Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model.

Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.

Risk of thrombosis and bleeding in gynecologic noncancer surgery: systematic review and meta-analysis.

OBJECTIVE: This study aimed to provide procedure-specific estimates of the risk for symptomatic venous thromboembolism and major bleeding in noncancer gynecologic surgeries. DATA SOURCES: We conducted comprehensive searches on Embase, MEDLINE, Web of Science, and Google Scholar. Furthermore, we performed separate searches for randomized trials that addressed the effects of thromboprophylaxis. STUDY ELIGIBILITY CRITERIA: Eligible studies were observational studies that enrolled ≥50 adult patients who underwent noncancer gynecologic surgery procedures and that reported the absolute incidence of at least 1 of the following: symptomatic pulmonary embolism, symptomatic deep vein thrombosis, symptomatic venous thromboembolism, bleeding that required reintervention (including re-exploration and angioembolization), bleeding that led to transfusion, or postoperative hemoglobin level <70 g/L. METHODS: A teams of 2 reviewers independently assessed eligibility, performed data extraction, and evaluated the risk of bias of the eligible articles. We adjusted the reported estimates for thromboprophylaxis and length of follow-up and used the median value from studies to determine the cumulative incidence at 4 weeks postsurgery stratified by patient venous thromboembolism risk factors and used the Grading of Recommendations Assessment, Development and Evaluation approach to rate the evidence certainty. RESULTS: We included 131 studies (1,741,519 patients) that reported venous thromboembolism risk estimates for 50 gynecologic noncancer procedures and bleeding requiring reintervention estimates for 35 procedures. The evidence certainty was generally moderate or low for venous thromboembolism and low or very low for bleeding requiring reintervention. The risk for symptomatic venous thromboembolism varied from a median of <0.1% for several procedures (eg, transvaginal oocyte retrieval) to 1.5% for others (eg, minimally invasive sacrocolpopexy with hysterectomy, 1.2%-4.6% across patient venous thromboembolism risk groups). Venous thromboembolism risk was <0.5% for 30 (60%) of the procedures; 0.5% to 1.0% for 10 (20%) procedures; and >1.0% for 10 (20%) procedures. The risk for bleeding the require reintervention varied from <0.1% (transvaginal oocyte retrieval) to 4.0% (open myomectomy). The bleeding requiring reintervention risk was <0.5% in 17 (49%) procedures, 0.5% to 1.0% for 12 (34%) procedures, and >1.0% in 6 (17%) procedures. CONCLUSION: The risk for venous thromboembolism in gynecologic noncancer surgery varied between procedures and patients. Venous thromboembolism risks exceeded the bleeding risks only among selected patients and procedures. Although most of the evidence is of low certainty, the results nevertheless provide a compelling rationale for restricting pharmacologic thromboprophylaxis to a minority of patients who undergo gynecologic noncancer procedures.

Systematic Reviews and Meta-analyses of the Procedure-specific Risks of Thrombosis and Bleeding in General Abdominal, Colorectal, Upper Gastrointestinal, and Hepatopancreatobiliary Surgery.

OBJECTIVE: To provide procedure-specific estimates of symptomatic venous thromboembolism (VTE) and major bleeding after abdominal surgery. BACKGROUND: The use of pharmacological thromboprophylaxis represents a trade-off that depends on VTE and bleeding risks that vary between procedures; their magnitude remains uncertain. METHODS: We identified observational studies reporting procedure-specific risks of symptomatic VTE or major bleeding after abdominal surgery, adjusted the reported estimates for thromboprophylaxis and length of follow-up, and estimated cumulative incidence at 4 weeks postsurgery, stratified by VTE risk groups, and rated evidence certainty. RESULTS: After eligibility screening, 285 studies (8,048,635 patients) reporting on 40 general abdominal, 36 colorectal, 15 upper gastrointestinal, and 24 hepatopancreatobiliary surgery procedures proved eligible. Evidence certainty proved generally moderate or low for VTE and low or very low for bleeding requiring reintervention. The risk of VTE varied substantially among procedures: in general abdominal surgery from a median of <0.1% in laparoscopic cholecystectomy to a median of 3.7% in open small bowel resection, in colorectal from 0.3% in minimally invasive sigmoid colectomy to 10.0% in emergency open total proctocolectomy, and in upper gastrointestinal/hepatopancreatobiliary from 0.2% in laparoscopic sleeve gastrectomy to 6.8% in open distal pancreatectomy for cancer. CONCLUSIONS: VTE thromboprophylaxis provides net benefit through VTE reduction with a small increase in bleeding in some procedures (eg, open colectomy and open pancreaticoduodenectomy), whereas the opposite is true in others (eg, laparoscopic cholecystectomy and elective groin hernia repairs). In many procedures, thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding VTE and bleeding.

