tbuckley/cabot-search huggingface dataset:
Prognostic and predictive effects of <i>TP53</i> mutation in patients with <i>EGFR</i>-mutated non-small cell lung cancer (NSCLC).
Authors: Catherine Labbe, Grzegorz Korpanty, Pascale Tomasini, Mark Doherty, Celine Mascaux, Kevin Jao, Bethany Pitcher, Melania Pintilie, Natasha B. Leighl, Ronald Feld, Geoffrey Liu, Penelope Ann Bradbury, Suzanne Kamel-Reid, Ming Sound Tsao, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2016)

11585 Background: TP53 mutations are common in NSCLC; they occur frequently with other driver mutations, and have been reported as prognostic of poor outcome. The impact of TP53 mutations in EGFR-mutated NSCLC is unclear. Methods: Tissue from 73 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre were analyzed by next-generation sequencing. TP53status was correlated with baseline demographics (sex, ethnicity, age, stage, CNS mets, smoking history, treatment) and outcomes (response [ORR], progression-free [PFS] and overall survival [OS]). Results: Dual TP53/EGFR mutations were found in 31 patients (42%), and were associated with younger age (median 53 v 64 y, p < 0.001). There were more patients with multiple EGFR mutations in the TP53 WT group (19% vs 0%) and more exon 19 deletions in TP53 mut group (68% vs 52%, p = 0.047). OS for all 73 patients was influenced by stage at diagnosis (HR 2.91 stage III, 4.27 stage IV, v I-II) and TP53 mut (HR 2.05, CI 1.02-4.12, p = 0.04). Only 59 patients (26 TP53 mut; 33 TP53 WT) received EGFR TKIs. ORR was not significantly different for TP53 WT v mut (64% v 54%, p = 0.62). In univariable analysis, non-Caucasian ethnicity (HR 0.47, CI 0.25-0.88, p = 0.02) and dual TP53/EGFR mut (HR 1.91, CI 1.04-3.49, p = 0.04) were associated with significant differences in PFS on EGFR TKIs, but not in multivariable analysis. Among 38 patients (19 in each group) treated with chemotherapy, ORR was not influenced by TP53 status. Among 12 patients tested, 4 (80%) TP53 WT and 3 (43%) TP53 mut had T790M mutations. All 6 patients treated with T790M inhibitors (2 TP53 mut; 4 TP53 WT) achieved partial response. There was a non-significant trend for more brain metastases with dual TP53/EGFR mut (58% v 37% at 5 years, p = 0.10); when excluding patients with brain metastases at diagnosis, time to brain metastases was significantly shorter in patients with dual TP53/EGFRmut (HR 2.2, CI 1.07-4.54, p = 0.03). Conclusions: In patients with EGFR-mutated NSCLC, TP53 mutation negatively impacts OS and PFS on EGFR TKIs, and may be associated with brain metastases. Larger datasets are required to validate whether TP53 mutational status is an independent factor predictive of differential benefit from EGFR TKIs.
Dexamethasone, rituximab and cyclophosphamide (DRC) in relapsed/refractory (R/R) and treatment naïve (TN) Waldenström macroglobulinemia (WM).
