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Background: Hepatocellular carcinoma (HCC) recurs after liver transplantation (LT) in ~17% of patients. We aimed to retrospectively compare the outcomes of patients treated with different tyrosine kinase inhibitors (TKIs) for recurrent HCC post-LT., Methods: Patients with recurrent HCC post-LT between 2006 and 2019 were included. The impact of sorafenib and lenvatinib treatment for recurrent disease was assessed using survival analysis with an a priori multivariable Cox regression (alpha-fetoprotein [AFP] at recurrence, recurrence lesion diameter, single-site versus multisite metastases)., Results: Seven hundred fifty-four patients underwent LT for HCC, of whom 120 (15.9%) developed recurrence. Of these patients, 56 received TKIs: sorafenib (n = 42) or lenvatinib (n = 14). The median age at LT was 60.8 y (interquartile range, 54.0-66.2); 52 (93%) were men and 26 (46%) were within Milan criteria at listing. Baseline characteristics at recurrence were comparable between the 2 groups, including largest tumor diameter (P = 0.15), receipt of local therapies before TKI (P = 0.33), and single-site recurrence (P = 0.75), and time from interventional treatment to start of TKI (P = 0.44). The AFP at recurrence was higher in the sorafenib group (95.0 versus 3.0 µg/L, P < 0.001). The median overall survival (OS) after initiation of TKI treatment was longer in the lenvatinib group (15.0 mo [95% confidence interval [CI], 11.5-31.5] versus 7.8 mo [95% CI, 4.0-15.4]; P = 0.02) with a 2.3-fold a priori adjusted effect on OS (adjusted hazard ratio 2.32 [95% CI, 1.03-5.20], P = 0.04)., Conclusions: Our findings suggest lenvatinib is a valuable treatment option for patients with HCC recurrence after LT., Competing Interests: S.P. received honoraria for talks from AstraZeneca and Amgen, as well as fees for scientific advisory boards from Taiho and Eisai. A.V. had been directly paid honoraria and has been paid consulting or advisory roles for AstraZeneca, BeiGene, Boehringer Mannheim, BMS, BTG, EISAI, GSK, Incyte, Ipsen, MSD, Hoffmann-La Roche, Servier, Sirtex, and Taiho. R.C.G. disclosed serving as a consultant for Incyte and Tempus and receiving grant/research support from Pfizer. J.J.K. received grants and personal fees from Roche and AstraZeneca and grants from Ibsen and Merck outside the submitted work. G.S. discloses consultancy for AstraZeneca, Roche, Novartis, Integra, and HepaRegeniX; received financial compensation for talks for Roche, AstraZeneca, Chiesi, and Integra; received a grant from Roche; and has research collaborations with AstraZeneca, Natera, Roche, Stryker, and HeparegeniX. G.M.O. received grants from Roche and AstraZeneca; consulting fees from AstraZeneca, Servier, and Incyte; payment for lectures from Roche; and support for attending meetings from MSD and Roche. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The incidence of esophageal and gastric carcinoma (GEC) in elderly patients is increasing, yet patients ≥75 years have historically been underrepresented in clinical trials. We sought to investigate palliative chemotherapy administration patterns and survival outcomes in older adults., Materials and Methods: A retrospective analysis identified patients aged 65-74 (young-old) and ≥75 years (older-old) diagnosed with advanced GEC. Patient and tumor characteristics were recorded, with descriptive analysis, time-to-event data analysis using Kaplan-Meier curves and multivariate Cox proportional hazards regression analysis performed., Results: One hundred and ninety-eight "young-old" and 109 'older-old' patients were identified. Patient characteristics were similar between groups except for Charlson Co-morbidity Index (CCI), with lower co-morbidities in the "young-old" compared to "older-old" cohort (P < .001; CCI = 0 in 103 (52%) "young-old" vs 31 (28%) "older-old"). The primary diagnosis in both groups was adenocarcinoma. 119 (60%) "young-old" and 25 (23%) "older-old" patients received chemotherapy (P < .001). Performance status was the primary explanation for chemotherapy non-receipt in both cohorts; age was the explanation in 21 (25%) "older-old" patients and none in the "young-old" patients. PFS for first-line systemic therapy in "young-old" patients was 6.4 (95% CI 5.9-7.6) versus 7.5 months (95% CI 5.1-11.3) in "older-old" patients (P = .69) whilst respective OS was 12.3 (95% CI 10.1-15.5) and 10.4 months (95% CI 9.0-14.6) (P = .0816). Toxicity prompted chemotherapy cessation in 17 (15%) "young-old" and 3 (13%) "older-old" patients (P = .97). Multivariate analysis identified CCI and ECOG performance status as predictive for PFS and OS, respectively. No causative relationship was identified with other variables., Conclusion: Our study of real-world older-adults show that significant number of "older-old" patients with GEC do not receive chemotherapy. Among "older-old" adults who do receive systemic therapy, outcomes are comparable; this underscores the importance of geriatric assessment-guided care and suggests that age alone should not be a barrier to receipt of chemotherapy in patients with advanced GEC., (© The Author(s) 2024. Published by Oxford University Press.)

