Machine learning models for prediction of postoperative venous thromboembolism in gynecological malignant tumor patients.

AIM: To identify risk factors that associated with the occurrence of venous thromboembolism (VTE) within 30 days after hysterectomy among gynecological malignant tumor patients, and to explore the value of machine learning (ML) models in VTE occurrence prediction. METHODS: A total of 1087 patients between January 2019 and January 2022 with gynecological malignant tumors were included in this single-center retrospective study and were randomly divided into the training dataset (n = 870) and the test dataset (n = 217). Univariate logistic regression analysis was used to identify risk factors that associated with the occurrence of postoperative VTE in the training dataset. Machine learning models (including decision tree (DT) model and logistic regression (LR) model) to predict the occurrence of postoperative VTE were constructed and internally validated. RESULTS: The incidence of developing 30-day postoperative VTE was 6.0% (65/1087). Age, previous VTE, length of stay (LOS), tumor stage, operative time, surgical approach, lymphadenectomy (LND), intraoperative blood transfusion and gynecologic Caprini (G-Caprini) score were identified as risk factors for developing postoperative VTE in gynecological malignant tumor patients (p < 0.05). The AUCs of LR model and DT model for predicting VTE were 0.722 and 0.950, respectively. CONCLUSION: The ML models, especially the DT model, constructed in our study had excellent prediction value and shed light upon its further application in clinic practice.

A nomogram for predicting good response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer: a retrospective, double-center, cohort study.

AIM: The purpose of this study was to explore the clinical factors associated with achieving good response after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) and to develop and validate a nomogram. METHODS: A total of 1724 consecutive LARC patients treated at Fujian Medical University Union Hospital from January 2010 to December 2021 were retrospectively evaluated as the training cohort; 267 consecutive LARC patients treated at Zhangzhou Affiliated Hospital of Fujian Medical University during the same period were evaluated as the external 2 cohorts. Based on the pathological results after radical surgery, treatment response was defined as follows: good response, stage ypT0∼2N0M0 and poor response, ypT3∼4N0M0 and/or N positive. Independent influencing factors were analyzed by logistic regression, a nomogram was developed and validated, and the model was evaluated using internal and external data cohorts for validation. RESULTS: In the training cohort, 46.6% of patients achieved good response after nCRT combined with radical surgery. The rate of the retained anus was higher in the good response group (93.5% vs. 90.7%, P < 0.001). Cox regression analysis showed that the risk of overall survival and disease-free survival was significantly lower among good response patients than poor response patients, HR = 0.204 (95%CI: 0.146-0.287). Multivariate logistic regression analysis showed an independent association with 9 clinical factors, including histopathology, and a nomogram with an excellent predictive response was developed accordingly. The C-index of the predictive accuracy of the nomogram was 0.764 (95%CI: 0.742-0.786), the internal validation of the 200 bootstrap replication mean C-index was 0.764, and the external validation cohort showed an accuracy C-index of 0.789 (95%CI: 0.734-0.844), with good accuracy of the model. CONCLUSION: We identified factors associated with achieving good response in LARC after treatment with nCRT and developed a nomogram to contribute to clinical decision-making.

Genetic factors involved in delayed methotrexate elimination in children with acute lymphoblastic leukemia.

BACKGROUND: Delayed excretion of methotrexate can lead to life-threatening toxicity that may result in treatment cessation, irreversible organ damage, and death. Various factors have been demonstrated to influence the pharmacokinetic process of methotrexate, including genetic and nongenetic factors. METHODS: We investigated the genetic factors primarily related to the metabolic pathway of methotrexate in children with acute lymphoblastic leukemia with delayed elimination, defined as C44-48h ≥ 1.0µmol/L in this study. A total of 196 patients (delayed excretion group: 98; normal excretion group: 98) who received CCCG-ALL-2015 protocol after propensity score-matched analysis were included in the study. Twenty-eight target single-nucleotide polymorphisms (SNPs) were analyzed by multiplex polymerase chain reaction and sequencing, and 25 SNPs were finally included in the study. RESULTS: The genotype distribution of SLCO1B1 rs2306283 SNP was different between the delayed and normal excretion groups. SLCO1B1 rs2306283 AA carriers had a significantly lower methotrexate C44-48h /D ratio than GG carriers in both groups. Furthermore, compared with the normal excretion group, SLCO1B1 rs2306283 AG and GG were risk factors for developing oral mucositis (odds ratio [OR]: 2.13; 95% confidence interval [CI]: 1.11-4.08; P < .001), hepatotoxicity (OR: 2.12; 95% CI: 1.26-3.56; P < .001), and myelosuppression (OR: 1.21; 95% CI: 1.04-1.41; P = .005) in delayed excretion group. CONCLUSIONS: The results from this study indicate the potential role of SLCO1B1 rs2306283 as a pharmacogenomic marker to guide and optimize methotrexate treatment for delayed elimination in children with acute lymphoblastic leukemia.

