10 years; n = 56). Cancer drugs continued to generate billion-dollar returns for the originator companies after the end-of-market exclusivity, particularly for biologics. <h3>Conclusions and Relevance</h3> Cancer drugs, through high prices, have generated returns for the originator companies far in excess of possible R&amp;D costs. Lowering prices of cancer drugs and facilitating greater competition are essential for improving patient access, health system's financial sustainability, and future innovation.
Improved access to tobacco cessation services for cancer patients using a statewide collaborative approach.
Authors: Jane Alcyne Severson, Hilary Baca, Douglas W Blayney, Karen Brown, Grayce Galiyas, Mara Minasian, Joan Schmidt, Anna Schulze, Graham Walter Warren
Journal: Journal of Clinical Oncology (2014)

6613 Background: The Michigan Oncology Quality Consortium (MOQC) collaborated with the Michigan Department of Community Health (MDCH) and Michigan Cancer Consortium (MCC) to implement a statewide Tobacco Cessation Demonstration Project to improve cancer patients' access to tobacco cessation services. Methods: Beginning in fall 2012, MOQC, MDCH, and MCC implemented a program to refer all cancer patients who use tobacco to the Michigan Tobacco Quitline. Referred patients were provided free counseling services and nicotine replacement therapy. A lean problem solving approach was deployed that included standard workflows, scripts, and visual management tools to support frontline staff in identifying all cancer patients who use tobacco and referring them to the Quitline. Eighteen oncology practices (63 physicians) participated in 3 learning sessions during which the following were provided: education by subject matter experts, data management and lean tools, and sharing of barriers and successes. Results: Between May and December of 2013, a total of 694 cancer patients were referred for cessation support and at least 1 contact attempt was made for 686 patients. A total of 308 patients (45%) were successfully contacted by the Quitline, only 3% were ineligible to participate, and 26% declined participation. Whereas total Michigan Quitline referrals increased by an average of 40% each month in this period, non-MOQC referrals decreased from 140 per month in May to 95 per month in December. In contrast, MOQC cancer patient referrals increased from 62 per month to 80-123 per month in the subsequent months representing an average of 43% of all Michigan Quitline referrals. Tobacco assessment rates for cancer patients were maintained above 95%, and an average of 61% of eligible cancer patients were referred to the Quitline, a four-fold increase from the baseline referral rate of 15%. Conclusions: Increasing access to dedicated statewide resources and providing oncology practices with lean resources including standardized workflows improves the tobacco cessation referral rate for oncology patients. Improvements in referral rates may significantly increase participation in dedicated tobacco cessation programs.
Abstract 2003: P38α suppresses tumor initiating cell phenotypes through inhibition of NFATc4 in non-small cell lung cancer
Authors: Zhi-Jie Xiao, Jing Liu, Si-Qi Wang, Xu-Yuan Gao, Vicky Pui-Chi Tin, Maria Pik Wong
Journal: Cancer Research (2018)

Abstract Lung cancer development is often mediated through oxidative and inflammatory stresses caused by tobacco and environmental carcinogens, suggesting dysregulation of stress mediators might play a role during carcinogenesis. The p38 MAPK pathway is activated by multiple stress stimuli and inflammatory cytokines, and mediates a wide range of cellular processes in a context-specific manner. P38α, a member of the p38 family, is known to regulate the self-renewal and differentiation of adult lung stem cells. While p38α has been reported to mediate tumor suppressive or supportive roles in different cancers, inactivation of p38α in the lung epithelium is involved in KRASG12V induced tumorigenesis. However, whether p38α could be involved in regulating tumor initiating cells (TIC) of lung cancer remains unclear. To investigate this possibility, immunohistochemistry was first used to analyse the nuclear expression of phosphorylation-activated p38α (p-p38α) in 90 human primary lung adenocarcinomas. Results showed higher expression of p-p38α was significantly correlated with longer progression free and overall survivals, as well as a more differentiated tumor histological phenotype, indicating p38α might play a tumor suppressive role and drive tumor differentiation in lung cancer. To further address its functional role on lung TIC, p38α was suppressed by siRNA or pharmacologically inhibited by SB203580. This led to increase of the TIC subset that coexpresses ALDH and CD44 (ALDH+/CD44+-TIC), as well as up-regulated expression of the pluripotency genes SOX2, OCT4, and NANOG in lung cancer cell lines. Functionally, p38α inhibition by SB203580 promoted tumor spheres formation for two consecutive generations. NFAT is a family of transcription factors reported to regulate TIC in various cancers which are activated via de-phosphorylation leading to nuclear translocation. We hypothesize the TIC supportive function of p38α inhibition might be mediated through loss of phosphorylation and subsequent activation of NFATc4. In line with this hypothesis, we showed, using Western blot, p38α inhibition increased the expression of nuclear NFATc4. Moreover, NFATc4 knockdown led to suppressed sphere formation and pluripotency genes expression in lung cancer cell lines. Together, our results indicated p38α mediates a tumor suppressor pathway through downstream NFATc4 inactivation and TIC inhibition. The p38α -NFATc4 stress pathway might serve as a potential target for long term lung cancer treatment through TIC regulation. Citation Format: Zhi-Jie Xiao, Jing Liu, Si-Qi Wang, Xu-Yuan Gao, Vicky Pui-Chi Tin, Maria Pik Wong. P38α suppresses tumor initiating cell phenotypes through inhibition of NFATc4 in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2003.
Outcomes of Follicular Lymphoma Patients Treated with Frontline Bendamustine and Rituximab: Impact of Histologic Grade and Early Progression on Overall Survival
Authors: Allison M. Winter, Loretta J. Nastoupil, Melody R. Becnel, James R. Cerhan, Thomas M. Habermann, Brian K. Link, Matthew J. Maurer, Bita Fakhri, Prathima Reddy, Stephen D. Smith, Dhruvika Mukhija, Deepa Jagadeesh, Amrita Desai, Juan Pablo Alderuccio, Izidore S. Lossos, Pooja Mehra, Craig A. Portell, Christopher R. D'Angelo, Vaishalee P. Kenkre, Max L. Goldman, Oscar Calzada, Jonathon B. Cohen, Mohammad Junaid Hussain, Nilanjan Ghosh, Yang Liu, Stefan Klaus Barta, Paolo F Caimi, Adam Kittai, Alexey V Danilov, Timothy Tiutan, Peter Martin, Nathalie Danielson, Manali Kamdar, Abhigna Kodali, Andrew M. Evens, Brad S Kahl, Brian T. Hill
Journal: Blood (2018)
Development of a patient-reported outcome (PRO) measure for assessing non-small cell lung cancer (NSCLC) symptoms in clinical trials: Interim report from the PRO Consortium’s NSCLC Working Group (WG).
Authors: Alicyn K. Campbell, Mona L. Martin, Jean Marie Arduino, Thomas Michael Atkinson, J. Jason Lundy, Juliane Lungershausen, Louis J. Denis, Astra M. Liepa
Journal: Journal of Clinical Oncology (2014)

e17620 Background: In collaboration with the FDA, the Critical Path Institute - PRO Consortium NSCLC WG is developing a new PRO measure to assess treatment (tx) benefit in advanced NSCLC trials and to support label claims. Methods: Symptoms relevant to the NSCLC patients (pts) were first identified from the literature. Next, interviews were conducted with NSCLC pts at 6 US sites. Transcripts were coded using Atlas.ti software and pt-elicited concepts were grouped by similar content then reviewed by the WG and an expert panel to identify symptoms most relevant for assessing tx benefit. Items were generated and combined into a draft measure for cognitive testing with NSCLC pts. Results: Characteristics of the 51 pts interviewed included: mean age 64.8 years [range 46–86]; 51% female; NSCLC Stage I (12%), III (37%), and IV (51%); and tx–naïve (29%), first-line (43%), or second/third-line (27%). The most commonly expressed symptom was fatigue, described by pts as tiredness, lack of energy, tires easily, and weakness. Other symptom concepts expressed included general pain, chest pain, cough, shortness of breath, difficulty breathing, appetite change, and coughing up blood. Items were drafted to assess either symptom frequency or severity for 9 distinct symptoms using a 7-day recall period. During cognitive interviews, an 11-point numerical rating scale and a 5-point verbal rating scale were tested. Preliminary cognitive testing indicates the 5-point verbal scale is better understood by pts. Conclusions: Pt-elicited NSCLC symptoms, across varied disease stages/tx, were concordant with the pathophysiology of disease. A new PRO measure of NSCLC symptoms has been developed in accordance with the FDA’s PRO Guidance. The content of the measure is supported by a review of existing literature, pt-reported experience, and expert opinion. The draft measure is now in cognitive testing, with quantitative testing planned in 2014. Once complete, the measure and supporting evidence will be submitted to the FDA for qualification as an endpoint to quantify tx benefit for product labeling.
A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors.
Authors: Leora Horn, Jeffrey R. Infante, George R. Blumenschein, Heather A. Wakelee, Hendrik-Tobias Arkenau, Gary Dukart, Chris Liang, Kimberly Harrow, Jay Gibbons, Christine Marie Lovly, William Pao
Journal: Journal of Clinical Oncology (2014)

8030^ Background: X-396 is a novel, potent anaplastic lymphoma kinase (ALK) small molecule TKI with significant anti-tumor activity in both ALK TKI naive and crizotinib resistant models of ALK fusion-positive NSCLC. Methods: In this multicenter phase I study, patients with advanced solid tumors were enrolled and given X-396 on a continuous 28-day schedule. This was an accelerated titration design with the dose starting at 25 mg once daily. At the first DLT cohorts were expanded to the classic 3+3 design up to 250 mg daily. All pts were assessed for adverse events (AEs) using CTCAE version 4.0, response to therapy was assessed using RECIST 1.1, and pharmacokinetics (PK) were measured. Results: As of the January 23, 2014 cutoff, 30 patients enrolled (21 NSCLC patients, 13 ALK+ - 3 crizotinib naïve and 10 crizotinib resistant), 4 H&N, 2 SCLC, 2 colorectal,1 breast). Median age 58, 12 ECOG PS 0 and 18 PS 1. The most common drug related AEs include rash (36%, G1-G3), fatigue (30%, G1-G2), nausea (27%, G1), vomiting (27%, G1) and edema (20%, G1-G2). Grade3/4 treatment related AEs were rash (2patients), edema (1patient). X-396 exhibited linear PK at doses 25 – 250mg. At 200mg QD, the t1/2 is ~23 hours, and the trough level (~300nM) is sufficient to inhibit most crizotinib resistant mutations in vitro. To date, 18 patients are evaluable for response; SD is 28% and PR 28%. Among 8 evaluable ALK+ NSCLC cases, responses occurred in crizotinib naïve and crizotinib treated patients. In the 6 ALK+ patients treated at doses ≥ 200 mg SD is 17% and PR 83%; 2 PRs were observed in patients treated with prior crizotinib. CNS responses have been observed in 2 patients, 1 crizotinib naïve and 1 crizotinib resistant. The median duration of treatment in evaluable ALK+ patients is 20+ weeks with the longest being 58+ weeks. Conclusions: X-396 is generally well tolerated at doses up to 250 mg daily and induces responses in both crizotinib naïve and crizotinib resistant ALK+ NSCLC patients. Enrollment is ongoing. Clinical trial information: NCT01625234.
Survival outcome of patient with primary gastric diffuse large B-cell lymphoma: A single center experience.
Authors: Sohail Athar, Sardar Ali Khan, Narjis Muzaffar, Abdul Hameed, Neelam Siddiqui
Journal: Journal of Clinical Oncology (2014)

e19527 Background: Primary gastric lymphoma (PGL) accounts for 3% of gastric malignancies and 10% of lymphoma. PGL is mainly of two histological subtypes, Primary gastric diffuse large B cell lymphoma (PGDLBCL) and MALT (mucosa associated lymphoid tissue) lymphoma. PGDLBCL term is used for lymphoma localized to stomach at presentation. PGDLBCL occurs as de-novo or can arise rarely from transformation of MALT lymphoma to diffuse large B cell lymphoma. Methods: In this retrospective study, 49 patients with PGDLBCL from 2003 to 2013 were included. Their base line IPI score, stage at presentation, bone marrow (BM) involvement and type of treatment were recorded. Results: Median age was 46 years (range 20-76yrs), with thirty seven males (76%) and twelve females (24%). BM involvement was in only two patients (4%). According to Ann Arbor staging, 29 patients (60%) were in stage I, 09 (18%) stage II, 03 (6%) stage III and 08 (16%) in stage IV. IPI risk categorizations, low risk 34 (69%), low intermediate risk 12 (25%), high intermediate risk 01 (2.0%) and high risk 02(4%). Thirty five patients (71.4%) were treated with CHOP chemotherapy and R- CHOP was given to 11 patients (22.4%). Radiation therapy was given as consolidative treatment in 21 (43%) patients. Helicobacter pylori treatment was given to 23 (47%) patients after antibody test positivity. Median follow up was 5.8 years (range 0.6-9.3 years). Kaplan Meir overall survival (OS) at 5 years was 47%. Median OS was 5.7 years (95% CI: 3.3-8.1). Five years OS in patients treated with chemotherapy + XRT with or without rituximab was 70% and 33% in patients treated with chemotherapy with or without rituximab (p=0.001). Patients who were treated for Helicobacter pylori had 5 years survival of 64.6% and 31.5% in patients who had either negative serology or were not tested for Helicobacter pylori (p=0.007). Conclusions: Consolidative radiation therapy has a statistical significant survival impact in patients with PGDLBCL. Eradication of H pylori infection during treatment of PGDLBCL can result in survival benefit. Prospective study is required to validate these results in our population.
Key components of chemotherapy for thymoma and thymic carcinoma: Anthracycline-, carboplatin-, or cisplatin-based chemotherapy.
Authors: Yusuke Okuma, Yukio Hosomi, Kageaki Watanabe, Yoshiro Nakahara, Yusuke Takagi, Makoto Saito, Tatsuru Okamura
Journal: Journal of Clinical Oncology (2014)