The regulatory mechanism of the transcription factor GATA3 in the differentiation and maturation process of extravillous trophoblasts (EVT) in early pregnancy placenta, as well as its relevance to the occurrence of pregnancy disorders, remains poorly understood. This study leveraged single-cell RNA sequencing data from placental organoid models and placental tissue to explore the dynamic changes in GATA3 expression during EVT maturation. The expression pattern exhibited an initial upregulation followed by subsequent downregulation, with aberrant GATA3 localization observed in cases of recurrent miscarriage (RM). By identifying global targets regulated by GATA3 in primary placental EVT cells, JEG3, and HTR8/SVneo cell lines, this study offered insights into its regulatory mechanisms across different EVT cell models. Shared regulatory targets among these cell types and activation of trophoblast cell marker genes emphasized the importance of GATA3 in EVT differentiation and maturation. Knockdown of GATA3 in JEG3 cells led to repression of GATA3-induced epithelial-mesenchymal transition (EMT), as evidenced by changes in marker gene expression levels and enhanced migration ability. Additionally, interference with GATA3 accelerated cellular senescence, as indicated by reduced proliferation rates and increased activity levels for senescence-associated β-galactosidase enzyme, along with elevated expression levels for senescence-associated genes. This study provides comprehensive insights into the dual role of GATA3 in regulating EMT and cellular senescence during EVT differentiation, shedding light on the dynamic changes in GATA3 expression in normal and pathological placental conditions., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Materials capable of efficiently converting near-infrared (NIR) light into heat are highly sought after in biotechnology. In this study, two new three-dimensional (3D) porphyrin-based metal-organic frameworks (MOFs) with a sra -net, viz. CoTCPP-Bi/NiTCPP-Bi, were successfully synthesized. These MOFs feature bismuth carboxylate nodes interconnected by metalloporphyrinic spacers, forming one-dimensional (1D) arrays of closely spaced metalloporphyrins. Notably, the CoTCPP-Bi exhibits an approximate Co⋯C distance of 3 Å, leading to enhanced absorption of NIR light up to 1400 nm due to the presence of strong interlayer van der Waals forces. Furthermore, the spatial arrangement of the metalloporphyrins prevents axial coordination at the centers of porphyrin rings and stabilizes a Co II -based metalloradical. These characteristics promote NIR light absorption and non-radiative decay, thereby improving photothermal conversion efficiency. Consequently, CoTCPP-Bi can rapidly elevate the temperature from room temperature to 190 °C within 30 seconds under 0.7 W cm -2 energy power from 808 nm laser irradiation. Moreover, it enables solar-driven water evaporation with an efficiency of 98.5% and a rate of 1.43 kg m -2 h -1 under 1 sun irradiation. This research provides valuable insights into the strategic design of efficient photothermal materials for effective NIR light absorption, leveraging the principles of aggregation effect and metalloradical chemistry., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This paper describes a two-year high-fidelity dataset for an ultra-low energy office building and living laboratory called HouseZero ® . The building integrates multiple low-energy technologies, such as natural ventilation with automatic windows, ground source heat pump, and thermally activated building systems. The building's performance is continuously monitored with an extensive sensor network. The dataset consists of breakdown energy end uses, photovoltaic (PV) production, zone-level indoor environment including indoor air temperature, CO 2 concentration, and relative humidity, micro-climatical conditions, building façade temperature, and detailed system operations including zone-level BTU meter, valve status, slab temperature, window/skylight opening status, heat pump, and geothermal well operations. The data can be used to support data analytics of ultra-low-energy building operations, and data-driven modeling of low-energy building systems., (© 2024. The Author(s).)

Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine, with its precise underlying causes remaining incompletely understood. In this study, we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis. Colitis patients produce significant higher levels of circNlgn. Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression, primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNlgn. Nlgn173 undergoes translocation into cell nuclei, where it interacts with actin, impeding the binding of actin-related protein 2 and 3 (Arp2/3) complex to actin molecules. Consequently, this leads to a reduction in actin polymerization. Mechanistically, Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin, diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels. These alterations in actin dynamics result in inhibited cell cycle progression, increased apoptosis, and decreased proliferation of colonic epithelial cells, thereby exacerbating colitis development and progression. In contrast, the silencing of circNlgn or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization, enhanced cell survival, and reduced apoptosis and ultimately improves the outcome of colitis in vivo. Interestingly, nuclear actin polymerization is highly related with expression of PIAS3, which modulates signal transducer and activator of transcription 3 and NF-κB activity in colitis. Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerative colitis clinical intervention., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 William W. Du et al.)

Background: Rheumatoid arthritis (RA) is one of the most common forms of arthritis. Extracorporeal shockwave therapy (ESWT) has been identified as a viable alternative therapeutic approach in light of the present protracted clinical course of pharmacological treatment, and changes in levels of marker proteins in the blood samples of RA patients can be utilized to assess treatment outcomes., Methods: A randomized controlled trial was conducted involving forty patients diagnosed with rheumatoid arthritis (RA) who were assigned randomly to two groups. The first group received a combination of diclofenac and methotrexate (MTX) consisting of 25 mg of diclofenac administered thrice daily and 15 mg of MTX administered once weekly. Individual follow-up assessments were carried out after 7 and 14 days. Meanwhile, patients in the second group underwent two sessions of Extracorporeal Shockwave Therapy (ESWT), with a 7-day interval between sessions. Evaluations were conducted on day 7 and day 14. Patients who displayed pain control and stability were advised to continue the treatment, whereas those who had inflammation and discomfort were administered specific medications, and their progress was closely monitored until day 28. Blood samples were collected from both groups prior to treatment, after the first treatment, and after the second treatment. Four marker proteins (NRP-1, CELF-6, COX-2, and RGS-1) and two inflammatory cytokines (IL-6 and IL-17) were measured using western blot and RT-PCR techniques. A statistical analysis was conducted on the levels of specific proteins and inflammatory factors before and after treatment to evaluate its impact., Result: Both groups exhibited statistically significant differences in the serum level of target biomarkers before and after the intervention. However, the ESWT group demonstrated a more noticeable effect, while the diclofenac + MTX group exhibited a delayed anti-inflammatory effect compared to ESWT., Conclusion: Both treatments significantly improved joint function, relieved pain, and reduced inflammation in patients. However, ESWT demonstrated a more prominent clinical analgesic effect compared to the combination treatment of diclofenac and MTX. Furthermore, ESWT produced a more immediate and noteworthy anti-inflammatory impact by regulating NRP-1 expression, a trophic factor receptor that facilitates vascular endothelial cell migration and tissue repair through angiogenesis, and regulating RGS-1 to limit inflammatory signal transmission and immune cell activation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Mei Zhang et al.)

Objective: The purpose of this study is to investigate the role of high mobility group protein B1 (HMGB1) in placental development and fetal growth., Methods: We employed the Cre-loxP recombination system to establish a placenta-specific HMGB1 knockout mouse model. Breeding HMGB1flox/flox mice with Elf5-Cre mice facilitated the knockout, leveraging Elf5 expression in extra-embryonic ectoderm, ectoplacental cone, and trophoblast giant cells at 12.5 days of embryonic development. The primary goal of this model was to elucidate the molecular mechanism of HMGB1 in placental development, assessing parameters such as placental weight, fetal weight, and bone development. Additionally, we utilized lentiviral interference and overexpression of HMGB1 in human trophoblast cells to further investigate HMGB1's functional role., Results: Our findings indicate that the HMGB1flox/floxElf5cre/+ mouse displays fetal growth restriction, characterized by decreased placental and fetal weight and impaired bone development. The absence of HMGB1 inhibits autophagosome formation, impairs lysosomal degradation, and disrupts autophagic flux. Depletion of HMGB1 in human trophoblast cells also suppresses cell viability, proliferation, migration, and invasion by inhibiting the ERK signaling pathway. Overexpression of HMGB1 observed the opposite phenotypes., Conclusions: HMGB1 participates in the regulation of autophagy through the ERK signaling pathway and affects placental development., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable., Methods: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression., Results: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS -wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo- RAS -WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness ( P = .41), archival BRAF/MEK/ERK -mutant status ( P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications ( P = 1.00)., Conclusion: We identified a 3.2%-6.3% prevalence of the neo- RAS -WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.