Whole exome sequencing reveals a broader variant spectrum of Charcot-Marie-Tooth disease type 2.

Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous inherited neuropathy. Although new causative and disease-associated genes have been identified for CMT2 in recent years, molecular diagnoses are still lacking for a majority of patients. We here studied a cohort of 35 CMT2 patients of Chinese descent, using whole exome sequencing to investigate gene mutations and then explored relationships among genotypes, clinical features, and mitochondrial DNA levels in blood as assessed by droplet digital PCR. We identified pathogenic variants in 57% of CMT2 patients. The most common genetic causes in the cohort were MFN2 mutations. Two patients with typical CMT phenotype and neuromyotonia were detected to harbor compound heterozygous variations in the HINT1 gene. In conclusion, our work supports that the molecular diagnostic rate of CMT2 patients can be increased via whole exome sequencing, and our data suggest that assessment of possible HINT1 mutations should be undertaken for CMT2 patients with neuromyotonia.

Lysosomal pH Decrease in Inflammatory Cells Used To Enable Activatable Imaging of Inflammation with a Sialic Acid Conjugated Profluorophore.

Inflammation causes significant morbidity and mortality, necessitating effective in vivo imaging of inflammation. Prior approaches often rely on combination of optical agents with entities specific for proteinaceous biomarkers overexpressed in inflammatory tissues. We herein report a fundamentally new approach to image inflammation by targeting lysosomes undergoing acidification in inflammatory cells with a sialic acid (Sia) conjugated near-infrared profluorophore (pNIR). Sia-pNIR contains a sialic acid domain for in vivo targeting of inflamed tissues and a pNIR domain which isomerizes into fluorescent and optoacoustic species in acidic lysosomes. Sia-pNIR displays high inflammation-to-healthy tissue signal contrasts in mice treated with Escherichia coli, Staphylococcus aureus, or lipopolysaccharide. In addition, inflammation-associated fluorescence is switched off upon antibiotics treatment in mice. This report shows the potentials of Sia-pNIR for activatable dual-modality inflammation imaging, and particularly the use of lysosomes of inflamed cells as a previously unappreciated biomarker for inflammation imaging.

Pazopanib in patients with metastatic renal cell carcinoma: a single-center, real-world, retrospective Chinese study.

BACKGROUND: The efficacy and safety of pazopanib in patients diagnosed with metastatic renal cell carcinoma (mRCC) have been demonstrated by a Chinese subgroup analysis of the COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial. However, the real-world data are still unknown. This single-center, retrospective study was designed to verify the real-world effects of pazopanib in Chinese patients with mRCC. METHODS: Patients with mRCC and a clinical decision to initiate pazopanib as first-line therapy were eligible. The primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and safety being evaluated as secondary endpoints. The effectiveness according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model, number of risk factors in the intermediate risk group, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and the number and site of organ metastasis were also assessed. RESULTS: A total of 32 patients were enrolled, including 23 (71.9%) males and 9 (28.1%) females. The median age was 57 years (range 29-75 years). With a median follow-up time of 23.8 months, a median PFS of 18.3 months, and an ORR of 37.5%. Median OS was not reached, and the 1-, 2-, and 3-year overall survival rates were 90.6%, 78.1, and 65.6%, respectively. According to IMDC risk model, 37.5% were placed in the favorable risk (FR) subgroup, 56.2% (the majority) were placed in the intermediate risk (IR) subgroup, and 6.3% were placed in the poor risk (PR) subgroup. Compared with the IR and PR groups, the FR group achieved the best ORR (58.3%) and median PFS (22.1 months). Having 1 risk factor, ECOG PS <2, 1 organ metastasis site, and only lung metastasis associated with a higher ORR and better median PFS. The IMDC risk model and number of metastases were associated with PFS. The most common adverse events were change in hair color (69.0%), diarrhea (63%), and hypertension (50%). CONCLUSIONS: Pazopanib showed efficacy and safety in real-world Chinese mRCC patients.

