Background: For non-small-cell lung cancer (NSCLC) patients who progressed after first-line chemotherapy, immunotherapy targeting programmed cell death (ligand) 1 has shown promising activity. However, the activity is relatively limited in patients harboring epidermal growth factor receptor (EGFR) mutations. Objectives: This study aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in previously treated patients with locally advanced and metastatic NSCLC. Design: A single-center, single-arm, phase II study. Methods: Previously treated patients with locally advanced and metastatic NSCLC were enrolled to receive camrelizumab (200 mg, administered intravenously every 3 weeks) and famitinib (20 mg, administered orally once daily). Patients harboring EGFR mutation genes had received at least one EGFR tyrosine kinase inhibitor and no more than two lines of chemotherapy regimen before the enrollment. The other patients had progressed on first-line chemotherapy with or without immunotherapy before the enrollment. The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by the investigator. Results: Our study encompassed 23 NSCLC patients between October 2019 and October 2022. For all patients, the confirmed ORR was 30.4%, and the disease control rate was 95.7%. The median progression-free survival (PFS) was 6.9 months (95% CI: 4.9 months–not reached). The median overall survival (OS) was not reached. 1- and 2-year OS rates were 85.6% (95% CI: 71.8%–100.0%) and 56.8% (95% CI: 37.7%–85.7%). Especially, for the 6 patients with EGFR genetic aberrations, the confirmed ORR was 33.3%, the median PFS was 10.3 months (95% CI: 1.8–18.8 months), and the median OS was 20.3 months (95% CI: 0.8–39.8 months). The most common grade 3 and above treatment-related adverse events were platelet count decreased, white blood cell count decreased, and hypertension. No unexpected adverse events were reported. Conclusion: Camrelizumab plus famitinib demonstrated encouraging clinical activity with a manageable safety profile in previously treated patients with locally advanced and metastatic NSCLC. The results warranted further validation. Trial registration: Chinese Clinical Trial Registry identifier: ChiCTR1900026641.

Objective Oncogenic alternation in RET is one of the important targets of non-small cell lung cancer (NSCLC). Pralsetinib has shown great efficacy in RET fusion-positive NSCLC, but a series of adverse reactions will inevitably occur in the meantime. We aimed to explore the clinical characteristics of patients with pneumonia and recognition it in early stage, so patients could longer benefit from pralsetinib. Methods This is a multicenter, retrospective study. RET fusion-positive advanced NSCLC patients who developed pneumonia during pralsetinib treatment from January 2020 to December 2022 were included. Clinical data, time to onset of pneumonia, methods of pneumonia diagnosis, treatment with pneumonia, prognosis of pneumonia, and the effect of pneumonia on the efficacy of pralsetinib. Results A total of 8 patients with pneumonia were included in the study, most of which were non-smoking female patients and the main fusion gene was KIF5B (87.5%), which was consistent with the general characteristics of RET fusion population. The median occurrence time of pralsetinib-associated pneumonia was 2.15 (range 1.1–6.63) months. All patients were infected by opportunistic pathogens, and the most common pathogen was human herpesviruses and pneumospora yerbii. Fever was always the first symptom, and timely anti-infective treatment including antibiotics, antiviral drugs, and antifungal drugs was effective. Until February 28, 2023, the median follow-up time was 18.7 months, the mean PFS of patients was 17.4 months, and the median PFS was not reached. Fortunately, patients who restarted pralsetinib after infection control continued to benefit. Conclusions Opportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment.

The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the model of antitumor therapy. With the continuous deepening of the research on the mechanism of immunotherapy, ICIs, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 inhibitors and cytotoxic T lymphocyte-associated protein 4 inhibitors, have been widely used in a variety of tumors. Nevertheless, the use of ICI can also lead to a series of immune-related adverse events. Common immune-related adverse events include gastrointestinal toxicity, pulmonary toxicity, endocrine system toxicity, and skin toxicity. Neurologic adverse events are relatively rare, but they seriously affect the quality of life and shorten the survival time of patients. This article reports cases of peripheral neuropathy mediated by PD-1 inhibitors and retrieves the relevant literatures at home and abroad to summarize the neurotoxicity caused by PD-1 inhibitors, so as to strengthen the awareness of clinicians and patients on neurologic adverse reactions and mitigate potential adverse effects of implemented therapies.

