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(1) Background: Robot-assisted laparoscopic prostatectomy (RALP) is preferred over open prostatectomy because it offers superior surgical outcomes and better postoperative recovery. The steep Trendelenburg position and pneumoperitoneum required in Robot-assisted laparoscopic prostatectomy, however, increase intracranial pressure (ICP). The present study aimed to evaluate the effects of elevated ICP on the quality of emergence from anesthesia. (2) Methods: Sixty-seven patients undergoing RALP were enrolled. We measured optic nerve sheath diameter at four timepoints during surgery. Primary outcome was inadequate emergence in the operating room (OR). Secondary outcomes were postoperative neurologic deficits of dizziness, headache, delirium, cognitive dysfunction, and postoperative nausea and vomiting (PONV). (3) Results: A total of 69 patients were screened for eligibility and 67 patients completed the study and were included in the final analysis. After establishing pneumoperitoneum with the Trendelenburg position, ONSD increased compared to baseline by 11.4%. Of the 67 patients, 36 patients showed an increase of 10% or more in optic nerve sheath diameter (ONSD). Patients with ΔONSD ≥ 10% experienced more inadequate emergence in the OR than those with ΔONSD < 10% (47.2% vs. 12.9%, p = 0.003). However, other variables related to the quality of emergence from anesthesia did not different significantly between groups. Similarly, neurologic deficits, and PONV during postoperative day 3 showed no significant differences. (4) Conclusions: ICP elevation detected by ultrasonographic ONSD measurement was associated with a transient, inadequate emergence from anesthesia.

Objectives: We investigated the association between protracted low-dose ionising radiation and the risk of cancer in medical radiation workers, the largest group of workers with occupational radiation exposures., Methods: Data of all South Korean diagnostic medical radiation workers enrolled at the National Dose Registry during 1996-2011 were merged with the death and cancer incidence data until 31 December 2017. SIRs, relative risks and excess relative risks (ERRs) for cancer were calculated to quantify the radiation dose-response relationship using Poisson regression models., Results: A total of 3392 first primary cancer cases were identified among 93 920 diagnostic medical radiation workers. The mean cumulative badge dose in the cohort was 7.20 mSv. The ERRs for solid cancer with a 5-year lag and haematopoietic cancers with a 2-year lag for all workers were 0.15 per 100 mGy (95% CI -0.20 to 0.51) and 0.09 per 100 mGy (95% CI -2.02 to 2.20), respectively. The ERRs for cancers did not significantly vary by job title, different lag years or after excluding thyroid and lung cancers. Sensitivity analyses restricted to workers employed for at least 1 year, or who were employed in or after 1996, or who had exposure to a cumulative badge dose of 1 mSv or more showed similar results., Conclusions: Occupational radiation doses were not significantly associated with cancer incidence among South Korean diagnostic medical radiation workers. However, cautious interpretation of ERRs is needed due to the limitations of short follow-up and low cumulative radiation doses., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors. However, 50%-60% do not respond to single-agent anti-programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6-12 months. This phase Ib trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors., Patients and Methods: Eligible patients ≥18 years without prior anti-PD-1/PD-L1 therapy received LY3300054 monotherapy ( N = 40) or combination ( N = 20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination ( N = 22). LY3300054 (700 mg) and anti-TIM-3 antibody (cycles 1-2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability., Results: Eighty-two patients were enrolled. Most had colorectal ( n = 39, 47.6%) or endometrial ( n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor-naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort., Conclusions: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI-H/dMMR tumors., (©2021 American Association for Cancer Research.)

Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011., (© 2021. The Author(s).)

Background: Both innate and adaptive immune responses are important components of anticancer immunity. The CD47-SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours., Methods: We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov, NCT03013218., Findings: Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]-NC) in the single-agent cohort, 27·0 months (25·1-28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0-32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7-43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1-24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1-45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab., Interpretation: The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC., Funding: ALX Oncology., Competing Interests: Declaration of interests NJL reports research funding from ALX Oncology, Ascentage, BeiGene, Constellation Pharma, Forty Seven, Alpine, Merck, Pfizer, Regeneron, Apexian, Formation Biologics (Forbius), Symphogen, CytomX, InhibRx, Incyte, Jounce, Livzon, Northern Biologics, Innovent Biologics, Ikena, Odonate, Loxo, Alpine Biosciences, Mersana, Astellas, Celgene, Seagen, Samumed, Sapience Therapeutics, Epizyme, and Mersana; and personal fees from Innovent Biologics, all outside the submitted work. LQMC reports receiving research funding from ALX Oncology; participation on an advisory board for Merck; and receipt of medical writing services from Merck, all outside the submitted work. JFG reports research support from Bristol-Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array, Merck, Adaptimmune, Novartis, and ALX Oncology; consulting fees from Genentech-Roche, Bristol-Myers Squibb, Takeda, Loxo-Lilly, Blueprint, Oncorus, Regeneron, Gilead, Moderna, AstraZeneca, EMD Serono, Pfizer, Novartis, Merck, GlydeBio, and Karyopharm; payment or honoraria from Pfizer for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and having a spouse who owns stock and has other ownership interests in Ironwood Pharmaceuticals, all outside the submitted work. PL reports participation on advisory boards or data safety monitoring boards for AbbVie, Agios, Five Prime, GenMab, Halozyme, Roche-Genentech, Genentech, CytomX, Takeda, Cybrexa, Agenus, Tyme, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GlaxoSmithKline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical Development, Kineta, Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCube Pharmaceuticals, Bayer, and I-Mab; and was a consultant for SOTIO, SK Life Science, and I-Mab, all outside the submitted work. K-WL reports research support to their institution from ALX Oncology, AstraZeneca, Ono Pharmaceutical, Merck Sharp & Dohme, Merck, Pfizer, BeiGene, Astellas Pharma, Zymeworks, Five Prime Therapeutics, Macrogenics, Seagen, Bolt Biotherapeutics, Trishula Therapeutics, Oncologie, Pharmacyclics, LSK BioPharma, MedPacto, Green Cross, ABLBIO, Y-BIOLOGICS, Genexine, Daiichi Sankyo, Taiho Pharmaceutical, InvetisBio, Leap Therapeutics; and personal fees from ISU ABXIS, Bayer, Daiichi Sankyo, Bristol-Myers Squibb (consultation), Ono Pharmaceutical, and Boryung Pharmaceutical (honorarium), all outside the submitted work. JL reports receiving consulting fees from Mirati, Seattle Genetics, Oncxerna, and AstraZeneca, all outside the submitted work. Y-JB reports receiving research support paid to their institution from AstraZeneca, Novartis, Genentech-Roche, Merck Sharp & Dohme, Bayer, Merck Serono, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Eli Lilly, Curis, Taiho, Takeda, Ono Pharmaceutical, Daiichi Sankyo, Astellas, BeiGene, Green Cross, and Genexine; and consulting fees from AstraZeneca, Novartis, Genentech-Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, Merck Serono, Daiichi-Sankyo, Astellas, BeiGene, Green Cross, Samyang Biopharm, Hanmi, and ALX Oncology, all outside the submitted work. FSH reports research support to their institution from ALX Oncology, Bristol-Myers Squibb, Novartis, and the National Institutes of Health; consulting fees from Bristol-Myers Squibb, Novartis, EMD Serono, Genentech, Sanofi, Bicara, Apricity, Surface, Compass, Aduro, Pionyr, 7 Hills Pharma, Checkpoint, Bioentre, Gossamer, Iovance, Trillium, Catalym, Immunocore, Amgen, and Rheos; and ownership of stock or stock options in Pionyr, Apricity, Bicara, Checkpoint, and Torque, all outside the submitted work. RS-D reports receiving grants or contracts through his institution from ALX Oncology outside the submitted work. PF reports employment at ALX Oncology, and owning stock or stock options in ALX Oncology. PS is employed by IDDI, and reports research support from ALX Oncology outside the submitted work. FJ reports having a consulting or advisory role at ALX Oncology. HIW reports employment at ALX Oncology, receiving support for travel expenses from ALX Oncology, and owning stock and having other ownership interests in ALX Oncology outside the submitted work. JP reports employment at ALX Oncology, owning stock and having other ownership interests in ALX Oncology, research funding from ALX Oncology, patents planned, issued, or pending at ALX Oncology, and reports a leadership or fiduciary role at Tallac Therapeutics, all outside the submitted work. SSR is employed by and is on the board of directors at ALX Oncology, and reports owning stock and having other ownership interests in ALX Oncology, all outside the submitted work. WAM reports receiving research funding from ALX Oncology outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate drug-drug interactions between the human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd; DS-8201a) and the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole., Patients and Methods: Patients with HER2-expressing advanced solid tumors were enrolled in this phase I, open-label, single-sequence crossover study (NCT03383692) and received i.v. T-DXd 5.4 mg/kg every 3 weeks. Patients received ritonavir (cohort 1) or itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3. Primary endpoints were maximum serum concentration ( C max ) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC 17d ) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment., Results: Forty patients were enrolled (cohort 1, n = 17; cohort 2, n = 23). T-DXd C max was similar whether combined with ritonavir [cohort 1, cycle 3/cycle 2; 90% confidence interval (CI): 1.05 (0.98-1.13)] or itraconazole [cohort 2, 1.03 (0.96-1.09)]. T-DXd AUC 17d increased from cycle 2 to 3; however, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts. For DXd (cycle 3/cycle 2), C max ratio was 0.99 (90% CI, 0.85-1.14) for cohort 1 and 1.04 (0.92-1.18) for cohort 2; AUC 17d ratio was 1.22 (1.08-1.37) and 1.18 (1.11-1.25), respectively. The safety profile of T-DXd plus ritonavir or itraconazole was consistent with previous studies of T-DXd monotherapy. T-DXd demonstrated promising antitumor activity across HER2-expressing solid-tumor types., Conclusions: T-DXd was safely combined with ritonavir or itraconazole without clinically meaningful impact on T-DXd or DXd pharmacokinetics., (©2021 The Authors; Published by the American Association for Cancer Research.)

