Henan Cancer Hospital

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
\nIraide Alloza642,888, Alexandru Almasan206, Maylin Almonte-Beceril524, Emad S Alnemri1212, Covadonga Alonso544,
\nNihal Altan-Bonnet848, Dario C Altieri1205, Silvia Alvarez1497, Lydia Alvarez-Erviti1395, Sandro Alves107,
\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
\nAmal O Amer918, Mohamed Amessou2089, Angelika Amon726, Zhenyi An1538, Frank A Anania291, Stig U Andersen6,
\nUsha P Andley2079, Catherine K Andreadi1690, Nathalie Andrieu-Abadie502, Alberto Anel2027, David K Ann58,
\nShailendra Anoopkumar-Dukie388, Manuela Antonioli832,858, Hiroshi Aoki1791, Nadezda Apostolova2007,
\nSaveria Aquila1500, Katia Aquilano1876, Koichi Araki292, Eli Arama2098, Agustin Aranda456, Jun Araya591,
\nAlexandre Arcaro1472, Esperanza Arias26, Hirokazu Arimoto1225, Aileen R Ariosa1749, Jane L Armstrong1930,
\nThierry Arnould1773, Ivica Arsov2120, Katsuhiko Asanuma675, Valerie Askanas1924, Eric Asselin1867, Ryuichiro Atarashi794,
\nSally S Atherton369, Julie D Atkin713, Laura D Attardi1131, Patrick Auberger1787, Georg Auburger379, Laure Aurelian1727,
\nRiccardo Autelli1992, Laura Avagliano1029,1755, Maria Laura Avantaggiati364, Limor Avrahami1166, Suresh Awale1986,
\nNeelam Azad404, Tiziana Bachetti568, Jonathan M Backer28, Dong-Hun Bae1933, Jae-sung Bae677, Ok-Nam Bae409,
\nSoo Han Bae2117, Eric H Baehrecke1729, Seung-Hoon Baek17, Stephen Baghdiguian1368,
\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
\nG abor B anhegyi1052, Haijun Bao2109, Benoit Barbeau1363, Maria D Barrachina2007, Esther Barreiro467, Bonnie Bartel997,
\nAlberto Bartolom e222, Diane C Bassham550, Maria Teresa Bassi1046, Robert C Bast Jr1273, Alakananda Basu1798,
\nMaria Teresa Batista1578, Henri Batoko1336, Maurizio Battino970, Kyle Bauckman2085, Bradley L Baumgarner1909,
\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
\nFrancesca Belleudi1041, Giovanni B enard497, Guy Berchem706, Daniele Bergamaschi983, Matteo Bergami1401,
\nBen Berkhout1441, Laura Berliocchi714, Am elie Bernard1749, Monique Bernard1354, Francesca Bernassola1880,
\nAnne Bertolotti791, Amanda S Bess272, S ebastien Besteiro1351, Saverio Bettuzzi1828, Savita Bhalla913,
\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
\nAlessandra Bolino2063, Andrea Boman693, Paolo Bonaldo1823, Matteo Bordi897, J€urgen Bosch608, Luis M Botana1308,
\nJoelle Botti1375, German Bou1405, Marina Bouch e1038, Marion Bouchecareilh1331, Marie-Jos ee Boucher1901,
\nMichael E Boulton481, Sebastien G Bouret1926, Patricia Boya133, Micha€el Boyer-Guittaut1345, Peter V Bozhkov1141,
\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