Purpose: Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold., Patients and Methods: CO.26 was a randomized phase II study of 180 patients, comparing durvalumab and tremelimumab (D + T, n = 119 patients) versus best supportive care (BSC; n = 61 patients). ctDNA sequencing was available for 168 patients (n = 118 D + T; n = 50), of whom 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on OS were determined using a minimal P value approach. This report includes the final OS analysis., Results: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D + T compared with BSC in microsatellite stable (MSS) metastatic CRC [HR, 0.71 (95% CI, 0.28-1.80); P = 0.47]. No tissue TMB threshold could identify a high TMB group that benefited from ICI. By contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D + T [HR, 0.34 (95% CI, 0.13-0.85); P = 0.022], as was clonal pTMB ≥10.6 mutations/Mb [HR, 0.10 (95% CI, 0.014-0.79); P = 0.029] and subclonal pTMB ≥25.9/Mb [HR, 0.20 (95% CI, 0.061-0.69); P = 0.010]. Higher pTMB was associated with length of time on cytotoxic agents (P = 0.021) and prior anti-EGFR exposure (P = 2.44 × 10-06)., Conclusions: pTMB derived from either clonal or subclonal mutations may identify a group likely to benefit from immunotherapy, although validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer., Patients and Methods: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory., Results: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed., Conclusion: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration., Gov Identifier: ClinicalTrials.gov; NCT03374254., Competing Interests: Disclosure R. Kim reports honoraria from Taiho; advisory/consultancy roles with Bayer Servier, Ipsen, and Roche; and speakers bureau for Eisai, Pfizer, and Incyte. M. Tehfe reports advisory/consultancy roles with Merck & Co., Inc., Rahway, NJ, USA, BMS, Taiho, and Pfizer; and speakers bureau for BMS and Taiho. P. Kavan reports advisory/consultancy role with Merck; expert testimony for Merck & Co., Inc., Rahway, NJ, USA; and an institutional educational grant to their institution. J. S. Kortmansky reports research funding to their institution from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Genentech. E. X. Chen reports advisory/consultancy roles from AstraZeneca, Eisai, and GSK and research funding to their institution from AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, BMS, Novartis, Roche, Zymeworks, and 1Globe. C. H. Lieu reports advisory/consultancy roles with Natera; and research funding to their institution from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. M. Fakih reports advisory/consultancy roles with AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Mirati, Nouscom, PsiOxus, Roche/Genentech, and Taiho. K. Spencer reports advisory/consultancy roles with QED Therapeutics, Helsinn, Lynx Group, and Caris. Q. Zhao reports stock ownership at Merck & Co., Inc., Rahway, NJ, USA. R. Predoiu, C. Li, P. Leconte, and D. Adelberg report employment with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. P. Leconte and D. Adelberg report stock ownership at Merck & Co., Inc., Rahway, NJ, USA. E. G. Chiorean reports advisory/consultancy roles with Astellas, Bayer, Cardiff, Foundation, G1 Therapeutics, Ipsen, Noxxon, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, and Stemline; research funding to their institution from Aadi, Biosplice, BioMed Valley, Boehringer Ingelheim, Clovis, Corcept, Erasca, Fibrogen, Lona, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Rafael, and Stemline; and travel/accommodations from G1 Therapeutics. J. Chaves and L. Wong report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer., Patients and Methods: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary., Results: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E., Conclusion: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E., Competing Interests: Disclosure E. X. Chen reports advisory/consultancy roles from AstraZeneca, Eisai, and GSK; research funding to their institution from AstraZeneca, Merck & Co., Inc., Rahway, NJ, USA, BMS, Novartis, Roche, Zymeworks, and 1Globe. P. Kavan reports advisory/consultancy role with Merck; Expert Testimony for Merck & Co., Inc., Rahway, NJ, USA; and an institutional educational grant to their institution. M. Tehfe reports advisory/consultancy roles with Merck & Co., Inc., Rahway, NJ, USA, BMS, Taiho, and Pfizer; and speaker bureau for BMS and Taiho. J. S. Kortmansky reports research funding to their institution from Merck & Co., Inc., Rahway, NJ, USA and Genentech. M. B. Sawyer reports honoraria from Ipsen, BMS, Mylan, Amgen, AstraZeneca, Eisai, Sandoz, Celgene, Servier, Novartis, Leo, Taiho, and Shire; advisory/consultancy roles with AstraZeneca, Leo, and Immuneering; expert testimony for AstraZeneca; research funding to their institution from AstraZeneca and BMS; and travel/accommodation expenses from Ipsen. E. G. Chiorean reports advisory/consultancy roles with Astellas, Bayer, Cardiff, Foundation, G1 Therapeutics, Ipsen, Noxxon, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, and Stemline; research funding to their institution from Aadi, Biosplice, BioMed Valley, Boehringer-Ingelheim, Clovis, Corcept, Erasca, Fibrogen, Lona, Merck & Co., Inc., Rahway, NJ, USA, Novartis, Rafael, and Stemline; and travel/accommodation from G1 Therapeutics. C. H. Lieu reports research funding to their institution from Merck & Co., Inc., Rahway, NJ, USA. M. Fakih reports advisory/consultancy roles with AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Mirati, Nouscom, PsiOxus, Roche/Genentech, and Taiho. K. Spencer reports advisory/consultancy roles from QED Therapeutics, Helsinn, Lynx Group, and Caris. C. Li, P. Leconte, and D. Adelberg report employment with Merck & Co., Inc., Rahway, NJ, USA; P. Leconte and D. Adelberg report stock ownership at Merck & Co., Inc., Rahway, NJ, USA. R. Kim reports honoraria from Taiho; advisory/consultancy roles with Bayer Servier, Ipsen and Roche; and speaker bureau for Eisai, Pfizer, and Incyte. B. Polite, L. Wong, and J. Chaves report no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Patient-reported outcomes measures (PROM) are self-reflections of an individual's physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS)., Methods: The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed., Results: In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients' cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38)., Conclusion: Patient's SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication., (© The Author(s) 2024. Published by Oxford University Press.)

