Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Correlation between sarcopenia index and cognitive function in older adult women: A cross-sectional study using NHANES data.

OBJECTIVES: The Sarcopenia Index (SI) has the potential as a biomarker for sarcopenia, which is characterized by muscle loss. There is a clear association between sarcopenia and cognitive impairment. However, the relationship between SI and cognitive impairment is yet to be fully understood. METHODS: We employed data extracted from the U.S. National Health and Nutrition Examination Survey (NHANES) spanning the years 1999 to 2002. Our study encompassed individuals aged 65 to 80 who possessed accessible information regarding both SI and cognitive evaluations with a GFR ≥ 90. Cognitive function was assessed using the digit symbol substitution test (DSST). SI was calculated by serum creatinine (mg/dL)/cystatin C (mg/L)*100. Employing multivariate modeling, we estimated the connection between SI and cognitive performance. Furthermore, to enhance the reliability of our data analysis, we categorized SI using tertiles and subsequently calculated the P-value for trend. RESULTS: After adjustment for potential confounders, we found SI was significantly and positively correlated with cognitive function scores both in older female in the American population [ß = 0.160, 95 % confidence interval (CI) 0.050 to 0.271, P = 0.00461]. Similarly, when the total cognitive function score was treated as a categorical variable according to tertiles, higher SI was related to better total cognitive function scores in females [odds ratio (OR) = 3.968, 95 % CI 1.863 to 6.073, P = 0.00025] following adjustment for confounders. CONCLUSIONS: Higher SI was correlated with a lower prevalence of cognitive impairment among older adult women with normal kidney function.

Single or continuous multiple intravenous re-induction in Crohn's disease patients who lost response to ustekinumab: Evidence from real-world data.

BACKGROUND AND AIMS: Re-induction optimization of ustekinumab is effective in Crohn's disease (CD) patients who experienced a loss of response (LOR) to ustekinumab. However, whether continuous multiple intravenous optimization is better than single dose re-induction remains unknown. We aimed to compare effectiveness of two strategies in CD patients with LOR to ustekinumab. METHODS: We retrospectively included CD patients who had LOR to standardized ustekinumab therapy. They were divided into three groups according to different times (one to three) for re-induction. RESULTS: This study included 50, 26 and 22 of 98 eligible patients in one intravenous re-induction subgroup, double intravenous re-induction subgroup and three intravenous re-induction subgroup, respectively. At week 24, 67.3%, 75.5%, 56.6%, 69.8% and 61.2% of all achieved steriod free clinical remission, clinical response, endoscopic remission, endoscopic response and C-reactive protein normalization, respectively. No differences were found in all endpoints between three groups. Ustekinumab trough level at week 24 but not times of re-induction showed a tendency to predict clinical remission. No serious adverse events were found in this cohort. CONCLUSION: Intravenous re-induction was safe and effective in CD patients who experienced LOR to ustekinumab. Trough level of ustekinumab but not times of intravenous re-induction may associated with clinical efficacy.

Comparative effectiveness of ustekinumab vs. vedolizumab for anti-TNF-naïve or anti-TNF-exposed Crohn's disease: a multicenter cohort study.

