A patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments.

Cancer models play critical roles in basic cancer research and precision medicine. However, current in vitro cancer models are limited by their inability to mimic the three-dimensional architecture and heterogeneous tumor microenvironments (TME) of in vivo tumors. Here, we develop an innovative patient-specific lung cancer assembloid (LCA) model by using droplet microfluidic technology based on a microinjection strategy. This method enables precise manipulation of clinical microsamples and rapid generation of LCAs with good intra-batch consistency in size and cell composition by evenly encapsulating patient tumor-derived TME cells and lung cancer organoids inside microgels. LCAs recapitulate the inter- and intratumoral heterogeneity, TME cellular diversity, and genomic and transcriptomic landscape of their parental tumors. LCA model could reconstruct the functional heterogeneity of cancer-associated fibroblasts and reflect the influence of TME on drug responses compared to cancer organoids. Notably, LCAs accurately replicate the clinical outcomes of patients, suggesting the potential of the LCA model to predict personalized treatments. Collectively, our studies provide a valuable method for precisely fabricating cancer assembloids and a promising LCA model for cancer research and personalized medicine.

Constructing nursing quality indicators for intraoperative acquired pressure injury in cancer patients based on guidelines.

Cancer patients have a high incidence of intraoperative acquired pressure injury (IAPI). Constructing IAPI quality indicators can reduce the incidence of pressure injury, but there are a lack of these indicators targeting cancer patients. Based on this, this study develops a system of quality indicators for IAPI. Thirty-four potential indicators were included based on the literature review. The 26 experts were asked to rate the importance and feasibility of each indicator using three rounds of email survey. The authoritative coefficient ranged from 0.92 to 0.94. After three rounds of Delphi expert consultation, nine nursing quality indicators were identified for IAPI in cancer patients. The mean importance or feasibility ratings ranged from 4.77 to 5.81 on a six-point scale, with variation coefficients ranging from 0.07 to 0.26. The percentage of full score for potential indicators ranged from 23.10% to 80.80%. Over three rounds, the Kendall's W coefficients ranged from 0.157 to 0.354 (P < .01). The absolute and relative importance and feasibility of the nine indicators were identified as potentially valid measures of nursing quality indicators for IAPI in cancer patients. This instrument is the first set of IAPI quality indicators developed specifically for cancer patients, and it should be useful for evaluating and improving the quality of IAPI in this population.

Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial.

OBJECTIVES: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been approved for EGFR-mutant non-small-cell lung cancer (NSCLC). We aimed to evaluate the efficacy and safety of neoadjuvant osimertinib in patients with EGFR-mutant resectable locally advanced NSCLC. MATERIALS AND METHODS: This single-arm, phase 2b trial (ChiCTR1800016948) was conducted at six centers in mainland China. Patients with a measurable stage IIA-IIIB (T3-4 N2) lung adenocarcinoma and EGFR exon 19 and/or 21 mutations were enrolled. The patients were treated with osimertinib 80 mg orally once per day for six weeks, followed by surgical resection. The primary endpoint was the objective response rate (ORR) assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. RESULTS: Between October 17, 2018, and June 08, 2021, 88 patients were screened for eligibility. Forty patients were enrolled and treated with neoadjuvant osimertinib therapy. The ORR was 71.1 % (27/38) (95 % confidence interval: 55.2-83.0) in 38 patients who completed the 6-week osimertinib treatment. Thirty-two patients underwent surgery, and 30 (93.8 %) underwent successful R0 resection. Thirty (75.0 %) of 40 patients had treatment-related adverse events during neoadjuvant treatment, and three (7.5 %) had treatment-related adverse events of grade 3. The most common treatment-related adverse events were rash (n = 20 [50 %]), diarrhea (n = 12 [30 %]), and oral ulceration (n = 12 [30 %]). CONCLUSIONS: The third-generation EGFR TKI osimertinib, with satisfying efficacy and acceptable safety profile, could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC.

Intermittent chest tube clamping decreases chest tube duration time and drainage volume after lung cancer surgery in patients without air leak: an open-label, randomized controlled trial.

