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Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery

Background

A previous pooled analysis of the STARS and ROSEL trials showed higher survival af-ter stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscop-ic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND).

Findings

Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in effi-cacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9–5·8). Overall survival was 91% (95% CI 85–98) at 3 years and 87% (79–95) at 5 years. SABR was toler-ated well, with no grade 4–5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Over-all survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85–98) at 3 years and 84% (76–93) at 5 years. Non-in-feriority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall surviv-al between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45–1·65], p=0·65) from a multivariable analysis.

Interpretation

Long-term survival after SABR is non-infe-rior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended.

Joe Y Chang, Reza J Mehran , Lei Feng, Vivek Verma, Zhongxing Liao , James W Welsh, Steven H Lin , Michael S O’Reilly, Melenda D Jeter, Peter A Balter, Stephen E McRae, Donald Berry, John V Heymach, Jack A Roth, on behalf of The STARS Lung Cancer Trials Group

Read more in The Lancet

Venetoclax combined with FLAG-IDA induction and consolidation in newly diagnosed and relapsed or refractory Acute Myeloid Leukemia

Purpose

Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving front-line therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refrac-tory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic op-tions. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML.

Materials and Methods

The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-es-calation algorithm for identification of maximum tol-erated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML.

Results

Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events oc-curring in ≥ 10% of patients included febrile neutro-penia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a com-posite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improve-ment in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML.

Conclusion

Fludarabine, cytarabine, granulocyte colony-stimu-lating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep re-missions and a high rate of transition to successful transplantation.

Courtney D. DiNardo, Curtis A. Lachowiez, Koichi Takahashi , Sanam Loghavi , Lianchun Xiao, Tapan Kadia , Naval Daver , Maria Adeoti, Nicholas J. Short , Koji Sasaki , Sa Wang , Gautam Borthakur , Ghayas Issa , Abhishek Maiti , Yesid Alvarado , Naveen Pemmaraju , Guillermo Montalban Bravo , Lucia Masarova , Musa Yilmaz , Nitin Jain, Michael Andreeff , Elias Jabbour , Guillermo Garcia-Manero , Steven Kornblau , Farhad Ravandi , Marina Y. Konopleva , Hagop M. Kantarjian

Read more in Journal of Clinical Oncology

Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis

Introduction

The association between tumors and inflammation is a long-established clinical ob-servation. Although many studies have demonstrat-ed that the inflammatory microenvironment can pro-mote tumor growth through the activation of survival and proliferation programs in cancer cells, the rea-son why inflammation, an evolutionarily conserved response to damage aimed at reestablishing tissue integrity upon injury, might be integral to tumorigen-esis remains unknown.

Results

By investigating the effects of inflamma-tion on normal pancreatic epithelial cells in differ-ent mouse models, we discovered that long after the complete resolution, a transient inflammatory event primes pancreatic epithelial cells to cooperate with oncogenic Kras to induce pancreatic tumors. Indeed, upon recovery from a single acute inflam-mation, epithelial pancreatic cells display an endur-ing adaptive response associated with sustained transcriptional and epigenetic reprogramming that leads to the activation of multiple gene expression programs, including embryonic programs activated during cancer progression. While promoting tumor development, such adaptation to tissue damage facilitates the prompt acquisition of acinar-to-ductal metaplasia upon subsequent inflammatory events. This rapid dedifferentiation program of acinar cells, that lasts for the length of the stimulus and from which the tissue promptly and apparently complete-ly recovers, represents a physiological mechanism for limiting tissue damage through the rapid de-crease of zymogen production that would otherwise fuel further damage and inflammation. As a result, pancreatic tissues exposed to initial inflammation undergo a markedly attenuated response and lim-ited tissue damage to subsequent inflammatory episodes. Because metaplastic lesions are medi-ated by the activation of mitogen-activated protein kinase (MAPK) signaling, we demonstrate that acti-vating mutations of Kras, maintaining an irreversible acinar-to-ductal metaplasia through MAPK constitu-tive signaling, are protective against tissue damage induced by pancreatic inflammation.