The understanding of electron transfer pathways and orbital interactions between analytes and adsorption sites in gas-sensitive studies, especially at the atomic level, is currently limited. Herein, we have designed eight isoreticular catechol-metalloporphyrin scaffolds, FeTCP-M and InTCP-M (TCP = 5,10,15,20-tetrakis-catechol-porphyrin, M = Fe, Co, Ni and Zn) with adjustable charge transfer schemes in the coordination microenvironment and precise tuning of orbital interactions between analytes and adsorption sites, which can be used as models for exploring the influence of these factors on gas sensing. Our experimental findings indicate that the sensitivity and selectivity can be modulated using the type of metals in the metal-catechol chains (which regulate the electron transfer routes) and the metalloporphyrin rings (which fine-tune the orbital interactions between analytes and adsorption sites). Among the isostructures, InTCP-Co demonstrates the highest response and selectivity to NO 2 under visible light irradiation, which could be attributed to the more favorable transfer pathway of charge carriers in the coordination microenvironment under visible light illumination, as well as the better electron spin state compatibility, higher orbital overlap and orbital symmetry matching between the N-2s2p z hybrid orbital of NO 2 and the Co-3d z 2 orbital of InTCP-Co., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objectives Anaplastic thyroid cancer (ATC) is an aggressive disease associated with poor outcomes and resistance to therapies. Our study aim was to evaluate the activity of a combinatorial regimen of sandwich sequencing of pembrolizumab immunotherapy and hypofractionated radiotherapy (RT). Methods In this case series, patients with ATC received hypofractionated RT (QUAD-shot) and intravenous pembrolizumab 200mg every 3-4 weeks. Pembrolizumab was continued until disease progression or up till 24 months. Concurrent Lenvatinib treatment was allowed. Primary endpoint was best overall response (BOR) and progression-free survival (PFS). Additionally, we performed immune profiling of circulating T cells in a responder to investigate the immune response to our combinatorial treatment. Results At median follow-up of 32.6 months (IQR: 26.4-38.8), of a cohort of 5 patients, BOR was 80%; with 2 complete responses (CR) and 2 partial responses (PR). Patients who achieved CR remained disease-free at last follow-up. Median PFS was 7.6 months (IQR: 6.2-NR), and 1-year PFS and overall survival rate was 40% (95% CI: 13.7-100) for both. Treatment was well-tolerated, with mostly grade 1-2 adverse events. Immune profiling of one partial responder revealed an increase in activated CD4 and CD8 T cells post-QUAD-shot RT, which was further enhanced during the maintenance phase of pembrolizumab. Conclusions Herein, we reported a case series of 5 patients with ATC, with 2 long-term survivors who were treated with surgical debulking followed by QUAD-shot RT and pembrolizumab, possibly due to synergy of local and systemic treatments in activating anti-tumour immunogenic cytotoxicity. This regimen warrants further investigation in a larger cohort of patients.

Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM)., Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer., Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments., Intervention: Durvalumab plus tremelimumab or best supportive care., Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR)., Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM., Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

Background: Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity., Methods: The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m 2 intravenously followed by weekly maintenance of 250 mg/m 2 , plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables., Results: Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea., Conclusion: The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS., Competing Interests: Disclosure The authors declare no potential conflicts of interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Hyperlipidemic acute pancreatitis (HLAP) remains one of the major digestive emergencies with increasing health risks. Oral refeeding tolerant (ORT) and enteral tube feeding tolerant (ETFT) are commonly used for nutritional management in HLAP. However, the differences between ORT and ETFT are yet to be characterized., Patients and Methods: This study included consecutive patients admitted to the Ordos Central Hospital between January 2019 and April 2023, with predefined inclusion criteria., Results: A total of 335 HLAP patients were recruited according to the inclusion criteria. 268 patients were diagnosed with moderately severe acute pancreatitis (MSAP), of which 193 were in the OFT group and 75 in the ETFT group. In the ETFT group, abdominal pain and abdominal distension were significantly higher than that in the OFT group. No significant result was identified in the laboratory data. However, the OFT group showed a higher hospitalization and cost, as well as exocrine insufficiency and newly onset diabetes, than the ETFT group., Conclusions: Based on the incidence of HLAP retrieved in this study, MSAP is the major type with increasing clinical value. From the nutritional management sense, patients who received OFT showed higher hospitalization and cost, as well as lower exocrine insufficiency and newly onset diabetes.

Objectives: To identify combined clinical, radiomic, and delta-radiomic features in metastatic gastroesophageal adenocarcinomas (GEAs) that may predict survival outcomes., Methods: A total of 166 patients with metastatic GEAs on palliative chemotherapy with baseline and treatment/follow-up (8-12 weeks) contrast-enhanced CT were retrospectively identified. Demographic and clinical data were collected. Three-dimensional whole-lesional radiomic analysis was performed on the treatment/follow-up scans. "Delta" radiomic features were calculated based on the change in radiomic parameters compared to the baseline. The univariable analysis (UVA) Cox proportional hazards model was used to select clinical variables predictive of overall survival (OS) and progression-free survival (PFS) (p-value <0.05). The radiomic and "delta" features were then assessed in a multivariable analysis (MVA) Cox model in combination with clinical features identified on UVA. Features with a p-value <0.01 in the MVA models were selected to assess their pairwise correlation. Only non-highly correlated features (Pearson's correlation coefficient <0.7) were included in the final model. Leave-one-out cross-validation method was used, and the 1-year area under the receiver operating characteristic curve (AUC) was calculated for PFS and OS., Results: Of the 166 patients (median age of 59.8 years), 114 (69%) were male, 139 (84%) were non-Asian, and 147 (89%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The median PFS and OS on treatment were 3.6 months (95% CI 2.86, 4.63) and 9 months (95% CI 7.49, 11.04), respectively. On UVA, the number of chemotherapy cycles and number of lesions at the end of treatment were associated with both PFS and OS (p < 0.001). ECOG status was associated with OS (p = 0.0063), but not PFS (p = 0.054). Of the delta-radiomic features, delta conventional HUmin, delta gray-level zone length matrix (GLZLM) GLNU, and delta GLZLM LGZE were incorporated into the model for PFS, and delta shape compacity was incorporated in the model for OS. Of the treatment/follow-up radiomic features, shape compacity and neighborhood gray-level dependence matrix (NGLDM) contrast were used in both models. The combined 1-year AUC (Kaplan-Meier estimator) was 0.82 and 0.81 for PFS and OS, respectively., Conclusions: A combination of clinical, radiomics, and delta-radiomic features may predict PFS and OS in GEAs with reasonable accuracy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SN declared a past co-authorship with the author SKr to the handling editor., (Copyright © 2023 Krishna, Sertic, Liu, Liu, Darling, Yeung, Wong, Chen, Kalimuthu, Allen, Suzuki, Panov, Ma, Bach, Jang, Swallow, Brar, Elimova and Veit-Haibach.)

