Search

BackgroundThe c-met proto-oncogene (MET) serves as a significant primary oncogenic driver in non-small cell lung cancer (NSCLC) and has the potential to fuse with other genes, such as KIF5B, although it occurs infrequently. Only a limited number of reported cases have examined the clinical efficacy of crizotinib in patients with KIF5B-MET gene fusion, with no known data regarding acquired resistance to crizotinib and its potential mechanisms. In this report, we present the clinical progression of a female patient diagnosed with NSCLC and harboring a KIF5B-MET gene fusion.Case descriptionThe patient initially exhibited partial response to first-line crizotinib treatment, albeit for a short duration and with limited efficacy. Subsequent disease progression revealed the emergence of a secondary MET mutation, specifically MET Y1230H, leading to acquired resistance to crizotinib.ConclusionThe reporting of this case is imperative for informing clinical practice, given the uncommon occurrence of NSCLC with MET fusion, displaying responsiveness to MET tyrosine kinase inhibitor therapy, as well as the emergence of the secondary Y1230H alteration as a potential resistance mechanism.

BackgroundMitochondrial metabolic reprogramming (MMR)-mediated immunogenic cell death (ICD) is closely related to the tumor microenvironment (TME). Our purpose was to reveal the TME characteristics of clear cell renal cell carcinoma (ccRCC) by using them.MethodsTarget genes were obtained by intersecting ccRCC differentially expressed genes (DEGs, tumor VS normal) with MMR and ICD-related genes. For the risk model, univariate COX regression and K-M survival analysis were used to identify genes most associated with overall survival (OS). Differences in the TME, function, tumor mutational load (TMB), and microsatellite instability (MSI) between high and low-risk groups were subsequently compared. Using risk scores and clinical variables, a nomogram was constructed. Predictive performance was evaluated by calibration plots and receiver operating characteristics (ROC).ResultsWe screened 140 DEGs, including 12 prognostic genes for the construction of risk models. We found that the immune score, immune cell infiltration abundance, and TMB and MSI scores were higher in the high-risk group. Thus, high-risk populations would benefit more from immunotherapy. We also identified the three genes (CENPA, TIMP1, and MYCN) as potential therapeutic targets, of which MYCN is a novel biomarker. Additionally, the nomogram performed well in both TCGA (1-year AUC=0.862) and E-MTAB-1980 cohorts (1-year AUC=0.909).ConclusionsOur model and nomogram allow accurate prediction of patients’ prognoses and immunotherapy responses.

Epidermal growth factor receptor (EGFR) mutations have been frequently detected in patients with pulmonary adenocarcinoma. EGFR Exon 19Del and 21L858R mutations are the two most common EGFR mutations. EGFR-tyrosine kinase inhibitors (TKIs) are widely employed to treat patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Recently, there has been rapid growth in clinical trials assessing neoadjuvant targeted therapy, indicating good application prospects owing to high efficiency and low toxicity. Herein, we discuss the case of a 56-year-old male patient who was initially diagnosed with stage IIIA pulmonary adenocarcinoma (AJCC,8th edition) of the left lower lung with an EGFR Exon 19Del mutation. The patient was treated with osimertinib but failed to undergo timely review and surgery. Subsequently, the patient underwent two cycles of neoadjuvant chemotherapy (NAC) combined with neoadjuvant targeted therapy. After the tumor load and size had significantly decreased, radical surgery was successfully performed under thoracoscopy. However, postoperative pathology revealed carcinosarcoma, pT2aN0M0, stage IB, and the pathological response was 50%. The present case report provides practical clinical evidence for the application of neoadjuvant targeted therapy combined with chemotherapy for locally advanced primary pulmonary carcinosarcoma with EGFR mutation.

ObjectiveTo investigate the association between radiotherapy and the risk of second malignant neoplasm (SMN) development among patients with bladder cancer (BC). Overall survival (OS) is compared among patients developing SMN and without.MethodWe identified patients diagnosed with BC from the Surveillance, Epidemiology, and End Results (SEER) database. The development of an SMN is defined as any SMN occurring more than 5 years after the diagnosis of BC. The Fine-Gray competing risk regression is used to estimate the probability of SMN. The radiotherapy-associated risk (RR) for SMNs is assessed by Poisson regression. The Kaplan–Meier method was used to evaluate the OS of patients with SMNs. Propensity score matching (PSM) is performed.ResultsA total of 76575 BC patients are enrolled in our study. The probability of SMNs in the radiotherapy cohort is statistically higher than in the non-radiotherapy cohort. In competing risk regression analysis, radiotherapy is proven to be associated with a higher risk of SMN (Hazard ratio: 1.23; 95% CI: 1.102–1.368). The radiotherapy-associated risks significantly increase in the radiotherapy cohort (RR: 1.28; 95% CI: 1.14–1.43). In site-specific analysis, statistically significant results are observed in lung and bronchus (LAB) cancer and hematological malignancies. The OS rate in patients developing SMN is significantly lower than that among matched patients with primary BC.ConclusionRadiotherapy for BC is associated with SMN. Radiotherapy increases the risk of secondary low-dose area cancer development, including LAB cancer or hematological malignancies. Notably, this effect is not observed in the high-dose area involving pelvic tumors. Patients developing SMN showed poorer OS.