To investigate the association between tumor protein 53 polymorphism and esophageal cancer cases using systematic review and meta-analysis, this provides a basis for future researches. All studies on tumor protein 53 mutations in patients with esophageal cancer and its influencing factors, which published before May 2021, were collected by searching Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure and Wanfang data. Meta-analysis was performed using RevMan 5.3. Ten eligible studies (Chinese n=7, English n=3) involving 1379 cases were included in this analysis. Meta-analysis showed that the odds ratio value (95 % confidence interval) of tumor protein 53 mutations in Caucasian patients with esophageal cancer was 70.51 (9.77, 508.88), z=4.22, p<0.0001; the odds ratio value (95 % confidence interval) of tumor protein 53 mutations in Chinese Han patients with esophageal cancer was 1.06 (0.63, 1.79), z=0.22, p=0.83; the odds ratio value (95 % confidence interval) of tumor protein 53 mutations in Chinese Uyghur patients with esophageal cancer was 18.48 (4.44, 76.90), z=4.01, p<0.0001. The odds ratio value (95 % confidence interval) of tumor protein 53 mutations in patients with esophageal cancer was 1.01 (0.60, 1.72), z=0.05, p=0.96; the odds ratio value (95 % confidence interval) of tumor protein 53 deletions in patients with esophageal cancer was 23.02 (9.04, 58.63), z=6.57, p=0.00001. There was no significant difference in tumor protein 53 mutations between patients with esophageal cancer and the control group. There is a certain correlation between tumor protein 53 polymorphism and the incidence of esophageal cancer and the change of tumor protein 53 gene will affect the risk and prognosis of esophageal cancer.

Objective Aberrant activation of Wnt/β-catenin signaling contributes to the maintenance of cancer stem cells and chemoresistance in colorectal cancer (CRC). Retinoic acid-induced 2 (RAI2) was proved to be a tumor suppressor in CRC in our previous report. In this study, the role of RAI2 in Wnt/β-catenin signaling was further investigated. Methods As a transcriptional co-regulator, C-terminal Binding Protein 2 (CtBP2) was reported to be involved in Wnt signaling in multiple and complex ways. The correlation of RAI2 and CtBP2 in CRC was analyzed by TCGA dataset, and the interaction between RAI2 and CtBP2 was explored by co-immunoprecipitation (Co-IP) in CRC cells. The effect of RAI2 on the activity of Wnt signaling and the location of β-catenin was detected by Dual-Luciferase reporter assay and Immunofluorescence respectively. Western blotting analysis was performed to detect the expression of target genes involved in Wnt signaling. Sphere formation assay was employed to detect the effect of RAI2 on stem cell like properties. Cell viability assay was used to detect the chemosensitivity of cells before and after transfection of RAI2. Results The interaction between RAI2 and CtBP2 was confirmed by Co-IP in CRC cells. Besides, the negative correlation of RAI2 and CtBP2 in CRC was found by analyzing the TCGA dataset. Re-expression of RAI2 in human colon cancer cells (HCT116 and LoVo) suppressed the fluorescent activity of Wnt signaling, increased the phosphorylation and inhibited nuclear translocation of β-catenin, with down-regulation of target genes like c-Myc, CyclinD1, ASCL2, and LGR5. In contrast, the mutated RAI2, which can’t interact with CtBP2, has no above effects. We observed low expression of RAI2 in 33.89% (101/298) of CRC patients, which was significantly associated with reduced phosphorylation of β-catenin (r=0.8866, P<0.0001), poor 5-year relapse-free survival (RFS) (P = 0.0029) and overall survival (OS) (P = 0.0102). Restoration of RAI2 in HCT116 and LoVo cells inhibited stem cell-like properties of CRC cells and increased chemosensitivity of these cells to oxaliplatin and fluorouracil. Conclusion Low expression of RAI2 can serve as an independent poor prognostic marker. RAI2 inhibits Wnt signaling by interacting with or down-regulating CtBP2, resulting in repression of stem cell-like properties and increased chemosensitivity of CRC cells.

article: microRNA-425 promoted the proliferation and migration of colorectal cancer cells by targeting KLF3 through the PI3K/AKT pathway - Minerva Medica 2021 August;112(4):537-8 - Minerva Medica - Journals