[Effect of number of resected lymph nodes on the prognosis of gastric cancer patients without lymphatic metastasis].

OBJECTIVE: To investigate the long-term correlation between the number of resected lymph nodes (LNs) and the prognosis of patients with node-negative gastric cancer. METHODS: From January 1995 to December 2004, 221 patients with gastric cancer underwent D2 radical resection and were proved with no nodal involvement. The clinical records of the patients were analyzed retrospectively. The relationships of the dissected LNs number to 5-year survival rate and post-operative complication rate were analyzed respectively. RESULTS: The overall 5-year survival rate of this group was 83.5%. The total number of dissected LNs was one independent prognostic factors in this group. Among patients with the same depth of tumor invasion, the more the number of dissected LNs, the better the survival would be (P < 0.05). The patients had better long-term survival outcomes with dissected LNs counts of more than 15 for cases with pT1-2 tumor, and more than 20 for cases with pT3 tumor. The post-operative complication rate was 10.8% and it was not significantly correlated with the number of dissected lymph nodes (P > 0.05). CONCLUSIONS: The number of dissected LNs is an independent prognostic predicting factor for lymph node-negative gastric cancer. Sufficient dissection of LNs is recommended to improve the patients' long-term survival. Suitable increment of dissected LNs count would not increase the post-operative complication rate.

[Efficiency of laparoscopic D2 radical gastrectomy in gastric cancer: experiences of 218 patients].

OBJECTIVE: To explore the feasibility and efficacy of laparoscopic D2 radical gastrectomy in patients with gastric cancer. METHODS: The clinical data of 529 patients with gastric cancer underwent D2 radical resection from January 2007 to March 2009 were analyzed retrospectively. Among the patients, 218 cases underwent laparoscopic D2 gastrectomy (LAG group) and 311 cases received open gastrectomy (OG group). The patients' operation, number of retrieved lymph nodes, recovery, postoperative morbidity and mortality were compared between the two groups. RESULTS: The operative time in LAG group was (237 +/- 42) min, and was significantly longer than that in OG group [(229 +/- 42) min, P < 0.05]. However, the mean blood loss [(81 +/- 100) ml vs. (171 +/- 211) ml], number of patients needed blood transfusion (7 vs. 44 cases), first flatus time [(4.1 +/- 2.3) d vs. (5.0 +/- 1.4) d], time to resume soft diet [(4.5 +/- 2.2) d vs. (5.5 +/- 1.4) d] and postoperative hospital stay [(12 +/- 4) d vs. (14 +/- 4) d] in the two groups were all different statistically (P < 0.05), and all were better in LAG group. In LAG group, the operative time of patients with total gastrectomy was (250 +/- 46) min, and was significantly longer than that with distal gastrectomy (228 +/- 37) min (P < 0.05), but there was no significant differences in other aspects of patients' recovery between the two operation types. The postoperative morbidity of LAG group and OG group were 11.9% and 19.0%, respectively (P < 0.05). For all patients, the mean number of retrieved lymph nodes was (29 +/- 10) and the median number was 28. The mean number of retrieved lymph nodes was not significantly different between the two groups [(28 +/- 10) in LAG group vs. (29 +/- 9) in OG group, P > 0.05]. Thirteen patients (6.0%) converted to open surgery in LAG group. CONCLUSION: Laparoscopic D2 radical gastrectomy is a safe and feasible procedure with quick recovery, and it is comparable with open gastrectomy in lymph node dissection.

[Analysis of the pattern of solitary lymph node metastasis in gastric cancer and its prognosis].