Authors: Jonas Paludo, Jithma P. Abeykoon, Morie A. Gertz, Shaji Kumar, Rebecca L King, Robert A. Kyle, Francis Buadi, Suzanne R. Hayman, Thomas Matthew Habermann, David Dingli, Thomas E. Witzig, Angela Dispenzieri, Martha Lacy, Carrie A. Thompson, Ronald S. Go, Wilson I. Gonsalves, John Anthony Lust, S. Vincent Rajkumar, Stephen Maxted Ansell, Prashant Kapoor
Journal: Journal of Clinical Oncology (2016)

7552 Background: WM remains an incurable cancer despite recent advances. While the DRC regimen is reportedly effective in TN patients (pts), data for R/R WM are lacking. Ibrutinib, for which the response is dictated by pts’ MYD88 status, has recently been approved for use as continuous therapy in WM. We assessed outcomes of pts receiving upto 6 cycles of DRC, with focus on R/R WM. Methods: We reviewed records of WM pts seen consecutively at Mayo Clinic, MN from 01/2007 to 12/2014. MYD88L265P status, as assessed by AS-PCR, was recorded when available. The Kaplan Meier method was used for all time-to-event analyses from the initiation of DRC. Results: Of 71 evaluable pts who received DRC, 51% had R/R WM. The Table shows baseline characteristics. DRC was 2nd line therapy (range 2-7) in 60% of R/R pts. In the R/R cohort, median time to maximal response (TTMR) was 39 (10-122) weeks, overall response rate (ORR) was 92% (VGPR 3%, PR 66%, MR 23%) and median follow up (FU) was 4.5 years (y) (CI 3.2-5.1) from DRC. The 2y disease specific survival (DSS) was 78%. Median progression free survival (PFS) and time-to-next therapy (TTNT) were 2.6 y (CI 1.2-3.4) and 3.7 y (CI 1.9-5), respectively. In TN pts, median TTMR was 52 (3-204) weeks from DRC. ORR was 100% (VGPR 15%, PR 76%, MR 9%). Median FU was 2.3 y (CI 1.5-2.7). DSS at 2y was 97%. Median PFS and TTNT were 3 y (CI 2-NR) and NR (CI 3.1-NR), respectively. Of 23 pts with available mutation status in the entire cohort, 19 (82%) showed MYD88L265P. The respective ORR and outcomes in the mutant and wild-type groups were similar. All Grade ≥ 3 adverse effects were hematologic (neutropenia 22%, thrombocytopenia 6%). Myelodysplastic syndrome or transformation was noted in 4 pts. Conclusions: DRC is an effective and well-tolerated regimen in both frontline and salvage setting. In contrast to ibrutinib, DRC offers a less expensive, limited-duration treatment option, with preliminary data suggesting activity independent of MYD88 mutation status. R/R (n=36) TN (n=35) median (range) Age, y 60 (40-89) 67 (37-84) Hemoglobin, g/dL 10 (6-15) 9.7 (6-14) Platelet count, x109/L 264 (80-664) 178 (27-415) B2 microglobulin, mcg/mL 2.8 (1.3-8) 3 (2-7) IgM, g/dL 3.3 (1.7-12.4) 3.2 (0.8-10)
Effect of GPC1 on epithelial-to-mesenchymal transition and stemness and interaction with ITGB1 in gastric cancer.
Authors: Shiqing Wang, Zhenzhen Wu, Minyu Zhou, Wangjun Liao
Journal: Journal of Clinical Oncology (2017)

e15580 Background: Gastric cancer is the fourth frequently diagnosed cancer worldwide and tumor metastasis plays an important role in its poor prognosis. EMT, which occurs during embryonic development and carcinoma progression, contributes to metastasis and regulates stemness. GPC1, a member of the heparan sulfate proteoglycans family, is overexpressed in many types of cancer, and associates with metastasis and tumor progression. However, it is unknown that the functions of GPC1 and its underlying mechanism in gastric cancer. Methods: Immunohistochemistry analysis was performed in 245 GC tissues to explore the relationship between GPC1 and tumor metastasis. Transwell migration and wound-healing assay were conducted to evaluate the effects of GPC1 on migration and invasiveness. Epithelial marker and mesenchymal markers expression in GC cells were detected by Western blot and immunofluorescence. GPC1 expression induced by TGF-β was detected by Western Blot. After GPC1 was knock downed, the metastatic effect and EMT markers induced by TGF-β were detected. Co-Immunoprecipitation was used to detect the interaction between ITGB1 and GPC1. Results: The expression of GPC1 was higher in GC tissues than in adjacent normal tissues and associated with poor prognosis. Knocking down GPC1 suppressed EMT and stemness which reduced metastasis in vivo and vitro by inhibiting Erk1/2 MAPK and FAK/Akt pathways. TGF-β stimulation significantly upregulated the expression of GPC1 whereas knocking down of GPC1 reversed TGF-β-mediated EMT and stemness. Moreover, we found that knocking down GPC1 could downregulate ITGB1 which was known to promote EMT in gastric cancer. Overexpression of ITGB1 counteracted the influence of knocking down GPC1 on EMT and stemness. Furthermore, GPC1 formed a complex with ITGB1, which indicated that the ability of GPC1 to stimulate EMT is ITGB1-dependent. Conclusions: We conclude that GPC1, through its interaction with ITGB1, plays an important role in regulating TGF-β-mediated EMT and stemness, and could be a potential future therapeutic target to prevent progression of gastric cancer.