One pseudopentasupertetrahedral chalcogenidometalate cluster, [(BuSn) 3 SnCd 4 S 13 (OH)]·6(H + DMP) (PPS-1; H + DMP = protonated 3,5-dimethylpiperidine), has been isolated by use of an organotin precursor. They are arranged to generate two types of tetrahedrally patterned cages, which further interconnect to form a diamond network. Owing to the covalent attachment of abundant alkyl groups, PPS-1 exhibits excellent hydrophobicity and could be used as an assembly substance for building liquid marbles.

Background: Sarcopenia indicates poor prognosis in various malignancies. We evaluated the association of sarcopenia with overall (OS) and progression-free survival (PFS) in metastatic esophageal cancer (MEC) patients, a population often presenting with poor nutritional status., Methods: In newly diagnosed MEC patients managed at the Princess Margaret (PM) Cancer Centre (diagnosed 2006-2015), total muscle area, visceral adiposity (VA), and subcutaneous adiposity (SA) were quantified on abdominal computed tomography at L3. Sarcopenia was determined using published cutoffs, based on sex and height., Results: Of 202 MEC patients, most were male (166/82%), < 65 years (116/57%), and had adenocarcinoma histology (141/70%); 110/54% had recurrent MEC after initial curative-intent treatment; 92/46% presented with de novo MEC. At stage IV diagnosis, 20/10% were underweight, 97/48% were normal-weight and 84/42% were overweight/obese; 103/51% were sarcopenic. Sarcopenia was associated with worse median OS (4.6 vs. 7.9 months; log-rank p = 0.03) and 1-year survival, even after adjusting for other body composition variables (e.g., BMI, VA, and SA): adjusted-HR 1.51 [95% CI 1.1-2.2, p = 0.02]. In post hoc analysis, sarcopenia was highly prognostic in adenocarcinomas (p = 0.003), but not squamous cell carcinomas (SCC). In patients receiving palliative systemic treatment (104/51%), sarcopenia was associated with shorter PFS (p = 0.004) in adenocarcinoma patients (75/72%)., Conclusions: In metastatic esophageal adenocarcinomas, sarcopenia is associated with worse PFS and OS. In metastatic esophageal SCC, there was a non-significant trend for worse PFS but no association with OS. In order to offset the poor prognosis associated with sarcopenia particularly in metastatic esophageal adenocarcinoma patients, future research should focus on possible countermeasures., (© 2023. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: The number of somatic mutations detectable in circulating tumor DNA (ctDNA) is highly heterogeneous in metastatic colorectal cancer (mCRC). The optimal number of mutations required to assess disease kinetics is relevant and remains poorly understood., Objectives: To determine whether increasing panel breadth (the number of tracked variants in a ctDNA assay) would alter the sensitivity in detecting ctDNA in patients with mCRC., Design: We used archival tissue sequencing to perform an in silico assessment of the optimal number of tracked mutations to detect and monitor disease kinetics in mCRC using sequencing data from the Canadian Cancer Trials Group CO.26 trial., Methods: For each patient, 1, 2, 4, 8, 12, or 16 of the most clonal (highest variant allele frequency) somatic variants were selected from archival tissue-based whole-exome sequencing and assessed for the proportion of variants detected in matched ctDNA at baseline, week 8, and progression timepoints., Results: Data from 110 patients were analyzed. Genes most frequently encountered among the top four highest VAF variants in archival tissue were TP53 (51.9% of patients), APC (43.3%), KRAS (42.3%), and SMAD4 (9.6%). While the frequency of detecting at least one tracked variant increased when expanding beyond variant pool sizes of 1 and 2 in baseline ( p  = 0.0030) and progression ( p  = 0.0030) ctDNA samples, we observed no significant benefit to increases in variant pool size past four variants in any of the ctDNA timepoints ( p  < 0.05)., Conclusion: While increasing panel breadth beyond two tracked variants improved variant re-detection in ctDNA samples from patients with treatment refractory mCRC, increases beyond four tracked variants yielded no significant improvement in variant re-detection., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Coordination polymers (CPs) based on metal-sulfur bonds are rare; we herein realize a series of thiol-functionalized linker-based CPs (thiol-CPs), MTBT (M = Fe, Co and Zn; TBT = dehydrated 4,4'-thiobisbenzenethiol), which feature an anionic two-dimensional (2D) network, [M(TBT) 2 ] n 2 n - , with the tetrahedral coordination unit {MS 4 } serving as a node. These compounds exhibit excellent hydrolytic stability, especially in alkaline solution (20M NaOH for five days), which is the highest value reported for CPs so far. In addition, among them, CoTBT displays favorable photo-thermal conversion effectiveness under an energy power of 0.5 W cm -2 808 nm laser irradiation for 15 s, with the temperature rising rapidly from room temperature to 135.2 °C.

Background: Prognostic scores that can identify patients at risk for early death are needed to aid treatment decision-making and patient selection for clinical trials. We compared the accuracy of four scores to predict early death (within 90 days) and overall survival (OS) in patients with metastatic gastric and esophageal (GE) cancer., Methods: Advanced GE cancer patients receiving first-line systemic therapy were included. Prognostic risks were calculated using: Royal Marsden Hospital (RMH), MD Anderson Cancer Centre (MDACC), Gustave Roussy Immune (GRIm-Score), and MD Anderson Immune Checkpoint Inhibitor (MDA-ICI) scores. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to analyze associations between prognostic scores and OS. The predictive discrimination was estimated using Harrell's c-index. Predictive ability for early death was measured using time-dependent AUCs., Results: In total, 451 patients with metastatic GE cancer were included. High risk patients had shorter OS for all scores (RMH high- vs. low-risk median OS 7.9 vs. 12.2 months, P < .001; MDACC 6.8 vs. 11.9 months P < .001; GRIm-Score 5.3 vs. 13 months, P < .001; MDA-ICI 8.2 vs. 12.2 months, P < .001). On multivariable analysis, each prognostic score was significantly associated with OS. The GRIm-Score had the highest predictive discrimination and predictive ability for early death., Conclusions: The GRIm-Score had the highest accuracy in predicting early death and OS. Clinicians may use this score to identify patients at higher risk of early death to guide treatment decisions including clinical trial enrolment. This score could also be used as a stratification factor in future clinical trial designs., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance., Methods: Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment., Results: ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR ( P = .0007), KRAS ( P = .0017), LRP1B ( P = .0046), ZNF217 ( P = .0086), MAP2K1 ( P = .018), PIK3CG ( P = .018), BRAF ( P = .048), and NRAS ( P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR ( P < .0001), SMO ( P < .0001), BRAF ( P < .0001), MET ( P = .0002), FLT3 ( P = .0002), NOTCH4 ( P = .0006), ERBB2 ( P = .004), and FGFR1 ( P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without ( P = .010). Although tumor mutation burden (TMB) did not differ pretreatment ( P = .63), anti-EGFR exposure increased TMB ( P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB ( P = .014)., Conclusion: Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

