End Point Research Articles

Predictive value of preoperative routine examination for the prognosis of patients with pT2N0M0 or pT3N0M0 colorectal cancer.

In recent years, the incidence of colorectal cancer (CRC) has been increasing. With the popularization of endoscopic technology, a number of early CRC has been diagnosed. However, despite current treatment methods, some patients with early CRC still experience postoperative recurrence and metastasis. To search for indicators associated with early CRC recurrence and metastasis to identify high-risk populations. A total of 513 patients with pT2N0M0 or pT3N0M0 CRC were retrospectively enrolled in this study. Results of blood routine test, liver and kidney function tests and tumor markers were collected before surgery. Patients were followed up through disease-specific database and telephone interviews. Tumor recurrence, metastasis or death were used as the end point of study to find the risk factors and predictive value related to early CRC recurrence and metastasis. We comprehensively compared the predictive value of preoperative blood routine, blood biochemistry and tumor markers for disease-free survival (DFS) and overall survival (OS) of CRC. Cox multivariate analysis demonstrated that low platelet count was significantly associated with poor DFS [hazard ratio (HR) = 0.995, 95% confidence interval (CI): 0.991-0.999, P = 0.015], while serum carcinoembryonic antigen (CEA) level (HR = 1.008, 95%CI: 1.001-1.016, P = 0.027) and serum total cholesterol level (HR = 1.538, 95%CI: 1.026-2.305, P = 0.037) were independent risk factors for OS. The cutoff value of serum CEA level for predicting OS was 2.74 ng/mL. Although the OS of CRC patients with serum CEA higher than the cutoff value was worse than those with lower CEA level, the difference between the two groups was not statistically significant (P = 0.075). For patients with T2N0M0 or T3N0M0 CRC, preoperative platelet count was a protective factor for DFS, while serum CEA level was an independent risk factor for OS. Given that these measures are easier to detect and more acceptable to patients, they may have broader applications.

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non−Small Cell Lung Cancer

Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. This prospective nonrandomized trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. The findings of this nonrandomized trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. ClinicalTrials.gov Identifier: NCT03046316.

Healthy lifestyle and prostate cancer risk in the Million Veteran Program.

This study aims to assess the impact of healthy lifestyle on prostate cancer (PCa) risk in a diverse population. Data for 281,923 men from the Million Veteran Program (MVP), a nationwide, health system-based cohort study, were analyzed. Self-reported information at enrollment included smoking status, exercise, diet, family history of PCa, and race/ethnicity. Body mass index (BMI) was obtained from clinical records. Genetic risk was assessed via a validated polygenic score. Cox proportional hazards models were used to assess associations with PCa outcomes. After accounting for ancestry, family history, and genetic risk, smoking was associated with an increased risk of metastatic PCa (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.64-2.02; p<10-16) and fatal PCa (HR, 2.73; 95% CI, 2.36-3.25; p<10-16). Exercise was associated with a reduced risk of fatal PCa (HR, 0.86; 95% CI, 0.76-0.98; p=.03). Higher BMI was associated with a slightly reduced risk of fatal PCa, and diet score was not independently associated with any end point. Association with exercise was strongest among those who had nonmetastatic PCa at MVP enrollment. Absolute reductions in the risk of fatal PCa via lifestyle factors were greatest among men of African ancestry (1.7% for nonsmokers vs. 6.1% for smokers) or high genetic risk (1.4% for nonsmokers vs. 4.3% for smokers). Healthy lifestyle is minimally related to the overall risk of developing PCa but is associated with a substantially reduced risk of dying from PCa. In multivariable analyses, both exercise and not smoking remain independently associated with reduced metastatic and fatal PCa.