OBJECTIVE: To explore the pattern of solitary lymph node(LN) metastasis in gastric cancer and its prognosis. METHODS: The clinical records of 83 patients with gastric cancer presenting solitary LN metastasis who underwent D2 radical resection from January 1995 to December 2003 were analyzed retrospectively. The precise stations of the metastasis of LN and their correlation with the location of primary tumor were studied. The 5-year survival rates were compared between patients with and without skipping LN metastasis. The prognostic factors were evaluated by using univariate and multivariate analyses. RESULTS: Among the 83 patients with pathologically proven solitary LN metastasis, 64 cases (77%) presented with the perigastric nodes metastasis (N1 area), and 19 cases (23%) in N2 area without N1 involvement (skipping LN metastasis). For tumors in the upper and middle third stomach, the No. 3 station was the most common first metastasized LN station (40% and 42%, respectively). While for tumors in the lower third stomach, the No.6 station was the mostly affected LN (33%). Of the patients, 77 cases were followed up for 5-14 years, the median survival time was 77.0 months, and the overall 5-year survival rate was 63%. The 5-year survival rates of the patients with and without skipping LN metastasis was 52% and 67% respectively, there was no significant difference between the two groups (P>0.05). The serosal invasion and pathological types were influencing factors of the 5-year survival rate on univariate analysis. But with multivariate analysis, only the serosal invasion was an independent factor affecting the survival. CONCLUSIONS: Perigastric nodes are the most common first sites of tumor metastasis, making them the main targets of operative sentinel lymphatic mapping procedures. The patients with serosal invasion have poorer prognosis.

Development and Testing of a Mobile App for Pain Management Among Cancer Patients Discharged From Hospital Treatment: Randomized Controlled Trial.

BACKGROUND: The incidence of cancer pain increases in discharged patients because of discontinued standard treatments and reductions in medication adherence. Motivated by the need for better pain management in discharged patients, we developed a mobile phone app (Pain Guard) to provide continuous treatment information and feedback to discharged cancer patients suffering from pain. OBJECTIVE: The aim was to design, construct, and test the Pain Guard app in patients managing cancer pain, evaluate the total remission rate of pain and the improvement in quality of life (QoL) to improve pain management for cancer pain patients, and assess patient acceptance of the app. METHODS: This randomized controlled double-arm study involved 58 patients with cancer pain symptoms. Participants were randomly assigned to a group receiving care through the Pain Guard app (n=31) or to a control group (n=27) who received only traditional pharmaceutical care. In a pretest, participants were rated using a baseline cancer pain assessment and QoL evaluation. During treatment, the consumption levels of analgesic drugs were recorded every week. After a 4-week study period, another round of cancer pain assessment and QoL evaluation was conducted. The system's usability, feasibility, app compliance, and satisfaction were also assessed. Our primary outcome was remission rate of pain, and secondary outcomes were medication adherence, improvements in QoL, frequency of breakthrough cancer pain (BTcP), incidence of adverse reactions, and satisfaction of patients. RESULTS: All participants (N=58) successfully completed the study. There were no significant differences in baseline pain scores or baseline QoL scores between groups. At the end of the study, the rate of pain remission in the trial group was significantly higher than that in the control group (P<.001). The frequency of BTcP in the app group was considerably lower than that in the control group (P<.001). The rate of medication adherence in the trial group was considerably higher than that in the control group (P<.001). Improvements in global QoL scores in the trial group were also significantly higher than those in the control group (P<.001). The incidence of adverse reactions in the trial group (7/31) was lower than that in the control group (12/27), especially constipation, with significant differences (P=.01). The 31 participants in the trial group completed a satisfaction survey regarding Pain Guard: 23 (74%) indicated that they were satisfied with receiving pharmaceutical care by Pain Guard, 5 (16%) indicated that they were somewhat satisfied, 2 (6%) indicated neutral feelings, and 1 (3%) indicated that they were somewhat dissatisfied; no participants indicated that they were very dissatisfied. CONCLUSIONS: Pain Guard was effective for the management of pain in discharged patients with cancer pain, and its operability was effective and easily accepted by patients. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR1800016066; http://www.chictr.org.cn/showproj.aspx?proj=27153.

The Effect Of Food On The Pharmacokinetic Properties And Bioequivalence Of Two Formulations Of Levocetirizine Dihydrochloride In Healthy Chinese Volunteers.