Risk of thrombosis and bleeding in gynecologic cancer surgery: systematic review and meta-analysis.

OBJECTIVE: This study aimed to provide procedure-specific estimates of the risk of symptomatic venous thromboembolism and major bleeding in the absence of thromboprophylaxis, following gynecologic cancer surgery. DATA SOURCES: We conducted comprehensive searches on Embase, MEDLINE, Web of Science, and Google Scholar for observational studies. We also reviewed reference lists of eligible studies and review articles. We performed separate searches for randomized trials addressing effects of thromboprophylaxis and conducted a web-based survey on thromboprophylaxis practice. STUDY ELIGIBILITY CRITERIA: Observational studies enrolling ≥50 adult patients undergoing gynecologic cancer surgery procedures reporting absolute incidence for at least 1 of the following were included: symptomatic pulmonary embolism, symptomatic deep vein thrombosis, symptomatic venous thromboembolism, bleeding requiring reintervention (including reexploration and angioembolization), bleeding leading to transfusion, or postoperative hemoglobin <70 g/L. METHODS: Two reviewers independently assessed eligibility, performed data extraction, and evaluated risk of bias of eligible articles. We adjusted the reported estimates for thromboprophylaxis and length of follow-up and used the median value from studies to determine cumulative incidence at 4 weeks postsurgery stratified by patient venous thromboembolism risk factors. The GRADE approach was applied to rate evidence certainty. RESULTS: We included 188 studies (398,167 patients) reporting on 37 gynecologic cancer surgery procedures. The evidence certainty was generally low to very low. Median symptomatic venous thromboembolism risk (in the absence of prophylaxis) was <1% in 13 of 37 (35%) procedures, 1% to 2% in 11 of 37 (30%), and >2.0% in 13 of 37 (35%). The risks of venous thromboembolism varied from 0.1% in low venous thromboembolism risk patients undergoing cervical conization to 33.5% in high venous thromboembolism risk patients undergoing pelvic exenteration. Estimates of bleeding requiring reintervention varied from <0.1% to 1.3%. Median risks of bleeding requiring reintervention were <1% in 22 of 29 (76%) and 1% to 2% in 7 of 29 (24%) procedures. CONCLUSION: Venous thromboembolism reduction with thromboprophylaxis likely outweighs the increase in bleeding requiring reintervention in many gynecologic cancer procedures (eg, open surgery for ovarian cancer and pelvic exenteration). In some procedures (eg, laparoscopic total hysterectomy without lymphadenectomy), thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding venous thromboembolism and bleeding.

Timing of symptomatic venous thromboembolism after surgery: meta-analysis.

BACKGROUND: The timing at which venous thromboembolism (VTE) occurs after major surgery has major implications for the optimal duration of thromboprophylaxis. The aim of this study was to perform a systematic review and meta-analysis of the timing of postoperative VTE up to 4 weeks after surgery. METHODS: A systematic search of MEDLINE, Scopus, and CINAHL databases was performed between 1 January 2009 and 1 April 2022. Prospective studies that recruited patients who underwent a surgical procedure and reported at least 20 symptomatic, postoperative VTE events by time were included. Two reviewers independently selected studies according to the eligibility criteria, extracted data, and evaluated risk of bias. Data were analysed with a Poisson regression model, and the GRADE approach was used to rate the certainty of evidence. RESULTS: Some 6258 studies were evaluated, of which 22 (11 general, 5 urological, 4 mixed, and 2 orthopaedic postoperative surgical populations; total 1 864 875 patients and 24 927 VTE events) were eligible. Pooled evidence of moderate certainty showed that 47.1 per cent of the VTE events occurred during the first, 26.9 per cent during the second, 15.8 per cent during the third, and 10.1 per cent during the fourth week after surgery. The timing of VTE was consistent between individual studies. CONCLUSION: Although nearly half of symptomatic VTE events in first 4 weeks occur during the first postoperative week, a substantial number of events occur several weeks after surgery. These data will inform clinicians and guideline developers about the duration of postoperative thromboprophylaxis.

