tbuckley/cabot-search huggingface dataset:
ARCHES: Efficacy of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Andrew J. Armstrong, Russell Zelig Szmulewitz, Daniel Peter Petrylak, Jeffrey M. Holzbeierlein, Arnauld Villers, Arun Azad, Antonio Alcaraz, Boris Yakovlevich Alekseev, Taro Iguchi, Neal D. Shore, Brad Rosbrook, Benoit Baron, Lucy F. Chen, Arnulf Stenzl
Journal: Journal of Clinical Oncology (2019)

5048 Background: ENZA has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ARCHES assessed the efficacy of ENZA with ADT in men with mHSPC, including pre-specified subgroups based on prior therapy. Methods: ARCHES, a multinational, double-blind, Phase 3 study (NCT02677896), randomized patients (pts) with mHSPC 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel (doce) use. Primary endpoint was radiographic progression-free survival (rPFS; centrally assessed radiographic progression or death within 24 weeks of treatment discontinuation). Secondary endpoints included time to initiation of new antineoplastic therapy and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n = 574) or PBO (n = 576). Overall, 63% had high-volume disease, 18% had prior doce, and 91% had prior ADT or orchiectomy (orch). Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); significant improvements in rPFS were also reported in prior treatment subgroups. Secondary endpoints improved with ENZA + ADT (Table), with no significant impact in time to deterioration in urinary symptoms. OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs. 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs. PBO + ADT in men with mHSPC. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Clinical trial information: NCT02677896. [Table: see text]
Circulating tumor DNA (ctDNA) mutation and epigenomic patterns in early-stage lung cancer patients and its utility in identifying patients at high risk for early recurrence.
Authors: Jong Ho Cho, Il-Jin Kim, Junghee Lee, Hong Kwan Kim, Jinseon Lee, Se-Hoon Lee, Matthew Shultz, Ariel Jaimovich, Justin Odegaard, AmirAli Talasaz, Jhingook Kim
Journal: Journal of Clinical Oncology (2019)

e14557 Background: Circulating tumor DNA (ctDNA) analysis has been successfully applied to therapy selection and treatment monitoring in advanced cancer patients. However, it is not yet established whether ctDNA can be used clinically for early cancer detection or predicting tumor recurrence in early stage lung cancer patients. Methods: We analyzed pre-operative plasma samples from 55 early stage NSCLC patients (stages I-IIIA) using next-generation sequencing to detect somatic mutations and differential epigenomics patterns, including methylation signatures. Results: Using somatic mutation analysis alone, ctDNA was detected in 42% (23/55) of patients, whereas combined mutational and epigenomic analysis detected ctDNA in 71%. ctDNA detection rate also varied markedly between lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC);using combined analysis of somatic mutations and epigenomic patterns, ctDNA was detected in all SCC patients, while only 55% of ADC (12/22) were ctDNA-positive (p= 0.006). Within the ADC subgroup, ctDNA detection rates using the combined approach were dependent on disease stage: 47% (8/17) in stage I, 100% (2/2) in stage II, and 100% (2/2) in stage IIIA. Importantly, pre-operative ctDNA status was correlated with tumor recurrence post-resection; three of eight (38%) ctDNA-positive stage I ADC patients recurred within 2 years of resection, while only one of nine (11%) ctDNA-negative stage I ADC patients recurred (p= 0.29). Conclusions: Taken together, we show that the combination of somatic mutation detection and epigenomic analysis outperforms each individual biomarker in the detection of ctDNA in early stage lung cancer. Importantly, we also demonstrate that pre-operative ctDNA detection may identify a high-risk population of early stage lung cancer patients that may benefit from (neo)adjuvant therapy.
Clinical response and long-term follow-up of 20 patients with refractory solar urticaria under treatment with omalizumab
Authors: Daniel Morgado-Carrasco, Macarena Giácaman-Von der Weth, Xavier Fustá-Novell, Sebastián Podlipnik, Amparo Pérez-Ferriols, Paula Aguilera
Journal: Journal of the American Academy of Dermatology (2019)
Role of metabolic reprogramming toward fatty acid oxidation on tumor lymph node metastasis.
Authors: Choong-kun Lee, Seung-hwan Jeong, Cholsoon Jang, Hosung Bae, Yoo Hyung Kim, Intae Park, Sang Kyum Kim, Gou Young Koh
Journal: Journal of Clinical Oncology (2019)