BACKGROUND: From 2003 to 2005, standardised 5-year cancer survival in China was much lower than in developed countries and varied substantially by geographical area. Monitoring population-level cancer survival is crucial to the understanding of the overall effectiveness of cancer care. We therefore aimed to investigate survival statistics for people with cancer in China between 2003 and 2015. METHODS: We used population-based data from 17 cancer registries in China. Data for the study population was submitted by the end of July 31, 2016, with follow-up data on vital status obtained on Dec 31, 2015. We used anonymised, individual cancer registration records of patients (aged 0-99 years) diagnosed with primary, invasive cancers from 2003 to 2013. Patients eligible for inclusion had data for demographic characteristics, date of diagnosis, anatomical site, morphology, behaviour code, vital status, and last date of contact. We analysed 5-year relative survival by sex, age, and geographical area, for all cancers combined and 26 different cancer types, between 2003 and 2015. We stratified survival estimates by calendar period (2003-05, 2006-08, 2009-11, and 2012-15). FINDINGS: There were 678 842 records of patients with invasive cancer who were diagnosed between 2003 and 2013. Of these records, 659 732 (97·2%) were eligible for inclusion in the final analyses. From 2003-05 to 2012-15, age-standardised 5-year relative survival increased substantially for all cancers combined, for both male and female patients, from 30·9% (95% CI 30·6-31·2) to 40·5% (40·3-40·7). Age-standardised 5-year relative survival also increased for most cancer types, including cancers of the uterus (average change per calendar period 5·5% [95% CI 2·5-8·5]), thyroid (5·4% [3·2-7·6]), cervix (4·5% [2·9-6·2]), and bone (3·2% [2·1-4·4]). In 2012-15, age-standardised 5-year survival for all patients with cancer was higher in urban areas (46·7%, 95% CI 46·5-47·0) than in rural areas (33·6%, 33·3-33·9), except for patients with oesophageal or cervical cancer; but improvements in survival were greater for patients residing in rural areas than in urban areas. Relative survival decreased with increasing age. The increasing trends in survival were consistent with the upward trends of medical expenditure of the country during the period studied. INTERPRETATION: There was a marked overall increase in cancer survival from 2003 to 2015 in the population covered by these cancer registries in China, possibly reflecting advances in the quality of cancer care in these areas. The survival gap between urban and rural areas narrowed over time, although geographical differences in cancer survival remained. Insight into these trends will help prioritise areas that need increased cancer care. FUNDING: National Key R&D Program of China, PUMC Youth Fund and the Fundamental Research Funds for the Central Universities, and Major State Basic Innovation Program of the Chinese Academy of Medical Sciences.

Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.

BACKGROUND: Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN-γ may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN-γ in the tumor microenvironment (TME) may be misleading in terms of its clinical application. MAIN BODY: Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN-γ in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN-γ acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1. CONCLUSION: Significant research efforts are required to decipher IFN-γ-dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN-γ in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN-γ responsive patients to improve their sensitivity to immuno-therapies.

The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

The fact that various immune cells, including macrophages, can be found in tumor tissues has long been known. With the introduction of concept that macrophages differentiate into a classically or alternatively activated phenotype, the role of tumor-associated macrophages (TAMs) is now beginning to be elucidated. TAMs act as "protumoral macrophages," contributing to disease progression. TAMs can promote initiation and metastasis of tumor cells, inhibit antitumor immune responses mediated by T cells, and stimulate tumor angiogenesis and subsequently tumor progression. As the relationship between TAMs and malignant tumors becomes clearer, TAMs are beginning to be seen as potential biomarkers for diagnosis and prognosis of cancers, as well as therapeutic targets in these cases. In this review, we will discuss the origin, polarization, and role of TAMs in human malignant tumors, as well as how TAMs can be used as diagnostic and prognostic biomarkers and therapeutic targets of cancer in clinics.

Many cellular processes in cancer are attributed to kinase signaling networks. V-akt murine thymoma viral oncogene homolog (AKT) plays a major role in the PI3K/AKT signaling pathways. AKT is activated by PI3K or phosphoinositide-dependent kinases (PDK) as well as growth factors, inflammation, and DNA damage. Signal transduction occurs through downstream effectors such as mTOR, glycogen synthase kinase 3 beta (GSK3β), or forkhead box protein O1 (FOXO1). The abnormal overexpression or activation of AKT has been observed in many cancers, including ovarian, lung, and pancreatic cancers, and is associated with increased cancer cell proliferation and survival. Therefore, targeting AKT could provide an important approach for cancer prevention and therapy. In this review, we discuss the rationale for targeting AKT and also provide details regarding synthetic and natural AKT-targeting compounds and their associated studies.

Importance: Standard first-line therapy for advanced or metastatic esophageal carcinoma is chemotherapy, but the prognosis remains poor. Camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) showed antitumor activity in previously treated advanced or metastatic esophageal squamous cell carcinoma. Objective: To evaluate the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as a first-line treatment in advanced or metastatic esophageal squamous cell carcinoma. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (ESCORT-1st study) enrolled patients from 60 hospitals in China between December 3, 2018, and May 12, 2020 (final follow-up, October 30, 2020). A total of 751 patients were screened and 596 eligible patients with untreated advanced or metastatic esophageal squamous cell carcinoma were randomized. Interventions: Patients were randomized 1:1 to receive either camrelizumab 200 mg (n = 298) or placebo (n = 298), combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were given intravenously every 3 weeks. Main Outcomes and Measures: Coprimary end points were overall survival (significance threshold, 1-sided P < .02) and progression-free survival (significance threshold, 1-sided P < .005). Results: Of the 596 patients randomized (median age, 62 years [interquartile range, 56-67 years]; 523 men [87.8%]), 1 patient in the placebo-chemotherapy group did not receive planned treatment. A total of 490 patients (82.2%) had discontinued the study treatment. The median follow-up was 10.8 months. The overall survival for the camrelizumab-chemotherapy group was a median of 15.3 months (95% CI, 12.8-17.3; 135 deaths) vs a median of 12.0 months (95% CI, 11.0-13.3; 174 deaths) for the placebo-chemotherapy group (hazard ratio [HR] for death, 0.70 [95% CI, 0.56-0.88]; 1-sided P = .001). Progression-free survival for camrelizumab plus chemotherapy was a median of 6.9 months (95% CI, 5.8-7.4; 199 progression or deaths) vs 5.6 months (95% CI, 5.5-5.7; 229 progression or deaths) for the placebo-chemotherapy group (HR for progression or death, 0.56 [95% CI, 0.46-0.68]; 1-sided P < .001). Treatment-related adverse events of grade 3 or higher occurred in 189 patients (63.4%) in the camrelizumab-chemotherapy group and 201 (67.7%) in the placebo-chemotherapy group, including treatment-related deaths among 9 patients (3.0%) and 11 patients (3.7%), respectively. Conclusions and Relevance: Among patients with advanced or metastatic esophageal squamous cell carcinoma, the addition of camrelizumab to chemotherapy, compared with placebo and chemotherapy, significantly improved overall survival and progression-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03691090.

Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

Limited population-based cancer registry data available in China until now has hampered efforts to inform cancer control policy. Following extensive efforts to improve the systematic cancer surveillance in this country, we report on the largest pooled analysis of cancer survival data in China to date. Of 21 population-based cancer registries, data from 17 registries (n = 138,852 cancer records) were included in the final analysis. Cases were diagnosed in 2003-2005 and followed until the end of 2010. Age-standardized relative survival was calculated using region-specific life tables for all cancers combined and 26 individual cancers. Estimates were further stratified by sex and geographical area. The age-standardized 5-year relative survival for all cancers was 30.9% (95% confidence intervals: 30.6%-31.2%). Female breast cancer had high survival (73.0%) followed by cancers of the colorectum (47.2%), stomach (27.4%), esophagus (20.9%), with lung and liver cancer having poor survival (16.1% and 10.1%), respectively. Survival for women was generally higher than for men. Survival for rural patients was about half that of their urban counterparts for all cancers combined (21.8% vs. 39.5%); the pattern was similar for individual major cancers except esophageal cancer. The poor population survival rates in China emphasize the urgent need for government policy changes and investment to improve health services. While the causes for the striking urban-rural disparities observed are not fully understood, increasing access of health service in rural areas and providing basic health-care to the disadvantaged populations will be essential for reducing this disparity in the future.

Importance: Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug's efficacy in advanced non-small cell lung cancer (NSCLC). Objective: To investigate the efficacy of anlotinib on overall survival of patients with advanced NSCLC progressing after second-line or further treatment. Design, Setting, and Participants: The ALTER 0303 trial was a multicenter, double-blind, phase 3 randomized clinical trial designed to evaluate the efficacy and safety of anlotinib in patients with advanced NSCLC. Patients from 31 grade-A tertiary hospitals in China were enrolled between March 1, 2015, and August 31, 2016. Those aged 18 to 75 years who had histologically or cytologically confirmed NSCLC were eligible (n = 606), and those who had centrally located squamous cell carcinoma with cavitary features or brain metastases that were uncontrolled or controlled for less than 2 months were excluded. Patients (n = 440) were randomly assigned in a 2-to-1 ratio to receive either 12 mg/d of anlotinib or a matched placebo. All cases were treated with study drugs at least once in accordance with the intention-to-treat principle. Main Outcomes and Measures: The primary end point was overall survival. The secondary end points were progression-free survival, objective response rate, disease control rate, quality of life, and safety. Results: In total, 439 patients were randomized, 296 to the anlotinib group (106 [36.1%] were female and 188 [64.0%] were male, with a mean [SD] age of 57.9 [9.1] years) and 143 to the placebo group (46 [32.2%] were female and 97 [67.8%] were male, with a mean [SD] age of 56.8 [9.1] years). Overall survival was significantly longer in the anlotinib group (median, 9.6 months; 95% CI, 8.2-10.6) than the placebo group (median, 6.3 months; 95% CI, 5.0-8.1), with a hazard ratio (HR) of 0.68 (95% CI, 0.54-0.87; P = .002). A substantial increase in progression-free survival was noted in the anlotinib group compared with the placebo group (median, 5.4 months [95% CI, 4.4-5.6] vs 1.4 months [95% CI, 1.1-1.5]; HR, 0.25 [95% CI, 0.19-0.31]; P < .001). Considerable improvement in objective response rate and disease control rate was observed in the anlotinib group over the placebo group. The most common grade 3 or higher adverse events in the anlotinib arm were hypertension and hyponatremia. Conclusions and Relevance: Among the Chinese patients in this trial, anlotinib appears to lead to prolonged overall survival and progression-free survival. This finding suggests that anlotinib is well tolerated and is a potential third-line or further therapy for patients with advanced NSCLC. Trial Registration: ClinicalTrials.gov identifier: NCT02388919.

Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

PURPOSE: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1. RESULTS: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3-46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4-31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4-7.4) and 5.5 months (95% CI, 3.7-5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5-83.5) and 68.2% (95% CI, 59.0-75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. CONCLUSIONS: .

GSDME-mediated target cell pyroptosis by CAR T cells activates macrophages to release proinflammatory cytokines for CRS.

Abstract Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD + activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.

PURPOSE: We evaluated the performance of the newly proposed radiomics of multiparametric MRI (RMM), developed and validated based on a multicenter dataset adopting a radiomic strategy, for pretreatment prediction of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer. EXPERIMENTAL DESIGN: A total of 586 potentially eligible patients were retrospectively enrolled from four hospitals (primary cohort and external validation cohort 1-3). Quantitative imaging features were extracted from T2-weighted imaging, diffusion-weighted imaging, and contrast-enhanced T1-weighted imaging before NAC for each patient. With features selected using a coarse to fine feature selection strategy, four radiomic signatures were constructed based on each of the three MRI sequences and their combination. RMM was developed based on the best radiomic signature incorporating with independent clinicopathologic risk factors. The performance of RMM was assessed with respect to its discrimination and clinical usefulness, and compared with that of clinical information-based prediction model. RESULTS: Radiomic signature combining multiparametric MRI achieved an AUC of 0.79 (the highest among the four radiomic signatures). The signature further achieved good performances in hormone receptor-positive and HER2-negative group and triple-negative group. RMM yielded an AUC of 0.86, which was significantly higher than that of clinical model in two of the three external validation cohorts. CONCLUSIONS: The study suggested a possibility that RMM provided a potential tool to develop a model for predicting pCR to NAC in breast cancer.

IMPORTANCE: Tumor mutational burden (TMB), as measured by whole-exome sequencing (WES) or a cancer gene panel (CGP), is associated with immunotherapy responses. However, whether TMB estimated by circulating tumor DNA in blood (bTMB) is associated with clinical outcomes of immunotherapy remains to be explored. OBJECTIVES: To explore the optimal gene panel size and algorithm to design a CGP for TMB estimation, evaluate the panel reliability, and further validate the feasibility of bTMB as a clinical actionable biomarker for immunotherapy. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, a CGP named NCC-GP150 was designed and virtually validated using The Cancer Genome Atlas database. The correlation between bTMB estimated by NCC-GP150 and tissue TMB (tTMB) measured by WES was evaluated in matched blood and tissue samples from 48 patients with advanced NSCLC. An independent cohort of 50 patients with advanced NSCLC was used to identify the utility of bTMB estimated by NCC-GP150 in distinguishing patients who would benefit from anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) therapy. The study was performed from July 19, 2016, to April 20, 2018. MAIN OUTCOMES AND MEASURES: Assessment of the Spearman correlation coefficient between bTMB estimated by NCC-GP150 and tTMB calculated by WES. Evaluation of the association of bTMB level with progression-free survival and response to anti-PD-1 and anti-PD-L1 therapy. RESULTS: This study used 2 independent cohorts of patients with NSCLC (cohort 1: 48 patients; mean [SD] age, 60 [13] years; 15 [31.2%] female; cohort 2: 50 patients; mean [SD] age, 58 [8] years; 15 [30.0%] female). A CGP, including 150 genes, demonstrated stable correlations with WES for TMB estimation (median r2 = 0.91; interquartile range, 0.89-0.92), especially when synonymous mutations were included (median r2 = 0.92; interquartile range, 0.91-0.93), whereas TMB estimated by the NCC-GP150 panel found higher correlations with TMB estimated by WES than most of the randomly sampled 150-gene panels. Blood TMB estimated by NCC-GP150 correlated well with the matched tTMB calculated by WES (Spearman correlation = 0.62). In the anti-PD-1 and anti-PD-L1 treatment cohort, a bTMB of 6 or higher was associated with superior progression-free survival (hazard ratio, 0.39; 95% CI, 0.18-0.84; log-rank P = .01) and objective response rates (bTMB ≥6: 39.3%; 95% CI, 23.9%-56.5%; bTMB <6: 9.1%; 95% CI, 1.6%-25.9%; P = .02). CONCLUSIONS AND RELEVANCE: The findings suggest that established NCC-GP150 with an optimized gene panel size and algorithm is feasible for bTMB estimation, which may serve as a potential biomarker of clinical benefit in patients with NSCLC treated with anti-PD-1 and anti-PD-L1 agents.

Cervical cancer is one of the leading causes of cancer death among females worldwide and its behavior epidemiologically likes a venereal disease of low infectiousness. Early age at first intercourse and multiple sexual partners have been shown to exert strong effects on risk. The wide differences in the incidence among different countries also influenced by the introduction of screening. Although the general picture remains one of decreasing incidence and mortality, there are signs of an increasing cervical cancer risk probably due to changes in sexual behavior. Smoking and human papillomavirus (HPV) 16/18 are currently important issues in a concept of multifactorial, stepwise carcinogenesis at the cervix uteri. Therefore, society-based preventive and control measures, screening activities and HPV vaccination are recommended. Cervical cancer screening methods have evolved from cell morphology observation to molecular testing. High-risk HPV genotyping and liquid-based cytology are common methods which have been widely recommended and used worldwide. In future, accurate, cheap, fast and easy-to-use methods would be more popular. Artificial intelligence also shows to be promising in cervical cancer screening by integrating image recognition with big data technology. Meanwhile, China has achieved numerous breakthroughs in cervical cancer prevention and control which could be a great demonstration for other developing and resource-limited areas. In conclusion, although cervical cancer threatens female health, it could be the first cancer that would be eliminated by human beings with comprehensive preventive and control strategy.

Abstract Objective To evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma. Design Multicentre, randomised, double blind, phase 3 trial. Setting 66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021. Participants 659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment. Intervention Participants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing &lt;60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m 2 plus paclitaxel 175 mg/m 2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m 2 continuous infusion on days 1-5). Main outcome measures Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1. Results 659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P&lt;0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P&lt;0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P&lt;0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively. Conclusions Compared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising. Trial registration ClinicalTrials.gov NCT03748134 .

BACKGROUND: In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available. METHODS: We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05. RESULTS: mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. CONCLUSIONS: In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).