Background The incidence and mortality of pancreatic cancer (PC) has gradually increased. The aim of this study was to identify survival-related DNA methylation (DNAm)-driven genes and establish a nomogram to predict outcomes in patients with PC. Methods The gene expression, DNA methylation database, and PC clinical samples were downloaded from TCGA. DNAm-driven genes were identified by integrating analyses of gene expression and DNA methylation data. Survival-related DNAm-driven genes were screened via univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to develop a risk score model for prognosis. Based on analyses of clinical parameters and risk score, a nomogram was built and validated. The independent cohort from GEO database were used for external validation. Results A total of 16 differentially expressed methylation-driven genes were identified. Based on LASSO Cox regression and multivariate Cox regression analysis, six genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) were chosen to develop the risk score model. In the Kaplan-Meier analysis, age, T stage, N stage, AJCC stage, radiation therapy history, tumor size, surgery type performed, pathological type, chemotherapy history, and risk score were potential prognostic factors in PC (P < 0.1). In the multivariate analysis, stage, chemotherapy, and risk score were significantly correlated to overall survival (P < 0.05). The nomogram was constructed with the three variables (stage, chemotherapy, and risk score) for predicting the 1-year, 2-year, and 3-year survival rates of PC patients. Nomogram performance was assessed by receiver operating characteristic (ROC) curves and calibration curves. 1-year, 2-year and 3-year AUC of nomogram model was 0.899, 0.765 and 0.776, respectively. Conclusions In our study, we successfully identified the six DNAm-driven genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) with a relationship to the outcomes of PC patients. The nomogram including stage, chemotherapy, and risk score could be used to predict survival in PC patients.

Backgrounds Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we surveyed the genomic features in Chinese UC patients and investigated the concordance of genetic alterations between circulating tumor DNA (ctDNA) in plasma and matched tumor tissue. Materials and methods A total of 112 UC patients were enrolled, of which 31 were upper tract UC (UTUC) and 81 were UC of bladder (UCB). Genomic alterations in 92 selected genes were analyzed by targeted next-generation sequencing. Results In the study cohort, 94.64, 86.61 and 62.50% of patients were identified as having valid somatic, oncogenic and actionable somatic alterations, respectively. The most frequently altered genes included TP53 , KMT2D , KDM6A , FAT4 , FAT1 , CREBBP and ARID1A . The higher prevalence of HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) was identified in UTUC than in UCB. Comparisons of somatic alterations of UCB and UTUC between the study cohort and western cohorts revealed significant differences in mutant prevalence. Notably, 28.57, 17.86 and 47.32% of the cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of the patients carried non-benign germline variants, but only two (1.79%) were pathogenic. The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0–100%). Notably, 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 54.14% of which were oncogenic mutations. Conclusions We found a unique genomic feature of Chinese UC patients. A reasonably good concordance of genomic features between ctDNA and tissue samples were identified.

BACKGROUND Metastasis of pancreatic cancer to the colon is rare and the features need to be further elucidated. Herein, we report a rare case of pancreatic cancer with simultaneous liver and colon metastases. CASE SUMMARY A 48-year-old man with intrahepatic space-occupying lesions based on a computed tomography scan was admitted to our hospital for further treatment. Abdominal magnetic resonance imaging revealed a 6.4 cm × 4.2 cm mass in the tail of the pancreas and multiple low-density masses in the liver parenchyma. In addition, a mass of 2.2 cm × 1.6 cm with surface congestive erosions in the sigmoid colon was detected by colonoscopy. Histopathological examination of biopsies from both the liver and colon lesions revealed a moderately to poorly differentiated adenocarcinoma. Immunohistochemical staining of the colon tumor was positive for cytokeratin (CK) 7 and CK, but negative for colorectal adenocarcinoma-related markers CK 20, CDX2, and SATB2, thus indicating that the metastasis originated from the pancreas. Next-generation sequencing for genomic profiling of the liver and colon metastases both found mutations in KRAS (p.G12D) and TP53 (c.376-1delG), with microsatellite stable and low tumor mutational burden without actionable or cancer-predisposing gene mutations detected. The patient was subsequently treated with 12 cycles of FOLFIRINOX which led to a sustainable response, followed by ongoing maintenance treatment with irinotecan plus fluorouracil. CONCLUSION For this rare case, careful evaluation of histopathological and immunohistochemical staining results are required. The genomic profiling of colon lesions was revealed for the first time, and FOLFIRINOX showed good treatment efficacy in this patient.

Background Nomograms are rarely employed to estimate the survival of patients with advanced and metastatic pancreatic cancer (PC). Herein, we developed a comprehensive approach to using a nomogram to predict survival probability in patients with advanced and metastatic PC. Methods: A total of 323 patients with advanced and metastatic PC were identified from the Chinese People's Liberation Army (PLA) General Hospital. A baseline nomogram was constructed using baseline variables of 323 patients. Additionally, 233 patients, whose tumors showed initial responses to first-line chemotherapy, were enrolled in the chemotherapy response-based model. 128 patients and 108 patients with advanced and metastatic PC from January 2019 to April 2021 were selected for external validating baseline model and chemotherapy response-based model. The 1-year and 2-year survival probability was evaluated using multivariate COX regression models. The discrimination and calibration capacity of the nomograms were assessed using C-statistic and calibration plots. The predictive accuracy and net benefit of the nomograms were evaluated using ROC curve and DCA, respectively. Results In the baseline model, six variables (gender, KPS, baseline TB, baseline N, baseline WBC and baseline CA19-9) were used in the final model. In the chemotherapy response-based model, nine variables (KPS, gender, ascites, baseline N, baseline CA 19-9, baseline CEA, change in CA 19-9 level at week, change in CEA level at week and initial response to chemotherapy) were included in the final model. The C-statistics of the baseline nomogram and the chemotherapy response-based nomogram were 0.67 (95% CI, 0.62-0.71) and 0.74 (95% CI, 0.69-0.77), respectively. Conclusion These nomograms were constructed to predict the survival probability of patients of advanced and metastatic PC. The baseline model and chemotherapy response-based model performed well in survival prediction.

Background Nanoparticle albumin-bound paclitaxel (nab-PTX) and docetaxel (DOC) both demonstrated favorable efficacy as neoadjuvant therapy in breast cancer. We retrospectively evaluated the efficacy and safety of nab-PTX-based chemotherapy (nPBC) and DOC-based chemotherapy (DBC) as neoadjuvant therapy in patients with breast cancer. Methods Breast cancer patients who received neoadjuvant nPBC or DBC and underwent surgery from January 2018 to June 2020 were consecutively analyzed. Pathologic complete response (pCR) was defined as no residual invasive cells in the breast and axillary nodes (ypT0/is ypN0) after surgery. The pCR, clinical complete response (cCR), and safety profiles were assessed in the two groups. Results A total of 104 breast cancer patients were included in this study. Fourty one patients received nPBC, and 63 patients received DBC The pCR was 34.1% in the nPBC group and 12.7% in the DBC group. Additionally, the cCR was 36.6% in the nPBC group and 15.9% in the DBC group. Peripheral sensory neuropathy was more common in the nPBC group, while hematologic toxicity was observed more frequently in the DBC group. Conclusions This study presented antitumor activity of nPBC and DBC in patients with early breast cancer receiving neoadjuvant treatment in a real-world setting. Further prospective research is warranted to confirm the results and to develop biomarkers for better patient selection.

Background Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we studied the genomic features in Chinese UC patients, and investigated the concordance of genetic alterations between serum circulating tumor free DNA (ctDNA) and matched tumor tissue. Methods A total of 112 UC patients were enrolled, and 31 of which were upper tract UC (UTUC) and 81 were UC of bladder (UCB), respectively. Utilizing target next-generation sequencing, we analyzed genomic alterations of 92 selected genes. Results 94.64%, 86.61% and 62.50% of patients in our cohort were identified as having valid, oncogenic or actionable somatic alterations, respectively, and the most altered genes were TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) were more altered in UTUC than in UCB in our cohort. Comparisons of somatic alterations of UCB and UTUC between our cohort and western cohorts revealed significant differences in gene prevalence. Notably, 28.57%, 17.86% and 47.32% of cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of patients carried non-benign germline variants, but only two (1.79%) were pathogenic. By comparison of ctDNA and matched tumor tissue, the overall concordance for genomic alterations was 42.97% (0-100%). 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 25.58% of which were oncogenic. Conclusions We found a unique genomic feature of Chinese UC patients. A good concordance of genomic features between ctDNA and tissue samples were identified.

Leucine-rich-alpha-2-glycoprotein1 (LRG1) is a number of leucine-rich repeat (LRR) family proteins.Abnormal high expression of LRG1 in tumor tissues, urinary exosomes, serum and cerebrospinal fluid is associated with progress of various malignancies, ulterative colitis, etc.Recently several studies demonstrated the important role of LRG1 in angiogenesis of malignancies.However, after blocking LRG1, the angiogenesis can also be inhibited.Therefore, LRG1 is a highly promising therapeutic target for controlling angiogenesis.This review introduced the latest research progress of LRG1.

Background: Leucine-rich alpha-2-glycoprotein-1 (encoded by LRG1) has been shown to be involved in multiple cancer progression and angiogenesis. LRG1 has been shown to be one of the five plasma proteins that can be used for colorectal cancer (CRC) diagnosis. The objective of the current study was to explore relationship between LRG1 protein expression and microvessel density (MVD) in stage III CRC. Methods: A single-center retrospective analysis of all stage III CRC who underwent surgery and adjuvant chemotherapy was carried out. LRG1 and CD34 were tested in tumor tissues by immunohistochemistry (IHC). Results: LRG1 protein expression was significantly associated with MVD (P < 0.001) and other clinicopathological parameters, including T stage (P=0.028), differentiation (P=0.035) and vascular invasion (P=0.007). Cox multivariate regression analysis showed that LRG1 protein expression was an independent poor predictive factor for both disease-free and overall survival. Conclusion: LRG1 protein expression can be used as a prognostic marker for stage III CRC along with its use as a diagnostic marker for CRC in general.

This study aims to investigate the efficacy of bevacizumab-combined chemotherapy (BCC) in Chinese stage IV colorectal cancer (CRC), and analyze the relationship between clinicopathological features with survival. Patients with stage IV CRC treated with BCC were analyzed retrospectively. 217 metastatic CRC (mCRC) patients were collected, out of which79 were right-sided CRCs and 138 were left-sided ones. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤2, single agent chemotherapy, poor/mucous/signet ring cell component, second-and further-line of bevacizumab administration, multiple metastasis sites had comparatively worse survival. Among 141 patients with known KRAS status, 55 patients harbored KRAS mutation and 86 had wild type KRAS. The ORR and DCR were 41.9% and 78.9%, respectively, in patients with wild type KRAS, while ORR and DCR was 38.7% and 77.9%, respectively, in patients with KRAS mutation. The median PFS of patients with wild type and mutant KRAS were 8.38, and9.59 months, respectively; whereas the OS was 23.00 and 21.26 months, respectively for mCRC patients with wild-type and mutant KRAS. Cumulatively, our study indicated that BCC was effective and beneficial for Chinese stage IV CRC patients. KRAS mutation status and tumor location were not a prognostic factor for survival.

In vitro tests for assessing the toxigenicity of strains of C. diphtheriae using the original agar plate precipitin method of Elek are unreliable. At high concentrations of antitoxin (500–1000 U/ml) multiple non-specific precipitin lines occur making interpretation difficult. Increased specificity was obtained by diluting the antitoxin but this in turn caused a delay in the appearance of toxin-antitoxin lines. Also. the failure of lines to appear on media enriched with unsuitable serum may lead to false-negative results. Final assessment of the toxigenicity of strains of C. diphtheriae can probably only be made reliably by guinea-pig tests.

OBJECTIVE:To summarize the prognostic factors of stage 3 colorectal cancer.METHODS:The clinical data of 433 patients with stage 3 colorectal cancer who were admitted to our hospital from January 2005 to December 2008 for radical surgery and adjuvant chemotherapy were retrospectively analyzed. Relationship of their clinicopathologic features and treatment with the prognosis were analyzed.RESULTS:Of these 433 stage 3 patients,the mean disease-free survival was (72.37 ± 2.11) months and mean overall survival was (79.91 ± 2.02) months; however, the median survival times were not reached. The 1-,3-, and 5-year disease-free survival rate were 86.8%,77.9%, and 57.0% and the overall survival rate were 91.5%,75.1%, and 63.3%. Multivariate COX regression analysis displayed that intestine obstruction before surgery, complications after surgery,tumor location,positive surgical margin, neural cell infiltration,vessel cancer embolus, TNM stage, lymph node ratio, adjuvant chemotherapy regimens, and chemotherapy duration were the independent factors affecting disease-free and overall survivals in patients with stage 3 colorectal cancer. The efficacies of FOLFOX and XELOX regimens were significantly correlated with patient's age, complications,tumor location,and chemotherapy duration.CONCLUSIONS:Complications,tumor location, TNM stage, and positive surgical margin are the independent prognostic factors of stage 3 colorectal cancer. FOLFOX and XELOX regimen can remarkably improve prognosis,and a longer duration of chemotherapy can achieve better survival.

抗血管生成的贝伐珠单抗已被广泛应用于多种恶性肿瘤的治疗.但因其受益人群有限及逐渐出现的获得性耐药,也限制了其对患者总生存的改善.迫切需要寻找有效的预测贝伐珠单抗疗效的预测因子指导临床应用.人们在生物标记物、影像学方面进行了大量探索,但目前尚没有一个公认的普遍适用的临床预测指标,仍需要从多角度出发,进行进一步的基础研究及临床研究去发现和验证有效的疗效预测指标.

Kartagener's综合征(kartagener's syndrome,KS)由支气管扩张、慢性鼻窦炎或鼻息肉、内脏反位三联征组成.主要表现为反复发生呼吸道化脓性感染、咯血为特征的支气管扩张症状及副鼻窦炎和右位心[1].笔者结合1例近期诊治患者并文献复习,现报告如下.