Porcine islet transplantation is an alternative to allo-islet transplantation. Retransplantation of islets is a routine clinical practice in islet allotransplantation in immunosuppressed recipients and will most likely be required in islet xenotransplantation in immunosuppressed recipients. We examined whether a second infusion of porcine islets could restore normoglycemia and further evaluated the efficacy of a clinically available immunosuppression regimen including anti-thymocyte globulin for induction; belimumab, sirolimus, and tofacitinib for maintenance and adalimumab, anakinra, IVIg, and tocilizumab for inflammation control in a pig to nonhuman primate transplantation setting. Of note, all nonhuman primates were normoglycemic after the retransplantation of porcine islets without induction therapy. Graft survival was >100 days for all 3 recipients, and 1 of the 3 monkeys showed insulin independence for >237 days. Serious lymphodepletion was not observed, and rhesus cytomegalovirus reactivation was controlled without any serious adverse effects throughout the observation period in all recipients. These results support the clinical applicability of additional infusions of porcine islets. The maintenance immunosuppression regimen we used could protect the reinfused islets from acute rejection., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: In the primary analysis population (i.e., PD-L1 combined positive score [CPS] ≥ 1) of the phase 3 KEYNOTE-061 study (NCT02370498), pembrolizumab did not significantly prolong overall survival or progression-free survival. Pembrolizumab had a favorable safety profile in the all-patient population. We present results of prespecified health-related quality of life (HRQoL) analyses., Methods: HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ gastric cancer questionnaire (QLQ-STO22), and EuroQol 5-dimension, 3-level questionnaire (EQ-5D-3L). Data were analyzed from patients who received ≥ 1 dose of study treatment and who completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 12 least-squares mean (LSM) change in global health status (GHS)/QoL, functional/symptom subscales, and time to deterioration (TTD; ≥ 10-point decrease from baseline) for specific subscales., Results: The HRQoL population included 371 patients (pembrolizumab, n = 188; paclitaxel, n = 183). Compliance and completion rates for all 3 questionnaires were similar in both groups at baseline and week 12. There was no difference in LSM change between groups (- 3.54; 95% CI - 8.92 to 1.84) in GHS/QoL at week 12. LSM change from baseline to week 12 for most QLQ-C30, QLQ-STO22, and EQ-5D-3L subscales indicated some worsening of QoL in both groups. TTD for GHS/QoL, nausea/vomiting, and appetite loss subscales in QLQ-C30 and the pain subscales in QLQ-STO22 were similar between treatment groups., Conclusions: In this population with advanced gastric and GEJ cancer receiving second-line treatment, HRQoL was similar in patients receiving pembrolizumab and those receiving paclitaxel., Clinical Trial Registry and Number: ClinicalTrials.gov, NCT02370498., (© 2021. The Author(s).)

Purpose: Despite curative resection, the 5-year survival for patients with resectable pancreatic cancer is less than 20%. Recurrence occurs both locally and at distant sites and effective multimodality adjuvant treatment is needed., Materials and Methods: Patients with curatively resected stage IB-IIB pancreatic adenocarcinoma were eligible. Treatment consisted of chemotherapy with gemcitabine 1,000 mg/m2 on days 1 and 8 and cisplatin 60 mg/m2 on day 1 every 3 weeks for two cycles, followed by chemoradiotherapy (50.4 Gy/28 fx) with weekly gemcitabine (300 mg/m2/wk), and then gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks for four cycles. The primary endpoint was 1-year disease-free survival rate. The secondary endpoints were disease-free survival, overall survival, and safety., Results: Seventy-four patients were enrolled. One-year disease-free survival rate was 57.9%. Median disease-free and overall survival were 15.0 months (95% confidence interval [CI], 11.6 to 18.4) and 33.0 months (95% CI, 21.8 to 44.2), respectively. At the median follow-up of 32 months, 57 patients (77.0%) had recurrence including 11 patients whose recurrence was during the adjuvant treatment. Most of the recurrences were systemic (52 patients). Stage at the time of diagnosis (70.0% in IIA, 51.2% in IIB, p=0.006) were significantly related with 1-year disease-free survival rate. Toxicities were generally tolerable, with 53 events of grade 3 or 4 hematologic toxicity and four patients with febrile neutropenia., Conclusion: Adjuvant gemcitabine and cisplatin chemotherapy followed by chemoradiotherapy with gemcitabine and maintenance gemcitabine showed efficacy and good tolerability in curatively resected pancreatic cancer.

Vitamin A and its derivative retinol are essential for the development of intestinal adaptive immunity. Retinoic acid (RA)–producing myeloid cells are central to this process, but how myeloid cells acquire retinol for conversion to RA is unknown. Here, we show that serum amyloid A (SAA) proteins—retinol-binding proteins induced in intestinal epithelial cells by the microbiota—deliver retinol to myeloid cells. We identify low-density lipoprotein (LDL) receptor–related protein 1 (LRP1) as an SAA receptor that endocytoses SAA-retinol complexes and promotes retinol acquisition by RA-producing intestinal myeloid cells. Consequently, SAA and LRP1 are essential for vitamin A–dependent immunity, including B and T cell homing to the intestine and immunoglobulin A production. Our findings identify a key mechanism by which vitamin A promotes intestinal immunity.