One-Month Versus Three-Month Dual-Antiplatelet Therapy in High Bleeding Risk Patients With Chronic Kidney Disease

Shortening the duration of dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) was shown to be effective and safe in patients at high bleeding risk (HBR). We aimed to investigate the effect of 1 versus 3-month DAPT on outcomes after drug-eluting stent in HBR patients with or without chronic kidney disease (CKD). Data from 3 prospective single-arm studies (XIENCE Short DAPT Program) enrolling HBR patients after successful coronary implantation of cobalt-chromium everolimus-eluting stent (XIENCE, Abbott) were analyzed. Subjects were eligible for DAPT discontinuation at 1 or 3 months if free from ischemic events. The primary end point was all-cause death or any myocardial infarction. The key secondary end point was Bleeding Academic Research Consortium Type 2 to 5 bleeding. Outcomes were assessed from 1 to 12 months after PCI. CKD was defined as baseline creatinine clearance <60 ml/min. Of 3,286 patients, 1,432 (43.6%) had CKD. One-month versus 3-month DAPT was associated with a similar 12-month risk of the primary outcome irrespective of CKD status (CKD: 9.5% vs 10.9%, adjusted hazard ratio 0.86, 95% confidence interval 0.60 to 1.22; no-CKD: 6.6% vs 5.6%, adjusted hazard ratio 1.15, 95% confidence interval 0.77 to 1.73; p interaction 0.299). Bleeding Academic Research Consortium 2 to 5 bleeding rates were numerically but not significantly lower with 1-month versus 3-month DAPT in both CKD (9.9% vs 12%) and no-CKD (6.4% vs 9.0%) patients. In conclusion, in HBR patients, 1-month versus 3-month DAPT was associated with a similar risk of ischemic complications and a trend toward fewer bleeding events at 12 months after PCI, irrespective of CKD status.

Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy

The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy. To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival. This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024. In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery. The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy. A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13). In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups. isrctn.org Identifier: ISRCTN59757862.

DNA mismatch and damage patterns revealed by single-molecule sequencing.

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancerpredisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.

Ertugliflozin for Functional Mitral Regurgitation Associated With Heart Failure: EFFORT Trial.

The morbidity and mortality rates of patients with heart failure (HF) and functional mitral regurgitation (MR) remain substantial despite guideline-directed medical therapy for HF. We evaluated the efficacy of ertugliflozin for reduction of functional MR associated with HF with mild to moderately reduced ejection fraction. The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was a multicenter, double-blind, randomized trial to examine the hypothesis that the sodium-glucose cotransporter 2 inhibitor ertugliflozin is effective for improving MR in patients with HF with New York Heart Association functional class II or III, 35%≤ejection fraction<50%, and effective regurgitant orifice area of chronic functional MR >0.1 cm2 on baseline echocardiography. We randomly assigned 128 patients to receive either ertugliflozin or placebo in addition to guideline-directed medical therapy for HF. The primary end point was change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, left ventricular (LV) volume indices, left atrial volume index, LV global longitudinal strain, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). The treatment groups were generally well-balanced with regard to baseline characteristics: mean age, 66±11 years; 61% men; 13% diabetes; 51% atrial fibrillation; 43% use of angiotensin receptor-neprilysin inhibitor; ejection fraction, 42±8%; and effective regurgitant orifice area, 0.20±0.12 cm2. The decrease in effective regurgitant orifice area was significantly greater in the ertugliflozin group than in the placebo group (-0.05±0.06 versus 0.03±0.12 cm2; P<0.001). Compared with placebo, ertugliflozin significantly reduced regurgitant volume by 11.2 mL (95% CI, -16.1 to -6.3; P=0.009), left atrial volume index by 6.0 mL/m2 (95% CI, -12.16 to 0.15; P=0.005), and LV global longitudinal strain by 1.44% (95% CI, -2.42% to -0.46%; P=0.004). There were no significant between-group differences regarding changes in LV volume indices, ejection fraction, or NT-proBNP levels. Serious adverse events occurred in one patient (1.6%) in the ertugliflozin group and 6 (9.2%) in the placebo group (P=0.12). Among patients with functional MR associated with HF, ertugliflozin significantly improved LV global longitudinal strain and left atrial remodeling, and reduced functional MR. Sodium-glucose cotransporter 2 inhibitors may be considered for patients with functional MR. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04231331.

Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair–Deficient Colon Cancer

BackgroundMismatch repair–deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.MethodsWe conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses.ResultsOf 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease.ConclusionsIn patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.)

Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis

AbstractThe ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non–transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); and patients in cohort 3A/3B had stable ruxolitinib treatment before and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary end point was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary end point. In cohorts 1 and 3A (NTD), 27% and 50% of patients, respectively, had mean hemoglobin increase of ≥1.5 g/dL from baseline. Among TD patients, ∼50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. This trial was registered at www.ClinicalTrials.gov as #NCT03194542.

Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D

BackgroundIn a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear.MethodsIn this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 μg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 μg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.ResultsA total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity.ConclusionsThe combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.)

Prospective Randomized Controlled Trial Comparing Anesthetic Management With Remimazolam Besylate and Flumazenil Versus Propofol During Awake Craniotomy Following an Asleep-awake-asleep Method.

Awake craniotomy is performed to resect brain tumors in eloquent brain areas to maximize tumor reduction and minimize neurological damage. Evidence suggests that intraoperative anesthetic management of awake craniotomy with remimazolam is safe. We compared the time to arousal and efficacy of anesthetic management with remimazolam and propofol during awake craniotomy. In a single-institution randomized, prospective study, patients who underwent elective awake craniotomy were randomized to receive remimazolam and reversal with flumazenil (group R) or propofol (group P). The primary end point was time to awaken. Secondary end points were time to loss of consciousness during induction of anesthesia, the frequency of intraoperative complications (pain, hypertension, seizures, nausea, vomiting, and delayed arousal), and postoperative nausea and vomiting. Intraoperative task performance was assessed using a numerical rating scale (NRS) score. Fifty-eight patients were recruited, of which 52 (26 in each group) were available for the efficacy analysis. Patients in group R had faster mean (±SD) arousal times than those in the P group (890.8±239.8 vs. 1075.4±317.5s; P=0.013)and higher and more reliable intraoperative task performance (NRS score 8.81±1.50 vs. 7.69±2.36; P=0.043). There were no significant intraoperative complications. Compared with propofol, remimazolam was associated with more rapid loss of consciousness and, after administration of flumazenil, with faster arousal times and improved intraoperative task performance.

Efficacy and Safety of Abrocitinib in Prurigo Nodularis and Chronic Pruritus of Unknown Origin

Prurigo nodularis (PN) and chronic pruritus of unknown origin (CPUO) are chronic pruritic diseases that dramatically impair quality of life, but therapeutic options are limited. Abrocitinib, a Janus kinase 1 inhibitor, represents a promising therapy for both conditions. To assess the efficacy and safety of 200-mg oral abrocitinib administered once daily in adults with moderate to severe PN or CPUO. This phase 2, open-label, nonrandomized controlled trial conducted between September 2021 and July 2022 took place at a single center in the US. A total of 25 adult patients with moderate to severe PN or CPUO were screened. Ten patients with PN and 10 patients with CPUO were enrolled. All 20 patients completed the 12-week treatment period, 18 of whom completed the 4-week follow-up period. Abrocitinib, 200 mg, by mouth once daily for 12 weeks. The primary efficacy end point was the percent change in weekly Peak Pruritus Numerical Rating Scale (PP-NRS) scores from baseline to week 12. Key secondary end points included the percentage of patients achieving at least a 4-point reduction in weekly PP-NRS score from baseline to week 12 and the percent change in Dermatology Life Quality Index (DLQI) scores. A total of 10 patients with PN (mean [SD] age, 58.6 [13.1] years; all were female) and 10 patients with CPUO (mean [SD] age, 70.7 [5.6] years; 2 were female) enrolled in the study. The mean (SD) baseline PP-NRS score was 9.2 (1.0) for PN and 8.2 (1.2) for CPUO. PP-NRS scores decreased by 78.3% in PN (95% CI, -118.5 to -38.1; P < .001) and 53.7% in CPUO (95% CI, -98.8 to -8.6; P = .01) by week 12. From baseline to week 12, 8 of 10 patients with PN and 6 of 10 patients with CPUO achieved at least a 4-point improvement on the PP-NRS. Both groups experienced significant improvement in quality of life as demonstrated by percent change in DLQI scores (PN: -53.2% [95% CI, -75.3% to -31.1%]; P = .002; CPUO: -49.0% [95% CI, -89.6% to -8.0%]; P = .02). The most common adverse event among patients was acneiform eruption in 2 of 20 patients (10%). No serious adverse events occurred. The results of this nonrandomized controlled trial suggest that abrocitinib monotherapy may be effective and tolerated well in adults with PN or CPUO. Randomized, double-blind, placebo-controlled trials are warranted to validate these findings. ClinicalTrials.gov Identifier: NCT05038982.

Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09).

Bempegaldesleukin (BEMPEG) is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8+ T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment. The open-label, phase III randomized controlled PIVOT-09 trial investigated the efficacy and safety of BEMPEG plus nivolumab (NIVO) as first-line treatment for advanced/metastatic clear cell renal cell carcinoma (ccRCC) with intermediate-/poor-risk disease. Patients with previously untreated advanced/metastatic ccRCC were randomly assigned (1:1) to BEMPEG plus NIVO, or investigator's choice of tyrosine kinase inhibitor (TKI; sunitinib or cabozantinib). Coprimary end points were objective response rate (ORR) by blinded independent central review and overall survival (OS) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate-/poor-risk disease. Overall, 623 patients were randomly assigned to BEMPEG plus NIVO (n = 311) or TKI (n = 312; sunitinib n = 225, cabozantinib n = 87), of whom 514 (82.5%) had IMDC intermediate-/poor-risk disease. In patients with IMDC intermediate-/poor-risk disease, ORR with BEMPEG plus NIVO versus TKI was 23.0% (95% CI, 18.0 to 28.7) versus 30.6% (95% CI, 25.1 to 36.6; difference, -7.7 [95% CI, -15.2 to -0.2]; P = .0489), and median OS was 29.0 months versus not estimable (hazard ratio, 0.82 [95% CI, 0.61 to 1.10]; P = .192), respectively. More frequent all-grade treatment-related adverse events (TRAEs) with BEMPEG plus NIVO versus TKI included pyrexia (32.6% v 2.0%) and pruritus (31.3% v 8.8%). Grade 3/4 TRAEs were less frequent with BEMPEG plus NIVO (25.8%) versus TKI (56.5%). First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI.

Early Implementation of Exercise to Facilitate Recovery After Breast Cancer Surgery

Recovery of shoulder function following breast cancer surgery is crucial for physical functioning and quality of life. While early implementation of shoulder rehabilitation exercises may enhance recovery, the optimal timing and exercise program remain unclear. To investigate whether an early exercise intervention, initiated 1 day postsurgery and continued for 1 month through subsequent visits, could improve shoulder range of motion (ROM) and strength in patients with breast cancer. A parallel-group, 2-arm randomized clinical trial was conducted between June 2020 and October 2021 at the Breast Cancer Center in Seoul, South Korea. Fifty-six patients (of 119 screened) with early-stage breast cancer who were scheduled for partial or total mastectomy were randomized into a tailored resistance exercise group (n = 28) or a usual care group (n = 28). Data were analyzed from November 2021 to June 2022. The exercise intervention commenced 1 day postsurgery and consisted of 4 supervised exercise education sessions corresponding with surgeon visits and daily home-based exercises for the first postoperative month. Tailored programs, including stretching and strength exercises, were adjusted based on individual shoulder function recovery status. Primary end points were shoulder ROM and strength at 1 and 6 months postsurgery. Physical activity, body composition, and quality of life were assessed at 6 months. Of 56 patients randomized (mean [SD] age, 50.3 [6.6] years), 54 completed the trial (96%), with 100% and 97% compliance to supervised and home-based exercise sessions, respectively. At 1 month postsurgery, 19 (67.9%) in the exercise group had fully recovered shoulder strength compared to 1 (3.6%) in the usual care group (P < .001). At 6 months, 22 (78.6%) in the exercise group had fully recovered shoulder ROM and 24 (85.7%) had fully recovered strength compared to 6 (21.4%) and 5 (17.9%), respectively, in the usual care group (P < .001). The exercise group exhibited less loss in muscle mass and improved physical activity and quality of life compared to the usual care group. In this trial, 1-month tailored exercise program, initiated immediately after breast cancer surgery and supplemented with supervised sessions coinciding with surgeon visits, significantly improved shoulder function in patients with breast cancer. WHO International Clinical Trials Registry identifier: KCT0006997.

Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Efficacy and safety of combined stent retriever and contact aspiration vs. stent retriever alone on revascularization in patients with acute ischemic stroke: a systematic review and meta-analysis.

