Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient.

We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.

Liraglutide Protects Pancreatic Islet From Ischemic Injury by Reducing Oxidative Stress and Activating Akt Signaling During Cold Preservation to Improve Islet Transplantation Outcomes.

BACKGROUND: Islet transplantation is a promising therapy for patients with type 1 diabetes. However, ischemic injury to the donor islets during cold preservation leads to reduced islet quality and compromises transplant outcome. Several studies imply that liraglutide, a glucagon-like peptide-1 receptor agonist, has a positive effect on promoting islet survival, but its impact on islet cold-ischemic injury remains unexplored. Therefore, the aim of this study was to investigate whether liraglutide can improve islet transplantation efficacy by inhibiting cold-ischemic injury and to explore the underlying mechanisms. METHODS: Liraglutide was applied in a mouse pancreas preservation model and a human islets cold-preservation model, and islet viability, function, oxidative stress levels were evaluated. Furthermore, islet transplantation was performed in a syngeneic mouse model and a human-to-nude mouse islet xenotransplantation model. RESULTS: The supplementation of liraglutide in preservation solution improved islet viability, function, and reduced cell apoptosis. Liraglutide inhibited the oxidative stress of cold-preserved pancreas or islets through upregulating the antioxidant enzyme glutathione levels, inhibiting reactive oxygen species accumulation, and maintaining the mitochondrial membrane integrity, which is associated with the activation of Akt signaling. Furthermore, the addition of liraglutide during cold preservation of donor pancreas or donor islets significantly improved the subsequent transplant outcomes in both syngeneic mouse islet transplantation model and human-to-nude mouse islet xenotransplantation model. CONCLUSIONS: Liraglutide protects islets from cold ischemia-related oxidative stress during preservation and hence improved islet transplantation outcomes, and this protective effect of liraglutide in islets is associated with the activation of Akt signaling.

Survival outcomes in locally advanced dMMR rectal cancer: surgery plus adjunctive treatment vs. surgery alone.

BACKGROUND: Recent studies have shown that deficient mismatch repair (dMMR) rectal cancer may be related to treatment resistance, resulting in a worse prognosis than proficient MMR (pMMR) rectal cancer. The purpose of this study was to explore whether surgery plus other treatments (radiotherapy and chemotherapy) can bring more benefits to these patients than surgery alone. METHODS: A retrospective study of 168 patients with rectal adenocarcinoma who underwent total mesorectal excision was conducted using immunohistochemical methods to determine MMR status and a propensity score matching model to minimize potential confounding factors between subgroups of patients with different treatment regimens. Kaplan-Meier analysis, log-rank tests, and Cox regression models were used to assess overall survival (OS) and disease-free survival (DFS) in patient subgroups. RESULTS: Only 6.9% (n = 168) of patients in the total cohort had dMMR rectal adenocarcinoma, and the most common cause of dMMR was a PMS2 deletion (103, 61.3%). The median DFS of the surgery alone group was 45.7 months (IQR, 40.9 to 77.8), and the median DFS of the surgery plus other treatment group was 43.9 months (IQR, 14.2 to 80.1). The surgery alone group was superior to the surgery plus other treatment group (HR, 0.16; 95% CI, 0.07 to 0.38; p = 0.005). There was no significant difference in OS (45.8 (IQR, 41.0 to 79.8) vs. 45.9 (IQR, 38.5 to 80.3)) between the two groups (HR, 0.57; 95% CI, 0.23 to 1.40; p = 0.263). CONCLUSIONS: For patients with locally advanced dMMR rectal adenocarcinoma, compared with surgery alone, surgery plus other treatment options (radiotherapy and chemotherapy) do not grant long-term survival benefits but rather shorten DFS.

Cancer Stem Cells and the Tumor Microenvironment in Tumor Drug Resistance.