Flagellin, a protein-based Toll-like receptor agonist, is a versatile adjuvant applicable to wide spectrum of vaccines and immunotherapies. Given reiterated treatments of immunogenic biopharmaceuticals should lead to antibody responses precluding repeated administration, the development of flagellin not inducing specific antibodies would greatly expand the chances of clinical applications. Here we computationally identified immunogenic regions in Vibrio vulnificus flagellin B and deimmunized by simply removing a B cell epitope region. The recombinant deimmunized FlaB (dFlaB) maintains stable TLR5-stimulating activity. Multiple immunization of dFlaB does not induce FlaB-specific B cell responses in mice. Intranasally co-administered dFlaB with influenza vaccine enhanced strong Ag-specific immune responses in both systemic and mucosal compartments devoid of FlaB-specific Ab production. Notably, dFlaB showed better protective immune responses against lethal viral challenge compared with wild type FlaB. The deimmunizing B cell epitope deletion did not compromise stability and adjuvanticity, while suppressing unwanted antibody responses that may negatively affected vaccine antigen-directed immune responses in repeated vaccinations. We explain the underlying mechanism of deimmunization by employing molecular dynamics analysis., (© 2021. The Author(s).)

Importance: Whether radioactive iodine (RAI) therapy for hyperthyroidism can increase cancer risk remains a controversial issue in medicine and public health., Objectives: To examine site-specific cancer incidence and mortality and to evaluate the radiation dose-response association after RAI treatment for hyperthyroidism., Data Sources: The Medline and Cochrane Library electronic databases, using the Medical Subject Headings terms and text keywords, and Embase, using Emtree, were screened up to October 2020., Study Selection: Study inclusion criteria were as follows: (1) inclusion of patients treated for hyperthyroidism with RAI and followed up until cancer diagnosis or death, (2) inclusion of at least 1 comparison group composed of individuals unexposed to RAI treatment (eg, the general population or patients treated for hyperthyroidism with thyroidectomy or antithyroid drugs) or those exposed to different administered doses of RAI, and (3) inclusion of effect size measures (ie, standardized incidence ratio [SIR], standardized mortality ratio [SMR], hazard ratio [HR], or risk ratio [RR])., Data Extraction and Synthesis: Two independent investigators extracted data according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Overall quality assessment followed the recommendations of United Nations Scientific Committee on the Effects of Atomic Radiation. The SIR and SMRs and the RRs and HRs were pooled using random-effects meta-analysis., Main Outcomes and Measures: Cancer incidence and mortality for exposure vs nonexposure to RAI therapy and by level of RAI administered activity., Results: Based on data from 12 studies including 479 452 participants, the overall pooled cancer incidence ratio was 1.02 (95% CI, 0.95-1.09) and the pooled cancer mortality ratio was 0.98 (95% CI, 0.92-1.04) for exposure vs nonexposure to RAI therapy. No statistically significant elevations in risk were observed for specific cancers except thyroid cancer incidence (SIR, 1.86; 95% CI, 1.19-2.92) and mortality (SMR, 2.22; 95% CI, 1.37-3.59). However, inability to control for confounding by indication and other sources of bias were important limitations of studies comparing RAI exposure with nonexposure. In dose-response analysis, RAI was significantly associated with breast and solid cancer mortality (breast cancer mortality, per 370 MBq: 1.35; P = .03; solid cancer mortality, per 370 MBq: 1.14; P = .01), based on 2 studies., Conclusions and Relevance: In this meta-analysis, the overall pooled cancer risk after exposure to RAI therapy vs nonexposure was not significant, whereas a linear dose-response association between RAI therapy and solid cancer mortality was observed. These findings suggest that radiation-induced cancer risks following RAI therapy for hyperthyroidism are small and, in observational studies, may only be detectable at higher levels of administered dose.