Background: Ustekinumab and vedolizumab are both effective for treating Crohn's disease (CD). However, no head-to-head trials have been conducted thus far. We aimed to compare the effectiveness of ustekinumab and vedolizumab in CD patients either naïve or exposed to tumor necrosis factor-alpha inhibitors (TNFi). Methods: Patients treated with vedolizumab or ustekinumab for luminal CD were included from six centers in China from May 2020 to July 2023. Steroid-free remission, clinical remission, objective response, and remission at Weeks 26 and 52 were evaluated in a retrospective multicenter propensity score-weighted cohort. Findings: A total of 536 patients were included (386 ustekinumab, and 150 vedolizumab). After adjustment, ustekinumab showed higher rates of clinical remission (56.4% vs. 47.8%, P = 0.005), steroid-free remission (55.4% vs. 46.1%, P = 0.003), and objective response (67.8% vs. 42.7%, P < 0.001) than vedolizumab at Week 26. At Week 52, ustekinumab exhibited significantly higher rates of clinical remission (65.8% vs. 37.5%, P < 0.001), steroid-free remission (65.8% vs. 37.5%, P < 0.001), objective response (66.7% vs. 23.8%, P < 0.001), and objective remission (31.4% vs. 12.7%, P < 0.001). Subgroup analyses revealed that ustekinumab had higher rates of clinical remission, steroid-free remission, and objective response at Weeks 26 and 52, and objective remission at Week 52 in TNFi-exposed patients, while ustekinumab showed higher rates of objective response at Weeks 26 and 52 and clinical remission, steroid-free remission and objective remission at Week 52 in TNFi-naïve patients. Adverse event rates were similar between the groups (4.9% ustekinumab vs. 6.7% vedolizumab, P = 0.423). Interpretation: Ustekinumab showed superior clinical and objective outcomes compared to vedolizumab, with comparable safety outcomes. The therapeutic superiority was observed in both short-term and long-term phases in TNFi-exposed patients, and the long-term phase in TNFi-naïve patients. Funding: National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Key Research Projects of the Sixth Affiliated Hospital, Sun Yat-sen University, the program of Guangdong Provincial Clinical Research Center for Digestive Diseases, and National Key Clinical Discipline.

Capecitabine maintenance therapy in metastatic colorectal cancer patients with no evidence of disease: CAMCO trial.

Background: In patients with metastatic colorectal cancer (mCRC) exhibiting no evidence of disease (NED), this study assessed the efficacy and safety of capecitabine maintenance therapy. Methods: The single-arm, phase II CAMCO trial enrolled mCRC-NED patients after first-line treatment, administering oral capecitabine maintenance for 1 year. Results: A total of 93 patients were enrolled. The primary end point, 3-year disease-free survival, yielded a rate of 51.6% (95% CI: 41.3-62.0%). Secondary end points included a 3-year overall survival rate of 83.9% (95% CI: 76.3-91.5%). Grade 3 adverse events (AE) were observed in seven patients (7.5%). Predominantly grade 1 and 2, the most common AE was hand-foot syndrome. Conclusion: In mCRC-NED patients, capecitabine maintenance demonstrated a manageable 3-year disease-free survival rate of 51.6%, accompanied by manageable AEs. Clinical Trial Registration: NCT01880658 (ClinicalTrials.gov).

China special issue on gastrointestinal tumors-Radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial.

Neoadjuvant programmed cell death protein 1 (PD-1) blockade exhibits promising efficacy in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC). However, discrepancies between radiological and histological findings have been reported in the PICC phase II trial (NCT03926338). Therefore, we strived to discern radiological features associated with pathological complete response (pCR) based on computed tomography (CT) images. Data were obtained from the PICC trial that included 36 tumors from 34 locally advanced dMMR CRC patients, who received neoadjuvant PD-1 blockade for 3 months. Among the 36 tumors, 28 (77.8%) tumors achieved pCR. There were no statistically significant differences in tumor longitudinal diameter, the percentage change in tumor longitudinal diameter from baseline, primary tumor sidedness, clinical stage, extramural venous invasion status, intratumoral calcification, peritumoral fat infiltration, intestinal fistula and tumor necrosis between the pCR and non-pCR tumors. Otherwise, tumors with pCR had smaller posttreatment tumor maximum thickness (median: 10 mm vs 13 mm, P = .004) and higher percentage decrease in tumor maximum thickness from baseline (52.9% vs 21.6%, P = .005) compared to non-pCR tumors. Additionally, a higher proportion of the absence of vascular sign (P = .003, odds ratio [OR] = 25.870 [95% CI, 1.357-493.110]), nodular sign (P < .001, OR = 189.000 [95% CI, 10.464-3413.803]) and extramural enhancement sign (P = .003, OR = 21.667 [2.848-164.830]) was observed in tumors with pCR. In conclusion, these CT-defined radiological features may have the potential to serve as valuable tools for clinicians in identifying patients who have achieved pCR after neoadjuvant PD-1 blockade, particularly in individuals who are willing to adopt a watch-and-wait strategy.