e14501 Background: Metastasis of tumors to lymph node (LN) is a strong predictor of cancer patient mortality and determinant of disease progression and treatment options. Despite the clinical significance of tumor LN metastasis, the mechanisms underlying this process remain largely unexplored. Methods: We used comparative transcriptomics and metabolomics analyses of the primary tumor and LN micro- and macro-metastatic tumors from B16F10 murine melanoma model. B16F10 melanoma footpad implantation model and MMTV-PyMT spontaneous breast cancer genetic mouse models were analyzed in vivo. We also investigated the LN-metastatic tumors from sentinel LNs in 21 patients with melanoma. Results: We found that tumor cells undergo dramatic metabolic reprogramming towards fatty acid oxidation (FAO) for successful LN metastasis. Mechanistically, transcription co-activator YAP is selectively activated in LN metastatic tumors, leading to stimulation of FAO gene programs. Pharmacological inhibition of FAO or genetic ablation of YAP in tumors markedly suppressed LN metastasis. Unexpectedly, metastatic tumors highly stimulated the bile acid synthesis pathway upon arrival at the LN, and these bile acids activated YAP of tumor cells via nuclear vitamin D receptor. Lastly, YAP activation in the metastatic LNs of melanoma patients was reversely correlated with distant metastasis–free survival. Conclusions: This study propose that inhibition of FAO or YAP signaling to prevent the metabolic reprogramming of metastatic tumors offers a potential therapeutic strategy for mitigating tumor LN metastasis.
Final results and OS of the randomized phase II VOLFI trial (AIO- KRK0109): mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer (mCRC).
Authors: Michael Geissler, Jorge Riera-Knorrenschild, Uwe Marc Martens, Swantje Held, Jobst Greeve, Axel Florschütz, Thomas Jens Ettrich, Stephan Kanzler, Andrea Tannapfel, Volker Heinemann, Anke C. Reinacher-Schick, Thomas Seufferlein, Swen Wessendorf, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2019)

3511 Background: This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. The final primary endpoint was presented at ASCO and ESMO 2018. Now we report for the first time the final results regarding OS and PFS. Methods: Prospective 2:1 randomized, controlled, open label multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Prospective strata were cohort 1: irresectable mCRC (n=65), and cohort 2: chance of secondary resection of metastatic lesions (n=31). Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 87.3% in arm A and 60.6% in arm B (p=0.0041, OR 4.47; 95%-CI 1.614-12.376). Secondary resections of metastases in the ITT population were observed in 33·3% (arm A Pmab) versus 12·1% (arm B) (OR=3.63; 95%-CI 1.13–11.67, p=0·029) and in cohort 2 in 75% (arm A Pmab) versus 36.4% (arm B) (OR=5.25; 95%-CI 1.07–25.8, p=0.05), respectively. Median PFS was similar in the study arms (9.7 mo in both arms, HR 1.071; 95%-CI 0.689-1.665, p=0.76). OS in the ITT population showed a strong trend in favour of the Pmab-containing arm A with a median OS of 35.7 mo compared to 29.8 mo in arm B (HR: 0·67; 95%-CI 0.41-1.11, P=0·12). mOS of cohort 2 was 52.0 mo in arm A versus 41.7 mo in arm B (HR 0.413; 95%-CI 0.15-1.12, p=0.07). Further results regarding to sidedness and BRAF mutational status will be presented. Conclusions: The addition of Pmab to a mFOLFOXIRI regimen in patients with RASwildtype metastatic colorectal cancer significantly improved objective response rate and the rate of secondary resection of metastases. Although PFS was comparable, there was a strong trend towards improved OS in the Pmab arm. Future studies are warranted to confirm this trend towards improved overall survival with this regimen. Clinical trial information: NCT01328171.
Impact of dental insurance coverage on presentation, long-term outcomes, and symptom burden in locally advanced head and neck cancer.
Authors: Alec Kacew, Ethan Harris, Glenn J. Hanna, Robert I. Haddad, Roy B. Tishler, Jonathan Daniel Schoenfeld, Danielle Nina Margalit, Alessandro Villa, Sewanti Atul Limaye, Matthew Sanborn, Ji Eun Bae, Umair Mahmood, Jennifer Cutler, Shana Criscitiello, Julian Huang, Ann H. Partridge, Jochen H. Lorch
Journal: Journal of Clinical Oncology (2019)