Background: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status., Patients and Methods: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used., Results: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1)., Conclusion: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status., Competing Interests: Disclosure KS reports honoraria for AbbVie, Novartis, and Yakult; consulting or advisory role for AbbVie, Astellas Pharma, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; researching funding for Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Medi Science, Ono Pharmaceutical, and Taiho Pharmaceutical. MÖ reports honoraria for Astellas Pharma, Janssen, and Roche; consulting or advisory role for Janssen; and travel, accommodations, expenses for AstraZeneca. Y-JB reports consulting/advisory for Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi Sankyo, Eli Lilly, Genentech/Roche, Genexine, Green Cross, Hammi, Merck Serono, MSD, Novartis, Samyang Biopharm, and Taiho; grants (to the institution for clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bostin Biomedical, BMS, CKD Pharma, Curis, Daiichi-Sankyo, Eli Lilly, Five Prime, Genentech/Roche, Genexine Green Cross, GSK, MacroGenics, Merck Serono, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda. MDB reports honoraria for Eli Lilly, Merck Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Servier; consulting or advisory role for Eli Lilly; speakers’ bureau for Eli Lilly and Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; researching funding for Eli Lilly; and travel, accommodations, expenses for Roche. MM reports honoraria for Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, and Pierre Fabre; consulting or advisory role for Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, and Pierre Fabre; speakers’ bureau for Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, and Pierre Fabre; and research funding for Novartis and Roche. M-HR reports honoraria for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho; and consulting or advisory role for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho. CC reports honoraria for Andes Biotechnologies; consulting or advisory role for Boehringer Ingelheim Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche; speakers’ bureau for Bristol Myers Squibb, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche; research funding for AstraZeneca, Astella Pharma, Bristol Myers Squibb, Medivation, and Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; and travel, accommodations, expenses for Bristol Myers Squibb and Roche. HCC reports honoraria for Eli Lilly and Merck Serono; consulting or advisory role for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Eli Lilly, Gloria, Merck Serono, Quintiles, Taiho, and Zymeworks; and research funding for Amgen, BeiGene, Bristol Myers Squibb/Ono Pharmaceutical, Eli Lilly, Glaxo Smith Kline, Merch Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Taiho. KM reports research funding (to his institution) from Daiichi Sankyo, MEDISCIENCE PLANNING, MSD, Parexel International, Pfizer, Sanofi, Solasia Pharma, and Sumitomo Dainippon Pharma; honoraria for speaking from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical, Takeda Pharmaceutical, and Sanofi; and advisory/consultancy for Amgen, AstraZeneca, and Ono Pharmaceutical Co., Ltd. EVC reports consulting or advisory role for Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly, Halozyme, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier; and research funding (to his institution) for Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier. JK is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. RC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. DA-G is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA and received travel, accommodations, or expenses from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JL is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. C-SS is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc, and received researching funding and travel, accommodations, or expenses for Exelixis. DA is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. ZAC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA, and in Bristol Myers Squibb. CSF served in an advisory/consultancy role for Agios, Amylin Pharmaceuticals, AstraZeneca, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Taiho, and Unum Therapeutics. He also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; is a cofounder of EvolveImmune Therapeutics and has equity in this private company; and has provided expert testimony for Amylin Pharmaceuticals and Eli Lilly., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: In the randomised phase III KEYNOTE-062 study, pembrolizumab was non-inferior to chemotherapy for overall survival in patients with programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (GEJ) cancer. We present findings of prespecified health-related quality-of-life (HRQOL) analyses for pembrolizumab versus chemotherapy in this population., Materials and Methods: HRQOL, a secondary endpoint, was measured in patients who received ≥1 dose of study treatment and completed ≥1 HRQOL questionnaire [European Organisation for the Research and Treatment of Cancer (EORTC) 30-question quality-of-life (QLQ-C30), EORTC 22-question quality-of-life gastric-cancer-specific module (QLQ-STO22)]. Least squares mean (LSM) change (baseline to week 18) in global health status/quality of life (GHS/QOL; EORTC QLQ-C30) and time to deterioration (TTD) in GHS/QOL, nausea/vomiting and appetite loss scores (EORTC QLQ-C30) and abdominal pain/discomfort scores (EORTC QLQ-STO22) were evaluated., Results: The HRQOL population comprised 495 patients with CPS ≥1 (pembrolizumab, 252; chemotherapy, 243). Compliance rates at week 18 were similar for pembrolizumab and chemotherapy (EORTC QLQ-C30, 87.9% and 81.9%; EORTC QLQ-STO22, 87.9% and 81.3%, respectively). There was no between-arm difference in LSM score change in GHS/QOL [-0.16; 95% confidence interval (CI) -5.01 to 4.69; P = 0.948]. The LSM score change for most subscales showed comparable worsening in both arms. TTD for GHS/QOL [hazard ratio (HR), 0.96; 95% CI, 0.67-1.38; P = 0.826], appetite loss (HR, 0.83; 95% CI, 0.58-1.20; P = 0.314) and pain (HR, 1.22; 95% CI, 0.78-1.91; P = 0.381) were similar between arms. Longer TTD was observed for pembrolizumab versus chemotherapy for nausea/vomiting (HR, 0.61; 95% CI, 0.44-0.85; P = 0.003)., Conclusions: HRQOL was maintained with first-line treatment with pembrolizumab in patients with PD-L1-positive advanced gastric/GEJ cancer and was similar between pembrolizumab and chemotherapy in this population., Competing Interests: Disclosure EVC reports advisory/consultancy fees from Array, AstraZeneca, Bayer, BioPharma, Bristol Myers Squibb, Celgene, Halozyme, Lilly, Merck KGaA, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Roche and Servier; and researching grant/funding (institution) from Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA., Merck KGaA, Novartis, Roche and Servier. AV is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Y-JB reports consulting/advisory role for Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Daichii-Sankyo, Eli Lilly, Genentech/Roche, Genexine, Green Cross, Hanmi, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Novartis, Samyang Biopharmaceuticals and Taiho; and grants (to the institution for clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Boehringer Ingelheim, Boston Biomedical, CKD Pharma, Curis, Daiichi Sankyo, Eli Lilly, Five Prime, Genentech/Roche, Genexine, Green Cross, GSK, MacroGenics, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono, Novartis, Ono, Pfizer, Taiho and Takeda. CSF reports consulting role for Agios, Amylin Pharmaceuticals, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Taiho and Unum Therapeutics. He also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health. He is a co-founder of EvolveImmune Therapeutics and has equity in this private company. KS reports grants and personal fees from Astellas Pharma, Eli Lilly and Company, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Ono Pharmaceutical and Taiho Pharmaceutical; personal fees from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Pfizer Inc., Takeda Pharmaceuticals and Yakult; and grants from Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma and Medi Science. YYJ reports advisory fees from Bristol Myers Squibb, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono and Pfizer; and research expenses from Amgen, Bayer, Boehringer Ingelheim, Genentech, Lilly and Roche. VS reports research funding from Bristol Myers Squibb, EMD-Serono and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. SSt reports advisory/consultancy role for Bayer, Bristol Myers Squibb, Exelixis, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and QED. JMN is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. UK is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. SSh is an employee and a stockholder of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MA reports scientific consultancy role for Bristol Myers Squibb, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Servier; and honoraria for speaking for Bristol Myers Squibb, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Servier. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Current guidelines recommend two-drug cytotoxic chemotherapy with a fluoropyrimidine (fluorouracil or capecitabine) and a platinum-based agent (oxaliplatin or cisplatin) as first-line treatment for advanced gastric cancer. Pembrolizumab monotherapy has demonstrated durable antitumor activity in patients with advanced programmed death ligand 1-positive (combined positive score ≥1) gastric/gastroesophageal junction adenocarcinoma. Accumulating evidence indicates that combining pembrolizumab with standard-of-care chemotherapy for the treatment of advanced or metastatic cancer improves clinical outcomes. We describe the rationale for and the design of the randomized, double-blind, placebo-controlled, Phase III KEYNOTE-859 study, which is investigating pembrolizumab in combination with chemotherapy as first-line treatment for patients with human epidermal growth factor receptor 2-negative advanced unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma. The planned sample size is 1542 patients, and the primary end point is overall survival. Clinical trial registration: NCT03675737 (ClinicalTrials.gov).

Patient's cooperation and respiration is necessary in percutaneous radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). We compared the respiratory patterns of dexmedetomidine and propofol sedation during this procedure. Participants were randomly allocated into two groups: the continuous infusions of dexmedetomidine-remifentanil (DR group) or the propofol-remifentanil (PR group). We measured the tidal volume for each patient's respiration during one-minute intervals at five points and compared the standard deviation of the tidal volumes (SDvt) between the groups. Sixty-two patients completed the study. SDvt at 10 min was not different between the groups (DR group, 108.58 vs. PR group, 149.06, p = 0.451). However, SDvt and end-tidal carbon dioxide (EtCO 2 ) level of PR group were significantly increased over time compared to DR group ( p = 0.004, p = 0.021; ß = 0.14, ß = -0.91, respectively). Heart rate was significantly decreased during sedation in DR group ( p < 0.001, ß = -2.32). Radiologist satisfaction was significantly higher, and the incidence of apnea was lower in DR group ( p = 0.010, p = 0.009, respectively). Compared with propofol-remifentanil, sedation using dexmedetomidine-remifentanil provided a lower increase of the standard deviation of tidal volume and EtCO 2 , and also showed less apnea during RFA of HCC.

There is an unmet need for new influenza vaccine strategies that compensate for impaired vaccine responses in elderly individuals. Here, we evaluated the effectiveness of a single-stranded RNA (ssRNA) as an adjuvant to enhance the efficacy of inactivated influenza vaccine (IIV) in mouse models. Immunization with the ssRNA along with IIV reduced viral titers as well as pathological and inflammatory scores in the lungs after influenza challenge in aged mice. ssRNA induced balanced Th1/Th2 responses with an increase in IgA titers. Moreover, the ssRNA adjuvant markedly increased the frequency of influenza HA-specific T cells and IFN-γ production along with the expression of genes related to innate and adaptive immune systems that could overcome immunosenescence in aged mice. Our findings indicate that ssRNA is an efficient vaccine adjuvant that boosts cellular and humoral immunity in aged mice, demonstrating its potential as a novel adjuvant for currently available influenza virus vaccines for elderly individuals.

Importance: Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors., Objective: To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received., Design, Setting, and Participants: This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively., Interventions: Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062., Main Outcomes and Measures: Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing., Results: At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy., Conclusions and Relevance: Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received., Trial Registration: ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.