Background: Our previous retrospective study proved the safety and effectiveness of chest tube clamping in terms of shortening chest tube duration. However, it needed to be verified by a prospective study. This study sought to determine if intermittent chest tube clamping decreases chest tube duration and total drainage volume after lung cancer surgery in patients without air leak. Methods: Patients with resectable lung cancer scheduled to undergo lobectomy were identified as potential candidates. Once the re-expansion of the lung was confirmed via radiography the morning of postoperative day 1 and no air leak was detected, 180 patients were randomly assigned to intermittent chest tube clamping (the clamping group, n=90) or continuous gravity drainage (the control group, n=90). The primary outcome was chest tube drainage duration. Pleural drainage volume and adverse events were also recorded. Results: Of 180 patients, 12 were subsequently withdrawn from the study for various reasons. In the intention-to-treat analysis, the chest tube drainage duration was significantly shorter {median [interquartile range]: 2 [2, 3] vs. 3 [2, 3] days; P=0.009}, and total drainage volume was much less (mean ± standard deviation: 516.73±410.9 vs. 657.8±448.2 mL; P=0.029) in the clamping group than the control group. In the per-protocol analysis, the chest tube drainage duration was significantly shorter {median [interquartile range]: 2 [2, 3] vs. 3 [2, 3] days; P=0.007}, and total drainage volume was much less (mean ± standard deviation: 437.8±213.9 vs. 604.8±352.8 mL; P=0.001) in the clamping group than the control group. Further, the clamping group showed a major improvement in plasma albumin declination at discharge (mean ± standard deviation: 7.7±2.9 vs. 9.0±5.2 g/L; P=0.040). No severe adverse events were observed in either 2 groups. Conclusions: Our study indicates that chest tube clamping decreased the duration of chest tube drainage and drainage volume without causing adverse effects. Its wider application may help reduce medical costs and increase patient comfort. Trial Registration: ClinicalTrials.gov NCT03379350.

[Occlusion with Bronchial Covered Stent in the Management of Bronchial Stump Fistula after Right Middle and Lower Lobectomy: A Case Report and Literature Review].

BACKGROUND: Bronchopleural fistula (BPF) is one of the most serious and rare postoperative complications, especially the bronchial stump fistula after lobectomy/pneumonectomy. Common treatment options include conservative medical treatment combined with surgery. However, due to the delayed healing of the fistula, the chest cavity continues to communicate with the outside world, and the patient is prone to complicated with severe thoracic infection and respiratory failure, so that the physical condition can hardly tolerate the second surgical procedure. Endoscopic treatment provides a new option for the treatment of this complication. METHODS: A case of right pulmonary squamous cell carcinoma was admitted to the Department of Thoracic Surgery II, Peking University Cancer Hospital in June 2016. The diagnosis and treatment was retrospectively analyzed, and the literature was reviewed. RESULTS: A 65 year old male patient was admitted to hospital because of "cough with blood in sputum for 3 months". Chest computed tomography (CT) showed soft tissue density mass shadow in the right lower lobe. A tumor could be seen in the opening of the right middle lobe and basal segment of lower lobe. Biopsy confirmed squamous cell carcinoma. Diagnosis consideration: squamous cell carcinoma of the middle and lower lobe of the right lung (cT2aN2, IIIa). Patients received gemcitabine plus cisplatin neoadjuvant chemotherapy for 2 cycles, and the effect of chemotherapy showed stable disease (SD). Four weeks after chemotherapy, the patient underwent video-assisted thoracic surgery (VATS) assisted right middle and lower lobectomy and mediastinal lymph node dissection. On the 5th day after operation, the patient developed acute respiratory distress syndrome (ARDS) and was transferred to intensive care unit (ICU) again after endotracheal intubation. On the 7th day after operation, the patient developed a right intermediate trunk bronchial stump fistula, but due to ARDS, the patient's physical condition could not tolerate the second operation. Under the support of extracorporeal membrane oxygenation (ECMO), a membrane covered, expandable, hinged stent was inserted into the intermediate trunk bronchial stump through rigid bronchoscope, and was successfully blocked. Due to no improvement in ARDS and irreversible pulmonary interstitial fibrosis, the patient received double lung transplantation successfully after systemic anti-infection treatment. CONCLUSIONS: Endoscopic implantation of covered stent is a simple, safe and effective method for closure of bronchial stump fistula. When the patient's clinical situation is not suitable for immediate surgery, endoscopic stent implantation can be used as a preferred treatment method to create opportunities for follow-up treatment.

[Correlation between Lymph Node Ratio and Clinicopathological Features and Prognosis of IIIa-N2 Non-small Cell Lung Cancer].

BACKGROUND: IIIa-N2 non-small cell lung cancer was significant different in survival, although N stage of lung cancer based on anatomic location of metastasis lymph node. Lymph node ratio considered of prognostic factor might be the evaluation index for IIIa-N2 non-small cell lung cancer prognosis. Therefore, the aim of the study was to evaluate the correlation between lymph node ratio and clinicopathological features and prognosis of IIIa-N2 non-small cell lung cancer prognosis. METHODS: A total of 288 cases of pathological IIIa-N2 non-small cell lung cancer were enrolled who received radical resection at the Department of Thoracic Surgery II, Peking University Cancer Hospital from January 2006 to December 2016. The univariate analysis between clinicopathological variables and lymph node ratio used Pearson's chi-squared test. Cox regression was conducted to identify the independent prognosis factors for IIIa-N2 non-small cell lung cancer. RESULTS: There were 139 cases in the lower lymph node ratio group, another 149 cases in the higher lymph node ratio group. Adenocarcinoma (χ²=5.924, P=0.015), highest mediastinal lymph node metastasis (χ²=46.136, P<0.001), multiple-number N2 metastasis (χ²=59.347, P<0.001), multiple-station N2 metastasis (χ²=77.387, P<0.001) and skip N2 lymph node metastasis (χ²=61.524, P<0.001) significantly impacted lymph node ratio. The total number of lymph node dissection was not correlated with the lymph node ratio (χ²=0.537, P=0.464). Cox regression analysis confirmed that adenocarcinoma (P=0.008), multiple-number N2 metastasis (P=0.025) and lymph node ratio (P=0.001) were the independent prognosis factors of disease free survival. The 5-year disease free survival was 18.1% in the higher lymph node ratio group, and 44.1% in the lower. Lymph node ratio was the independent prognosis factor of overall survival (P<0.001). The 5-year overall survival was 36.7% in the higher lymph node ratio group, and 64.1% in the lower. CONCLUSIONS: Lymph node ratio was correlative with the pathology, highest mediastinal lymph node metastasis, multiple-number N2 metastasis, multiple-station N2 metastasis and skip N2 lymph node metastasis. Lymph node ratio was the independent prognosis factor for IIIa-N2 non-small cell lung cancer.

Distinct Molecular Mechanisms Analysis of Three Lung Cancer Subtypes Based on Gene Expression Profiles.

The purpose was to explore distinct molecular mechanisms of three lung cancer subtypes. GSE6044 microarray data downloaded from Gene Expression Omnibus (GEO) database were applied for identifying the differentially expressed genes (DEGs). Genetic global network was constructed to analyze the network annotation. The DEGs in the genetic global network related to small-cell lung carcinoma (SCLC), lung squamous cell carcinoma (SCC), and lung adenocarcinoma (AC) were screened. Protein-protein international networks of DEGs were constructed. Pathway enrichment analyses of DEGs in three subtypes were performed, followed by construction of interactional network among pathways. There were more DEGs screened in SCLC than in AC and SCC. The genetic global network with 341 genes and 1569 interaction edges was constructed. After annotating these DEGs into a protein interactional network, a total of 695 protein interactions related to these 36 DEGs were obtained. HSP90AA1 was the hub node with the highest degree of 81 in the annotation network. DEGs in SCLC and SCC were mainly enriched in some pathways, including cell cycle, DNA replication, and histidine metabolism; whereas DEGs in AC were enriched in complement and coagulation cascades, and extracellular matrix (ECM)-receptor interaction. Pathway interactional network was constructed with the hub node of a neuroactive ligand receptor interaction. The identified DEGs such as retinoid X receptor alpha (RXRA), cyclin-dependent kinase 2 (CDK2), histone deacetylase 2 (HDAC2), and KIT might be the target genes of lung cancer by participating in different pathways such as ECM-receptor interaction. Complement and coagulation cascades, and ECM-receptor interaction might be the specific pathways for AC; smoking might have a closer relationship with SCC.

Left sleeve lobectomy versus left pneumonectomy for the management of patients with non-small cell lung cancer.

BACKGROUND: The study was conducted to compare the outcomes of sleeve lobectomy (SL) and pneumonectomy (PN) for management of the left lung in patients with non-small cell lung cancer (NSCLC). METHODS: One hundred and thirty-five patients who underwent left SL (n = 87) or left PN (n = 48) for NSCLC from January 2006 to December 2011 were enrolled in this retrospective study. Left SL was performed when technically possible. The clinicopathological features and treatment outcomes in both groups were compared. Survival was evaluated using the Kaplan-Meier method, and significant differences were calculated using the log-rank test. Multivariate analysis was conducted using the Cox proportional hazards model to analyze significant variables associated with the outcomes of left SL. RESULTS: There were no significant differences in general clinicopathological features (age, gender, lymph node metastasis, pathological stage, and complications of bronchial fistula) between patients who underwent left SL and left PN. The operation duration was markedly longer and the extent of bleeding was greater for left SL than left PN; however patients who underwent left SL achieved significantly longer overall survival than patients who underwent left PN. The outcomes of left SL were only associated with pathological stage. CONCLUSIONS: Our results indicate that left SL may offer superior survival than left PN in selected patients. If anatomically feasible, left SL may be a preferred alternative to left PN for NSCLC patients. Pathological stage is an important factor to determine the outcome of SL.

Impact of maximum standardized uptake value of non-small cell lung cancer on detecting lymph node involvement in potential stereotactic body radiotherapy candidates.

BACKGROUND: The retrospective study investigated the association between the maximum standardized uptake value (SUVmax) of primary tumor and lymph node involvement in potential stereotactic body radiotherapy (SBRT) candidates. METHODS: A total of 185 patients with clinical stage I NSCLC were enrolled in the current study. All patients underwent lobectomy with systematic lymph node dissection following preoperative FDG-PET/CT scanning. The association between clinicopathological variables and lymph node involvement was analyzed by univariate and multivariate analysis. Spearman's correlation test was used to evaluate the correlation between them. Receiver operating characteristic (ROC) analysis was performed to calculate the area under the curve. RESULTS: Among these patients, 22.1% had occult lymph node involvement, 15.1% were N1 and 7.0% were N2. Greater tumor size (P=0.007), elevated CEA (P=0.006), central location (P=0.002), higher SUVmax (P<0.001), solid nodule type (P=0.002), visceral pleural invasion (P=0.001) and presence of micropapillary and solid patterns (P=0.002) were significantly associated with lymph node involvement. In multivariate analysis, lymph node involvement was associated with central location (OR 5.784, 95% CI: 1.584-21.114, P=0.008), SUVmax (increase of 1 unite, OR 1.147, 95% CI: 1.035-1.272, P=0.009) and visceral pleural invasion (OR 3.044, 95% CI: 1.369-6.769, P=0.006). ROC area under the curve of SUVmax for lymph node involvement was 0.770 (95% CI: 0.698-0.841), the sensitivity and specificity were 85.4% and 63.2%, respectively. Spearman's correlation test showed that SUVmax of tumor mostly depended on tumor size and nodule type. CONCLUSIONS: SUVmax of primary tumor was a predictor of lymph node involvement for potential SBRT candidates. Centrally located tumor and visceral pleural invasion were related to higher rate of nodal metastasis. Lobectomy and systemic lymph node dissection should be performed in these patients, instead of SBRT.

Effect of visceral pleural invasion on the prognosis of patients with lymph node negative non-small cell lung cancer.

BACKGROUND: Visceral pleural invasion (VPI) is an adverse prognostic factor in non-small cell lung cancer (NSCLC); however, its effect in relation to tumor size remains under debate. To better understand the prognostic impact and potential consequences for staging, we examined correlations between VPI and clinicopathologic characteristics in patients with NSCLC, particularly those with lymph node negative NSCLC. METHODS: We retrospectively analyzed 813 cases of radically resected NSCLC treated in our institution between December 2005 and December 2011. Patients were divided into two groups according to VPI status to compare their clinicopathologic characteristics. Survival analysis was performed in 521 cases with pN0 NSCLC. RESULTS: VPI was diagnosed in 379 (46.6%) cases. It was more common in women, patients with non-squamous cell carcinoma, elevated preoperative serum carcinoembryonic antigen levels, moderately or poorly differentiated tumors, and larger-sized tumors. The incidence of mediastinal lymph node metastasis, particularly multi-station metastasis, was higher in patients with VPI. Patients with pN0 NSCLC, 2-3 cm tumors, and VPI had a significantly poorer prognosis (VPI vs. non-VPI: five-year overall survival 78.3% vs. 84.5%, P = 0.039; five-year disease-free survival 69.2% vs. 80.0%, P = 0.046, respectively); however, no significant effect was observed for tumors ≤2, 3-5, and 5-7 cm. P-N0 patients with VPI had a significantly higher incidence of postoperative local recurrence and distant metastasis than those without VPI (P = 0.01), especially ipsilateral pleural recurrence. CONCLUSION: VPI was an adverse prognostic factor in radically resected pN0 NSCLC, especially for tumors 2-3 cm in size.

Biological features of novel avian influenza A (H7N9) virus.

Human infection associated with a novel reassortant avian influenza H7N9 virus has recently been identified in China. A total of 132 confirmed cases and 39 deaths have been reported. Most patients presented with severe pneumonia and acute respiratory distress syndrome. Although the first epidemic has subsided, the presence of a natural reservoir and the disease severity highlight the need to evaluate its risk on human public health and to understand the possible pathogenesis mechanism. Here we show that the emerging H7N9 avian influenza virus poses a potentially high risk to humans. We discover that the H7N9 virus can bind to both avian-type (α2,3-linked sialic acid) and human-type (α2,6-linked sialic acid) receptors. It can invade epithelial cells in the human lower respiratory tract and type II pneumonocytes in alveoli, and replicated efficiently in ex vivo lung and trachea explant culture and several mammalian cell lines. In acute serum samples of H7N9-infected patients, increased levels of the chemokines and cytokines IP-10, MIG, MIP-1ß, MCP-1, IL-6, IL-8 and IFN-α were detected. We note that the human population is naive to the H7N9 virus, and current seasonal vaccination could not provide protection.

A pilot study: sequential gemcitabine/cisplatin and icotinib as induction therapy for stage IIB to IIIA non-small-cell lung adenocarcinoma.

BACKGROUND: A phase II clinical trial previously evaluated the sequential administration of erlotinib after chemotherapy for advanced non-small-cell lung cancer (NSCLC). This current pilot study assessed the feasibility of sequential induction therapy in patients with stage IIB to IIIA NSCLC adenocarcinoma. METHODS: Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 and cisplatin 75 mg/m(2) on day 1, followed by oral icotinib (125 mg, three times a day) on days 15 to 28. A repeat computed tomography(CT) scan evaluated the response to the induction treatment after two 4-week cycles and eligible patients underwent surgical resection. The primary objective was to assess the objective response rate (ORR), while EGFR and KRAS mutations and mRNA and protein expression levels of ERCC1 and RRM1 were analyzed in tumor tissues and blood samples. RESULTS: Eleven patients, most with stage IIIA disease, completed preoperative treatment. Five patients achieved partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (ORR = 45%) and six patients underwent resection. Common toxicities included neutropenia, alanine transaminase (ALT) elevation, fatigue, dry skin, rash, nausea, alopecia and anorexia. No serious complications were recorded perioperatively. Three patients had exon 19 deletions and those with EGFR mutations were more likely to achieve a clinical response (P= 0.083). Furthermore, most cases who achieved a clinical response had low levels of ERCC1 expression and high levels of RRM1. CONCLUSIONS: Two cycles of sequentially administered gemcitabine/cisplatin with icotinib as an induction treatment is a feasible and efficacious approach for stage IIB to IIIA NSCLC adenocarcinoma, which provides evidence for the further investigation of these chemotherapeutic and molecularly targeted therapies.

Retrospective study of surgical resection in the treatment of limited stage small cell lung cancer.

BACKGROUND: Patients with small cell lung cancer (SCLC) are mainly treated by chemotherapy/radiotherapy, either alone or combined. Surgical resection is an optional treatment for few SCLC patients. The efficacy of surgical intervention for SCLC remains controversial. This study evaluates the validity of surgery for patients with limited stage SCLC. METHODS: We conducted a retrospective review of 59 patients with limited stage SCLC who received trimodal therapy from 2004 to 2011. Progression-free survival (PFS) and overall survival (OS) were calculated using the statistic methods of Kaplan-Meier and the log-rank test. RESULTS: Among the 59 limited stage SCLC patients, 54 patients with stage I-III SCLC received surgical treatment with curative intent, and 42.6% (23/54) patients received preoperative chemotherapy. The radical resection rate of the group of preoperative chemotherapy and the group of initial surgical resection were 82.6% (19/23) and 54.8% (17/31), respectively. The corresponding five-year survival rates were 59% and 22% with significant differences (P = 0.032 and 0.041, respectively). In total, 36 (66.7%) patients underwent radical surgery with resection of the primary mass and mediastinal lymph nodes. In the radical surgery series, five-year survival, according to stage I-III categories, were 59%, 53%, and 26%, respectively. For the 30 stage III patients, the five-year survival of the radical group of 26% was lower than the non-radical group of 67%, and PFS analysis showed similar tendencies. CONCLUSION: Preoperative chemotherapy is the most favorable initial treatment for patients with limited disease SCLC. Complete surgical resection is considered for patients with stage I and II. Surgical resection remains of no benefit for stage III SCLC patients with persistent N2/N3 after chemotherapy.

[Diagnostic accuracy research of needle puncture biopsy during operation for pulmonary single nodules].

OBJECTIVE: To investigate the diagnostic accuracy of needle puncture biopsy and pathological examination of frozen during operation for pulmonary nodules, and whether this diagnostic method can replace tumor resection examination. METHODS: Totally 50 patients (28 males and 22 females, average age was 59 years) who had the single nodule after imaging examination without any pathological diagnostic from January to October 2010 were selected in this research work. During open operation or video assisted thoracic surgery, needle (14 G model) was used to puncture biopsy for pathological examination of frozen. All the adverse events during puncture biopsy would be recorded. The resection specimens would be accepted paraffin pathological examination. The relationship between puncture frozen pathological and paraffin pathological examination was analyzed. RESULTS: All tumor sizes were ranged from 1.0 cm × 0.6 cm to 5.6 cm × 9.0 cm. The paraffin pathological examination after operation as the golden standard, there were 7 cases of benign tumor and 43 cases of malignant tumor. The diagnostic sensitivity of puncture biopsy was 90.7%, the specificity was 100%, the positive predictive value was 100% and the negative predictive value was 63.6%. There were 11 cases of benign tumor diagnosed by needle puncture biopsy, among which 4 cases were proved as malignant tumor by paraffin pathology, and the false negative rate was 9.3%. The main risk of puncture biopsy was bleeding after puncture immediately, and the rate was 4.0% (2/50). CONCLUSIONS: The puncture biopsy during operation had a high specificity for malignant lung tumor, and there was a certain false negative rate for benign tumor. Puncture biopsy and pathological examination of frozen tissue can replace tumor section biopsy in a way.