e18230 Background: Medical insurance coverage is known to correlate with improved long-term (LT) outcomes in head and neck cancers (HNC) patients. However, associations with dental insurance coverage (DI) are not established. Methods: In 2012, we sent surveys to determine DI and LT symptom (Sx) burden (EORTC QLQ-30, National Health and Nutrition Examination Survey Oral Health, and Vanderbilt Head and Neck Sx Survey) to patients who had completed definitive chemoradiotherapy (sequential or concurrent) for locally advanced (LA) HNC at the Dana-Farber Cancer Institute from 2002-2011 (2013 ASCO annual meeting, abstract 9530). In 2019, we retrospectively collected demographic and clinical information from patient charts and publicly available records and correlated these data with 2012 survey data. We used Fisher’s exact tests for association of categorical variables and Student’s t-tests for continuous variables. We used univariate and multivariate Cox proportional hazard modeling for hazard ratios (HRs). Results: Of the 103 survey responders, 84% were male. Most had oropharyngeal (90, 88%) or unknown primary (9, 9%) and 52 (50%) tested positive for human papilloma virus-associated disease (40% not tested). 71 (69%) had DI, while 100 (98%) had medical health insurance. Subjects with DI were diagnosed (Dxed) at a younger age (53 vs. 59, p &lt; 0.01). Stage at Dx did not vary by DI status (p = 0.27). At median follow-up of 10.4 years from Dx (range 2.0 -16.6), recurrence was not associated with DI status (6 (8%) for DI vs. 4 (13%) for no DI, p = 0.27, HR 0.55, 95% CI 0.15-1.93, p = 0.35). We identified 9 subjects (9%) who had died of any cause. Subjects with DI experienced lower mortality from all causes than those without (3% vs. 19%, p = 0.01) and longer median overall survival (OS) (range 4.3 - 16.6 years, HR 0.19, 95% CI 0.05-0.76, p = 0.02) on univariate analysis. The longer OS was not significant when controlling for age and stage at Dx (p = 0.12). DI was also associated with less frequent need for liquid supplements to maintain weight (p = 0.01). Conclusions: In our cohort, DI was associated with Dx at a younger age and longer OS, although future work should consider possible confounding factors such as differences in socioeconomic status. Our data highlight the need for further research to investigate the importance of DI in improving LT outcomes in HNC patients.
Imaging features of genomic instability in circulating tumor cells (CTCs) from metastatic triple-negative breast cancer (metTNBC) patients (pts) who received PIKTOR.
Authors: Priscilla Ontiveros, Maren K. Levin, Yipeng Wang, Beverly Hom, Ryan Dittamore, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2019)