Although there has been some progress in the efficacy of anti-cancer drugs, drug resistance remains challenging. Cancer stem cells (CSCs) are self-renewing and differentiate into cancer tissues with tumor heterogeneity. CSCs are associated with the progression of breast, colon, and lung cancers. Hence, recent studies have focused on the role of CSCs in resistance to anti-cancer drugs. Increasing evidence suggests that CSCs interact with components of the tumor microenvironment (TME), such as vascular and immune cells, as well as various cytokines, and are regulated by multiple signaling pathways, thereby promoting drug resistance in various cancers. Therefore, it is important to clarify the mechanisms underlying the crosstalk between CSCs and the TME for the development of targeted anti-cancer therapies.

Stage III deficient mismatch repair colon patients get greater benefit from earlier starting oxaliplatin-based chemotherapy regimen.

We evaluate the prognostic value of chemotherapy and other prognostic factors on overall survival among colon patients with deficient mismatch repair (dMMR), and determine the optimum time to start chemotherapy after surgery. Data of 306 colon cancer patients with dMMR who received radical surgery were collected from three Chinese centers between August 2012 and January 2018. Overall survival (OS) was assessed with the Kaplan-Meier method and log-rank. Cox regression analysis were used to assess influencing prognosis factors. The median follow-up time for all patients was 45.0 months (range, 1.0-100). There was a nonsignificant OS benefit from chemotherapy for patients with stage I and stage II disease, including high-risk stage II disease (log-rank p: 0.386, 0.779, 0.921), and a significant OS benefit for patients with stage III and stage IV disease for receiving post-operation chemotherapy (log-rank p = 0.002, 0.019). Stage III patients benefitted from chemotherapy regimens that contained oxaliplatin (log-rank p = 0.004), and Starting chemotherapy with oxaliplatin treatment earlier resulted in better outcomes (95% CI 0.013-0.857; p = 0.035). Chemotherapy regimens containing oxaliplatin can prolong the survival time of stage III and IV dMMR colon cancer patients. This beneficial manifestation was more pronounced after starting chemotherapy treatment early post operation. High risk stage II dMMR colon patients including T4N0M0 cannot benefit from chemotherapy.

The stool syndecan2 methylation test is more robust than blood tests for methylated septin9, CEA, CA19-9 and CA724: a diagnostic test for the early detection of colorectal neoplasms.

Background: Methylated syndecan2 (mSDC2) in stool samples has been found to be associated with colorectal cancer (CRC) and precancerous lesions. However, the available data are limited, and no previous studies have compared the analysis of mSDC2 with other diagnostic tests. Thus, we aimed to evaluate the clinical performance of a stool mSDC2 test and compare its performance with that of blood-based tests for methylated septin9 (mSEPT9), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 724 (CA724) in detecting colorectal neoplasms. Methods: The gold standard diagnostic technique that was used was colonoscopy combined with a pathological analysis of biopsied tissue. Stool DNA was extracted from 1,002 stool samples (445 from CRCs, 115 from adenomas, and 442 from controls) and then bisulfite-converted, followed by real-time quantitative methylation-specific polymerase chain reaction. Blood mSEPT9 levels were quantified by the Epi proColon 2.0 assay, and serum CEA, CA19-9 and CA724 levels were measured by electrochemiluminescence. The main indexes used during the evaluation were sensitivity, specificity and the area under the receiver operating characteristic curve (AUC). Results: Stool mSDC2 detected 69.7% of CRCs, which was significantly higher than 53.8% by plasma mSEPT9, 37.2% by CEA, 13.1% by CA19-9 and 17.5% by CA724; for adenoma, the detection rates were 31.3%, 11.1%, 2.3% and 11.9%, respectively. The AUC of mSDC2 in detecting CRC was 0.83, compared to 0.72, 0.75, 0.63 and 0.54 for mSEPT9, CEA, CA19-9 and CA724, respectively. mSDC2 identified patients with stage I-III CRC with a sensitivity of 71.6%, which was significantly higher than that of mSEPT9, CEA, CA19-9 and CA724 (54.2%, 35.5%, 11.9%, and 15.0%, respectively); for stage IV CRC, the sensitivities of mSDC2, mSEPT9, CEA, CA19-9 and CA724 were 75.9%, 82.6%, 79.3%, 36.0% and 56.5%, respectively. SDC2 and CEA had a significantly higher sensitivity for distal CRC than for proximal CRC. Conclusions: The stool SDC2 methylation test had a better performance in detecting nonmetastatic CRC and adenoma than evaluations of mSEPT9, CEA, CA19-9 and CA724 in blood. Our findings could be used to modify approaches for CRC prevention and early detection.