Whether the efficacy of combined stent retriever and contact aspiration (S + A) is superior to stent retriever (S) alone for revascularisation in patients with large vessel occlusive stroke remains uncertain. The aim of this meta-analysis was to assess the safety and efficacy of combined stent retriever and contact aspiration for the treatment of acute ischaemic stroke with large vessel occlusion by comparing it with stent retriever alone. We systematically searched the PubMed, Embase, Web of Science, and The Cochrane Library databases for randomised controlled trials and observational studies (case-control and cohort studies) published before 1 October 2023 comparing the efficacy of combined stent retriever and contact aspiration versus tent retriever alone in patients with large vessel occlusive stroke. The end point of the primary efficacy observed in this meta-analysis study was the rate of first pass nearly complete or complete recanalisation (mTICI 2c-3). Secondary effectiveness nodes were: rate of first pass successful recanalisation (mTICI 2b-3), rate of near-complete or complete recanalisation of the postoperative vessel, rate of successful recanalisation of the postoperative vessel, and MRS 0-2 within 90 days. Safety endpoints were interoperative embolism, symptomatic intracranial haemorrhage, and mortality within 90 days. A total of 16 studies were included in the literature for this meta-analysis, with a total of 7,320 patients (S + C group: 3,406, S group: 3,914). A comprehensive analysis of the included literature showed that combined stent retriever and contact aspiration had a higher rate of near-complete or complete recanalisation of the postoperative vessel [OR = 1.53, 95% CI (1.24, 1.88), p < 0.0001] and rate of successful recanalisation of the postoperative vessel compared to stent retriever alone [OR = 1.83, 95% CI (1.55, 2.17), p < 0.00001]; there were no statistically significant differences between the two groups in terms of the rate of first pass nearly complete or complete recanalisation [OR = 1.00, 95% CI (0.83, 1.19), p = 0.96], rate of first pass successful recanalisation [OR = 1.02, 95% CI (0.85, 1.24), p = 0.81], interoperative embolism [OR = 0.93, 95% CI (0.72, 1.20), p = 0.56], symptomatic intracranial haemorrhage [OR = 1.14, 95% CI (0.87, 1.48), p = 0.33], MRS 0-2 within 90 days [OR = 0.89, 95% CI (0.76, 1.04), p = 0.14] and mortality within 90 days [OR = 1.11, 95% CI (0.94, 1.31), p = 0.22]. Combined stent retriever and contact aspiration has a higher rate of postprocedural revascularisation (mTICI 2c-3/mTICI 2b-3) compared with stent retriever alone in patients with large vessel occlusion stroke. In addition, it was not superior to stenting alone in terms of the rate of first pass recanalisation (mTICI 2c-3/mTICI 2b-3), interoperative embolisation, symptomatic intracranial haemorrhage, good functional prognosis within 90 days and mortality within 90 days.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer.

Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy. Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC. One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Chronic Obstructive Pulmonary Disease Exacerbations Increase the Risk of Subsequent Cardiovascular Events: A Longitudinal Analysis of the COPDGene Study.

Cardiovascular disease (CVD) is the most important comorbidity in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations not only contribute to COPD progression but may also elevate the risk of CVD. This study aimed to determine whether COPD exacerbations increase the risk of subsequent CVD events using up to 15 years of prospective longitudinal follow-up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. The COPDGene study is a large, multicenter, longitudinal investigation of COPD, including subjects at enrollment aged 45 to 80 years with a minimum of 10 pack-years of smoking history. Cox proportional hazards models and Kaplan-Meier survival curves were used to assess the risk of a composite end point of CVD based on the COPD exacerbation rate. Frequent exacerbators exhibited a higher cumulative incidence of composite CVD end points than infrequent exacerbators, irrespective of the presence of CVD at baseline. After adjusting for covariates, frequent exacerbators still maintained higher hazard ratios (HRs) than the infrequent exacerbator group (without CVD: HR, 1.81 [95% CI, 1.47-2.22]; with CVD: HR, 1.92 [95% CI, 1.51-2.44]). This observation remained consistently significant in moderate to severe COPD subjects and the preserved ratio impaired spirometry population. In the mild COPD population, frequent exacerbators showed a trend toward more CVD events. COPD exacerbations are associated with an increased risk of subsequent cardiovascular events in subjects with and without preexisting CVD. Patients with COPD experiencing frequent exacerbations may necessitate careful monitoring and additional management for subsequent potential CVD. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00608764.

Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minutes, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03855332.

Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.

Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment. Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.