High-throughput proteomics profiling-derived signature associated with chemotherapy response and survival for stage II/III colorectal cancer.

Adjuvant chemotherapy (ACT) is usually used to reduce the risk of disease relapse and improve survival for stage II/III colorectal cancer (CRC). However, only a subset of patients could benefit from ACT. Thus, there is an urgent need to identify improved biomarkers to predict survival and stratify patients to refine the selection of ACT. We used high-throughput proteomics to analyze tumor and adjacent normal tissues of stage II/III CRC patients with /without relapse to identify potential markers for predicting prognosis and benefit from ACT. The machine learning approach was applied to identify relapse-specific markers. Then the artificial intelligence (AI)-assisted multiplex IHC was performed to validate the prognostic value of the relapse-specific markers and construct a proteomic-derived classifier for stage II/III CRC using 3 markers, including FHL3, GGA1, TGFBI. The proteomics profiling-derived signature for stage II/III CRC (PS) not only shows good accuracy to classify patients into high and low risk of relapse and mortality in all three cohorts, but also works independently of clinicopathologic features. ACT was associated with improved disease-free survival (DFS) and overall survival (OS) in stage II (pN0) patients with high PS and pN2 patients with high PS. This study demonstrated the clinical significance of proteomic features, which serve as a valuable source for potential biomarkers. The PS classifier provides prognostic value for identifying patients at high risk of relapse and mortality and optimizes individualized treatment strategy by detecting patients who may benefit from ACT for survival.

Neoadjuvant versus adjuvant imatinib in primary localized gastrointestinal stromal tumor.

Background: The effect of neoadjuvant therapy (NAT) with imatinib versus upfront resection (UR) followed by adjuvant therapy (AT) with imatinib on the outcomes of gastrointestinal stromal tumors (GIST) is unknown. Methods: This is a retrospective study at a high-volume center. All the patients with primary localized GIST were identified in a hospital database from 2007 to 2021. The endpoints included local recurrence-free survival (LRFS), distance recurrence-free survival (DRFS), and overall survival (OS). Cox regression was used to perform multivariate survival analyses. The sensitivity analysis was conducted with the inverse probability of treatment weighting (IPTW) method. Results: A total of 211 patients were included (Group A: UR + AT, n=140; Group B: NAT + resection + AT, n=71). In the entire cohort, 5-year DRFS, LRFS, and OS were 85.6%, 90.7%, and 92.5%, respectively. In the multivariate analysis, better DRFS was linked to NAT, tumor size of 5 cm, and AT. Sixteen patients (11.4%) in Group A and 1 (1.4%) in Group B had distant recurrences after AT discontinuation. The sensitivity analysis by IPTW provided approximately similar results. An interaction effect was observed between NAT and tumor location on DRFS. In non-gastric GISTs, NAT was associated with better DRFS [hazard ratio =0.131, 95% confidence interval (CI): 0.017-0.989, P=0.049], which was not the case in gastric GIST (P=0.08). NAT was not independently associated with LRFS or OS. Conclusions: When compared to UR + AT, NAT + resection + AT may reduce the risk of distant recurrence in localized GIST and may be especially beneficial for patients with non-gastric GISTs.

Molecular Typing and Clinical Characteristics of Synchronous Multiple Primary Colorectal Cancer.