Conclusion

We have uncovered a new physi-ologic role of somatic mutations in preserving tis-sue homeostasis during repeated damages. We propose that KRAS mutations, independent from the eventual contribution to tumorigenesis, may be beneficial and under strong positive selection in the context of recurrent pancreatitis, perhaps repre-senting a nearly universal event in the development of pancreatic cancer.

Edoardo Del Poggetto, I. Lin Ho, Chiara Balestrieri, Er Yen Yen, Shaojun Zhang, Francesca Citron, Rutvi Shah, Denise Corti, Giuseppe R. Diaferia, Chieh Yuan Li, Sara Loponte, Federica Carbone, Yoku Hayakawa, Giovanni Valenti, Shan Jiang, Luigi Sapio, Hong Jiang, Prasenjit Dey, Sisi Gao, Angela K. Deem, Stefan Rose-John, Wantong Yao, Haoqiang Ying, Andrew D. Rhim, Giannicola Genovese, Timothy P. Heffernan, Anirban Maitra, Timothy C. Wang, Linghua Wang, Giulio F. Draetta, Alessandro Carugo, Gioacchino Natoli, Andrea Viale

Read more in Science

Third-party BK virus-specific cytotoxic T lymphocyte therapy for hemorrhagic cystitis following allotransplantation

Purpose

BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of al-logenic hematopoietic stem cell transplanta-tion (AHSCT), particularly in recipients of al-ternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option.

Methods

We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of adminis-tering most closely HLA-matched third-par-ty BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed.

Results

Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-ver-sus-host disease, graft failure, or infusion-re-lated toxicities. BKV-CTLs were identified in patient blood samples up to 3 months post-infusion and their in vivo expansion predicted for clinical response. A matched-pair analy-sis revealed that, compared with standard of care, after accounting for prognostic covari-ate effects, treatment with BKV-CTLs result-ed in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement.

Conclusion

Off-the-shelf BKV-CTLs are a safe and effec-tive therapy for the management of patients with BKV-HC after AHSCT.

Amanda Olson, Ruitao Lin , David Marin , Hind Rafei , Mustafa H. Bdaiwi, Peter F. Thall , Rafet Basar , Ala Abudayyeh , Pinaki Prosad Banerjee , Fleur M. Aung , Indresh Kaur, Glorette Abueg, Sheetal Rao, Roy Chemaly , Victor Mulanovich , Gheath Al-Atrash , Amin M. Alousi , Borje S. Andersson, Paolo Anderlini , Qaiser Bashir, Karla M. Castro, May Daher , Isabel M. Galvan, Chitra Hosing , Jin S. Im , Roy B. Jones, Partow Kebriaei , Issa Khouri , Rohtesh Mehta , Jeffrey Molldrem , Yago Nieto , Betul Oran , Uday Popat , Muzaffar Qazilbash , Gabriela Rondon , Neeraj Saini , Bryan Spencer, Samer Srour , Dominique Washington, Melissa Barnett, Richard E. Champlin , Elizabeth J. Shpall , Katayoun Rezvani

Read more in Journal of Clinical Oncology

Medium-chain Acyl-CoA dehydrogenase protects mitochondria from lipid peroxidation in glioblastoma

Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes mediumchain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM.

Significance: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-prod-ucts in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demon-stration of a nonenergetic role for depen-dence on fatty acid metabolism in cancer.

Francesca Puca, Fei Yu, Caterina Bartolacci, Piergiorgio Pettazzoni, Alessandro Carugo, Emmet Huang-Hobbs, Jintan Liu, Ciro Zanca, Federica Carbone, Edoardo Del Poggetto, Joy Gumin, Pushan Dasgupta, Sahil Seth, Sanjana Srinivasan, Frederick F. Lang, Erik P. Sulman, Philip L. Lorenzi, Lin Tan, Mengrou Shan, Zachary P. Tolstyka, Maureen Kachman, Li Zhang, Sisi Gao, Angela K. Deem, Giannicola Genovese, Pier Paolo Scaglioni, Costas A. Lyssiotis, Andrea Viale, Giulio F. Draetta

Read more in Cancer Discovery