PURPOSE: The aim of this study is to assess the bioequivalence of a new generic formulation and the branded formulation of levocetirizine dihydrochloride in healthy Chinese volunteers under fasting and fed conditions, and food-intake effect on the pharmacokinetic properties is also evaluated. PATIENTS AND METHODS: Volunteers were randomly allocated into two groups to receive a single oral dose of generic formulation and branded formulation under fasting or fed conditions, respectively. Blood samples were collected at designated time points. Plasma concentrations of levocetirizine were determined by UFLC-MS/MS. Safety evaluations were carried out through the study. The main pharmacokinetic parameters of the two formulations of levocetirizine were calculated using non-compartmental analysis incorporated in WinNonlin® 7.0 software. RESULTS: Forty-nine volunteers were enrolled; 46 completed the studies. Under fasting and fed conditions, the 90% confidence intervals for the geometric mean of generic/branded ratios were in the range of 94.75-107.24% and 99.98-114.69% for the maximum observed concentration, and 97.13-102.50% and 98.36-103.98% for the area under the concentration-time curve. As a result of food intake before administration, the reduced rate and extent of absorption of levocetirizine were observed. Both formulations were generally well tolerated, with no serious adverse reactions reported. CONCLUSION: The two formulations demonstrated essentially identical pharmacokinetic profiles and were all well within the FDA/CFDA bioequivalence standards. Meanwhile, food intake can delay the absorption rate and reduced the bioavailability of levocetirizine in healthy Chinese volunteers.

Prognostic impact of metastatic lymph node ratio in advanced gastric cancer from cardia and fundus.

AIM: To investigate the prognostic impact of the metastatic lymph node ratio (MLR) in advanced gastric cancer from the cardia and fundus. METHODS: Two hundred and thirty-six patients with gastric cancer from the cardia and fundus who underwent D2 curative resection were analyzed retrospectively. The correlations between MLR and the total lymph nodes, positive nodes and the total lymph nodes were analyzed respectively. The influence of MLR on the survival time of patients was determined with univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. And the multiple linear regression was used to identify the relation between MLR and the 5-year survival rate of the patients. RESULTS: The MLR did not correlate with the total lymph nodes resected (r = -0.093, P = 0.057). The 5-year overall survival rate of the whole cohort was 37.5%. Kaplan-Meier survival analysis identified that the following eight factors influenced the survival time of the patients postoperatively: gender (c2 = 4.26, P = 0.0389), tumor size (c2 = 18.48, P < 0.001), Borrmann type (c2 = 7.41, P = 0.0065), histological grade (c2 = 5.07, P = 0.0243), pT category (c2 = 49.42, P < 0.001), pN category (c2 = 87.7, P < 0.001), total number of retrieved lymph nodes (c2 = 8.22, P = 0.0042) and MLR (c2 = 34.3, P < 0.001). Cox proportional hazard model showed that tumor size (c2 = 7.985, P = 0.018), pT category (c2 = 30.82, P < 0.001) and MLR (c2 = 69.39, P < 0.001) independently influenced the prognosis. A linear correlation between MLR and the 5-year survival was statistically significant based on the multiple linear regression (beta = -0.63, P < 0.001). Hypothetically, the 5-year survival would surpass 50% when MLR was lower than 10%. CONCLUSION: The MLR is an independent prognostic factor for patients with advanced gastric cancer from the cardia and fundus. The decrease of MLR due to adequate number of total resected lymph nodes can improve the survival.

Effect of lymphadenectomy extent on advanced gastric cancer located in the cardia and fundus.

AIM: To analyze the prognostic impact of lymphade-nectomy extent in advanced gastric cancer located in the cardia and fundus. METHODS: Two hundred and thirty-six patients with advanced gastric cancer located in the cardia and fundus who underwent D2 curative resection were analyzed retrospectively. Relationships between the numbers of lymph nodes (LNs) dissected and survival was analyzed among different clinical stage subgroups. RESULTS: The 5-year overall survival rate of the entire cohort was 37.5%. Multivariate prognostic variables were total LNs dissected (P < 0.0001; or number of negative LNs examined, P < 0.0001), number of positive LNs (P < 0.0001), T category (P < 0.0001) and tumor size (P = 0.015). The greatest survival differences were observed at cutoff values of 20 LNs resected for stage II (P = 0.0136), 25 for stage III(P < 0.0001), 30 for stage IV (P = 0.0002), and 15 for all patients (P = 0.0024). Based on the statistically assumed linearity as best fit, linear regression showed a significant survival enhancement based on increasing negative LNs for patients of stages III (P = 0.013) and IV (P = 0.035). CONCLUSION: To improve the long-term survival of patients with advanced gastric cancer located in the cardia and fundus, removing at least 20 LNs for stage II, 25 LNs for stage III, and 30 LNs for stage IV patients during D2 radical dissection is recommended.

[Impact of negative lymph node number on prognosis advanced cancer of cardiac and stomach fundus].

OBJECTIVE: To analyze the impact of negative lymph node number on the prognosis of advanced cancer of the cardia and stomach fundus. METHODS: 236 patients with advanced cancer of the cardia and stomach fundus underwent D2 radical resection. 5-year survival rate and recurrence rate were followed up and the relationships of lymph node (LN) number to 5-year survival rate and recurrence rate were analyzed respectively, according to LN count subgroups. RESULTS: The 5-year survival rate of the entire cohort was 37.5%. The number of metastasis negative LNs was positively correlated with the LNs examined (P < 0.05). For the cancer at the same stage, the higher the number of metastasis negative LNs the higher the 5-year survival rate (P < 0.05). Linear correlation analysis showed that along with the increase of the number of negative LNs the post-operative survival rate increased. In the cancers at the stages III and IV, the 5-year survival rate increased by 6.09% and 7.65% respectively compared to the predicted values (P = 0.013 and P = 0.035). The overall recurrence rate was 61.0% within 5 years after surgery. For the cancers at the stages III and IV, the more the number of negative LNs the higher the 5-year survival rates (P < 0.05). In the cancers at the stages II and IV there were significant differences in the recurrence rates among the subgroups with different numbers of negative LNs (all P < 0.002). CONCLUSION: Number of negative LNs has a close relation with stage-based survival prediction. Dissection of sufficient lymph nodes in the procedure of D2 dissection should be recommended so as to improve the long-term therapeutic effects and reduce the recurrence rate.

[Efficiency of D2 radical resection combined with splenectomy in T3 cancer of upper stomach].

OBJECTIVE: To analyze the efficacy and influence of D2 radical resection combined with splenectomy in T3 cancer of upper stomach. METHODS: From January 1980 to June 2002, 613 patients with T3 cancer of upper stomach received D2 radical resection. Of these cases, 102 underwent simultaneous splenectomy (splenectomy group), while 511 did not (spleen-preserved group). The metastatic rate of lymph nodes in splenic hilum and along the splenic artery (No. 10, No. 11), 5-year survival rates, recurrence rate, the postoperative complication rate and mortality rate were followed up and compared in the two groups. RESULTS: The metastasis rate of No. 10 was 23.5% for splenectomy group and 14.9% for spleen-preserved group (P < 0.05). No significant difference was found in No. 11 metastasis between the two groups. The 5-year survival rate of splenectomy group was 39.8%, and was 32.3% in spleen-preserved group (P > 0.05). The recurrence rate of splenectomy group was 55.9%, and was 60.3% in spleen-preserved group (P > 0.05). In the splenectomy group, the 5-year survival rates were similar between patients with and without No. 10 metastasis (P > 0.05). The postoperative complication rate and mortality rate of the splenectomy group were 19.6% and 4.9%, and were 13.7% and 3.1% in the spleen-preserved group, respectively; and no significant difference was found between the two groups (P > 0.05). CONCLUSIONS: D2 radical excision combined splenectomy should be recommended for stage T3 cancer of upper stomach when suspected with No. 10, No. 11 lymph nodes metastasis. Simultaneous splenectomy would not increase the postoperative complication rate and mortality rate.

Redirecting immunity via covalently incorporated immunogenic sialic acid on the tumor cell surface.

Techniques eliciting anti-tumor immunity are of interest for immunotherapy. We herein report the covalent incorporation of a non-self immunogen into the tumor glycocalyx by metabolic oligosaccharide engineering with 2,4-dinitrophenylated sialic acid (DNPSia). This enables marked suppression of pulmonary metastasis and subcutaneous tumor growth of B16F10 melanoma cells in mice preimmunized to produce anti-DNP antibodies. Located on the exterior glycocalyx, DNPSia is well-positioned to recruit antibodies. Given the high levels of natural anti-DNP antibodies in humans and ubiquitous sialylation across many cancers, DNPSia offers a simplified route to redirect immunity against diverse tumors without recourse to preimmunization.

A sialic acid-targeted near-infrared theranostic for signal activation based intraoperative tumor ablation.

Agents enabling tumor staging are valuable for cancer surgery. Herein, a targetable sialic acid-armed near-infrared profluorophore (SA-pNIR) is reported for fluorescence guided tumor detection. SA-pNIR consists of a sialic acid entity effective for in vivo tumor targeting and a profluorophore which undergoes lysosomal acidity-triggered fluorogenic isomerization. SA-pNIR displays a number of advantageous biomedical properties in mice, e.g. high tumor-to-normal tissue signal contrast, long-term retention in tumors and low systemic toxicity. In addition, SA-pNIR effectively converts NIR light into cytotoxic heat in cells, suggesting tumor-activatable photothermal therapy. With high performance tumor illumination and lysosome-activatable photothermal properties, SA-pNIR is a promising agent for detection and photothermal ablation of surgically exposed tumors.

A carbohydrate-grafted nanovesicle with activatable optical and acoustic contrasts for dual modality high performance tumor imaging.

Activatable molecular systems enabling precise tumor localization are valuable for complete tumor resection. Herein, we report sialic acid-capped polymeric nanovesicles encapsulating the near infrared profluorophore (pNIR@P@SA) for lysosome activation based dual modality tumor imaging. The probe features surface-anchored sialic acid for tumor targeting and a core of near infrared profluorophore (pNIR) which undergoes lysosomal acidity triggered isomerization to give optical and optoacoustic signals upon cell internalization. Imaging studies reveal high-efficiency uptake and signal activation of pNIR@P@SA in subcutaneous tumors and millimeter-sized liver tumor foci in mice. The high tumor-to-healthy organ signal contrasts and discernment of tiny liver tumors from normal liver tissues validate the potential of pNIR@P@SA for high performance optical and optoacoustic imaging guided tumor resection.

A fluorescently labelled sialic acid for high performance intraoperative tumor detection.

Surgical resection is widely used for tumor treatment, necessitating approaches for the precise locating of elusive tumor foci. We report the high performance detection of tumors in mice with fluorescein-isothiocyanate (FITC) labelled sialic acid (FITC-SA), a fluorescent monosaccharide with low cytoxicity. Analysis of mice intravenously injected with FITC-SA revealed high target-to-background fluorescence ratios in subcutaneous tumors and liver tumor implants with 0.2-5 mm diameters, which are significantly below the clinical threshold of minimal residual cancer (∼1 cm clearance). Extracellular FITC-SA is quickly cleared from circulation whereas the intracellular FITC-SA could be metabolically incorporated into glycoproteins via a cellular sialylation pathway. Compared with FITC-SA-laden nanoparticles, free FITC-SA is preferentially and quickly taken up by tumors in mice and displays high tumor-to-background signal contrast, suggesting the potential for fluorescence directed surgical ablation of tumors.

A targetable nanogenerator of nitric oxide for light-triggered cytotoxicity.

Nanoscale-vesicles that can target pathogens are valuable for biomedical applications. In this study, a photo-responsive nanogenerator of nitric oxide (NO) comprised of a hydrophobic core of 3-trifluoromethyl-4-nitroaniline (TFNA) and a hydrophilic shell of mannosylated poly[styrene-alter-(maleic acid)] was constructed to target and kill lectin-expressing cells. The release of NO from the nanogenerator (T@P-M) was effectively induced by luminol-derived chemiluminescence (CL), leading to high-efficiency killing of Escherichia coli (E. coli) treated with T@P-M. In addition, the uptake of T@P-M by Raw 264.7 macrophages was achieved by cell surface lectin-mediated endocytosis, enabling the intracellular release of NO from the internalized T@P-M upon the induction of extracellular chemiluminescence. Because in vivo-generated CL can overcome the limited penetration of exogenous light into biological tissues, T@P-M has potential uses as a targetable photo-activatable microbicide to combat pathogens bearing lectins or residing in macrophages.