Outcomes by hypomagnesemia in the randomized phase III ASPECCT trial in patients with chemorefractory wild-type <i>KRAS</i> exon 2 metastatic colorectal cancer (mCRC).
Authors: Timothy Jay Price, Tae Won Kim, Jin Li, Stefano Cascinu, Paul Ruff, Attili Venkatasatya Suresh, Anne Thomas, Sergei Tjulandin, Xuesong Guan, Marc Peeters
Journal: Journal of Clinical Oncology (2016)

e15050 Background: ASPECCT demonstrated that panitumumab (pmab) was noninferior to cetuximab (cmab) for overall survival (OS). Ad hoc analyses from ASPECCT suggested that hypomagnesemia(hypomag) was associated with better outcomes for pmab and cmab (Price et al. Lancet Oncol 2014;15:569). However, results from the phase 3 NCIC CTG/AGITG CO.17 trial indicated hypomag at day 28 was associated with worse outcomes for cmab (Vickers et al. Ann Oncol 2013;24:953). Methods: Patients (pts) with chemorefractory wild-type (WT) KRASexon 2 mCRC were randomized 1:1 to receive pmab or cmab. Ad hoc analyses by hypomag were performed from the final analysis of ASPECCT at week 5, consistent with the NCIC CTG/AGITG CO.17 trial analysis (Vickers, 2013). Results: 999 pts were treated: 496 received pmab and 503 received cmab. Any grade hypomag was 29.0% and grade ≥3 was 7.3% in the pmab arm vs 19.3% and 2.8% in the cmab arm, respectively. In the pmab arm, 1.2% of pts discontinued treatment and 5% of pts had dose modifications due to hypomag vs 0.4% and 3% in the cmab arm, respectively. Efficacy results by hypomag are shown (Table). Conclusions: In ASPECCT, rates of hypomag were higher in the pmab vs the cmab arm. Pts who developed any grade hypomag with pmab or cmab had longer median OS compared with those pts who did not. Consistent with previous analyses, development of hypomag at week 5 was associated with worse median OS for cmab. Clinical trial information: NCT01001377. Pmab N Cmab N Median OS –mo (95% CI) HR (95% CI) Median OS – mo (95% CI) HR (95% CI) Any Grade Hypomag* 144 13.6 (11.6–15.4) 0.63 (0.51–0.78) 97 12.6 (10.2–14.8) 0.71 (0.56–0.90) No Hypomag 352 8.7 (8.0–9.8) 406 9.3 (8.3–10.1) Worst Grade 2–4 Hypomag 69 13.6 (11.4–15.4) 1.12 (0.78–1.60) 37 10.3 (8.0–14.8) 1.31 (0.83–2.05) Worst Grade 1 Hypomag 75 13.9 (10.6–19.1) 60 12.6 (11.0–17.3) Any Grade Hypomag at Wk 5 37 12.0 (6.3–14.6) 1.20 (0.83–1.73) 23 8.1 (6.0–10.3) 1.67 (1.09–2.56) No Hypomag at Wk 5 403 11.3 (10.1–12.4) 417 10.5 (9.6–11.7) ≥20% Decrease in mg Levels at Wk 5 54 10.8 (7.3–14.3) 1.18 (0.87–1.61) 36 7.3 (4.9–8.6) 2.16 (1.52–3.08) <20% Decrease in mg Levels at Wk 5 384 11.3 (10.3–12.6) 402 10.8 (9.8–12.0) *Refers to pts who developed hypomag anytime during the study.
