On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O2 ratio (PaO2/FiO2) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO2/FiO2 ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.

Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.

On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesized that the anti-VEGF drug bevacizumab might be beneficial for treating Covid-19 patients. We recruited 26 patients from 2-centers (China and Italy) with confirmed severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O2 ratio (PaO2/FiO2) >100mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest radiological imaging. This trial was conducted from Feb 15 to April 5, 2020, and followed up for 28 days. Relative to comparable control patients with severe Covid-19 admitted in the same centers, bevacizumab showed clinical efficacy by improving oxygenation and shortening oxygen-support duration. Among 26 hospitalized patients with severe Covid-19 (median age, 62 years, 20 [77%] males), bevacizumab plus standard care markedly improved the PaO2/FiO2 ratios at days 1 and 7 (elevated values, day 1, 50.5 [4.0,119.0], p<0.001; day 7, 111.0 [85.0,165.0], p<0.001). By day 28, 24 (92%) patients showed improvement in oxygen-support status, 17 (65%) patients were discharged, and none showed worsen oxygen-support status nor died. Significant reduction of lesion areas and ratios were shown in chest CT or X-ray analysis within 7 days. Of 14 patients with fever, body temperature normalized within 72 hours in 13 (93%) patients. Lymphocyte counts in peripheral blood were significantly increased and CRP levels were markedly decreased as shown in available data. Our findings suggested bevacizumab plus standard care was highly beneficial for treating patients with severe Covid-19. Clinical efficacy of bevacizumab warrants double blind, randomized, placebo-controlled trials.

4061 Background: The prognosis of cT4a/bN+ gastric cancer (GC) is poor due to low R0 resection rate and frequent recurrence. We evaluated the feasibility, safety, and efficacy of a combination of immunotherapy, anti-angiogenesis, and chemotherapy for neoadjuvant/conversion treatment of cT4a/bN+ GC. Methods: Patients with T4a/bN+ GC were enrolled to receive camrelizumab (200mg d1), apatinib (250mg d1-14), S-1 (50mg bid d1-10) ± oxaliplatin (85 mg/m2 d1) for at least 2 cycles, followed by re-evaluation and operation. Peri-treatment samples were collected for whole-exome, transcriptome, and T cell receptor (TCR) sequencing. Pathological response (PR) and its relationship with genomic biomarkers are primary endpoints. Results: 25 patients were enrolled, with median age 63 (48-70), 19 male, 11 cT4aN2-3 and 14 cT4bN2-3. The radiological response (RR) rate of the treatments was 33.3% (8/24), and tumor down-staging rate 79.2% (19/24). 24 patients completed re-evaluation, with 3 failed conversion, 2 refused surgery, and 1 postponed surgery for immune-related pneumonia. Among the 18 patients with R0 resection, 3 got complete PR (CPR), 2 major PR (MPR, ≤10% residual cancer cells), and 3 partial PR (11̃49% residual cancer cells), with a PR rate of 44.4% and MPR+ (MPR & CPR) rate of 27.8%. 62.5% patients with PR and 83.3% patients with RR overlapped with each other. At a median of 12.5 (3.4-19.5) months of follow-up, 13 of 17 patients (76.5%) with R0 resection were recurrence-free. No ≥3 toxicity was found. Besides high microsatellite instability, tumor mutation/neoantigen burden (TMB/TNB), mutation signatures (“DNA damage repair” and “DNA mismatch repair”) and related gene mutations (BRCA2, PRKDC, ATM, POLD1, POLE), several novel driver mutations (SSPO, TRPS1, and DOCK2) and copy number variants (DUSP15 loss, FDFT1 gain, and RBBP8NL loss) were related to MPR+ GC. The combination therapy decreased TMB/TNB, facilitated infiltration of active immune cells (CD4+ memory T, CD8+ T, activated and plasmacytoid dendritic cells, and M1 macrophage), and specifically boosted TCR clonality in MPR+ patients. Besides, numbers of mesenchymal stem cells decreased in MPR+ but increased in MPR- GC after the treatment. Conclusions: Combination of camrelizumab, apatinib, S-1 ± oxaliplatin is feasible, safe, and efficient in neoadjuvant/conversion therapy for cT4a/bN+ GC. It may remodel immune microenvironments and induce anti-tumor immune responses. Clinical trial information: NCT03878472. [Table: see text]

Purpose: The aim of this study is to evaluate the influence of arm movements from adduction to abduction on intracavitary electrocardiogram and the position of a catheter tip. Methods: Overall, 192 peripherally inserted central catheter lines were placed under intracavitary electrocardiogram guidance and 188 of them were enrolled in the study. The catheter was first placed at a time point corresponding to the peak P wave with the arm in adduction. The arm was then abducted to 90° without changing catheter insertion length. During the procedure, basal electrocardiogram, intracavitary electrocardiogram, and radiographs with the arm in adduction and abduction were recorded. Amplitude wave changes and catheter movements were measured on electrocardiogram records and radiographs, respectively. Results: In 188 cases, the P wave displayed typical changes, and 97.8% (184/188) catheters were successfully placed correctly. At the peak P wave, the amplitude of the peak P wave was 8.64 times greater than that of the basal P wave, and the P/R ratio was 0.61. When the arm was abducted to 90°, the amplitude of the P wave dropped to 57% of its peak, P/R decreased from 0.61 to 0.34, and the catheter tip moved cephalad 1.00 and 0.77 vertebral body units in male and female patients, respectively. Conclusion: Peripherally inserted central catheter moves toward the heart when the arm position changes from abduction to adduction. Peripherally inserted central catheter tip placement at the peak P wave with patient’s arm in adduction is accurate and can prevent the catheter from advancing too low. R wave can function as a reference for observing P wave changes during peripherally inserted central catheter placement.