PurposeTo develop and validate nomograms for pre-treatment prediction of malignant histology (MH) and unfavorable pathology (UP) in patients with endophytic renal tumors (ERTs).MethodsWe retrospectively reviewed the clinical information of 3245 patients with ERTs accepted surgical treatment in our center. Eventually, 333 eligible patients were included and randomly enrolled into training and testing sets in a ratio of 7:3. We performed univariable and multivariable logistic regression analyses to determine the independent risk factors of MH and UP in the training set and developed the pathological diagnostic models of MH and UP. The optimal model was used to construct a nomogram for MH and UP. The area under the receiver operating characteristics (ROC) curves (AUC), calibration curves and decision curve analyses (DCA) were used to evaluate the predictive performance of models.ResultsOverall, 172 patients with MH and 50 patients with UP were enrolled in the training set; and 74 patients with MH and 21 patients with UP were enrolled in the validation set. Sex, neutrophil-to-lymphocyte ratio (NLR), R score, N score and R.E.N.A.L. score were the independent predictors of MH; and BMI, NLR, tumor size and R score were the independent predictors of UP. Single-variable and multiple-variable models were constructed based on these independent predictors. Among these predictive models, the malignant histology-risk nomogram consisted of sex, NLR, R score and N score and the unfavorable pathology-risk nomogram consisted of BMI, NLR and R score performed an optimal predictive performance, which reflected in the highest AUC (0.842 and 0.808, respectively), the favorable calibration curves and the best clinical net benefit. In addition, if demographic characteristics and laboratory tests were excluded from the nomograms, only the components of the R.E.N.A.L. Nephrometry Score system were included to predict MH and UP, the AUC decreased to 0.781 and 0.660, respectively (P=0.001 and 0.013, respectively).ConclusionIn our study, the pathological diagnostic models for predicting malignant and aggressive histological features for patients with ERTs showed outstanding predictive performance and convenience. The use of the models can greatly assist urologists in individualizing the management of their patients.

B7-H3 is over-expressed in multiple types of solid tumors, making it an ideal target for chimeric antigen receptor (CAR)-T therapy. Here, we first report a case of multiple basal cell carcinoma (BCC) patient treated with humanized monoclonal anti-B7-H3 CAR-T cells through direct intratumoral injection. After three dose-escalated injections, the lesion in the abdomen decreased by 40% in volume, shrank from bulging to flat, but was not eradicated completely. The large lesion in the forehead became dry from original ulcer and bleeding. The adverse events observed were itching, myalgia, and redness. Immunohistochemistry analysis demonstrated that B7-H3-positive tumor cells and B7-H3 expression intensity were reduced after injections of CAR-T cells. The number of infiltrating CD3 T cells increased significantly but mainly located outside the tumor region. Subsequently, high levels of TGF-β in the tumor area were observed, suggesting that solid tumor microenvironment may hinder the infiltration and effect of CAR-T cells. In summary, in this particular case report, intratumoral injection of B7-H3 CAR-T cells partially controls tumor growth in the BCC patient with minor adverse events. The efficacy and safety of B7-H3 CAR-T therapy need to be further investigated with a larger cohort of patients. Although only one clinical case is reported here, the anti-B7-H3 CAR-T cell therapy should be considered as a treatment option for solid tumors in the future. This clinical trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) with registration number ChiCTR2100044386.

PurposeThe study aimed to compare operative, functional, and oncological outcomes between partial nephrectomy (PN) and radical nephrectomy (RN) for entophytic renal tumors (ERTs) by propensity score matching (PSM) analysis.MethodsA total of 228 patients with ERTs who underwent PN or RN between August 2014 and December 2021 were assessed. A PSM in a 1:1 ratio was conducted to balance the differences between groups. Perioperative characteristics, renal functional, and oncological outcomes were compared between groups. Univariate and multivariate logistic and Cox proportional hazard regression analyses were used to determine the predictors of functional and survival outcomes.ResultsAfter PSM, 136 cases were matched to the PN group (n = 68) and the RN group (n = 68). Patients who underwent RN had shorter OT, less EBL, and lower high-grade complications (all p

Primary pulmonary enteric adenocarcinoma (PEAC) is a rare invasive adenocarcinoma clinically similar to metastatic colorectal adenocarcinoma (MCRC). Although many studies have addressed the differential diagnosis of PEAC, few have described the treatment of PEAC, especially using immunotherapy. This report describes a 61-year-old man who presented initially with pain in the ribs. Pathological analysis of biopsy samples shows malignant tumors of the right pleura, and next-generation sequencing of 26 genes showed a KRAS gene mutation. Positron emission tomography-computed tomography (PET-CT) found no evidence of gastrointestinal malignancy. Due to multiple metastases, the patient could not undergo radical surgery. The patient was treated with a combination chemotherapy regimen of paclitaxel plus carboplatin, along with sindilizumab immunotherapy, but, after one cycle of treatment, the tumor showed a hyperprogressive state. The patient is still being monitored regularly. These findings indicate that chemotherapy combined with immunotherapy may be ineffective in the treatment of primary PEAC with positive driver genes.

PurposeTo construct a prognostic model to predict the cancer-specific survival (CSS) for bladder cancer patients with lymph node-positive.Patients and MethodsWe enrolled 2,050 patients diagnosed with lymph node-positive bladder cancer from the Surveillance Epidemiology and End Results (SEER) database (2004–2015). All patients were randomly split into development cohort (n = 1,438) and validation cohort (n = 612) at a ratio of 7:3. The univariate and multivariate Cox regression analysis were performed to identify prognostic factors. A nomogram predicting CSS was established based on the results of multivariate Cox analysis. Its performance was evaluated by calibration curves, the receiver operating characteristic (ROC) curves, and the concordance index (C-index). Internal verification was performed in the validation cohort. The Kaplan–Meier method with the log-rank test was applied in the different risk groups.ResultsThe nomogram incorporated summary stage, tumor size, chemotherapy, regional nodes examined and positive lymph nodes. The C-index of the nomogram in the development cohort was 0.716 (0.707–0.725), while the value of the C-index was 0.691 (0.689–0.693) in the validation cohort. The AUC of the nomogram was 0.803 for 3-year and 0.854 for 5-year in the development cohort, while was 0.773 for 3-year and 0.809 for 5-year in the validation cohort. Calibration plots for 3-year and 5-year CSS showed good concordance. Significant differences were observed between high, medium, and low risk groups (P

BackgroundIt is a critical challenge to diagnose leptomeningeal metastasis (LM), given its technical difficulty and the lack of typical symptoms. The existing gold standard of diagnosing LM is to use positive cerebrospinal fluid (CSF) cytology, which consumes significantly more time to classify cells under a microscope.ObjectiveThis study aims to establish a deep learning model to classify cancer cells in CSF, thus facilitating doctors to achieve an accurate and fast diagnosis of LM in an early stage.MethodThe cerebrospinal fluid laboratory of Xijing Hospital provides 53,255 cells from 90 LM patients in the research. We used two deep convolutional neural networks (CNN) models to classify cells in the CSF. A five-way cell classification model (CNN1) consists of lymphocytes, monocytes, neutrophils, erythrocytes, and cancer cells. A four-way cancer cell classification model (CNN2) consists of lung cancer cells, gastric cancer cells, breast cancer cells, and pancreatic cancer cells. Here, the CNN models were constructed by Resnet-inception-V2. We evaluated the performance of the proposed models on two external datasets and compared them with the results from 42 doctors of various levels of experience in the human-machine tests. Furthermore, we develop a computer-aided diagnosis (CAD) software to generate cytology diagnosis reports in the research rapidly.ResultsWith respect to the validation set, the mean average precision (mAP) of CNN1 is over 95% and that of CNN2 is close to 80%. Hence, the proposed deep learning model effectively classifies cells in CSF to facilitate the screening of cancer cells. In the human-machine tests, the accuracy of CNN1 is similar to the results from experts, with higher accuracy than doctors in other levels. Moreover, the overall accuracy of CNN2 is 10% higher than that of experts, with a time consumption of only one-third of that consumed by an expert. Using the CAD software saves 90% working time of cytologists.ConclusionA deep learning method has been developed to assist the LM diagnosis with high accuracy and low time consumption effectively. Thanks to labeled data and step-by-step training, our proposed method can successfully classify cancer cells in the CSF to assist LM diagnosis early. In addition, this unique research can predict cancer’s primary source of LM, which relies on cytomorphologic features without immunohistochemistry. Our results show that deep learning can be widely used in medical images to classify cerebrospinal fluid cells. For complex cancer classification tasks, the accuracy of the proposed method is significantly higher than that of specialist doctors, and its performance is better than that of junior doctors and interns. The application of CNNs and CAD software may ultimately aid in expediting the diagnosis and overcoming the shortage of experienced cytologists, thereby facilitating earlier treatment and improving the prognosis of LM.

Chimeric antigen receptor T (CAR-T) cells are not effective in solid tumor treatment due to reduced invasion and expansion, and short survival time. This study aimed to explore whether interleukin (IL)-7 and CCR2b expression could improve GD2-CAR-T cell survival and infiltration in neuroblastoma and melanoma treatment. IL-7 and CCR2b were inserted into the classical second-generation CAR structure to construct 7×2b CAR. The 7×2b CAR-T cell phenotypes were evaluated by flow cytometry and the chemokine levels by ELISA. The 7×2b CAR-T cell migration and anti-tumor abilities were detected by Transwell assay and animal experiments in vivo. We report that compared with that of CAR-T cells, 7×2b CAR-T cell IL-7 secretion and CCR2b expression did not affect the T cell surface expression of CAR or CAR-T specificity and efficacy against tumor cells. The 7×2b CAR-T cells could induce IFN-γ secretion in GD2-positive tumor cells, killing them as well as conventional CAR-T cells. Moreover, IL-7 and CCR2b co-expression enhanced the 7×2b CAR-T cell survival and migration. Similar to conventional CAR-T, 7×2b CAR-T cells could also inhibit tumor growth and increase IFN-γ, Gzms-B, and IL-2 expression. Finally, unlike in mice injected with CAR-T cells, CD3 expression was the most abundant in the spleen and tumor tissues in mice injected with 7×2b CAR-T cells. Our study demonstrates that IL-7 and CCR2b co-expression in GD2-CAR-T cells exhibit stronger anti-tumor activity than classical second-generation CAR-T cells, shedding light on the potential novel GD2-positive neuroblastoma and melanoma treatment approach.

ObjectiveWe aimed to analyze the perioperative, functional, and oncologic outcomes following robot-assisted radical prostatectomy (RARP) and laparoscopic radical prostatectomy (LRP) for patients with localized prostate cancer (PCa) characterized by a large prostate volume (PV; ≥50 ml) over a minimum of 2 years follow-up.Materials and MethodsPatients undergoing RARP and LRP for localized PCa with a large PV were included in the final analysis. The perioperative, functional, and oncologic outcomes were analyzed between the two groups.ResultsAll operations were successfully completed without open conversion in both groups. The mean operative time and estimated blood loss in the RARP group were significantly decreased compared to those in the LRP group (139.4 vs. 159.0 min, p = 0.001, and 124.2 vs. 157.3 ml, p = 0.003, respectively). Patients in the RARP arm had significantly lower proportions of grade II or lower and of higher than grade II postoperative complications compared with those in the LRP group (7.9% vs. 17.1%, p = 0.033, and 1.6% vs. 6.7%, p = 0.047, respectively). No significant differences in terms of the rates of pT3 disease, positive surgical margin, and positive lymph node were noted between the two groups. Moreover, no significant difference in the median specimen Gleason score was observed between the RARP and LRP groups (6 vs. 7, p = 0.984). RARP vs. LRP resulted in higher proportions of urinary continence upon catheter removal (48.4% vs. 33.3%, p = 0.021) and at 3 (65.1% vs. 50.5%, p = 0.025) and 24 (90.5% vs. 81.0%, p = 0.037) months post-operation. The median erectile function scores at 6 and 24 months post-operation in the RARP arm were also significantly higher than those in the LRP arm (15 vs. 15, p = 0.042, and 15 vs. 13, p = 0.026, respectively). Kaplan–Meier analyses indicated that the biochemical recurrence-free survival and accumulative proportion of continence were statistically comparable between the two groups (p = 0.315 and p = 0.020, respectively).ConclusionsFor surgically managing localized PCa with a large prostate (≥50 ml), RARP had a tendency toward a lower risk of postoperative complications and better functional preservation without cancer control being compromised when compared to LRP.

ObjectivesTo estimate the safety and efficiency of transvesical Retzius-sparing robot-assisted radical prostatectomy (T-RARP) compared with standard robot-assisted radical prostatectomy (S-RARP) for localized prostate cancer (PCa).Materials and Methods174 patients bearing localized PCa and undergoing T-RARP or S-RARP between October 2017 and January 2020 were retrospectively enrolled in our analysis. All potential baseline confounders were strictly restrained with propensity-score matching (PM) method (1: 1). Within the matched setting, the perioperative and functional outcomes were compared between the T-RARP and S-RARP groups, while the oncological results and functional recovery of the two arms were presented with Kaplan-Meier curves.ResultsFinally, 114 and 60 eligible patients harbouring localized PCa were identified in the S-RARP and T-RARP group, respectively. No significant differences between the two groups were found in all baseline characteristics after PM. Within the matched cohort, no case was converted to open surgery in either group. The T-RARP group was significantly related to a higher mean operative time (p = 0.001) and shorter median hospital stay length (p < 0.001). There were not significant differences in the median estimated blood loss and specimen Gleason score between the two arms. The proportions of transfusion, pT3a disease, postoperative complication, and positive surgical margin in the T-RARP group were also comparable to that in the S-RARP group. The mean prostate-specific antigen and median erectile functional scores did not differ significantly between the two groups at postoperative 3 months and last follow-up. T-RARP vs. S-RARP had significantly improved urinary continence (UC) rates at the removal of catheter (p < 0.001) and postoperative 3 months (p < 0.001), but the significant difference between the two groups in UC recovery disappeared at last follow-up (p = 0.119). No significant difference in biochemical recurrence-free survival was observed following the two surgeries (p = 0.727).ConclusionsT-RARP by experienced hands was feasible for selected patients with clinically localized PCa, yielding significantly improved early return to UC and similar erectile functional preservation without compromising oncological control when compared with the standard approach.

BackgroundThe long non-coding RNA LINC00467 plays a vital role in many malignancies. Nevertheless, the role of LINC00467 in prostate carcinoma (PC) is unknown. Herein, we aimed to explore the mechanism by which LINC00467 regulates PC progression.MethodsWe used bioinformatics analyses and RT-qPCR to investigate the expression of LINC00467 in PC tissues and cells. The function of LINC00467 in the progression of PC was confirmed by loss-of-function experiments. PC cell proliferation was assessed by CCK-8 and EdU assays. The cell cycle progression of PC cells was examined by flow cytometry. Moreover, Transwell assays were used to investigate the migration and invasion of PC cells. Western blot assays were used to detect the expression of factors associated with epithelial–mesenchymal transition. The interactions of LINC00467 with prostate cancer progression and M2 macrophage polarization were confirmed by RT-qPCR. The subcellular localization of LINC00467 was investigated via the fractionation of nuclear and cytoplasmic RNA. Bioinformatics data analysis was used to predict the correlation of LINC00467 expression with miR-494-3p expression. LINC00467/miR-494-3p/STAT3 interactions were identified by using a dual-luciferase reporter system. Finally, the influence of LINC00467 expression on PC progression was investigated with an in vivo nude mouse model of tumorigenesis.ResultsWe established that LINC00467 expression was upregulated in PC tissues and cells. Downregulated LINC00467 expression inhibited PC cell growth, cell cycle progression, migration, and invasion. Downregulated LINC00467 expression similarly inhibited PC cell migration via M2 macrophage polarization. Western blot analysis showed that LINC00467 could regulate the STAT3 pathway. We established that LINC00467 is mainly localized to the cytoplasm. Bioinformatics analysis and rescue experiments indicated that LINC00467 promotes PC progression via the miR-494-3p/STAT3 axis. Downregulated LINC00467 expression was also able to suppress PC tumor growth in vivo.ConclusionsOur study reveals that LINC00467 promotes prostate cancer progression via M2 macrophage polarization and the miR-494-3p/STAT3 axis.

ObjectivesTo assess the perioperative, functional, and oncological outcomes of transvesical robot-assisted radical prostatectomy (T-RARP) and posterior robot-assisted radical prostatectomy (P-RARP) for localized prostate cancer.Materials and MethodsWe analyzed the data of 96 patients who underwent T-RARP or P-RARP for localized prostate cancer between January 2017 and June 2019 in a retrospective fashion.ResultsNo significant differences in the baseline characteristics existed between the T-RARP and P-RARP arms. Both interventions were successfully performed without open conversion in either group. T-RARP was associated with a slightly more operative time (135.3 vs. 127.3 min) and estimated blood loss (105.2 vs. 94.2 mL) than P-RARP, but the differences were not significant (both p > 0.05). The likelihood of transfusion, ≤Grade II, and >Grade II postoperative complications, pT3a disease and positive surgical margins in the T-RARP group was comparable with that in the P-RARP group. No significant differences were noted between these two arms in terms of UC at the removal of catheter and nocturia (p = 0.750 and p = 0.684, respectively), and all included patients recovered UC at 3 months postoperatively. The median International Index of Erectile Function-5 score in both groups remains comparable before and after RARP. The patients in the T-RARP and P-RARP groups had a similar biochemical recurrence-free survival (p = 0.387).ConclusionsBoth T-RARP and P-RARP by experienced hands are feasible for well-selected patients with prostate cancer, obtaining similar outcomes in terms of perioperative results, UC and erectile function, and oncological control within short-term follow-up.

ObjectivesTumor enucleation (TE) optimizes parenchymal preservation with promising short-term oncologic outcomes compared with standard partial nephrectomy (SPN). However, researches/literatures about long-term oncologic outcomes for TE after minimally invasive surgery are scarce. We aim to analyze long-term oncologic outcomes after laparoscopic and robotic tumor enucleation for renal cell carcinoma (RCC).Patients and MethodsWe retrospectively analyzed 146 patients who underwent TE with either laparoscopic or robotic approach for localized RCC in our center. Local recurrence, cancer specific survival (CSS), recurrence free survival (RFS), and overall survival (OS) were the main outcomes. Survival curves were generated using a Kaplan-Meier method. Perioperative outcomes and pathological outcomes were also analyzed.ResultsOverall, 98 male and 48 female patients were eligible for the study. The median tumor size was 3.4 cm with a median R.E.N.A.L. score of seven. Warm ischemia was used in 143 patients with a median ischemia time of 20 min and three patients had zero ischemia. Five patients (3.4%) had major complications (> Clavien IIIa) and only two were related to urinary system. The median global glomerular filtration rate (GFR) preserved after surgery was 93%. Pseudocapsule invasion was reported in 50 tumors (34%) and positive surgical margins were found in 3/146 (2.1%) tumors. At a median follow-up of 66 months, local recurrence happened in two patients (1.4%), and systemic recurrence happened in six patients (4.2%). The 5-year CSS, RFS, OS were 95.7, 89.6, and 91.9%, and the 10-year CSS, RFS, OS were 93.8, 89.6, and 90.0%, respectively.ConclusionThis study indicates that tumor enucleation with laparoscopic or robotic approach in experienced hands for the treatment of RCC appears oncologically safe with a median follow-up of more than 5 years. Prospective studies with more patients and longer follow-up will be required to further evaluate oncologic safety after TE.

Purpose: The aim of this study was to review the clinicopathologic characteristics, treatments, and outcomes of patients with primary large cell neuroendocrine carcinoma of the bladder (LCNEC).Patients and Methods: We report one patient diagnosed with primary pure LCNEC of the bladder in Sun Yat-sen Memorial Hospital. In addition, we performed a systematic literature review, in April 2020, on case report and case series of LCNEC of the bladder. The clinicopathologic characteristics, treatments and outcomes of this rare disease were analyzed.Results: A total of 39 patients were included in our analysis (1 case from our institution and 38 cases from the literature). Most patients (79.5%) were male. The average age at the surgery for the patients is 61.5 years (range 19–85 years). The most common symptom was hematuria (n = 20, 76.9%). Almost all patients (38, 97.4%) underwent surgery, with 26 (66.7%) receiving multimodality therapy. Out of 24 patients with available data, regional or distant recurrences developed in 14 patients (58.3%). The median overall survival of the patients was 11.5 months, with 1- and 3-year survival rates of 54.0 and 21.4%, respectively. In the survival analysis, theT1–2 tumors (P = 0.025), no distant metastases at diagnosis (P = 0.001), and multimodality therapy (P = 0.017) were associated with better overall survival (OS).Conclusions: LCNEC of the bladder is an extremely rare neoplasm. The available data suggest that the disease has an aggressive natural history with poor prognosis. Early pathologic stage and multimodality treatment may be important factors in determining prognosis.

MicroRNAs (miRNAs) have been implicated in regulating the development and metastasis of human cancers. MiR-221 is reported to be an oncogene in multiple cancers, including bladder cancer (BC). Deregulation of autophagy is associated with multiple human malignant cancers. Whether and how miR-221 regulates autophagy and how miR-221 has been regulated in BC are poorly understood. This study explored the potential functions and mechanisms of miR-221 in the autophagy and tumorigenesis of BC. We showed that the downregulation of miR-221 induces autophagy via increasing TP53INP1 (tumor protein p53 inducible nuclear protein 1) and inhibits migration and invasion of BC cells through suppressing activation of extracellular signal-regulated kinase (ERK). Furthermore, the expression of miR-221 is regulated by high-mobility group AT-hook 1 (HMGA1) which is overexpressed in BC. And both miR-221 and HMGA1 are correlated with poor patient survival in BC. Finally, the downregulation of HMGA1 suppressed the proliferative, migrative, and invasive property of BC by inducing toxic autophagy via miR-221/TP53INP1/p-ERK axis. Collectively, our findings demonstrate that the downregulation of miR-221 and HMGA1 mediates autophagy in BC, and both of them are valuable therapeutic targets for BC.

Background: Current expectations are that surgeons should be technically proficient in minimally invasive low anterior resection (LAR)-both laparoscopic and robotic-assisted surgery. However, methods to effectively train surgeons for both approaches are under-explored. We aimed to compare two different training programs for minimally invasive LAR, focusing on the learning curve and perioperative outcomes of two trainee surgeons., Methods: We reviewed 272 consecutive patients undergoing laparoscopic or robotic LAR by surgeons A and B, who were novices in conducting minimally invasive colorectal surgery. Surgeon A was trained by first operating on 80 cases by laparoscopy and then 56 cases by robotic-assisted surgery. Surgeon B was trained by simultaneously performing 80 cases by laparoscopy and 56 by robotic-assisted surgery. The cumulative sum (CUSUM) method was used to evaluate the learning curves of operative time and surgical failure., Results: For laparoscopic surgery, the CUSUM plots showed a longer learning process for surgeon A than surgeon B (47 vs. 32 cases) for operative time, but a similar trend in surgical failure (23 vs. 19 cases). For robotic surgery, the plots of the two surgeons showed similar trends for both operative times (23 vs. 25 cases) and surgical failure (17 vs. 19 cases). Therefore, the learning curves of surgeons A and B were respectively divided into two phases at the 47th and 32nd cases for laparoscopic surgery and at the 23rd and 25th cases for robotic surgery. The clinicopathological outcomes of the two surgeons were similar in each phase of the learning curve for each surgery., Conclusions: For surgeons with rich experience in open colorectal resections, simultaneous training for laparoscopic and robotic-assisted LAR of rectal cancer is safe, effective, and associated with accelerated learning curves., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Wen, Zhang, Wang and Zhang.)

Current liquid biopsy assays lack sufficient sensitivity to detect copy number loss, which limits the interrogation of critical tumor suppressor gene deletions during cancer progression and treatment. Here we describe a liquid biopsy assay with improved sensitivity for detection of copy number loss in blood samples with low levels of circulating tumor DNA, and demonstrate its utility by profiling PTEN , RB1 , and TP53 genetic loss in metastatic prostate cancer patients., Competing Interests: XD, TZ, CD, PD, BK, SJ, and JY are stockholders of Predicine, Inc. PD, SJ, and JY are part of the leadership team of Predicine, Inc. FX, YZ, JD and YH are stockholders of Huidu Shanghai Medical Sciences, Ltd. MZ, RZ, and CL are stockholders of Laekna Therapeutics Shanghai Co., Ltd. YL and DW, and HL are stockholders of Shanghai Lide Biotech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dong, Zheng, Zhang, Dai, Wang, Wang, Zhang, Long, Wen, Xie, Zhang, Huang, Dong, Liu, Du, King, Tan, Jia, Lu, Kohli, Wang and Yu.)

Purpose: The present study aims to comprehensively investigate the prognostic value of a radiomic nomogram that integrates contrast-enhanced computed tomography (CECT) radiomic signature and clinicopathological parameters in kidney renal clear cell carcinoma (KIRC)., Methods: A total of 136 and 78 KIRC patients from the training and validation cohorts were included in the retrospective study. The intraclass correlation coefficient (ICC) was used to assess reproducibility of radiomic feature extraction. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) as well as multivariate Cox analysis were utilized to construct radiomic signature and clinical signature in the training cohort. A prognostic nomogram was established containing a radiomic signature and clinicopathological parameters by using a multivariate Cox analysis. The predictive ability of the nomogram [relative operating characteristic curve (ROC), concordance index (C-index), Hosmer-Lemeshow test, and calibration curve] was evaluated in the training cohort and validated in the validation cohort. Patients were split into high- and low-risk groups, and the Kaplan-Meier (KM) method was conducted to identify the forecasting ability of the established models. In addition, genes related with the radiomic risk score were determined by weighted correlation network analysis (WGCNA) and were used to conduct functional analysis., Results: A total of 2,944 radiomic features were acquired from the tumor volumes of interest (VOIs) of CECT images. The radiomic signature, including ten selected features, and the clinical signature, including three selected clinical variables, showed good performance in the training and validation cohorts [area under the curve (AUC), 0.897 and 0.712 for the radiomic signature; 0.827 and 0.822 for the clinical signature, respectively]. The radiomic prognostic nomogram showed favorable performance and calibration in the training cohort (AUC, 0.896, C-index, 0.846), which was verified in the validation cohort (AUC, 0.768). KM curves indicated that the progression-free interval (PFI) time was dramatically shorter in the high-risk group than in the low-risk group. The functional analysis indicated that radiomic signature was significantly associated with T cell activation., Conclusions: The nomogram combined with CECT radiomic and clinicopathological signatures exhibits excellent power in predicting the PFI of KIRC patients, which may aid in clinical management and prognostic evaluation of cancer patients., Competing Interests: Authors XL and XW were employed by GE, Shanghai. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gao, Qin, Lin, Ma, Li, Wen, Huang, Wan, Wen, Liang, Huang, Li, Wang, Chen, He and Yang.)

Background: Increasing evidence has indicated that abnormal epigenetic factors such as RNA m6A modification, histone modification, DNA methylation, RNA binding proteins and transcription factors are correlated with hepatocarcinogenesis. However, it is unknown how epigenetic modification-associated genes contribute to the occurrence and clinical outcome of hepatocellular carcinoma (HCC). Thus, we constructed the epigenetic modification-associated models that may enhance the diagnosis and prognosis of HCC., Methods: In this study, we focused on the clinical value of epigenetic modification-associated genes for HCC. Our gene expression data were collected from TCGA and HCC data sets from the GEO database to ensure the reliability of the data. Their functions were analyzed by bioinformatics methods. We used lasso regression, Support vector machine (SVM), logistic regression and Cox regression to construct the diagnostic and prognostic models. We also constructed a nomogram of the practicability of the above-mentioned prognostic model. The above results were verified in an independent liver cancer data set from the ICGC database and clinical samples. Furthermore, we carried out pan-cancer analysis to verify the specificity of the above model and screened a wide range of drug candidates., Results: Many epigenetic modification-associated genes were significantly different in HCC and normal liver tissues. The gene signatures showed a good ability to predict the occurrence and survival of HCC patients, as verified by DCA and ROC curve analysis., Conclusion: Gene signatures based on epigenetic modification-associated genes can be used to identify the occurrence and prognosis of liver cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Qiu, Jiang, Wen, Zhang and Liu.)

Thyroid cancer is the most common type of endocrine malignancy. Although the general prognosis is good, the treatment of advanced disease is still challenging. Exosomes are vesicle units containing specific components that transmit information between cells. In order to explore its role in papillary thyroid cancer (PTC), our study screened exosome enriched lncRNA SNHG9 by lncRNA chip and explored its biological function. We used lncRNA chips combined with bioinformatics analysis to screen lncRNA SNHG9 enriched in exosomes. GO analysis suggested its relationship with autophagy and apoptosis. Quantitative PCR showed SNHG9 was highly expressed in PTC cells and exosomes and its correlation with PTC tumor size was analyzed by clinical characteristics. SNHG9 could inhibit the protective cell autophagy induced by starvation of human normal thyroid epithelial cell line Nthy-ori-3 and promote its apoptosis through PTC cell exosomes. RNA-pull down combined with protein spectrum showed that SNHG9 could interact with YBOX3. Western blot and RNA immunoprecipitation further confirmed their interaction. Western blot showed that SNHG9 could induce degradation of YBOX3, thus interfering with the stability of P21 mRNA and inducing cell apoptosis. In conclusion, our study identified SNHG9 as a PTC cell exosome-enriched lncRNA. SNHG9 could inhibit cell autophagy and promote apoptosis of Nthy-ori-3 cell through YBOX3/P21 pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wen, Liu, Lu, Cao, Ji and Wei.)

Background: Because of the low rate of lymph node metastasis in stage I rectal cancer (RC), local resection (LR) can achieve high survival benefits and quality of life. However, the indications for postoperative adjuvant therapy (AT) remain controversial. Methods: A retrospective analysis was performed in 6,486 patients with RC (pT1/T2) using the Surveillance, Epidemiology, and End Results (SEER) database. Patients were initially diagnosed from 2004 to 2016; following LR, 967 received AT and 5,519 did not. Propensity score matching (PSM) was used to balance the confounding factors of the two groups; the Kaplan-Meier method and the log-rank test were used for survival analysis. Cox proportional hazards regression analysis was used to screen independent prognostic factors and build a nomogram on this basis. X-tile software was used to divide the patients into low-, moderate-, and high-risk groups based on the nomogram risk score. Results: Multivariate analysis found that age, sex, race, marital status, tumor size, T stage, and carcinoembryonic antigen (CEA) in the non-AT group were independent prognostic factors for stage I RC and were included in the nomogram prediction model. The C-index of the model was 0.726 (95% CI, 0.689-0.763). We divided the patients into three risk groups according to the nomogram prediction score and found that patients with low and moderate risks did not show an improved prognosis after AT. However, high-risk patients did benefit from AT. Conclusion: The nomogram of this study can effectively predict the prognosis of patients with stage I RC undergoing LR. Our results indicate that high-risk patients should receive AT after LR; AT is not recommended for low-risk patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Chen, Wen, Zhang and Wang.)

Background: In China, esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) differ in terms of multiple primary cancer (MPC) and male-to-female sex ratio (MFSR)., Methods: We studied site-specific variation in familial cancer by comparing family history (FH), MPC, age at onset (AO), and MFSR among 8768 patients with ESCC/GCA., Results: ESCC/GCA patients with a positive FH are associated with a significantly higher rate of MPC and a younger AO than those without (sex-specifically: MPC 1.6% vs. 0.7%, P <0.01 and 3.2% vs. 0.8%, P <0.01; AO 53.1 ± 8.1 vs. 54.5 ± 8.2, P =0.000 and 52.9 ± 7.4 vs. 54.0 ± 8.0, P =0.005). Among patients with a positive FH, MPC decreases significantly from upper-, middle-, and lower-third ESCC to GCA (sex-specifically: 53.6%, 1.8%, 1.6%, 0.8%, P =0.000; and 71.4%, 1.5%, 2.2%, 1.6%, P =0.000). From MPC, upper-, middle-, and lower-third ESCC to GCA, AO increased sex-specifically: 51.9 ± 7.2, 52.8 ± 7.9, 52.1 ± 8.3, 54.3 ± 8.4, 55.6 ± 7.6 ( P =0.000) and 49.3 ± 6.5, 51.8 ± 9.8, 52.6 ± 7.8, 54.4 ± 8.0, 55.7 ± 7.2 ( P =0.000), and FH decreased: 43.8%, 35.1%, 28.2%, 29.5%, 24.4% ( P =0.000) and 55.2%, 26.7%, 25.0%, 24.3%, 22.3% ( P =0.000). The preponderance of males, smoking, alcohol consumption, and patients ≥50 years old increased from 2.2:1, 1.7:1, 1.0:1, 2.0:1 in ESCC to 6.1:1, 2.8:1, 2.5:1, 4.0:1 in GCA, yet more MPCs were associated with non-preponderant than preponderant counterparts; particularly in GCA, the difference was statistically significant., Conclusion: The proportion of familial cancer may decrease from upper-, middle-, and lower-third ESCC to GCA. This entails molecular investigation, and appreciating this may help us devise a better screening strategy or individualize cancer treatment., (Copyright © 2020 Wen, Wen, Zou, Yang, Wen, Chen, Akazawa, Geng and Shan.)

Lung squamous cell carcinomas (SCCs) are highly aggressive tumors, and there is currently no effective targeted therapy owing to the lack of specific mutation targets. Compared with lung adenocarcinoma (ADCs), lung SCCs reportedly utilized higher levels of glucose metabolism to meet the anabolic and catabolic needs required to sustain rapid tumor growth. Hexokinase 2 (HK2) is an enzyme that catalyzes the rate-limit and first committed step in glucose metabolism. Here, we investigated the expression and effect of HK2 in lung SCCs. We found a significantly higher HK2 expression in lung SCCs, but not lung ADC or normal tissues. HK2 depletion or inhibition decreased the glycolysis and tumor growth via activating AMPK signaling pathway, which downregulated mTORC1 activity. Furthermore, we found an increased oxygen respiration rate compensating for HK2 depletion. Thus, metformin treatment showed combinatorial therapeutic value, which resulted in greater induction of lung SCC apoptosis in vitro and in vivo . Our study suggests that HK2 depletion in combination with metformin might be a novel effective strategy for lung SCCs therapy., (Copyright © 2020 Guo, Kuang, Wu, Wen, Zhou, Liao, Song, Xu, Wang, Jing, Li, Hu, Ling, Wang and Wu.)