Importance: Synchronous multiple primary colorectal cancer (sMPCC) is clinically rare, but its incidence has increased over the past decade. However, little is known about the molecular and clinical features of sMPCC, which may differ from those of single primary colorectal cancer (SPCRC). Objective: To evaluate the clinical characteristics and pathogenic variations in lesions and the molecular typing of sMPCC. Design, Setting, and Participants: From November 2012 to April 2021, patients with colorectal cancer (CRC) treated at the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this cohort study. Follow-up ended on January 31, 2022. Main Outcomes and Measures: The primary outcome was mismatch repair (MMR) status of each lesion in all patients examined using immunohistochemistry (IHC). Microsatellite instability (MSI) and tumor mutation burden (TMB) were also calculated. Results: A total of 13 276 patients with CRC were enrolled, and 239 patients with sMPCC (mean [SD] age, 63.3 [12.2] years; 173 men [72.4%]) with available clinical data were evaluated. Seventy-eight patients with sMPCC and 94 with SPCRC also underwent next-generation sequencing (NGS)-based molecular testing. The deficient MMR (dMMR)/MSI-H frequencies in sMPCC were significantly higher than those in SPCRC, which was confirmed by both IHC (50 of 239 patients vs 872 of 13 037 patients) and NGS (17 of 78 patients vs 5 of 94 patients). According to the MMR/MSI status of different lesions in patients with sMPCC, they were further divided into 3 subgroups: all dMMR/MSI-H, dMMR/MSI-H and proficient MMR (pMMR)/microsatellite stability (MSS), and all pMMR/MSS. The EGFR and PIK3CA variants were more common, whereas TP53 variants were less prevalent in patients with sMPCC than in those with SPCRC. Moreover, higher tumor mutation burden was associated with higher MSI in patients with sMPCC rather than in those with SPCRC. Conclusions and Relevance: In this cohort study of sMPCC, the incidence of dMMR/MSI-H in patients with sMPCC was significantly higher than that in patients with SPCRC. These findings suggest that sMPCC can be classified into 3 subgroups according to the MMR/MSI status of each lesion, which might be applied to guide personalized therapies for better disease management.

Impact of long-course neoadjuvant radiation on postoperative low anterior resection syndrome and stoma status in rectal cancer: long-term functional follow-up of a randomized clinical trial.

BACKGROUND: Neoadjuvant radiation has been increasingly associated with postoperative bowel dysfunction, including low anterior resection syndrome (LARS). Although permanent stoma often results from severe bowel dysfunction and significantly impacts quality of life, the presence of stoma paradoxically excludes patients from functional follow-up. Hence, stoma status is rarely reported along with LARS, while assessment of both is essential for the comprehensive evaluation of bowel dysfunction in long-term survivors of rectal cancer. METHOD: Patients enrolled into the Neoadjuvant FOLFOX6 Chemotherapy with or without Radiation in Rectal Cancer (FOWARC) multicentre randomized clinical trial were randomized to receive long-course neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT) followed by sphincter-saving proctectomy and longitudinal follow-up. The primary outcome of the trial was disease-free survival. LARS score and stoma status were assessed secondarily for postoperative bowel function in the largest single-centre cohort of the trial. RESULTS: Overall, 327 patients with locally advanced rectal cancer were enrolled in the original trial and 203 responded after a median follow-up of 83.4 months, of whom 24 (11.8 per cent) had persistent stoma, and 48 patients (23.6 per cent) reported major LARS. Compared with the nCT group, the nCRT group reported more persistent stomas (16.5 per cent versus 4.9 per cent, P = 0.014), and more major LARS in patients without persistent stoma (34.7 per cent versus 16.7 per cent, P = 0.003). The combined prevalence of persistent stoma and major LARS was significantly higher in the nCRT group (45.5 per cent versus 20.7 per cent, P < 0.001). Long-course neoadjuvant radiation (OR 2.20, 95 per cent c.i. 1.10 to 4.40, P = 0.027), height of anastomosis (OR 0.74, 95 per cent c.i. 0.61 to 0.91, P = 0.004), and anastomotic leak (OR 4.97, 95 per cent c.i. 2.24 to 11.05, P < 0.001) were associated with persistent stoma and major LARS in multivariate analysis. CONCLUSION: More than one-third of patients receiving sphincter-saving proctectomy reported major LARS or persistent stoma at long-term follow-up. Long-course neoadjuvant radiation, low anastomosis, and postoperative leak are independent risk factors for persistent stoma and major LARS.

Association between migration paths and mental health of new-generation migrants in China: The mediating effect of social integration.