Using reconditioned pacemakers to treat bradycardia in Africa
Authors: Kevin Wunderly, Zaheer Yousef, Aimé Bonny, Kevin J. Weatherwax, Balasundaram Lavan, Craig Allmendinger, Brad Wasserman, George Samson, Sheldon Davis, George Nel, James Russell, Constantine Akwanalo, Mahmoud U. Sani, Ashely Chin, Olujimi A. Ajijola, Bongani M. Mayosi, Kim A. Eagle, Thomas C. Crawford
Journal: Nature Reviews Cardiology (2018)
Association of dairy intake with cardiovascular disease and mortality in 21 countries from five continents (PURE): a prospective cohort study
Authors: Mahshid Dehghan, Andrew Mente, Sumathy Rangarajan, Patrick Sheridan, Viswanathan Mohan, Romaina Iqbal, Rajeev Gupta, Scott Lear, Edelweiss Wentzel-Viljoen, Alvaro Avezum, Patricio Lopez-Jaramillo, Prem Mony, Ravi Prasad Varma, Rajesh Kumar, Jephat Chifamba, Khalid F Alhabib, Noushin Mohammadifard, Aytekin Oguz, Fernando Lanas, Dorota Rozanska, Kristina Bengtsson Bostrom, Khalid Yusoff, Lungiswa P Tsolkile, Antonio Dans, AfzalHussein Yusufali, Andres Orlandini, Paul Poirier, Rasha Khatib, Bo Hu, Li Wei, Lu Yin, Ai Deeraili, Karen Yeates, Rita Yusuf, Noorhassim Ismail, Dariush Mozaffarian, Koon Teo, Sonia S Anand, Salim Yusuf
Journal: The Lancet (2018)
P8 INCREASING ENDOTHELIAL INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR EXPRESSION REDUCES CIRCULATING LEUKOCYTES AND PROTECTS AGAINST ATHEROSCLEROSIS
Authors: M Drozd, N Y Yuldasheva, A Maqbool, H Viswambharan, N T Watt, V Palin, S Galloway, A Skromna, N Makava, S B Wheatcroft, M T Kearney, R M Cubbon
Journal: Cardiovascular Research (2018)
Toxicities in immunotherapy: Can they predict response?
Authors: Lisa Mary Prior, Emily Harrold, Connor Gerard O'Leary, Killian Nugent, Jack Patrick Gleeson, Geoffrey Alan Watson, Marvin Chang Jui Lim, Deirdre Kelly, John McCaffrey, Catherine Margaret Kelly
Journal: Journal of Clinical Oncology (2016)

e14534 Background: Checkpoint inhibitors have been shown to improve survival outcomes in patients with metastatic malignant melanoma. However, the use of these agents is associated with a unique spectrum of immune related toxicities. Despite this, durable responses on immunotherapy are still possible even in patients who experience grade 3 toxicities. Furthermore, trials to date have shown that steroids do not appear to affect survival. We present the long term data on real world toxicities and response rates for patients treated previously with Ipilimumab at a national academic cancer centre. Methods: All patients treated previously with Ipilimumab at our centre were identified from pharmacy records. We performed a retrospective paper and electronic review and extracted relevant demographic data (age, sex) and clinical data (number of cycles, incidence and grade of immune related adverse events, interruption/cessation of therapy, need for immunosuppression, initial response to treatment and time to progression). Results: 33 patients with metastatic malignant melanoma were treated with Ipilimumab at our centre from 2011 to 2016. The incidence of G1, G2 and G3 toxicities was 33% (n = 11), 6% (n = 2) and 29% (n = 9), respectively. 23% (n = 7) of patients required steroids and 6% (n = 2) required TNF-a inhibitors. Treatment was stopped in 23% of patients due to Grade 3 toxicites. Of the grade 3 toxicities, colitis was the most common (46%, n = 6). In addition, rare toxicities were idenfied including orbital myositis (1 patient) and myelitis (1 patient). The response rate in the patient subset that required steroids was 42% vs. 15% in those that did not. The median duration of response in those that required and did not require steroids was 8 and 7 months respectively. Conclusions: Higher response rates and a longer median duration of response was seen in patients with grade 3 toxicities requiring steroids. The incidence of toxicities may reflect increased immunotherapy activity, thus leading to superior response rates. Further studies are needed to assess if earlier use of steroids to mitigate toxicities and the possibility of
Impact of patient reported functional limitation on overall survival in older adults undergoing autologous hematopoietic cell transplant (AutoHCT).