Case report: Camrelizumab associated with central retinal vein occlusion.

Immunotherapy has revolutionized cancer treatment and become one of the five pillars of cancer therapy. The clinical applications of immunotherapy have been adapted to range from the management of melanoma to most tumor types. As the clinical applications of cancer immunotherapies expand, understanding the treatment-related adverse events of these drugs becomes critical in clinical practice. We report a rare case of ocular immune-related side effects associated with camrelizumab that resulted in vision loss. A 56-year-old male patient was diagnosed with small cell lung cancer. The tumor involved the porta pulmonis and mediastinum upon initial diagnosis; therefore, surgery was not possible. Upon receiving the 10th immunotherapy session with camrelizumab 200 mg, the patient's visual acuity began to decrease in his right eye and a central retinal vein occlusion. Optical coherence tomography revealed significant cystoid exudation in the macular area and vitreous hemorrhage. The patient underwent vitrectomy, phacoemulsification and intraocular lens implantation after symptom onset. Following surgery, the patient's vision was limitedly restored. This is the first clinical report in China of central retinal vein occlusion and vitreous hemorrhage associated with anti-PD-1 therapy, ultimately leading to blindness. Although rare, clinical practitioners should be concerned about ocular adverse events associated with anti-PD-1 immunotherapy and develop a high index of suspicion for this possibility since ophthalmic manifestations that are rapidly detected, closely monitored, and appropriately managed are treatable.

Young Patients With Colorectal Cancer Have Higher Early Mortality but Better Long-Term Survival.

INTRODUCTION: To define the prognosis of colorectal cancer (CRC) in young patients and to compare their postoperative treatment with that of older patients. METHODS: This multicenter study enrolled 5,457 patients with primary CRC who underwent surgical resection. The overall survival (OS), clinicopathologic characteristics, and postoperative treatment of 253 young patients aged 18-44 years and 5,204 older patients aged 44-80 years were analyzed. RESULTS: The OS rate was 77.1% for young and 74.2% for older patients (P = 0.348). Landmark analysis showed a significant difference in survival between young and older patients, with 63.8% of deaths among young patients being within 25 months of surgery compared with 42.4% among older patients (P = 0.002). Among those who survived more than 25 months, young patients had significantly better survival than older patients (P = 0.009). Multivariable analysis of young patients revealed that the tumor location, perineural invasion, and stage were associated with poor survival within 25 months; after this period, stage was the only prognostic marker. Young patients were more likely to receive chemotherapy, particularly multiagent regimens. For young patients, no significant difference in OS was found based on the chemotherapy regimen, regardless of disease stage (II, III, or IV, all P > 0.05). In addition, unlike in older patients, no difference in OS was found in young patients regardless of the drug regimen administered (all P > 0.05). DISCUSSION: Young-onset CRC may have a unique disease biology that warrants further research and therapy development.

Effects of deficient mismatch repair on the prognosis of patients with stage II and stage III colon cancer during different postoperative periods.

BACKGROUND: We evaluated the prognostic role of deficient mismatch repair (dMMR) systems in stage II and stage III colon cancer patients during different postoperative periods. We also assessed whether patients aged ≥75 could benefit from chemotherapy. METHODS: This retrospective study was conducted across three medical centers in China. Kaplan-Meier survival methods and Cox proportional hazards models were used to evaluate the differences in overall survival (OS) and disease-free survival (DFS) rates. Propensity score matching was performed to reduce imbalances in the baseline characteristics of the patients. Landmark analysis was performed to evaluate the role of dMMR during different postoperative periods. RESULTS: The median follow-up time for all patients was 45.0 months (25-75 IQR: 38.0-82.5). There was no significant OS (p = 0.350) or DFS (p = 0.752) benefit associated with dMMR for stage II and III patients during the first postoperative year. However, significant OS (p < 0.001) and DFS (p < 0.001) benefits were observed from the second postoperative year until the end of follow-up. These differences remained after propensity score matching. Moreover, chemotherapy produced no OS (HR = 0.761, 95% CI: 0.43-1.34, p = 0.341) or DFS (HR = 0.98, 95% CI: 0.51-1.88, p = 0.961) benefit for patients aged ≥75 years. CONCLUSION: The benefits of dMMR in stage III patients were observed from the second postoperative year until the end of follow-up. However, the prognosis of patients with dMMR is not different from that of patients with proficient mismatch repair (pMMR) during the first postoperative year. In addition, elderly patients aged ≥75 years obtained no significant survival benefits from postoperative chemotherapy.

The prognostic and clinical value of p53 upregulated modulator of apoptosis expression in solid tumors: a meta-analysis and TCGA data review.

BACKGROUND: Previous studies have reported the prognostic value of p53 upregulated modulator of apoptosis (PUMA) in numerous human tumors, but the conclusions have not been consistent. Therefore, this meta-analysis and the Cancer Genome Atlas (TCGA) data analysis were performed to estimate the prognostic significance of PUMA in solid tumors. RESEARCH DESIGN AND METHODS: A search was conducted in PubMed, Embase, Web of Science, Cochrane Library and CNKI up to 21 July 2022. In total, 10 studies with 2,207 patients were included. We extracted the overall survival (OS) and disease-free survival (DFS) data. The hazard ratios (HRs) and 95% confidence intervals (95% CI) were adopted for evaluating the association. RESULTS: Decreased PUMA expression was significantly associated with worse OS (HR = 0.54, 95% CI = 0.38-0.78) and worse DFS (HR = 0.54, 95% CI = 0.42-0.70). Subgroup analysis showed that the prognostic role of PUMA for OS was most significant in the digestive system (HR = 0.52, 95% CI = 0.38-0.69). Furthermore, the expression of PUMA was not affected by tumor differentiation or clinical stage, and TCGA dataset analysis confirmed these results. CONCLUSIONS: We proved that expression of PUMA may serve as an independent prognostic factor for patients with solid tumors.

Circulating Methylated SEPT9 DNA Analyses to Predict Recurrence Risk and Adjuvant Chemotherapy Benefit in Stage II to III Colorectal Cancer.

BACKGROUND We aimed to evaluate the ability of circulating cell-free methylated SETP9 DNA (mSEPT9) to identify recurrence and to determine its clinical utility in adjuvant chemotherapy (ACT) regimen decisions. MATERIAL AND METHODS This study enrolled 426 patients with stage II-III CRC who received radical resection between January 8, 2018, and November 30, 2020. The median follow-up duration was 15.8 months (range, 8.1-43.4 months). The primary endpoint was recurrence-free survival (RFS). A propensity score matching model was used to minimize potential confounding covariates and to confirm our findings. RESULTS In stage II-III CRC patients, postoperative (within 1 month after surgery) mSEPT9 positivity was significantly correlated with worse RFS (HR=6.21, P<0.001), and it remained the strongest independent predictor in multivariate Cox regression analysis (HR=5.83, P<0.001), which was significantly superior to CEA, CA19-9, and CA242. During disease surveillance, mSEPT9 positivity preceded radiographic recurrence by a median of 5.0 months. The postoperative mSEPT9-positive patients benefited more from CAPEOX compared to FOLFOX (HR=3.97, P=0.017), while for mSEPT9-negative patients, CAPEOX and FOLFOX resulted in similar RFS (HR=1.70, P=0.322). Furthermore, 3 months of CAPEOX was more effective than 3 and 6 months of FOLFOX (HR=4.40, P=0.065; HR=1.56, P=0.073, respectively). CONCLUSIONS Our results revealed that mSEPT9 detection after radical resection could identify minimal residual disease (MRD) and could predict a high risk of recurrence in patients with stage II-III CRC. Furthermore, we show pioneering work that mSEPT9 detection could be used to guide the selection of an adjuvant chemotherapy regimen to improve RFS.

Clinicopathological and prognostic value of SIRT6 in patients with solid tumors: a meta-analysis and TCGA data review.

PURPOSES: In addition to its role in cellular progression and cancer, SIRT6, a member of nicotinamide adenine dinucleotide (NAD+)-dependent class III deacylase sirtuin family, serves a variety of roles in the body's immune system. In this study, we sought to determine the relationship between the expression of SIRT6 and the clinicopathological outcomes of patients with solid tumours by conducting a meta-analysis of the available data. METHODS: The databases PubMed and ISI Web of Science were searched for relevant literature, and the results were presented here. Using Stata16.0, a meta-analysis was conducted to determine the impact of SIRT6 on clinicopathological characteristics and prognosis in malignancy patients. The results were published in the journal Cancer Research. The dataset from the Cancer Genome Atlas (TCGA) was used to investigate the prognostic significance of SIRT6 in various types of tumors. RESULTS: The inclusion and exclusion criteria were met by 15 studies. In patients with solid tumours, reduced SIRT6 expression was found to be related with improved overall survival (OS) (HR = 0.66, 95% CI = 0.45-0.97, P < 0.001) as well as improved disease-free survival (DFS) (HR = 0.48, 95% CI = 0.26-0.91, P < 0.001). Low SIRT6 expression was found to be associated with a better OS in breast cancer (HR = 0.49, 95% CI = 0.27-0.89, P = 0.179), but was found to be associated with a worse OS in gastrointestinal cancer (gastric cancer and colon cancer) (HR = 1.83, 95% CI = 1.20-2.79, P = 0.939) after subgroup analysis. In terms of clinicopathological characteristics, SIRT6 expression was found to be linked with distant metastasis (OR = 2.98, 95% CI = 1.59-5.57, P = 0.694). When the data from the TCGA dataset was compared to normal tissue, it was discovered that SIRT6 expression was significantly different in 11 different types of cancers. Meanwhile, reduced SIRT6 expression was shown to be associated with improved OS (P < 0.05), which was consistent with the findings of the meta-analysis. Aside from that, the expression of SIRT6 was found to be associated with both gender and clinical stage. CONCLUSION: The overall data of the present meta-analysis indicated that low expression of SIRT6 may predict a favorable survival for patients with solid tumors.

Mismatch repair system deficiency is associated with chemoradiotherapy resistance in locally advanced rectal adenocarcinoma patients.

BACKGROUND AND OBJECTIVES: Previous studies have concluded that colorectal cancer patients with deficient mismatch repair (dMMR) usually have a good prognosis. However, some studies have suggested that the prognosis of rectal cancer patients with dMMR appears to be worse. Our aim was to investigate chemoradiotherapy resistance in dMMR rectal tumors. METHODS: A retrospective study of 217 patients with locally advanced rectal adenocarcinoma treated with chemoradiotherapy and total mesorectal excision surgery was conducted using immunohistochemistry to determine MMR status and propensity score matching models to reduce potential confounders. Kaplan-Meier analysis, log-rank test, and Cox regression models were used to assess overall survival (OS) and disease-free survival (DFS) in patient subgroups. RESULTS: The 3-year DFS rates were 77.1% and 56.7% in the pMMR and dMMR groups, respectively. The pMMR group had significantly better DFS than the dMMR group (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.10-3.91; p = 0.019). However, there was no significant difference in OS between the two groups (45.7 [interquartile range, IQR], 39.3-72.1] vs. 47.5 [IQR, 29.5-72.1]) (HR, 1.39; 95% CI, 0.70-2.77; p = 0.35). Neither OS nor DFS was significantly different between the neoadjuvant chemoradiotherapy and postoperative chemoradiotherapy groups. CONCLUSION: Locally advanced dMMR rectal adenocarcinoma exhibits greater chemoradiotherapy resistance than pMMR.