Hundreds of millions of surgical procedures are performed annually worldwide. Blood clots in legs and lungs represent serious, and sometimes fatal, complications of surgery. To prevent these complications, clinicians often give blood thinners to patients. To optimize the starting time and duration of use of blood thinners, it is crucial to know when blood clots occur after surgery. This study summarized the timing of blood clots after surgery based on a systematic review and meta-analysis of 22 prospective studies including thousands of patients with blood clots from various surgical fields. Of blood clots occurring within 4 weeks after surgery, 47 per cent occurred by the first, 74 per cent by the second, and 90 per cent by the third week after surgery. These research results are useful for patients, clinicians, and guideline developers to guide the starting time and duration of use of blood thinners after surgery.

Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial.

We report the first long-term follow-up of a randomized trial (NCT04978259) addressing the effects of remdesivir on recovery (primary outcome) and other patient-important outcomes one year after hospitalization resulting from COVID-19. Of the 208 patients recruited from 11 Finnish hospitals, 198 survived, of whom 181 (92%) completed follow-up. At one year, self-reported recovery occurred in 85% in remdesivir and 86% in standard of care (SoC) (RR 0.94, 95% CI 0.47-1.90). We infer no convincing difference between remdesivir and SoC in quality of life or symptom outcomes (p > 0.05). Of the 21 potential long-COVID symptoms, patients reported moderate/major bother from fatigue (26%), joint pain (22%), and problems with memory (19%) and attention/concentration (18%). In conclusion, after a one-year follow-up of hospitalized patients, one in six reported they had not recovered well from COVID-19. Our results provide no convincing evidence of remdesivir benefit, but wide confidence intervals included possible benefit and harm.

Systematic reviews of observational studies of Risk of Thrombosis and Bleeding in General and Gynecologic Surgery (ROTBIGGS): introduction and methodology.

BACKGROUND: Venous thromboembolism (VTE) and bleeding are serious and potentially fatal complications of surgical procedures. Pharmacological thromboprophylaxis decreases the risk of VTE but increases the risk of major post-operative bleeding. The decision to use pharmacologic prophylaxis therefore represents a trade-off that critically depends on the incidence of VTE and bleeding in the absence of prophylaxis. These baseline risks vary widely between procedures, but their magnitude is uncertain. Systematic reviews addressing baseline risks are scarce, needed, and require innovations in methodology. Indeed, systematic summaries of these baseline risk estimates exist neither in general nor gynecologic surgery. We will fill this knowledge gap by performing a series of systematic reviews and meta-analyses of the procedure-specific and patient risk factor stratified risk estimates in general and gynecologic surgeries. METHODS: We will perform comprehensive literature searches for observational studies in general and gynecologic surgery reporting symptomatic VTE or bleeding estimates. Pairs of methodologically trained reviewers will independently assess the studies for eligibility, evaluate the risk of bias by using an instrument developed for this review, and extract data. We will perform meta-analyses and modeling studies to adjust the reported risk estimates for the use of thromboprophylaxis and length of follow up. We will derive the estimates of risk from the median estimates of studies rated at the lowest risk of bias. The primary outcomes are the risk estimates of symptomatic VTE and major bleeding at 4 weeks post-operatively for each procedure stratified by patient risk factors. We will apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate evidence certainty. DISCUSSION: This series of systematic reviews, modeling studies, and meta-analyses will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding in general and gynecologic surgeries. Our work advances the standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at the best estimates of risk (including modeling of the timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the GRADE approach. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021234119.