Authors: Mariam T. Nawas, Charalambos Andreadis, Thomas G. Martin, Jeffrey Lee Wolf, Weiyun Z. Ai, Lawrence D. Kaplan, Gabriel N. Mannis, Aaron Logan, Lloyd Earl Damon, Chiung-Yu Huang, Rebecca L. Olin
Journal: Journal of Clinical Oncology (2018)

10030 Background: The optimal means of assessing fitness for AutoHCT in older adults with hematologic malignancies is unknown. Few studies have evaluated the impact of patient reported function on AutoHCT outcomes. Methods: Comprehensive geriatric assessment (GA) including the FACT-BMT quality of life tool was administered to 184 patients ≥50 years old (median 61, range 50-75) at a median of 21 days prior to AutoHCT (range 1-186 days). Associations between GA/QOL metrics and post-transplant outcomes were evaluated using Cox regression. Results: The indication for AutoHCT was multiple myeloma / amyloid in 139 patients (76%), lymphoma in 39 patients (21%) and acute leukemia in 6 patients (3%). Median progression-free survival (PFS) was 28 months, and median overall survival (OS) was not reached (median follow up time 23 months). Both PFS and OS were significantly associated with 5 GA components: limitation in instrumental activities of daily living (IADL), patient reported Karnofsky performance status (KPS), and FACT physical, functional and BMT subscale scores (Table). In multivariate analysis, each GA component was adjusted for known prognostic factors (age, provider reported KPS, disease status, comorbidity index). Three components – IADL limitation, patient reported KPS, and FACT-BMT physical subscale score – remained predictive of both PFS and OS. Age was not associated with PFS or OS. Conclusions: In patients ≥50 years old undergoing AutoHCT, limitation in any one of three patient reported measures of functional status is independently associated with inferior PFS and OS, even when adjusting for known prognostic factors. Importantly, chronologic age is not associated with outcomes in this population. Measure Univariate HR (p value) Multivariate HR (p value) Any IADL limitation PFS 1.94 (0.003) 1.76 (0.02) OS 2.99 (0.003) 2.68 (0.02) Patient reported KPS (per decile) PFS 0.80 (0.004) 0.78 (0.01) OS 0.69 (0.004) 0.74 (0.06) FACT physical score PFS 0.94 (0.001) 0.96 (0.02) OS 0.91 (0.001) 0.93 (0.03) FACT functional score PFS 0.95 (0.02) 0.96 (NS) OS 0.91 (0.008) 0.94 (NS) FACT BMT score PFS 0.96 (0.02) 0.97 (NS) OS 0.93 (0.01) 0.96 (NS)
Market capitalism in cancer pharmaceuticals.