Background: The new-generation migrants born in 1980 and later are large and vulnerable internal migrants in China. Migration paths and social integration are important factors to explain for their mental health. However, they faced difficulties in social integration varying from migration paths. We aimed to explore the mediating role of social integration between migration paths and the mental health of new-generation migrants. Methods: The migration paths included urban-to-urban, urban-to-rural, rural-to-urban and rural-to-rural. Mental health was assessed by the Kessler Screening Scale for Psychological Distress (K6) and the Perceived Stress Scales (PSS-4). Social integration was measured by economic integration, life integration, maintenance of the local culture, acceptance of the host culture and psychological integration. Multiple linear regressions with bootstrapping were used to examine the mediating effect. Results: A total of 9,830 new-generation migrants were included in this study. The mean age was 26.92 (SD = 4.47) years and the proportion of rural-to-urban migrants was 63.7%. Compared with the new generation of rural-to-rural migrants, rural-to-urban migrants had higher psychological distress (ß = 0.305, 95% CI: 0.152-0.458) and perceived stress (ß = 0.328, 95% CI: 0.199-0.456). The bootstrapping test found that two dimensions ("life integration" and "acceptance of the host culture") of social integration as a mediator weakened the negative effect of the rural-to-urban migration path on the mental health of new-generation migrants. Conclusion: Rural-to-urban migrants had poorer mental health, and the association was mediated by their poorer social integration. The migration policies developed to enhance social integration could effectively improve the mental health of new-generation migrants.

Aprepitant plus palonosetron versus dexamethasone plus palonosetron in preventing chemotherapy-induced nausea and vomiting in patients with moderate-emetogenic chemotherapy: A randomized, open-label, phase 3 trial.

Background: Despite significant progress in the prevention of chemotherapy-induced nausea and vomiting (CINV) by using dexamethasone combined with palonosetron for patients who received moderate-emetogenic chemotherapy (MEC), some of these patients still suffer from CINV. We evaluated whether aprepitant combined with palonosetron can improve the efficacy in the prevention of CINV in patients receiving MEC. Methods: This was a single-centre, open-label, phase III, randomized controlled trial, which was done at the Sixth Affiliated Hospital of Sun Yat-sen University of China. The registered patients planned to receive mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) but had not received any chemotherapy previously. The patients were randomized in a 1:1 ratio to the aprepitant group (aprepitant 125 mg orally on day 1, 80 mg on day 2-3) and the dexamethasone group (dexamethasone 10 mg intravenously on day 1, 5 mg on days 2 and 3), both groups with palonosetron 0.25 mg intravenously on day 1. The primary endpoint was the proportion of patients who achieved a complete response (CR), defined as the absence of vomiting and no use of rescue medications in the overall phase (0-120 h). The primary outcome and safety were assessed in the modified intention-to-treat population, which excluded all patients who used estazolam within 24 h before registration and those who refused to keep a diary documenting the severity of nausea, frequency of vomiting, and the use of rescue therapy. This trial is registered with ClinicalTrials.gov, NCT02909478. Findings: Between Sep 1, 2017, and Oct 23, 2019, 320 patients were enrolled, and 315 patients were evaluated. The proportion of patients who achieved CR was significantly higher with aprepitant than that noted with dexamethasone in the overall phase (88.8% vs. 74.2%; P = 0.0010; rate difference, RD 15%, 95% CI, 6% to 23%) and in the delayed phase (25-120 h), 90.6% vs. 75.5%, (P < 0.0001; RD 15%, 95%CI, 7% to 23%). No significant difference of CR rate was observed in the acute phase (0-24 h), 93.8% vs. 93.5%, (P = 0.94; RD 0%, 95% CI, -5% to 6%)). In the overall phase, the incidence of insomnia (P < 0.0010), dyspepsia (P = 0.038), and flushing (P = 0.0010) reported by the patients was significantly higher in the dexamethasone group than that in the aprepitant group. Interpretation: Aprepitant combined with palonosetron is superior to dexamethasone combined with palonosetron in patients who received the MEC regimen mFOLFOX6 in terms of preventing CINV. Funding: The National Key R&D Program of China (2019YFC1316000) and the National Natural Science Foundation of China (81974369).

mFOLFOXIRI with or without bevacizumab for conversion therapy of RAS/BRAF/PIK3CA mutant unresectable colorectal liver metastases: the FORBES non-randomized phase II trial.

Background: The aim of this non-randomized single-center phase II trial was to prospectively assess the clinical efficacy of triplet chemotherapy with modified 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (mFOLFOXIRI) plus bevacizumab as conversion therapy for initially unresectable rat sarcoma viral oncogene homolog (RAS)/v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/phosphatidylinositol-3 kinase catalytic alpha (PIK3CA) mutant colorectal liver-limited metastases (CRLMs). Methods: Patients with RAS/BRAF/PIK3CA mutant initially unresectable CRLMs were recruited at a ratio of 2:1 to receive mFOLFOXIRI plus bevacizumab (experimental group) or mFOLFOXIRI alone (control group). The rate of patients attaining no evidence of disease (NED) was the primary endpoint. The secondary endpoints included objective response rate (ORR), depth of tumor response (DpR), secondary resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: The rate of NED achieved was 40.7% and 30.8%, respectively, in the experimental (n=54) and control groups (n=26); the adjusted odds ratio was 4.519 [95% confidence interval (CI): 1.247-16.375, P=0.022]. The ORR was 77.4% in the experimental group and 60.0% in the control group (P=0.112). The median DpR was significantly greater in the experimental group (45.6% vs. 34.9%, P=0.041). The median PFS was 12.6 months in the experimental group and 9.1 months in the control group [adjusted hazard ratio (HR): 0.584, 95% CI: 0.304-1.121, P=0.106]. Median OS was prolonged in the experimental group compared with the control group (42.6 vs. 35.3 months, adjusted HR: 0.443, 95% CI: 0.195-1.006, P=0.052). Thirty patients (55.6%) in the experimental group and 16 (61.5%) in the control group experienced grade 3/4 adverse events. Conclusions: We observed that the combination of mFOLFOXIRI and bevacizumab increased the rate of clinical NED and showed a trend toward improved survival compared with mFOLFOXIRI alone. This could represent a conversion therapy option for fit patients with initially unresectable RAS/BRAF/PIK3CA mutant CRLMs.

Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial.

BACKGROUND: PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers. METHODS: The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T with lymph node positivity (N+), Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. FINDINGS: Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9 months (IQR 8·8-17·0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an R0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64-99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38-86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group had grade 1-2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels. INTERPRETATION: Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. FUNDING: The National Key R&D Program of China, the National Natural Science Foundation of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Improvement of low anterior resection syndrome beyond 2 years after total mesorectal excision.

AIM: Bowel dysfunction after sphincter-preserving proctectomy, also known as low anterior resection syndrome (LARS), has significant impact on survivors of rectal cancer. This study aimed to assess the temporal change of LARS beyond 2 years after proctectomy, which has not been fully studied. METHODS: We longitudinally enrolled consecutive patients who had received total mesorectal excision in a tertiary academic medical center, with preoperative neoadjuvant therapy if indicated. LARS score was longitudinally assessed by two serial follow-ups, with a fixed interval of 18 months. RESULTS: Overall, 107 patients responded for the first follow-up after a median of q20 months, 96 of whom responded for the second follow-up after a median of 38 months. At the first follow-up, 48 patients (44.9%) reported major LARS, compared with 23 (24.0%) at the second follow-up (p < 0.001). Mean LARS score improved from 27.3 to 18.6, mostly from "urgency" (12.2 vs. 6.2, p < 0.001) and "clustering of stools" (9.7 vs. 7.7, p = 0.001). Anastomosis less than 3 cm from the anal verge was independently associated with LARS improvement. CONCLUSION: Bowel dysfunction continues to improve 2 years after total mesorectal excision, with most symptom relief in urgency and stool clustering, especially in patients with lower anastomosis.

The Trends of Psychological Status of People Entering from High-Risk Areas of COVID-19 Coronavirus During the Quarantine in Dedicated Hotels: A Longitudinal Survey Study from Guangzhou, China.