Objective: The aim of our study was to elucidate the clinical characteristics of alcoholic-hyperlipidemic etiologically complex acute pancreatitis., Patients and Methods: We reviewed complete data from 233 patients with acute pancreatitis treated in our hospital during the period January 2017-January 2022. They were divided into three groups according to etiology: alcoholic acute pancreatitis (AAP), hyperlipidemic acute pancreatitis (HLAP), and alcoholic-hyperlipidemic acute pancreatitis (AHAP). General clinical data, co-morbidities, laboratory results, imaging data, and disease severity were analyzed and compared between groups., Results: The proportion of male individuals in the AHAP group was significantly higher than that in the HLAP group (p<0.001). Age of onset was lower and the number of cases with antibiotic use was higher in the AHAP group than in the AAP group (p<0.05). Additionally, the average alcohol intake each time and weekly alcohol intake were also higher in the AHAP group than in the AAP group (p<0.05). Comparison of disease severity (moderate and severe acute pancreatitis, severe acute pancreatitis, and modified computed tomography severity index score) revealed the disease condition to be more severe in the AHAP group than in the AAP and HLAP groups (p<0.05). Accordingly, patients in the AHAP group had longer hospital stays than those in the other two groups (p<0.05). There were no significant differences in alcohol consumption, severity, or length of hospital stay in the AHAP group (p>0.05)., Conclusions: The clinical characteristics of patients in the AHAP, AAP and HLAP groups were different, and the patients in the AHAP group were more likely to have a moderate to severe disease course, with longer hospital stay. As a new AP classification concept, AHAP would offer high significance for diagnosis, treatment, and prognosis.

Background: Growing evidence indicates fractal analysis (FA) has potential as a computational tool to assess tumor microvasculature in glioblastoma (GBM). As fractal parameters of microvasculature have shown to be reliable quantitative biomarkers in brain tumors, there has been similar success in measuring the architecture of tumor tissue using FA in other tumor types. However, evaluating fractal parameters of tissue structure in relation to the microvasculature has not yet been implemented in GBM. We aimed to assess the utility of this methodology in quantifying structural characteristics of GBM cytoarchitecture and vascularity by correlating fractal parameters with gene expression., Methods: Formalin-fixed paraffin-embedded specimens were retrospectively collected from 43 patients following resection of a newly diagnosed GBM; 4 normal brain specimens were obtained from epilepsy surgeries as controls. Tumor samples were processed using FA employing a software-based box-counting method algorithm and custom messenger RNA expression assays. Fractal parameters were then correlated with clinical features, outcomes, and a panel of 92 genes associated with vascularity and angiogenesis., Results: Statistical analysis demonstrated that fractal-based indices were not adequate parameters for distinction of GBM cytoarchitecture compared with normal brain specimens. Correlation analysis of our gene expression findings suggested that hematoxylin and eosin-based FA may have adequate sensitivity to detect associations with vascular gene expression., Conclusions: The combination of neuropathological assessment and histology does not provide optimized data for FA in GBM. However, an association between FA and gene expression in GBM of genes pertaining to cytoarchitecture and angiogenesis warrants further investigation., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: The aim of this study was to determine if radiomic features combined with sarcopenia measurements on pretreatment 18 F-FDG PET/CT can improve outcome prediction in surgically treated adenocarcinoma esophagogastric cancer patients., Patients and Methods: One hundred forty-five esophageal adenocarcinoma patients with curative therapeutic intent and available pretreatment 18 F-FDG PET/CT were included. Textural features from PET and CT images were evaluated using LIFEx software ( lifexsoft.org ). Sarcopenia measurements were done by measuring the Skeletal Muscle Index at L3 level on the CT component. Univariable and multivariable analyses were conducted to create a model including the radiomic parameters, clinical features, and Skeletal Muscle Index score to predict patients' outcome., Results: In multivariable analysis, we combined clinicopathological parameters including ECOG, surgical T, and N staging along with imaging derived sarcopenia measurements and radiomic features to build a predictor model for relapse-free survival and overall survival. Overall, adding sarcopenic status to the model with clinical features only (likelihood ratio test P = 0.03) and CT feature ( P = 0.0037) improved the model fit for overall survival. Similarly, adding sarcopenic status ( P = 0.051), CT feature ( P = 0.042), and PET feature ( P = 0.011) improved the model fit for relapse-free survival., Conclusions: PET and CT radiomics derived from combined PET/CT integrated with clinicopathological parameters and sarcopenia measurement might improve outcome prediction in patients with nonmetastatic esophagogastric adenocarcinoma., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Many randomized control trials (RCTs) evaluating programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) targeting monoclonal antibodies (mAbs) have been completed or are in progress. We examined hypothesized hazard ratios (HHRs) and observed hazard ratios (OHRs) from published RCTs evaluating these mAbs., Methods: Publications of RCTs evaluating at least one PD-1/PD-L1 targeting mAbs approved by the US Food and Drug Administration were identified through PubMed searches. The primary reports of RCTs were retrieved. Two investigators extracted HHR, OHR for the primary endpoint among other data elements independently. The differences (∆HR) in HHR and OHR were analyzed statistically. A separate search was conducted for secondary reports after longer follow-ups, the updated OHR was extracted., Results: Forty-nine RCTs enrolling 36 867 patients were included. The mean HHR and OHR were 0.672 and 0.738 respectively. The mean ∆HR was 0.067 (range: -0.300 to 0.895; 95% confidence interval (CI), 0.003-0.130). HHR was met or exceeded in 22 (45%) RCTs. OHR was ≥ 1.0 in 6 RCTs (12%). PD-L1 expression was not associated with the magnitude of effect. Of 18 RCTs with follow-up reports, the magnitude of benefit decreased in 8 RCTs with extended follow-ups., Conclusion: The majority of published RCTs evaluating PD-1/PD-L1 targeting mAbs did not achieve their hypothesized magnitude of benefit. The optimism bias requires attention from the cancer clinical research community given the number of these agents in development and the intense interest in evaluating these agents in a variety of disease settings., (© The Author(s) 2022. Published by Oxford University Press.)

Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes; similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro , itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation., Significance: The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer., Competing Interests: S. Marastoni reports a Canadian patent number 3,116,081 pending. A. Madariaga reports personal fees from Clovis and AstraZeneca outside the submitted work. Z.J. Li reports a Canadian patent number to CA3,116,081 pending. I. Colombo reports personal fees from MSD; other from GSK, AstraZeneca, MSD, Bayer, and Oasmia outside the submitted work. J.P. Bruce reports other from Bowhead Health outside the submitted work. M. Koritzinsky reports other from The Princess Margaret Cancer Foundation during the conduct of the study; in addition, M. Koritzinsky has a Canadian patent number number 3,116,081 pending. B.G. Wouters reports grants from Ontario Institute for Cancer Research, Canadian Institutes for Cancer Research, and Princess Margaret Cancer Foundation during the conduct of the study; other from Northern Biologics outside the submitted work; in addition, B.G. Wouters has a Canadian patent number 3,116,081 issued. A.M. Oza is PI and on clinical trial steer- ing committees for trials with Clovis, GSK, AstraZeneca—all uncompensated. A.M. Oza is uncompensated CEO of Ozmosis Research, a Not For Profit Clin- ical Trials Management company associated with UHN. A.M. Joshua reports non-financial support from Mayne Pharma during the conduct of the study; other from Pricilium outside the submitted work; in addition, A.M. Joshua has a Canadian patent number 3,116,081 pending. S. Lheureux reports grants from OICR - TRI Ovarian Cancer during the conduct of the study; grants and personal fees from AstraZeneca, GSK; personal fees from Eisai, Merck, Shattuck Labs; grants from Roche, and outside the submitted work. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: Maintaining and improving quality of life (QOL) are important goals of anal cancer management. This disease is generally curable, with many long-term survivors., Objective: Long-term QOL after chemoradiation for patients with anal cancer was evaluated., Design: This was a prospective cohort study., Settings: This study used data from a prospective study of patients with anal cancer who were treated with chemoradiation between 2008 and 2013., Patients: Patients with anal cancer who were treated with image-guided intensity-modulated radiation therapy were included., Interventions: English-speaking patients completed European Organization for Research and Treatment of Cancer cancer-specific (C30) and site-specific (CR29) QOL questionnaires at baseline, at end of radiation, at 3 and 6 months, and then annually., Main Outcomes Measures: Long-term QOL was evaluated clinically (a change in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing the subscale scores at 1, 2, and 3 years with baseline scores. Subanalysis compared patients who received a radiation dose of 45 to 54 Gy versus 63 Gy., Results: Ninety-six patients were included (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decline at the end of treatment with improvement by 3 months after treatment. There was a long-term statistically significant decline in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss, and there was long-term statistically and clinically significant worsening of impotence. Higher radiation dose (63 Gy) was not associated with significantly worse QOL., Limitations: Limitations included single-institution, single-arm study design, and lack of dose reconstruction (ie, analyses were based on prescribed, rather than delivered, dose)., Conclusions: Patients with anal cancer treated with chemoradiation reported recovery of overall QOL to baseline levels. Specific symptoms remained bothersome, emphasizing the need to address and manage the chemoradiation-induced symptoms, during treatment and in the long term. See Video Abstract at http://links.lww.com/DCR/B905., Impacto De La Quimiorradiacin Definitiva En Cambios En La Calidad De Vida De Los Pacientes Con Cncer Anal Resultados a Largo Plazo De Un Estudio Prospective: ANTECEDENTES:Mantener y mejorar la calidad de vida son objetivos importantes del tratamiento del cáncer anal, ya que esta enfermedad generalmente es curable, con muchos sobrevivientes a largo plazo.OBJETIVO:Se evaluó la calidad de vida a largo plazo después de la quimiorradiación en pacientes con cáncer anal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Utilizamos datos de un estudio prospectivo en pacientes con cáncer anal tratados con quimiorradiación entre 2008-2013.PACIENTES:Los pacientes con cáncer anal fueron tratados con radioterapia de intensidad modulada guiada por imágenes.INTERVENCIONES:Los pacientes de habla inglesa completaron los cuestionarios de calidad de vida específicos de cáncer (C30) y específicos del sitio (CR29) de la Organización Europea para la Investigación y el Tratamiento del Cáncer al inicio, al final de la radiación, 3 y 6 meses, y luego anualmente.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluó a largo plazo la calidad de vida clínicamente (un cambio en la puntuación de ≥10 puntos se consideraron clínicamente significativo) y estadísticamente (usando análisis de medición repetida) comparando las subescalas de puntuación al 1, 2, y 3 años. Con puntuaciones de referencia. El subanálisis comparó pacientes que recibieron 45-54 Gy versus 63 Gy.RESULTADOS:Se incluyeron un total de 96 pacientes (mediana de seguimiento: 56,5 meses). La mayoría de las escalas funcionales y de síntomas mostraron una disminución clínicamente significativa al final del tratamiento con una mejoría a los 3 meses posteriores al tratamiento. Hubo una disminución estadísticamente significativa a largo plazo en disnea, imagen corporal, vergüenza intestinal, incontinencia fecal y pérdida de cabello; y hubo un empeoramiento a largo plazo estadística y clínicamente significativo en impotencia. La dosis de radiación más alta (63 Gy) no se asoció con una calidad de vida significativamente peor.LIMITACIONES:Institución única, diseño de estudio de un solo brazo y falta de recomposición de la dosis (es decir, los análisis se basan en la dosis prescrita, en lugar de la administrada).CONCLUSIÓNES:Los pacientes con cáncer anal tratados con quimiorradiación reportaron una recuperación de la QOL en general a los niveles de base. Síntomas específicos siguieron siendo molestos, lo que enfatiza la necesidad de resolver y tartar los síntomas inducidos por la quimiorradiación no solo durante el tratamiento, sino a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B905. (Traducción- Dr. Francisco M. Abarca-Rendon)., (Copyright © The ASCRS 2022.)

Background: Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD)., Methods: Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on "3 + 3" design within each HD group. PK samples were collected at cycle 1 days 15-16., Results: Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26)., Conclusions: RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients - 1.5 mg QD in Mod group, and 1 mg QD in Sev group., Trial Registration: This study was registered in the ClinicalTrials.gov website ( NCT02070549 ) on February 25, 2014. ., (© 2022. The Author(s).)