Since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), various vaccines are being developed, with most vaccine candidates focusing on the viral spike protein. Here, we developed a previously unknown subunit vaccine comprising the receptor binding domain (RBD) of the spike protein fused with the tetanus toxoid epitope P2 (RBD-P2) and tested its efficacy in rodents and nonhuman primates (NHPs). We also investigated whether the SARS-CoV-2 nucleocapsid protein (N) could increase vaccine efficacy. Immunization with N and RBD-P2 (RBDP2/N) + alum increased T cell responses in mice and neutralizing antibody levels in rats compared with those obtained using RBD-P2 + alum. Furthermore, in NHPs, RBD-P2/N + alum induced slightly faster SARS-CoV-2 clearance than that induced by RBD-P2 + alum, albeit without statistical significance. Our study supports further development of RBD-P2 as a vaccine candidate against SARS-CoV-2. Also, it provides insights regarding the use of N in protein-based vaccines against SARS-CoV-2., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

GC1118 is a monoclonal antibody for epidermal growth factor receptor (EGFR) that is currently under clinical development to treat patients with solid tumors. In this study, the pharmacokinetics (PKs) of GC1118 were modeled in solid tumor patients who received a 2-h intravenous infusion of GC1118 at 0.3, 1, 3, 5, or 4 mg/kg once-weekly (Q1W) on days 1, 8, 15, and 22 or 8 mg/kg every other week on days 1 and 15. A target-mediated drug disposition population PK model adequately described the concentration-time profiles of GC1118. Monte-Carlo simulation experiments of the PK profiles and EGFR occupancies (ROs) by GC1118 based on the final model showed that Q1W at 4 or 5 mg/kg will produce a better antitumor effect than Q2W at 8 mg/kg. Because GC1118 was safer at 4 mg/kg than 5 mg/kg in the phase I study, we suggest to test the 4 mg/kg Q1W regimen in further clinical trials with GC1118. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GC1118, a fully human IgG 1 monoclonal antibody (mAb) for epidermal growth factor receptor (EGFR), showed a nonlinear pharmacokinetic (PK) profile in monkeys and humans. The total clearance of GC1118 decreased as the dose was increased up to 3-4 mg/kg in humans, beyond which it remained stable. The recommended phase II dose for GC1118 was 4 mg/kg intravenously infused over 2 h once weekly. WHAT QUESTION DID THIS STUDY ADDRESS? We developed a target-mediated drug disposition (TMDD) population PK model that described the nonlinear PK profile of GC1118 in patients with solid tumors. We also simulated the PK profiles and receptor occupancies for different dosage regimens. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The TMDD population PK model adequately described the nonlinear and multiphasic PK profiles of GC1118 in humans. The simulation experiment showed that once-weekly GC1118 at 4-5 mg/kg could be more efficacious than the biweekly regimen at 8 mg/kg. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The pharmacometrics analysis could support better informed drug development decisions for GC1118, particularly for determining an optimal dosage regimen., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor., Patients and Methods: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis., Results: No dose-limiting toxicities were observed in the monotherapy ( N = 30) or combination ( N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%-70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non-small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [ N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders ( N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts ( N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients., Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation., (©2021 American Association for Cancer Research.)

The national dose registry (NDR) contains essential information to help protect radiation workers from radiation-related health risks and to facilitate epidemiological studies. However, direct validation of the reported doses has not been considered. We investigated the validity of the NDR with a personal dosimeter monitoring conducted among Korean interventional radiologists. Among the 56 interventional radiologists, NDR quarterly doses were compared with actively monitored personal thermoluminescent dosimeter (TLD) doses as standard measures of validation. We conducted analyses with participants categorized according to compliance with TLD badge-wearing policies. A correlation between actively monitored doses and NDR doses was low (Spearman ρ = 0.06), and the mean actively monitored dose was significantly higher than the mean NDR dose (mean difference 0.98 mSv) in all participants. However, interventional radiologists who wore badges irregularly showed a large difference between actively monitored doses and NDR doses (mean difference 2.39 mSv), and participants who wore badges regularly showed no apparent difference between actively monitored doses and NDR doses (mean difference 0.26 mSv). This study indicated that NDR data underestimate the actual occupational radiation exposure, and the validity of these data varies according to compliance with badge-wearing policies. Considerable attention is required to interpret and utilize NDR data based on radiation workers' compliance with badge-wearing policies.

Purpose: To lessen the physical, cosmetic, and psychological burden of donors, purely laparoscopic donor hepatectomy (PLDH) has been proposed as an ideal method for living donors. Our study aimed to prospectively compare the effect of PLDH and 2 other types of open living donor hepatectomy (OLDH) on postoperative pain and recovery., Methods: Sixty donors scheduled to undergo donor hepatectomy between March 2015 and November 2017 were included. Donors were divided into 3 groups by surgical technique: OLDH with a subcostal incision (n = 20), group S; OLDH with an upper midline incision (n = 20), group M; and PLDH (n = 20), group L. The primary outcomes were postoperative pain and analgesic requirement during postoperative day (POD) 3. Other variables regarding postoperative recovery were also analyzed., Results: Although pain relief during POD 3, assessed by visual analog scale (VAS) score and analgesic requirement, was similar among the 3 groups, group L showed lower VAS scores and opioid requirements than group M. Moreover, group L was associated with a rapid postoperative recovery evidenced by the shorter hospital length of stay and more frequent return to normal activity on POD 30., Conclusion: This pilot study failed to verify the hypothesis that PLDH reduces postoperative pain. PLDH did not reduce postoperative pain but showed faster recovery than OLDH., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2021, the Korean Surgical Society.)

Purpose: Pembrolizumab demonstrated efficacy in PD-L1-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (G/GEJ) cancer in the first-, second-, and third-line setting in KEYNOTE-062, KEYNOTE-061, and KEYNOTE-059, respectively. To better delineate the specificity of CPS as a predictor of clinical outcomes, we analyzed pembrolizumab efficacy in patients with CPS ≥ 10 in these trials., Patients and Methods: Included were patients with CPS ≥ 10 tumors from KEYNOTE-059 cohort 1 (pembrolizumab, n = 46; post hoc ), KEYNOTE-061 (pembrolizumab, n = 53; chemotherapy, n = 55; post hoc ), and KEYNOTE-062 (pembrolizumab, n = 92; chemotherapy, n = 90; primary). Efficacy outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR)., Results: In KEYNOTE-059, median follow-up was 6 months, median OS was 8 months [95% confidence interval (CI), 5.8-11.1], ORR was 17%, and median (range) DOR was 21 months (3+ to 35+). In KEYNOTE-061, median follow-up was 9 months, median OS (pembrolizumab vs. chemotherapy) was 10 versus 8 months (HR, 0.64; 95% CI, 0.41-1.02), median PFS was 3 months versus 3 months (HR, 0.86; 95% CI, 0.56-1.33), ORR was 25% versus 9%, and median (range) DOR was not reached (4 to 26+ months) versus 7 months (3-7). In KEYNOTE-062, median follow-up was 11 months, median OS (pembrolizumab vs. chemotherapy) was 17 months versus 11 months (HR, 0.69; 95% CI, 0.49-0.97), median PFS was 3 months versus 6 months (HR, 1.09, 95% CI; 0.79-1.49), ORR was 25% versus 38%, and median (range) DOR was 19 months (1+ to 34+) versus 7 months (2+ to 30+)., Conclusions: This comprehensive analysis showed consistent improvements toward more favorable clinical outcomes with pembrolizumab across lines of therapy in patients with CPS ≥ 10 G/GEJ cancer., (©2021 American Association for Cancer Research.)