Authors: Henry Jacob Conter
Journal: Journal of Clinical Oncology (2017)

e18295 Background: How can health technology assessments be deployed in a market-based healthcare system to improve value and sustainability? Methods: The pan-Canadian Oncology Drug Review (pCODR) is an evidence-based, cancer drug review process that guides formulary decision-making. As of 1/1/17, data from all 98 reviews and economic guidances were abstracted for price of medication, total health care cost per patient, cost-utility provided by the submitter and re-analysis by pCODR. Regression analysis identified correlations. Expected use of therapy was estimated employing data from the Canadian Cancer Society. An optimal formulary was developed, optimizing value for money. Results: Of the 98 reviews, 13 were not finalized, 3 were withdrawn, 1 was suspended. 4 reviews were excluded since the base-case was ambiguous. The median drug price per 28-day cycle was $7,567 (range $2,800-$18,435), with no annual difference from 2012-2016 (p = 0.49). The median best-estimate of cost-utility was $190,858/QALY (IQR $125,585/QALY) with a median net increase in health system cost of $62,771/patient (IQR $89,260) and 0.48 LYG/patient (range 0.04-2.43). Cost per 28-day cycle was a weak predictor of value (R² = 0.02, p &lt; 0.01), and not of health system cost (R² = 0.14, p = 0.06). Funding all efficacious medications by a single payer insurance plan in Canada would require $5.91 billion producing 31,705 QALYs, annually. 26% of the cumulative budget would buy 41% of the health benefit, 56% of the budget would buy 70% of the effect. Once a budget is determined, new medication would replace drugs of higher cost per QALY. Employing this method increased QALY yield of the budget by 67%, 21%, 15%, and 14% at $1B, $2B, $3B, and $4B, respectively. The formulary turnover would be 66%, 44%, 37%, and 22% at each respective budget level. Conclusions: An optimized formulary requires practical deployment of HTA, the ability to shift resources across budgets, and the ability to continuously renegotiate prices based on incremental value. Future work is needed on publically acceptable divestment methods for lower value pharmaceuticals.
Clinical significance and next-generation sequencing of Chinese pulmonary sarcomatoid carcinoma.
Authors: Jun Chen
Journal: Journal of Clinical Oncology (2018)

e20553 Background: Pulmonary Sarcomatoid carcinomas (PSC) are a heterogeneous group of non–small-cell lung carcinomas (NSCLC) with a poor prognosis despite aggressive surgical resection and other multiple treatments. So far, the characteristics of gene mutations in patients with PSC are still poorly understood. Methods: A cohort including 7 patients with PSC was studied by light microscopy, immunohistochemistry (IHC) to establish their clinical and histologic characteristics. Then a whole-exome sequencing (WES) was performed to investigate the somatic mutation status of PSC. Results: The patient populations were comprised of 4 men and 3 women with age range 38–73 years. Under light microscopy, all 7 cases were pleomorphic carcinoma subtype, of which 5 cases (71.4%) comprised entirely of malignant sarcomatoid components (spindle cells and giant cells), 2 cases (28.6%) comprised of malignant sarcomatoid components and at least 10% adenocarcinoma elements. Immunohistochemically, the PSC components of all 7 cases were positive for vemintin and cytokeratins, inculding cytokeratin (CK) and cytokeratin7 (CK7). After WES, a total of 136 putative somatic variants (SNP, INDEL) and one gene fusion were identified, of which 16 variants were considered as hot spot mutation (COSMIC), including EGFR, EML4-ALK, MET. S203F, BRAF p.G469A, PIK3CA.H1047R and PIK3CA. H1048R. In these hot spot mutations, one sample with EML4-ALK fusion event with allele fraction of 0.12 was further confirmed by Ventana IHC, and an EGFR exon19 deletion in one sample with allele fraction of 0.50 was detected. Conclusions: The WES results imply that TP53 mutations were more often appeared in PSC, also EML4-ALK fusion event and EGFR exons mutation were existed in these rare tumors. For now, early detection, accurate diagnosis and a complete surgical resection without metastasis are the mainstay treatments of PSC with the best chances for long-term survival. Molecular target therapy may be a new treatment strategy for these rare tumors of the lung.
Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy
Authors: Priyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey Ager, Courtney Nicholas, Ashvin R. Jaiswal, Yanqiu Sun, Krishna Shah, Sadhana Balasubramanyam, Nan Li, Guocan Wang, Jing Ning, Anna Zal, Tomasz Zal, Michael A. Curran
Journal: Journal of Clinical Investigation (2018)

Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy.