Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study

<p>Abstract</p> <p>Background</p> <p>Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered as a promising treatment modality for gastric cancer with peritoneal carcinomatosis (PC). However, there have also been many debates regarding the efficacy and safety of this new approach. Results from experimental animal model study could help provide reliable information. This study was to investigate the safety and efficacy of CRS + HIPEC to treat gastric cancer with PC in a rabbit model.</p> <p>Methods</p> <p>VX2 tumor cells were injected into the gastric submucosa of 42 male New Zealand rabbits using a laparotomic implantation technique, to construct rabbit model of gastric cancer with PC. The rabbits were randomized into control group (n = 14), CRS alone group (n = 14) and CRS + HIPEC group (n = 14). The control group was observed for natural course of disease progression. Treatments were started on day 9 after tumor cells inoculation, including maximal removal of tumor nodules in CRS alone group, and maximal CRS plus heperthermic intraperitoneal chemoperfusion with docetaxel (10 mg/rabbit) and carboplatin (40 mg/rabbit) at 42.0 ± 0.5°C for 30 min in CRS + HIPEC group. The primary endpoint was overall survival (OS). The secondary endpoints were body weight, biochemistry, major organ functions and serious adverse events (SAE).</p> <p>Results</p> <p>Rabbit model of gastric cancer with PC was successfully established in all animals. The clinicopathological features of the model were similar to human gastric PC. The median OS was 24.0 d (95% confidence interval 21.8 - 26.2 d ) in the control group, 25.0 d (95% CI 21.3 - 28.7 d ) in CRS group, and 40.0 d (95% CI 34.6 - 45.4 d ) in CRS + HIPEC group (<it>P </it>= 0.00, log rank test). Compared with CRS only or control group, CRS + HIPEC could extend the OS by at least 15 d (60%). At the baseline, on the day of surgery and on day 8 after surgery, the peripheral blood cells counts, liver and kidney functions, and biochemistry parameters were all comparable. SAE occurred in 0 animal in control group, 2 animals in CRS alone group including 1 animal death due to anesthesia overdose and another death due to postoperative hemorrhage, and 3 animals in CRS + HIPEC group including 1 animal death due to anesthesia overdose, and 2 animal deaths due to diarrhea 23 and 27 d after operation.</p> <p>Conclusions</p> <p>In this rabbit model of gastric cancer with PC, CRS alone could not bring benefit while CRS + HIPEC with docetaxel and carboplatin could significantly prolong the survival with acceptable safety.</p

A portrait of the Higgs boson by the CMS experiment ten years after the discovery

A Correction to this paper has been published (18 October 2023) : https://doi.org/10.1038/s41586-023-06164-8.Data availability: Tabulated results are provided in the HEPData record for this analysis. Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use and open acess policy.Code availability: The CMS core software is publicly available on GitHub (https://github.com/cms-sw/cmssw).In July 2012, the ATLAS and CMS collaborations at the CERN Large Hadron Collider announced the observation of a Higgs boson at a mass of around 125 gigaelectronvolts. Ten years later, and with the data corresponding to the production of a 30-times larger number of Higgs bosons, we have learnt much more about the properties of the Higgs boson. The CMS experiment has observed the Higgs boson in numerous fermionic and bosonic decay channels, established its spin–parity quantum numbers, determined its mass and measured its production cross-sections in various modes. Here the CMS Collaboration reports the most up-to-date combination of results on the properties of the Higgs boson, including the most stringent limit on the cross-section for the production of a pair of Higgs bosons, on the basis of data from proton–proton collisions at a centre-of-mass energy of 13 teraelectronvolts. Within the uncertainties, all these observations are compatible with the predictions of the standard model of elementary particle physics. Much evidence points to the fact that the standard model is a low-energy approximation of a more comprehensive theory. Several of the standard model issues originate in the sector of Higgs boson physics. An order of magnitude larger number of Higgs bosons, expected to be examined over the next 15 years, will help deepen our understanding of this crucial sector.BMBWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, FAPERGS, and FAPESP (Brazil); MES and BNSF (Bulgaria); CERN; CAS, MoST, and NSFC (China); MINCIENCIAS (Colombia); MSES and CSF (Croatia); RIF (Cyprus); SENESCYT (Ecuador); MoER, ERC PUT and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRI (Greece); NKFIH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); MES (Latvia); LAS (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MOS (Montenegro); MBIE (New Zealand); PAEC (Pakistan); MES and NSC (Poland); FCT (Portugal); MESTD (Serbia); MCIN/AEI and PCTI (Spain); MOSTR (Sri Lanka); Swiss Funding Agencies (Switzerland); MST (Taipei); MHESI and NSTDA (Thailand); TUBITAK and TENMAK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA). Individuals have received support from the Marie-Curie programme and the European Research Council and Horizon 2020 Grant, contract Nos. 675440, 724704, 752730, 758316, 765710, 824093, 884104, and COST Action CA16108 (European Union); the Leventis Foundation; the Alfred P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the F.R.S.-FNRS and FWO (Belgium) under the “Excellence of Science – EOS” – be.h project n. 30820817; the Beijing Municipal Science & Technology Commission, No. Z191100007219010; the Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; the Stavros Niarchos Foundation (Greece); the Deutsche Forschungsgemeinschaft (DFG), under Germany’s Excellence Strategy – EXC 2121 “Quantum Universe” – 390833306, and under project number 400140256 - GRK2497; the Hungarian Academy of Sciences, the New National Excellence Program - ÚNKP, the NKFIH research grants K 124845, K 124850, K 128713, K 128786, K 129058, K 131991, K 133046, K 138136, K 143460, K 143477, 2020-2.2.1-ED-2021-00181, and TKP2021-NKTA-64 (Hungary); the Council of Science and Industrial Research, India; the Latvian Council of Science; the Ministry of Education and Science, project no. 2022/WK/14, and the National Science Center, contracts Opus 2021/41/B/ST2/01369 and 2021/43/B/ST2/01552 (Poland); the Fundação para a Ciência e a Tecnologia, grant CEECIND/01334/2018 (Portugal); the National Priorities Research Program by Qatar National Research Fund; MCIN/AEI/10.13039/501100011033, ERDF “a way of making Europe”, and the Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia María de Maeztu, grant MDM-2017-0765 and Programa Severo Ochoa del Principado de Asturias (Spain); the Chulalongkorn Academic into Its 2nd Century Project Advancement Project, and the National Science, Research and Innovation Fund via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation, grant B05F650021 (Thailand); the Kavli Foundation; the Nvidia Corporation; the SuperMicro Corporation; the Welch Foundation, contract C-1845; and the Weston Havens Foundation (USA)

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Establishment and identification of a rabbit model of peritoneal carcinomatosis from gastric cancer

Abstract Background Gastric cancer peritoneal carcinomatosis is a common clinical problem, but there are no suitable large animal models to study this problem. This study was to establish a stable rabbit peritoneal carcinomatosis model of gastric cancer using VX2 tumor, and analyze the clinico-pathological features. Methods VX2 tumor was implanted into 36 New Zealand rabbits by 3 methods: laparotomic orthotopic injection of cancer cells into the submucosal layer of the stomach (Group A), laparotomic implantation of tumor tissue into the greater omentum immediately beneath the gastric antrum (Group B), and percutaneous injection of tumor cells directly into the peritoneal cavity (Group C), 12 rabbits in each group. The animals were closely observed and detailed clinico-pathological studies were conducted. Results The success rates of peritoneal carcinomatosis formation were 100% (12/12), 91.7% (11/12) and 58.3% (7/12), respectively, for Groups A, B and C (P = 0.019, A versus C; P = 0.077, B versus C; P = 0.500, A versus B, Fisher's exact test). Two weeks after submucosal cancer cells injection in Group A, ulcerative gastric cancer with peritoneal carcinomatosis showed typical VX2 tumor pathology, with widespread intraperitoneal metastatic nodules, bloody ascites and perspicuous pulmonary metastases. The clinico-pathological progression pattern was very similar to patients of advanced gastric cancer with peritoneal carcinomatosis. Groups B and C showed similar pattern of cancer progression, but less aggressive. Conclusions First large animal model of peritoneal carcinomatosis from gastric cancer has been established by laparotomic orthotopic injection of VX2 cancer cells into the submucosal layer of the stomach, providing a more suitable model for surgical interventional studies. The clinico-pathological features of this model resemble human peritoneal carcinomatosis.</p

Causal associations between thyroid cancer and IgA nephropathy: a Mendelian randomization study

Abstract Background The incidence of kidney disease caused by thyroid cancer is rising worldwide. Observational studies cannot recognize whether thyroid cancer is independently associated with kidney disease. We performed the Mendelian randomization (MR) approach to genetically investigate the causality of thyroid cancer on immunoglobulin A nephropathy (IgAN). Methods and results We explored the causal effect of thyroid cancer on IgAN by MR analysis. Fifty-two genetic loci and single nucleotide polymorphisms were related to thyroid cancer. The primary approach in this MR analysis was the inverse variance weighted (IVW) method, and MR‒Egger was the secondary method. Weighted mode and penalized weighted median were used to analyze the sensitivity. In this study, the random-effect IVW models showed the causal impact of genetically predicted thyroid cancer across the IgAN risk (OR, 1.191; 95% CI, 1.131–1.253, P < 0.001). Similar results were also obtained in the weighted mode method (OR, 1.048; 95% CI, 0.980–1.120, P = 0.179) and penalized weighted median (OR, 1.185; 95% CI, 1.110–1.264, P < 0.001). However, the MR‒Egger method revealed that thyroid cancer decreased the risk of IgAN, but this difference was not significant (OR, 0.948; 95% CI, 0.855–1.051, P = 0.316). The leave-one-out sensitivity analysis did not reveal the driving influence of any individual SNP on the association between thyroid cancer and IgAN. Conclusion The IVW model indicated a significant causality of thyroid cancer with IgAN. However, MR‒Egger had a point estimation in the opposite direction. According to the MR principle, the evidence of this study did not support a stable significant causal association between thyroid cancer and IgAN. The results still need to be confirmed by future studies