BACKGROUND: The quarantine in dedicated hotels has become an inevitable safety measure due to the frequent cross-border travel since the outbreak of COVID-19. The aim of the present study was to explore the trends in the psychological status of individuals entering from high-risk areas of COVID-19 coronavirus while quarantining in dedicated hotels. METHODS: A total of 591 individuals who isolated in dedicated hotels were recruited between March and June 2020. Participants self-reported mental symptoms [Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS)] every three days during the quarantine. A mixed-effects linear regression model was used to assess the trends. RESULTS: Participants reporting anxiety and depression symptoms at least one time during quarantine accounted for 4.5% and 18.4%, respectively. Their psychological status was alleviated during some first 9 days, and then it slightly deteriorated, which was suggested by SAS and SDS scores that were negatively correlated with the days of quarantine (T) (adjusted coefficient [ß] -0.81, 95% CI -1.00 to -0.62; and ß -0.75, 95% CI -0.97 to -0.53, respectively), and were positively correlated with the square of T (ß 0.04, 95% CI 0.02 to 0.06; and ß 0.04, 95% CI 0.02 to 0.06, respectively). The unemployed and 18~30-year-old participants were prone to greater levels of psychological distress. No significant difference in the trend of mental health was found among different subgroups. CONCLUSION: The mental health of the people entering Guangzhou from high-risk areas of COVID-19 coronavirus resulted positive during the early period of quarantine in dedicated hotels, after which it deteriorated. The psychological status of individuals should be closely monitored at the beginning and after more than 9 days of quarantine, especially for individuals who are unemployed and 18~30-year-old ones.

Comparison of outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal GIST: An inverse probability of treatment weighting analysis.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal gastrointestinal stromal tumors (GIST) patients. METHODS: Eighty-five patients with localized rectal GIST were divided into two groups: upfront surgery ± adjuvant imatinib (Group A, n = 33) and the neoadjuvant imatinib + surgery + adjuvant imatinib (Group B, n = 52). Baseline characteristics between groups were controlled for with inverse probability of treatment weighting (IPTW) adjusted analysis. RESULTS: The response rate to neoadjuvant imatinib was 65.9%. After the IPTW-adjusted analysis, patients who underwent neoadjuvant therapy had better distant recurrence-free survival (DRFS) and disease-specific survival (DSS) compared with those who underwent upfront surgery (5-year DRFS 97.8 vs. 71.9%, hazard ratio [HR], 0.15; 95% CI, 0.03-0.87; p = 0.03; 5-year DSS 100 vs. 77.1%; HR, 0.11; 95% CI, 0.01-0.92; p = 0.04). While no significant association was found between overall survival (OS) and treatment groups (p = 0.07), 5-year OS was higher for the neoadjuvant group than upfront surgery group (97.8% vs. 71.9%; HR, 0.2; 95% CI, 0.03-1.15). CONCLUSIONS: In patients with localized rectal GIST, neoadjuvant imatinib not only shrunk the tumor size but also decreased the risk of metastasis and tumor-related deaths when compared to upfront surgery and adjuvant imatinib alone.

Spatiotemporal distribution and sociodemographic and socioeconomic factors associated with primary and secondary syphilis in Guangdong, China, 2005-2017.

BACKGROUND: Previous studies exploring the factors associated with the incidence of syphilis have mostly focused on individual-level factors. However, recent evidence has indicated that social-level factors, such as sociodemographic and socioeconomic factors, also affect the incidence of syphilis. Studies on the sociodemographic and socioeconomic factors associated with syphilis incidence are scarce, and they have rarely controlled for spatial effects, even though syphilis shows spatial autocorrelation. METHODOLOGY/PRINCIPAL FINDINGS: Syphilis data from 21 cities in Guangdong province between 2005 and 2017 were provided by the National Notifiable Infectious Disease Reporting Information System. The incidence time series, incidence map, and space-time scanning data were used to visualize the spatiotemporal distribution. The spatial panel data model was then applied to explore the relationship between sociodemographic factors (population density, net migration rate, male:female ratio, and the number of health institutions per 1,000 residents), socioeconomic factors (gross domestic product per capita, the proportion of secondary/tertiary industry), and the incidence of primary and secondary syphilis after controlling for spatial effects. The incidence of syphilis increased slowly from 2005 (11.91 per 100,000) to 2011 (13.42 per 100,000) and then began to decrease, reaching 6.55 per 100,000 in 2017. High-risk clusters of syphilis tended to shift from developed areas to underdeveloped areas. An inverted U-shaped relationship was found between syphilis incidence and gross domestic product per capita. Moreover, syphilis incidence was significantly associated with population density (ß = 2.844, P = 0.006), the number of health institutions per 1,000 residents (ß = -0.095, P = 0.007), and the net migration rate (ß = -0.219, P = 0.002). CONCLUSIONS/SIGNIFICANCE: Our findings suggest that the incidence of primary and secondary syphilis first increase before decreasing as economic development increases further. These results emphasize the necessity to prevent syphilis in regions at the early stages of economic growth.