e14527 Background: A subset of TNBCs have homologous recombination deficiency (HRD) with upregulation of compensatory DNA repair pathways. A combination of TAK-228 and TAK-117 (PIKTOR), investigational oral TORC1/2 and PI3Kα selective inhibitors, respectively, is hypothesized to increase genomic instability (GI) and decrease double strand DNA repair. CTCs from metTNBC pts are being characterized for imaging features that may correlate GI in blood obtained at baseline (BL) prior to beginning PIKTOR, and at disease progression (PD) on PIKTOR. Pts are treated with a cisplatin-based regimen after PD on PIKTOR. Methods: Following IRB-approved informed consent, metTNBC pts received 4 mg PO TAK-228 and 200 mg PO TAK-117 QDx3d QW until PD. Blood samples collected at BL and at PD were sent to Epic Sciences for CTC analyses including enumeration, cell morphology, phenotypic heterogeneity, and GI analysis via a previously developed GI prediction algorithm based on cell phenotypes (Jendrisak et al AACR 2018). Results: The 9 pts treated with PIKTOR to date had mets in lymph nodes (n = 8), lung (n = 5), chest wall (n = 2), and bone (n = 2). Median number of prior regimens for metTNBC was 2; median duration of PIKTOR treatment was 8 wks (range, 5-15). CTCs were detected in 62.5% (5/8) BL and 100% (9/9) PD samples. 2 pts had high phenotypic CTC heterogeneity at both BL and PD (pt#36: 0.69 to 0.64; pt#80: 0.93 to 1.41), 1 pt had increased heterogeneity (pt#75: 0 to 1.68) and 1 pt had decreased heterogeneity (pt#67: 1.26 to 0) post-PIKTOR. 1 pt had predicted phenotypic GI (pGI+) CTCs detected at both BL and PD (pt#80), 1 pt had pGI+ CTCs at BL only (pt#36) and 1 pt at PD only (pt#75). Higher expression of the epithelial marker, cytokeratin (CK), and larger cell size were observed in the PD samples. Conclusions: Following treatment with and PD on PIKTOR, higher CK expression, higher phenotypic heterogeneity, and more pGI+ CTCs were observed in a subset of pts, suggesting that these TN CTCs may have developed epithelial transition and greater GI with PIKTOR treatment. Accrual continues and CTC GI biomarkers will be correlated with pts’ response to subsequent cisplatin-based therapy.
Cost-effectiveness of primary prophylaxis with pegfilgrastim in early-stage breast cancer patients receiving chemotherapy in China.
Authors: Wen Xia, Shusen Wang, Hao Hu, Fei Xu, Kuikui Jiang, Zhongyu Yuan, Yanxia Shi, Kun Zhao, Jia Jia Huang, Cong Xue, XiWen Bi, Qianyi Lu
Journal: Journal of Clinical Oncology (2019)

e18349 Background: Guidelines recommend primary prophylaxis(PP) use for patients receiving chemotherapy regimens with a high risk of febrile neutropenia (FN), which is 20% or higher. This study aim to evaluate the cost effectiveness of PP with pegfilgrastim (Brand name:Jinyouli), PP with filgrastim or no prophylaxis in women with early-stage breast cancer(BC) in China. Methods: A two-phase Markov model was developed for a hypothetical cohort of patients age 45 with stage II BC. First phase modeled costs/outcomes of 4 cycles docetaxel combined cyclophosphamide(TC×4) chemotherapy, with assumptions based on literature reviews including FN rates(Base-case (DSA range),0.29(0.24–0.35)) and related events (FN case-fatality, 3.4 (2.7–4.1)). Second phase models the long term survival which was suggested to link with the relative dose intensity (RDI)( Mortality HR for RDI &lt; 85% vs. ≥85%,1.45 (1.00–2.32)). Clinical effectiveness, costs, and utilities were estimated from peer-reviewed publications and expert opinions in case of unavailability of published evidences. Results: Compared to PP filgrastim and no prophylaxis, PP pegfilgrastim was associated with higher costs 5208.19RMB and 5222.73RMB respectively, and increased quality-adjusted life-year (QALY) gained 0.066 and 0.297 respectively. Accordingly, the incremental cost effectiveness ratios (ICERs) are 79146.3RMB and 17558.77 RMB per QALY, which are both below the three times GDP per capita as the willingness to pay (WTP) threshold suggested by the WHO. Conclusions: Although the cost of PP pegfilgrastim is higher, considering the additional benefits, the administrating of PP pegfilgrastim is likely to be a cost-effective alternative to PP filgrastim and no prophylaxis in patients with early stage breast cancer in China.
Exploring the Association of Sex Differences and Exposure to Maternal Smoking With Low Fetal Growth—Reply
Authors: Erik Pettersson, Brian D’Onofrio, Paul Lichtenstein
Journal: JAMA Psychiatry (2019)