Gastroesophageal cancers carry poor prognoses, and are a leading cause of cancer-related morbidity and mortality worldwide. Even in those with resectable disease, more than half of patients treated with surgery alone experience disease recurrence. Multimodality approaches using preoperative and postoperative chemotherapy and/or radiotherapy have been established, resulting in incremental improvements in outcomes. Globally, there is no standardized approach, and treatment varies with geographic location. The question remains of how to select the optimal perioperative treatment that will maximize benefit for patients while avoiding toxicities from unnecessary therapies. This article reviews currently available evidence supporting preoperative and postoperative therapy in gastroesophageal cancers, with an emphasis on recent practice-changing trials and ongoing areas of investigation, including the role of immune checkpoint inhibition and biomarker-guided treatment.

Purpose: To determine the prognostic value of sarcopenia measurements done on staging 2-[18F] FDG PET/CT together with metabolic activity of the tumor in patients with adenocarcinoma esophagogastric cancer with surgical treatment., Methods: Patients with early-stage, surgically treated esophageal adenocarcinoma and available pre-treatment 2-[18F] FDG PET/CT were included. The standard uptake value (SUV) and SUV normalized by lean body mass (SUL) were recorded. Skeletal muscle index (SMI) was measured at the L3 level on the CT component of the PET/CT. Sarcopenia was defined as SMI < 34.4cm 2 /m 2 in women and < 45.4cm 2 /m 2 in men., Results: Of the included 145 patients. 30% were sarcopenic at baseline. On the univariable Cox proportional hazards analysis, ECOG, surgical T and N staging, lymphovascular invasion (LVI) positive lymph nodes, and sarcopenia were significant prognostic factors concerning RFS and OS. On multivariable Cox regression analysis, surgical N staging (p = 0.025) and sarcopenia (p = 0.022) remained significant poor prognostic factors for OS and RFS. Combining the clinical parameters with the imaging-derived nutritional evaluation of the patient but not metabolic parameters of the tumor showed improved predictive ability for OS and RFS., Conclusion: Combining the patients' imaging-derived sarcopenic status with standard clinical data, but not metabolic parameters, offered an overall improved prognostic value concerning OS and RFS., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined., Objective: This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma., Design: This is a retrospective cohort study., Setting: This study was conducted at a quaternary cancer center., Patients: Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected., Interventions: Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection., Main Outcome Measures: Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome., Results: There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p < 0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease., Limitations: This study is limited by its small sample size and retrospective nature., Conclusions: Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO., Antecedentes: El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo., Objetivo: Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal., Diseo: Estudio de cohorte retrospectivo., Entorno Clinico: Centro de cáncer cuaternario., Pacientes: Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016., Intervenciones: Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica., Principales Medidas De Valoracion: Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados., Resultados: Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p < 0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos., Limitaciones: Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva., Conclusiones: Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon)., (Copyright © The ASCRS 2021.)

Background: Testicular cancer survivors often have impaired gonadal function possibly related to chemotherapy. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility., Methods: Adult cisplatin-treated testicular cancer survivors were enrolled. High-Performance Liquid Chromatography-tandem mass spectrometry was used to measure semen and serum platinum levels. Semen quality and DNA Fragmentation Index (DFI) were assessed., Results: From 11/2017 to 12/2019, 38 patients (median age 32 years; range: 19-52) were enrolled. Median cumulative cisplatin dose was 301 mg/m 2 (range: 274-404). Platinum levels were higher in semen than in blood (p = 0.03). Semen platinum levels were not significantly associated with time from last cisplatin dosing (r = -0.34; p = 0.09) nor cumulative dose (r = -0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p < 0.001) but not with semen platinum level (r = -0.15, p = 0.46). DFI was not significantly associated with time from last cisplatin dosing (r = 0.55, p = 0.08) or semen platinum level (r = -0.32, p = 0.33). In four patients with serial semen samples, platinum level decreased and sperm concentration and motility increased over time., Conclusions: Platinum is detected in semen of testicular cancer survivors at higher levels than matched blood samples. These preliminary findings may have important implications for the reproductive health of survivors of advanced testicular cancer, further study is needed to assess the relationship between platinum persistence in semen and recovery of fertility postchemotherapy., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Two new chemically stable metalloporphyrin-bridged metal-catechol frameworks, InTCP-Co and FeTCP-Co, were constructed to achieve artificial photosynthesis without additional sacrificial agents and photosensitizers. The CO 2 photoreduction rate over FeTCP-Co considerably exceeds that obtained over InTCP-Co, and the incorporation of uncoordinated hydroxyl groups, associated with catechol, into the network further promotes the photocatalytic activity. The iron-oxo coordination chain assists energy band alignment and provides a redox-active site, and the uncoordinated hydroxyl group contributes to the visible-light absorptance, charge-carrier transfer, and CO 2 -scaffold affinity. With a formic acid selectivity of 97.8 %, FeTCP-OH-Co affords CO 2 photoconversion with a reaction rate 4.3 and 15.7 times higher than those of FeTCP- Co and InTCP-Co, respectively. These findings are also consistent with the spectroscopic study and DFT calculation., (© 2021 Wiley-VCH GmbH.)

Introduction: Metastatic gastroesophageal adenocarcinoma (GEA) is a heterogeneous disease with an overall poor prognosis. The impact of sites of metastatic dissemination on survival is not well characterized. This study aimed to evaluate whether certain sites of metastatic disease impacts survival., Methods: A retrospective analysis of 375 patients with metastatic GEA treated at the Princess Margaret Cancer Centre from 2006 to 2016 was performed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to assess the association between sites of metastases and OS adjusting for baseline patient characteristics., Results: Median duration of follow-up was 47.8 months. Median OS in this cohort was 11.8 months (95% CI: 10.2-12.9 months). Patients with lymph node only disease, compared to those with other sites of metastases, had the longest median OS (20.4 vs. 10.6 months; p < 0.001) and PFS (11.4 vs. 6.3 months; p < 0.001). On multivariable analysis adjusting for relevant clinical factors including age, sex, and Eastern Cooperative Oncology Group performance status, the presence of lung (HR 1.67, 95% CI: 1.23-2.26; p < 0.001) or bone metastases (HR 1.84, 95% CI: 1.31-2.59; p < 0.001) were independently associated with shorter OS. The majority of patients (68%) were treated with palliative intent first-line platinum-based chemotherapy., Discussion/conclusion: Patients with metastatic GEA have an overall poor prognosis. The presence of lung or bone metastases is an independent risk factor for decreased survival. Prognostic models incorporating sites of metastasis should be considered in the clinical evaluation of metastatic GEA., (© 2022 The Author(s). Published by S. Karger AG, Basel.)