Gastrointestinal cancers in China, the USA, and Europe.

Gastrointestinal (GI) cancers, including colorectal cancer, gastric cancer, and esophageal cancer, are a major medical and economic burden worldwide and have the largest number of new cancer cases and cancer deaths each year. Esophageal and gastric cancers are most common in developing countries, while colorectal cancer forms the major GI malignancy in Western countries. However, a great shift in the predominant GI-cancer type is happening in countries under economically transitioning and, at the same time, esophageal and gastric cancers are reigniting in Western countries due to the higher exposure to certain risk factors. The development of all GI cancers is highly associated with lifestyle habits and all can be detected by identified precancerous diseases. Thus, they are all suitable for cancer screening. Here, we review the epidemiological status of GI cancers in China, the USA, and Europe; the major risk factors and their distribution in these regions; and the current screening strategies.

Time-varying associations of pre-migration and post-migration stressors in refugees' mental health during resettlement: a longitudinal study in Australia.

BACKGROUND: Understanding the time-varying association of pre-migration and post-migration stressors in refugees' mental health could help in designing tailored health promotion services at different resettlement stages and improving the efficiency of resource allocation. In this study, we explored these time-varying associations. METHODS: We used data from the first four waves (October, 2013, to February, 2017) of a national refugee-based longitudinal study, the Building a New Life in Australia (BNLA) project. Post-traumatic stress disorder (PTSD) and high risk of severe mental illness (HR-SMI) were used to assess mental health. The independent variables included the number of potentially traumatic events experienced during the pre-migration process, and a range of post-migration stressors. We used logistic regression models to analyse the relative importance of variables and time-varying associations between the pre-migration potentially traumatic events, post-migration resettlement stressors, and refugees' mental health. Analyses were stratified by gender, and sociodemographic covariates included age, marital status, education level, country of birth, and weekly income. RESULTS: 2399 participants were surveyed in Wave 1 of the BNLA project in 2013-14, of whom 2009 (83·7%) responded in Wave 2 in 2014-15, 1894 (78·9%) in Wave 3 in 2015-16, and 1929 (80·4%) in Wave 4 in 2016-17. The three most important factors associated with mental health in each wave differed for male and female refugees, but the socioeconomic stressors of loneliness and adjustment to life in Australia were consistently prominent. Positive associations between socioeconomic stressors and mental ill-health were found for both genders, with a peak at Wave 2 (adjusted odds ratio [AOR] among men, 1·60 [95% CI 1·26-2·03], p=0.0001 for PTSD; AOR 1·86 [1·35-2·55], p=0·0001 for HR-SMI; and among women, AOR 1·81 [1·27-2·57], p=0·0009 for PTSD; AOR 2·24 [1·49-3·38], p=0·0001 for HR-SMI). Associations between loneliness and mental health fluctuated, but were significant for both genders in Wave 4 (among men, AOR 1·90 [1·21-2·99], p=0·0051 for PTSD; AOR 3·70 [2·18-6·27], p<0·0001 for HR-SMI; and among women, AOR 3·65 [2·08-6·39], p<0·0001 for PTSD; AOR 3·68 [2·02-6·69], p<0·0001 for HR-SMI). The association between difficulties in adjustment to life in Australia and male refugees' mental ill-health increased continuously during the resettlement period. INTERPRETATION: Gender-specific and time-sensitive services should be considered to improve refugees' mental health. For both genders, improved economic conditions that complement social security benefits deserve attention and are relevant throughout the resettlement process. At the later stage of resettlement, services to reduce loneliness could be carried out, and reducing stressors related to adjustment to life in the host country is especially needed for male refugees. FUNDING: None.