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Single institution preliminary analysis of geriatric head and neck squamous carcinomas treated with modulated radiotherapy.
Authors: Trinanjan Basu, Ashay Karpe, Pradip Kendre, Pradeep Bhaskar, Vijay Sharnanghat, Sachin Gawde, Amrita Kasat, Priyanka Raina, Neelam Behera
Journal: Journal of Clinical Oncology (2019)

e17566 Background: Geriatric head and neck squamous carcinomas (GHNC) treatment remains challenging due to multiple patient and treatment related factors. We analysed preliminary data for fifty HNC patients beyond 70 years of age treated by modulated radiotherapy (MRT). Methods: There were 50 patients (M:46,F:4) with median age of 78 years (70-96) treated by MRT at our centre. They were analysed for efficacy and acute side effects. Besides demographic and disease related parameters compliance to treatment, rate of hospitalisation, dependency of WHO ladder 3 analgesia and early clinico-radiological outcomes were analysed. Results: The median follow up was 10 months. 65% patients were locally advanced stage and 65% received radical MRT. For radical MRT the dose ranged between 66-70 Gy in 30-33 fractions and 5 patients received palliative MRT. 83% completed intended treatment with 30% had MRT interruptions. 48% patients required hospitalisation. 60% had comorbidities with 35% two or more types. 3 patients had concurrent chemotherapy and 48% had hospitalisation and 60% had feeding tubes.65% and 30% had post MRT endoscopic evaluation and imaging respectively. Among them 80% are loco-regionally controlled. 30% patients are long term (more than 3 months) tube dependent and morphine dependent. There were 5 deaths while on MRT both due to associated cardiac and pulmonary comorbidities. 40% and 65% of palliative and radical MRT patients respectively had complete response post MRT. All patients underwent psychological counselling and dietician evaluation. The median G8 screening score was 15. Conclusions: GHNC are a unique group with its own challenge. In specialised setting and with MRT treatment compliance and effective outcome is highly promising. Non disease related concerns like alteration in daily quality of life (QOL), social engagement related issues, age related dementia and end of life care emerged as prominent issues beyond disease control.
Case 19-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely
Journal: New England Journal of Medicine (1987)

Case Records of the Massachusetts General Hospital from The New England Journal of Medicine — Case 19-1987 — A 64-Year-Old Woman with Liver Dysfunction and Abnormal Mononuclear Cells in the Blood Smears
Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells
Authors: Yuanyuan Yang, Xiaolong Zhang, Fangzhen Lin, Mengshang Xiong, Dongmei Fan, Xiangfei Yuan, Yang Lu, Yuewen Song, Yizi Zhang, Mu Hao, Zhou Ye, Yanjun Zhang, Jianxiang Wang, Dongsheng Xiong
Journal: Journal of Hematology & Oncology (2019)

PD-1/PD-L1 blockade can confer durable benefits in the treatment of metastatic cancers, but the response rate remains modest and potential adverse effects occur sometimes. Concentrating immunotherapeutic agents at the site of disease was believed to break local immune tolerance and reduce systemic toxicity. E1A-engineered mesenchymal stromal cell (MSC.E1A) was an attractive transfer system that preferentially homing and treating cancer metastasis, through which the tumor cells were modified by locally replicated adenoviruses to release CD3-HAC, a bifunctional fusion protein that anti-CD3 scfv linked with high-affinity consensus (HAC) PD-1. Subsequently, CD3-HAC, wbich was bound on PD-L1-positive breast cancer cells, recruited T cells to exhibit a potent antitumor immunity incombination with immune checkpoint blockade. We constructed the CD3-HAC gene driven by human telomerase reverse transcriptase (hTERT) promoter into an adenoviral vector and the E1A gene into the lentiviral vector. The homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC.Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by CD3-HAC towards PD-L1-positive cells was detected in vitro and in vivo in combination with 5-FU. Our data suggest that CD3-HAC could specifically bind to PD-L1-positive tumor cells and induce lymphocyte-mediated lysis effectively both in vitro and in vivo. The intervention with HAC diminished the effects of PD-1/PD-L1 axis on T cells exposed to MDA-MB-231 cells and increased lymphocytes activation. MSCs infected by AdCD3-HAC followed by LentiR.E1A could specially migrate to metastasis of breast cancer and produce adenoviruses in the tumor sites. Furthermore, treatment with MSC.CD3-HAC.E1A in combination with 5-FU significantly inhibited the tumor growth in mice. This adenovirus-loaded MSC.E1A system provides a promising strategy for the identification and elimination of metastasis with locally released immuno-modulator.