Purpose: The role of maintenance therapy for gastric (GC) or gastroesophageal junction cancer (GEJC) is unclear. We investigated avelumab (anti-programmed death ligand-1 [PD-L1]) maintenance after first-line induction chemotherapy for GC/GEJC., Patients and Methods: JAVELIN Gastric 100 was a global, open-label, phase III trial. Eligible patients had untreated, unresectable, human epidermal growth factor receptor 2-negative, locally advanced or metastatic GC or GEJC. Patients without progressive disease after 12 weeks of first-line chemotherapy with oxaliplatin plus a fluoropyrimidine were randomly assigned 1:1 to avelumab 10 mg/kg every 2 weeks or continued chemotherapy, stratified by region (Asia v non-Asia). The primary end point was overall survival (OS) after induction chemotherapy in all randomly assigned patients or the PD-L1-positive randomly assigned population (≥ 1% of tumor cells; 73-10 assay)., Results: A total of 805 patients received induction; 499 were randomly assigned to avelumab (n = 249) or continued chemotherapy (n = 250). Median OS was 10.4 months (95% CI, 9.1 to 12.0 months) versus 10.9 months (95% CI, 9.6 to 12.4 months) and 24-month OS rate was 22.1% versus 15.5% with avelumab versus chemotherapy, respectively (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .1779). In the PD-L1-positive population (n = 54), the HR for OS was 1.13 (95% CI, 0.57 to 2.23; P = .6352). In an exploratory analysis of the PD-L1-positive population, defined as combined positive score ≥ 1 (22C3 assay; n = 137), median OS was 14.9 months (95% CI, 8.7 to 17.3 months) with avelumab versus 11.6 months (95% CI, 8.4 to 12.6 months) with chemotherapy (unstratified HR, 0.72; 95% CI, 0.49 to 1.05). With avelumab and chemotherapy, treatment-related adverse events (TRAEs) occurred in 149 (61.3%) and 184 (77.3%) patients, including grade ≥ 3 TRAEs in 31 (12.8%) and 78 (32.8%) patients, respectively., Conclusion: JAVELIN Gastric 100 did not demonstrate superior OS with avelumab maintenance versus continued chemotherapy in patients with advanced GC or GEJC overall or in a prespecified PD-L1-positive population.

Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334)., Patients and Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy ( N = 15) or combined with ramucirumab ( N = 10), abemaciclib ( N = 24), or merestinib ( N = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety., Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months., Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens., (©2020 American Association for Cancer Research.)

Treatment options for patients with HER2-positive advanced gastric cancer are limited, and the prognosis for these patients is poor. Pembrolizumab has demonstrated promising antitumor activity in patients with advanced gastric or gastroesophageal junction adenocarcinoma as monotherapy, in combination with chemotherapy and in combination with trastuzumab. Combining pembrolizumab with trastuzumab and chemotherapy may therefore provide a benefit for patients with advanced HER2-positive gastric cancer. Here we aimed to describe the design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Clinical trial registration: NCT03615326 (ClinicalTrials.gov).

A novel intelligent pH-responsive color indicator was prepared by adsorbing a natural naphthoquinone pigment, shikonin, onto cellulose paper. FTIR results indicated that shikonin was crosslinked with the cellulose of the indicator paper. The addition of shikonin increased antioxidant activity, thermal stability, and water resistance properties of the paper. The indicator changed the color from red to dark blue, depending on the pH of buffer solutions. Also, the indicator showed high stability after 4 months of storage and maintained high sensitivity to pH changes. This indicator was used to monitor fish and pork freshness during storage at room temperature, and the results showed a high correlation between the color change of the indicator and the pH change of the sample. The shikonin-adsorbed indicator with stable and sensitive color change depending on pH can be used in the intelligent food packaging applications to monitor the quality of packaged food in real-time., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Preeclampsia (PE) is a placental disorder caused by endothelial dysfunction via trophoblast inadequate invasion activity. Adrenomedullin (ADM) and ADM2 are multifunctional peptides that can support vascular activity and placental growth. However, correlation between ADMs and trophoblast functions is currently unclear. The objective of this study was to analyze changes in expression of ADMs in placenta and HTR-8/SVneo trophoblast cells under hypoxia and their effects on invasion activity of trophoblast cells and expression of HLA-G. In placental tissues of PE, expression levels of ADM and HLA-G were significantly increased (P < 0.05) whereas expression of ADM2 was decreased compared to that in normal term placenta. Under hypoxia, expression levels of ADM, ADM2, and HLA-G and invasion ability of trophoblast cells were increased in hypoxia-inducible factor-1 (HIF-1α)- dependent manner (P < 0.05). Treatment with ADMs agonists reduced HIF-1α activity whereas enhanced invasion ability under hypoxia. However, they were not changed after cotreatment of ADMs and HIF-1α inhibitor, YC-1, although expression levels of invasion-related genes MMP2, MMP9, and Rac1 were altered (P < 0.05). ADMs also increased HLA-G expression under normoxia whereasADM2 or cotreatment of ADMs under hypoxia attenuated HLA-G expression (P < 0.05). Our findings demonstrate that altered expression of ADMs plays a critical role in placental physiology, especially in trophoblast invasion and immune-modulation under hypoxia., (© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

Purpose: Interventional medical radiation workers represent an under-studied population worldwide, although they receive relatively high occupational radiation doses. This study aimed to estimate the lifetime cancer risk from occupational radiation exposure among workers at interventional radiology departments., Methods: A field survey of interventional medical workers in nationwide branches of the Korean Society of Interventional Radiology was conducted in 2017. Organ-specific radiation doses were estimated using national dose registry data and conversion coefficients provided by the International Commission on Radiological Protection. Lifetime attributable risk (LAR) and lifetime fractional risk (LFR) were calculated based on realistic exposure scenarios using a radiation risk assessment tool., Results: LARs from occupational radiation exposure until the age of retirement for all cancers combined were 338 (90.3-796.1), 121 (33.5-288.7), and 156 (41.1-390.6) per 100,000 individuals for male radiologists, male radiologic technologists, and female nurses, respectively. LFR for all cancers combined ranged from 0.22% (0.06-0.53) to 0.63% (0.17-1.47). Regarding the organ site, the highest LAR and LFR among all groups were observed for thyroid cancer., Conclusion: This study provides timely evidence of potential cancer burden from the current levels of occupational radiation exposure among workers at interventional radiology departments. The risks varied by occupational groups, and workers, particularly interventional radiologists, need to be carefully monitored for radiation.

Background: We aimed to investigate the analgesic efficacy of an erector spinae plane block (ESPB) in immediate breast reconstruction (IBR) with a tissue expander., Methods: Adult women undergoing IBR with a tissue expander after mastectomy were randomly assigned to either intravenous patient-controlled analgesia (IV-PCA) alone (group P) or IV-PCA plus ESPB (group E). The primary outcome was the total amount of opioid consumption during 24 hours postoperatively between the two groups. Secondary outcomes were patient satisfaction, pain score at rest and on shoulder movement using numerical rating scale, incidences of postoperative nausea and vomiting (PONV), and a short form of the brief pain inventory (BPI-SF) at 3 and 6 months after surgery between the groups., Results: Fifty eight patients completed the study. At 24 hours postoperatively, total opioid consumption was significantly less in group E than in group P (285.0 ± 92.0, 95% confidence interval [CI]: 250.1 to 320.0 vs. 223.2 ± 83.4, 95% CI: 191.5 to 254.9, P = 0.005). Intraoperative and cumulative PCA fentanyl consumption at 3, 6, 9, and 24 hours were also less in group E than in group P ( P = 0.004, P = 0.048, P = 0.020, P = 0.036, and P < 0.001, respectively). Patient satisfaction was higher in group E (6.9 ± 1.8 vs. 7.8 ± 1.4, P = 0.042). The incidences of PONV was similar., Conclusions: The ESPB decreased postoperative opioid consumption and increased patient satisfaction without significant complications after IBR with a tissue expander after mastectomy.