Higher titer hepatitis B core antibody predicts a higher risk of liver metastases and worse survival in patients with colorectal cancer.

BACKGROUND: There have been controversial voices on if hepatitis B virus infection decreases the risk of colorectal liver metastases or not. This study aims to the find the association between HBV infection and postoperative survival of colorectal cancer and the risk of liver metastases in colorectal cancer patients. METHODS: Patients who underwent curative surgical resection for colorectal cancer between January 2011 and December 2012 were included. Patients were grouped according to anti-HBc. Differences in overall survival, time to progress, and hepatic metastasis-free survival between groups and significant predictors were analyzed. RESULTS: Three hundred twenty-seven colorectal cancer patients were comprised of 202 anti-HBc negative cases and 125 anti-HBc positive cases, and anti-HBc positive cases were further divided into high-titer anti-HBc group (39) and low-titer anti-HBc group (86). The high-titer anti-HBc group had significantly worse overall survival (5-Yr, 65.45% vs. 80.06%; P < .001), time to progress (5-Yr, 44.26% vs. 84.73%; P < .001), and hepatic metastasis-free survival (5-Yr, 82.44% vs. 94.58%; P = .029) than the low-titer group. Multivariate model showed anti-HBc ≥ 8.8 S/CO was correlated with poor overall survival (HR, 3.510; 95% CI, 1.718-7.17; P < .001), time to progress (HR, 5.747; 95% CI, 2.789-11.842; P < .001), and hepatic metastasis-free survival (HR, 3.754; 95% CI, 1.054-13.369; P = .041) in the anti-HBc positive cases. CONCLUSIONS: Higher titer anti-HBc predicts a potential higher risk of liver metastases and a worse survival in anti-HBc positive colorectal cancer patients.

Sterol metabolism and protein metabolism are differentially correlated with sarcopenia in Asian Chinese men and women.

OBJECTIVES: Our aim was to investigate the prevalence and predictive variables of sarcopenia. METHODS: We recruited participants from the Peking Union Medical College Hospital Multicenter Prospective Longitudinal Sarcopenia Study (PPLSS). Muscle mass was quantified using bioimpedance, and muscle function was quantified using grip strength and gait speed. Logistic regression revealed the relationships between sarcopenia and nutritional, lifestyle, disease, psychosocial and physical variables. RESULTS: The prevalence of sarcopenia and sarcopenic obesity was 9.2%-16.2% and 0.26%-9.1%, respectively. Old age, single status, undernourishment, higher income, smoking, low physical activity, poor appetite and low protein diets were significantly associated with sarcopenia. Multiple logistic regression analysis showed that age was a risk factor for all stages of sarcopenia, and participants above 80 years were greater than fivefold more susceptible to sarcopenia, while lower physical activity was an independent risk factor. The optimal cut-off value for age was 71 years, which departs from the commonly accepted cut-off of 60 years. Female participants were greater than twofold less susceptible to sarcopenia than male participants. The sterol derivative 25-hydroxyvitamin D was associated with fourfold lower odds of sarcopenia in male participants. Several protein intake variables were also correlated with sarcopenia. Based on these parameters, we defined a highly predictive index for sarcopenia. CONCLUSIONS: Our findings support a predictive index of sarcopenia, which agglomerates the complex influences that sterol metabolism and nutrition exert on male vs female participants.