e18556 Background: Thymic epithelial tumor, comprising of thymoma and thymic carcinoma, is a rare cancer, therefore, optimal chemotherapy for advanced thymic epithelial tumor is still controversial. Platinum-based chemotherapy is currently the consensus treatment based on results of single-arm phase II trials and retrospective investigations. However, the comparison of cisplatin-based and carboplatin-based is yet to be done, and whether addition of anthracycline is effective also remains uncertain. Methods: Clinical trials and retrospective investigations of platinum-based chemotherapy were analyzed. The endpoints in this study were the response rates of each chemotherapy. For advanced thymoma, we compared platinum with anthracycline- vs. platinum with non-anthracycline-based chemotherapy. For advanced thymic carcinoma, anthracycline- vs. non-anthracycline-based chemotherapy and carboplatin- vs. cisplatin-based chemotherapy were compared. This analysis included a retrospective study of irinotecan and cisplatin for advanced thymic carcinoma in our institution. Results: The response rate for the 314 patients from 15 studies with advanced thymoma, including both prospective and retrospective data, was 69.4% (95% confidence interval (CI): 63.1%-75.0%) for platinum with anthracycline-based chemotherapy and 37.8% (95% CI: 28.1%-48.6%; P < 0.0001) for platinum with non-anthracycline-based chemotherapy. Also, the response rates with anthracycline-based and non-anthracycline-based chemotherapy for advanced thymic carcinoma were similar (40.2% vs. 41.2%; P < 0.89), whereas the response rates with cisplatin- and carboplatin-based chemotherapy for advanced thymic carcinoma were significantly different (52.4% vs. 32.8%; P = 0.0049) in 206 patients from 10 studies. Conclusions: Platinum with anthracycline-based chemotherapy is an optimal combination of chemotherapy for advanced thymoma. For advanced thymic carcinoma, cisplatin-based chemotherapy may be superior to carboplatin-based chemotherapy.
Access and Referral Barriers to Autologous and Allogeneic Hematopoietic Cell Transplantation in Adult Patients with Cancer: A Systematic Review with a Specific Focus on Geriatric Population
Authors: Kah Poh Loh, Jian Liang Tan, Colin M. McHugh, Jane L. Liesveld, Kristen M. O'Dwyer, Michael W. Becker, Jason H. Mendler, Omar S. Aljitawi, Heidi D. Klepin, Wendy Stock, Tanya Wildes, Andrew S Artz, Areej El-Jawahri, Navneet S. Majhail
Journal: Blood (2018)
Effect of inhibition of α-secretase activity on cleavage of p75 neurotrophin receptor (p75NTR) and proliferation of brain tumor initiating cells (BTICs) and malignant gliomas (MGs).
Authors: Rajappa Kenchappa, Niveditha Krishna, Peter A. J. Forsyth
Journal: Journal of Clinical Oncology (2014)

2086 Background: MGs are highly invasive, proliferative, and are resistant to treatment. The identification of Glioma Stem Cells (GSCs a.k.a. BTICs) suggests MGs may arise from these cells. By using an unbiased strategy of serial in vivo selection, we identified p75NTR as a novel mediator of invasion of MGs/BTICs, and p75NTR proteolysis by γ-Secretase was required for glioma invasion (Johnston et al., 2007; Wang et al., 2008). However, p75NTR’s role in glioma proliferation is unknown. We hypothesized that p75NTR also mediates BTICs proliferation via proteolysis by γ-Secretase. Methods: We used frozen human MG tissues and BTICs isolated from fresh human MGs, examined the expression of neurotrophin receptors and their ligands, and studied their role in proliferation. Gene expression data from TCGA and a validation set from the Moffitt Cancer Center MG datasets were also used. Results: We show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB and TrkC), their ligands (NGF, BDNF and NT3), and predominantly secrete NGF. Down regulation of p75NTR significantly decreased BTICs proliferation. Conversely, exogenouous NGF, stimulated BTIC proliferation through γ-secretase mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR-ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF stimulated p75NTR cleavage and BTIC proliferation; suggesting the Trk receptors role in p75NTR signaling and BTIC proliferation. Further, knockdown of p75NTR or pharmacologic inhibition of cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR mediated proliferation. We also found that p75NTR, Trk receptors, α-secretase and the γ-secretase enzymes were elevated in GBM patients. Importantly, the ICD of p75NTR was commonly found in MG patient specimens suggesting that the receptor is activated and cleaved in patient tumors. Conclusions: These results show that p75NTR proteolysis is required for BTIC proliferation and is a novel clinical target.