Immune checkpoint inhibitors become a standard therapy for malignant melanoma. As immune checkpoint inhibitor monotherapies proved to have limited efficacy in significant portion of patients, it is envisaged that combination with other therapeutic modalities may improve clinical outcomes. We investigated the effect of combining photodynamic therapy (PDT) and TLR5 agonist flagellin-adjuvanted tumor-specific peptide vaccination (FlaB-Vax) on the promotion of PD-1 blockade-mediated melanoma suppression using a mouse B16-F10 implantation model. Using a bilateral mouse melanoma cancer model, we evaluated the potentiation of PD-1 blockade by the combination of peritumoral FlaB-Vax delivery and PDT tumor ablation. A photosensitizing agent, pheophorbide A (PhA), was used for laser-triggered photodynamic destruction of the primary tumor. The effect of combination therapy in conjunction with PD-1 blockade was evaluated for tumor growth and survival. The effector cytokines that promote the activation of CD8 + T cells and antigen-presenting cells in tumor tissue and tumor-draining lymph nodes (TDLNs) were also assayed. PDT and FlaB-Vax combination therapy induced efficacious systemic antitumor immune responses for local and abscopal tumor control, with a significant increase in tumor-infiltrating effector memory CD8 + T cells and systemic IFNγ secretion. The combination of PDT and FlaB-Vax also enhanced the infiltration of tumor antigen-reactive CD8 + T cells and the accumulation of migratory CXCL10-secreting CD103 + dendritic cells (DCs) presumably contributing to tumor antigen cross-presentation in the tumor microenvironment (TME). The CD8 + T-cell-dependent therapeutic benefits of PDT combined with FlaB-Vax was significantly enhanced by a PD-1-targeting checkpoint inhibitor therapy. Conclusively, the combination of FlaB-Vax with PDT-mediated tumor ablation would serve a safe and feasible combinatorial therapy for enhancing PD-1 blockade treatment of malignant melanoma.

Objectives: We investigated the association between low-dose external occupational radiation exposure and circulatory disease morbidity among diagnostic medical radiation workers., Methods: A cohort of 11 500 diagnostic medical radiation workers was linked with the National Dosimetry Registry data and the National Health Insurance Service data. Relative risks (RRs) were calculated to explore the association between occupational factors and circulatory disease morbidity, and excess relative risks per 100 milligray (ERR/100 mGy) were estimated to quantify the radiation dose-response relationship., Results: Overall, there were 2270 cases of circulatory diseases during 93 696 person-years of observation (average follow-up=8.1 years). RRs for hypertension were significantly increased for individuals who started working before 2000 compared with those who started in 2005 and later. ERR/100 mGy for all circulatory diseases was 0.14 (95% CI -0.57 to 0.99). Radiation risks of cerebrovascular diseases and ischaemic heart disease were non-significantly increased with estimates of individual cumulative doses to the heart (ERR/100 mGy=3.10 (-0.75 to 11.59) and 1.22 (-0.71 to 4.73), respectively). However, ERR estimates were generally more strongly positive for female versus male workers and for younger workers versus more than 50-year-old workers., Conclusions: This study provides little evidence in support of a positive association between occupational radiation exposure and the overall risk of circulatory disease over a short follow-up period among medical radiation workers in South Korea. However, significantly increased RR with earlier year first worked, elevated ERR in female workers and young workers should be further followed up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Microsatellite instability (MSI) status may affect the efficacy of adjuvant chemotherapy in gastric cancer. In this study, the clinical characteristics of MSI-high (MSI-H) gastric cancer and the predictive value of MSI-H for adjuvant chemotherapy in large cohorts of gastric cancer patients were evaluated., Material and Methods: This study consisted of two cohorts. Cohort 1 included gastric cancer patients who received curative resection with pathologic stage IB-IIIC. Cohort 2 included patients with MSI-H gastric cancer who received curative resection with pathologic stage II/III. MSI was examined using two mononucleotide markers and three dinucleotide markers., Results: Of 359 patients (cohort 1), 41 patients (11.4%) had MSI-H. MSI-H tumors were more frequently identified in older patients (p < 0.001), other histology than poorly cohesive, signet ring cell type (p=0.005), intestinal type (p=0.028), lower third tumor location (p=0.005), and absent perineural invasion (p=0.027). MSI-H status has a tendency of better disease-free survival (DFS) and overall survival (OS) in multivariable analyses (hazard ratio [HR], 0.4; p=0.059 and HR, 0.4; p=0.063, respectively). In the analysis of 162 MSI-H patients (cohort 2), adjuvant chemotherapy showed a significant benefit with respect to longer DFS and OS (p=0.047 and p=0.043, respectively). In multivariable analysis, adjuvant chemotherapy improved DFS (HR, 0.4; p=0.040)., Conclusion: MSI-H gastric cancer had distinct clinicopathologic findings. Even in MSI-H gastric cancer of retrospective cohort, adjuvant chemotherapy could show a survival benefit, which was in contrast to previous prospective studies and should be investigated in a further prospective trial.

Various cheese products are involved in outbreaks of listeriosis worldwide due to high consumption and prolonged refrigerated storage. The objective of this study was to determine the efficacy of using lactic acid bacteria and packaging with grapefruit seed extract (GSE) for controlling Listeria monocytogenes growth in soft cheese. Leuconostoc mesenteroides and Lactobacillus curvatus isolated from kimchi were used as a starter culture to make a soft cheese, which was inoculated with a cocktail strain of L. monocytogenes. The soft cheese was packed with low-density polyethylene, biodegradable polybutylene adipate-co-terephthalate (PBAT), low-density polyethylene with GSE, or PBAT with GSE and stored at 10°C and 15°C. Leuconostoc mesenteroides (LcM) better inhibited the growth of L. monocytogenes than Lb. curvatus. The PBAT with GSE film showed the best control for the growth of L. monocytogenes. When both LcM and PBAT with GSE were applied to the soft cheese, the growth of L. monocytogenes was inhibited significantly more than the use of LcM or PBAT with GSE alone. In all test groups, water activity, pH, and moisture on a fat-free basis decreased, and titratable acidity increased compared with the control group. These results suggest that LcM isolated from kimchi and PBAT with GSE packaging film can be used as a hurdle technology to lower the risk of L. monocytogenes in soft cheese at the retail market., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Objectives: Suicide is a leading cause of death in the working-age population. We investigated suicide mortality among diagnostic medical radiation workers in relation to their demographic and occupational factors in South Korea., Methods: The study population consisted of all diagnostic medical radiation workers enrolled in the National Dosimetry Registry from 1996 to 2011. The registry data were linked with mortality data through the end of 2017. We calculated age-standardised suicide rates, standardised mortality ratios (SMRs) and rate ratios (RRs) by demographic and occupational factors., Results: A total of 207 suicides were identified among 94 367 medical radiation workers, exhibiting a suicide rate of 14.0 per 100 000 person-years. Compared with the general population, suicide rates were lower for both male and female workers (SMR 0.49, 95% confidence interval (CI) 0.42 to 0.57; SMR 0.54, 95% CI 0.41 to 0.70, respectively). Similarly, decreased SMRs were observed across job titles and other work-related factors. However, a shorter duration of employment was positively associated with RRs for suicide; risks were 2.74 (95% CI 1.56 to 4.81) and 4.66 (95% CI 1.53 to 14.20) times higher in male and female workers with less than 1 year of employment, respectively, than in those with at least 10 years of employment., Conclusions: Diagnostic medical radiation workers in South Korea showed lower suicide rates than in the general population. However, a shorter duration of employment was associated with higher risk of suicide. Suicide prevention efforts could target workers engaged in short-term employment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours., Methods: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing., Findings: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0-38·3). Objective responses were observed in 30 (29%; 95% CI 21-39) of 102 patients in the tTMB-high group and 43 (6%; 5-8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3-5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related., Interpretation: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours., Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need., Objective: To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater., Design, Setting, and Participants: The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017., Interventions: Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2 twice daily), or chemotherapy plus placebo, every 3 weeks., Main Outcomes and Measures: Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater., Results: A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03; P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17; P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02; P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively., Conclusions and Relevance: This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested., Trial Registration: ClinicalTrials.gov Identifier: NCT02494583.

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C ., Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1., Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma., Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)., (Copyright © 2020 Massachusetts Medical Society.)

Influenza vaccination is considered the most valuable means to prevent and control seasonal influenza infections, which causes various clinical symptoms, ranging from mild cough and fever to even death. Among various influenza vaccine types, the inactivated subunit type is known to provide improved safety with reduced reactogenicity. However, there are some drawbacks associated with inactivated subunit type vaccines, with the main ones being its low immunogenicity and the induction of Th2-biased immune responses. In this study, we investigated the role of a single-stranded RNA (ssRNA) derived from the intergenic region in the internal ribosome entry site of the Cricket paralysis virus as an adjuvant rather than the universal vaccine for a seasonal inactivated subunit influenza vaccine. The ssRNA adjuvant stimulated not only well-balanced cellular (indicated by IgG2a, IFN-γ, IL-2, and TNF-α) and humoral (indicated by IgG1 and IL-4) immune responses but also a mucosal immune response (indicated by IgA), a key protector against respiratory virus infections. It also increases the HI titer, the surrogate marker of influenza vaccine efficacy. Furthermore, ssRNA adjuvant confers cross-protective immune responses against heterologous influenza virus infection while promoting enhanced viral clearance. Moreover, ssRNA adjuvant increases the number of memory CD4 + and CD8 + T cells, which can be expected to induce long-term immune responses. Therefore, this ssRNA-adjuvanted seasonal inactivated subunit influenza vaccine might be the best influenza vaccine generating robust humoral and cellular immune responses and conferring cross-protective and long-term immunity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti-PD-L1 IgG1, in previously treated patients with advanced non-small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC)., Patients and Methods: A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0-1, progression on prior therapy, no prior ramucirumab or immunotherapy and any PD-L1 status. Patients received ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC)., Results: Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment-related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression., Conclusion: Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression., (Copyright © 2020 Eli Lilly and Company. Published by Elsevier Ltd.. All rights reserved.)

Background: The use of fluoroscopically-guided interventional (FGI) procedures by orthopedic surgeons has been increasing. This study aimed to investigate the occupational radiation exposure among orthopedic surgeons in South Korea., Methods: A nationwide survey of orthopedic surgeons was conducted in South Korea in October 2017. The dosimetry data of the participants were obtained from the National Dosimetry Registry. The orthopedic surgeons were categorized by job specialty [spine or trauma specialists, other orthopedic specialists, and residents], and descriptive statistics for the demographics and work-related characteristics were presented. Multivariable logistic regression analysis was used to evaluate the risk factors for the orthopedic surgeons who were not linked with the dosimetry data., Results: Among the total participants ( n  = 513), 40.5% of the orthopedic surgeons spent more than 50% of their time working with the FGI procedures when compared with their overall work. The average frequency of the FGI procedures among the orthopedic surgeons was 12.3 days per month. Less than 30% of the participants were regularly provided with radiation monitoring badges. The proportion of subjects who always wore lead aprons and thyroid shields were 52 and 29%, respectively. The residents group experienced more unfavorable working conditions of radiation exposure than the other specialists. The dosimetry data were not significantly linked among the residents (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.11-3.95) and orthopedic surgeons working at small hospitals (OR 4.76, 95% CI 1.05-21.51)., Conclusions: Although orthopedic surgeons often performed FGI procedures, they wore protective gear less frequently, and a large proportion of orthopedic surgeons were not monitored by the national radiation dosimetry system. As the number of radiation procedures performed by the orthopedic surgeons increases, more intensive approaches are needed to reduce radiation exposure, especially for spine and trauma surgeons., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer., Methods: We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m 2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m 2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593., Findings: Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia)., Interpretation: TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients., Funding: Taiho Pharmaceutical and Yakult Honsha., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma., Methods: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing., Findings: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients., Interpretation: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab)., Funding: MacroGenics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA)., Patients and Methods: FPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer., Results: Seventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of ≥ 10 mg/kg every 2 weeks for ≥ 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade ≥ 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response., Conclusion: Overall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA.

The potential paravertebral space includes spinal nerves, dorsal rami, rami communicants, and sympathetic chains. This study evaluated correlations between paravertebral spread of injectate and clinical efficacy in lumbar transforaminal block. We retrospectively analysed the data of 88 patients who received transforaminal blocks for lumbar radicular pain. We categorized patients into two groups: patients with ≥ 50% pain reduction on a numeric rating scale at 30 min following a block (responder group), and patients with < 50% pain reduction (non-responder group). Paravertebral spread of injectate was graded as limited to the anterior, middle, and posterior 1/3 of the anterolateral aspect of vertebral bodies; spread between the posterolateral margins of bodies and the posterior epidural space was considered no spread. Clinical and fluoroscopic data, perfusion index, temperature, and cold sensation were compared between the groups. Among 54 patients analysed, 26 (48.1%) experienced ≥ 50% and 28 (51.9%) < 50% pain reduction. Paravertebral spread occurred in 33 (61.1%) patients; 19 (57.6%) responders and 14 (42.4%) non-responders. On analysis, paravertebral spread, epidural spread patterns, perfusion index change ratios, temperature changes, and cold sensation changes showed no differences between responder and non-responder groups. Paravertebral spread occurred in 61.1%, with no correlation with the clinical efficacy of lumbar transforaminal block.

Purpose: Patients with advanced gastric/gastroesophageal junction cancer (GC/GEJC) have limited treatment options after first-line therapy. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (a TGFβ "trap") fused to a human IgG1 antibody against programmed death ligand 1 (PD-L1), potentially offering a new treatment approach for these patients. We report results for bintrafusp alfa in GC/GEJC., Patients and Methods: Asian patients with recurrent GC/GEJC for whom standard therapy does not exist or for whom standard therapy has failed enrolled in this expansion cohort of an ongoing phase I trial and received bintrafusp alfa 1,200 mg once every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary objective was to assess safety/tolerability., Results: By July 23, 2018, 31 heavily pretreated patients received bintrafusp alfa for a median of 10.1 weeks; 3 patients remained on treatment. Six patients (19%) experienced grade 3 treatment-related adverse events (AE); no grade 4 events occurred. One on-treatment death occurred (sudden death); rupture of a preexisting thoracic aortic aneurysm was the suspected cause. Ten patients (32%) had immune-related AEs. The confirmed objective response rate per independent review committee was 16%; disease control rate was 26%. Median duration of response was 8.7 months (range, 2.4-12.4+). Responses occurred irrespective of PD-L1 expression or microsatellite instability status and appeared to correlate with high tumor TGFB1 levels., Conclusions: In this first evaluation in Asian patients with heavily pretreated advanced GC/GEJC, bintrafusp alfa demonstrated a manageable safety profile and clinical activity., (©2020 American Association for Cancer Research.)

Purpose: Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC., Materials and Methods: In this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models., Results: AZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy., Conclusion: Taken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

Background: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer., Methods: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety., Results: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group., Conclusions: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.)., (Copyright © 2020 Massachusetts Medical Society.)