Clinical option of pemetrexed-based versus paclitaxel-based first-line chemotherapeutic regimens in combination with bevacizumab for advanced non-squamous non-small-cell lung cancer and optimal maintenance therapy: evidence from a meta-analysis of randomized control trials.

BACKGROUND: In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. METHODS: All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP ± B) and paclitaxel-carboplatin with bevacizumab (PC + B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem + B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events. RESULTS: Data of 3139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP ± B and PC + B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP ± B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC + B (all P < 0.05). PP ± B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC + B (all P < 0.001). The other three RCTs were included in an analysis that compared Pem + B and B as a maintenance treatment. Compared with B, Pem + B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P < 0.001). CONCLUSION: Although the first-line PP + B regimen had longer PFS and PFSR1y than the PC + B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.

Short-term outcomes and safety of radiotherapy for immediate breast reconstruction with autologous flap transfer following breast-conserving surgery.

BACKGROUND: The outcomes of immediate autologous breast reconstruction (IABR) after partial mastectomy followed by postoperative radiotherapy (RT) in terms of aesthetics, treatment-related complications, and local control are unclear. In this study, we evaluated the efficacy of IABR after partial mastectomy with or without breast RT, and thus the impact of radiation on autologous flap transfer. METHOD: A retrospective cohort study involving consecutive breast cancer patients who underwent IABR after partial mastectomy between July 2011 and December 2017 at Shengjing Hospital was performed. Patients were divided into two groups based on whether or not they received RT after IABR. We compared aesthetic outcomes and changes in the flap size over the three-dimensional coordinates at various timepoints (pre-RT, 1, 6, and 12 months post-RT), as well as postoperative complications, survival, and recurrence rates between the two groups. RESULTS: In total, 84 breast cancer patients were enrolled, with 32 patients in the RT group and 52 in the non-RT group. At a median follow-up time of 33.3 months, no significant difference was found in the rate of regional recurrence between the two groups (3.13% vs. 3.85%, P = 1.00), and no local recurrences occurred in either group. At the timepoints pre-RT, 1, and 6 months post-RT (approximately 4, 7, and 12 months after IABR, respectively), 77 (91.7%), 70 (83.3%), and 83 (98.8%) patients, respectively, had achieved very good or good cosmetic outcomes, and only changes in breast skin color at 1 month after RT significantly differed between the RT and non-RT groups, with very good or good cosmetic result rates of 62.5% vs. 96.2%, respectively (P < 0.001). No significant difference in the reduction of flap size was observed at any timepoint between the two groups. There were no significant differences between the two groups in the rates of postoperative complications including necrosis of the flap, infection, hematoma, or seroma (all P > 0.05). Additionally, no grade 3 or greater RT-associated adverse events occurred during or after RT. CONCLUSION: RT following IABR provides aesthetically satisfactory results without intolerable adverse complications and may safely be performed in patients who underwent IABR after partial mastectomy.

Rational Application of First-Line EGFR-TKIs Combined with Antiangiogenic Inhibitors in Advanced EGFR-Mutant Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: A meta-analysis of randomized controlled trials (RCTs) was conducted to compare the difference in efficacy and safety between epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with antiangiogenic inhibitors (A + T) and EGFR-TKI monotherapy in patients with treatment-naïve advanced EGFR-mutant non-small-cell lung cancer (NSCLC). METHODS: PubMed, Embase, Web of Science, and Cochrane electronic databases were searched for relevant RCTs. Meeting abstracts were also reviewed to identify appropriate studies. The endpoints included progression-free survival (PFS), overall survival (OS), 1- and 2-year OS rates, objective response rate (ORR), and grade ≥ 3 adverse events. All pooled outcomes were expressed using hazard ratios (HRs) or relative risk ratios (RRs). RESULTS: Data were collected from six eligible RCTs, which included 1,244 participants (619 in the A + T group and 625 in the TKI alone group). PFS was significantly improved with A + T compared to TKI alone (HR = 0.60; P < 0.01) regardless of EGFR mutation types (exon 19 deletion or L858R) and brain metastasis status (with or without brain metastases). There was no significant difference in median OS between the A + T and TKI alone groups (HR = 0.933; P = 0.551) regardless of EGFR mutation type. The ORR for A + T combination therapy was significantly increased compared to TKI monotherapy in exon 19 deletion subgroups (RR = 0.774; P = 0.008). There was no difference in the positive rates of acquired T790M mutation between the two groups (RR = 0.967; P = 0.846). More patients in the TKI alone group received a variety of subsequent systemic treatments than those in the A + T group (RR = 0.881; P = 0.002). CONCLUSION: Addition of antiangiogenic inhibitors to first-line EGFR-TKI therapy significantly reduced the risk of disease progression for patients with advanced EGFR-mutant NSCLC regardless of EGFR mutation type and brain metastasis status. The lack of OS benefit may be explained by differences in subsequent treatments rather than drug resistance mechanisms.

Impact of pulmonary interstitial lesions on efficacy and prognosis of EGFR-TKI-treated advanced non-small cell lung cancers.

BACKGROUND: This study aimed to assess the impact of pre-existing pulmonary interstitial lesions (PIL) on the efficacy and prognosis of patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitor (TKI). METHODS: Patients with advanced NSCLC harboring EGFR exon 19 deletion (E19 del) or exon 21 (E21) L858R were enrolled in this study. All patients underwent high resolution computed tomography (HRCT) chest scans prior to EGFR-TKI treatment. Pre-existing PIL was graded according to HRCT imaging (PIL 0, 1, 2, and 3). Cox proportional-hazards regression models were used to identify the prognostic factors for progression-free survival (PFS). RESULTS: A total of 134 eligible patients were enrolled. The overall objective response rate (ORR) and median PFS were 73.1% and 10.0 months (95% CI: 7.51-12.49), respectively. There were 62 (46.3%), 25 (18.7%), 28 (20.9%), and 19 (14.1%) cases of PIL grade 0, 1, 2, and 3, respectively, with median PFS and ORR of 12.9 months and 80.6%, 11.0 months and 72.0%, 10.0 months and 71.4%, and 7.0 months and 52.6%, respectively. Multivariate analysis showed that squamous cell carcinoma (vs. adenocarcinoma, HR =4.33), E21 L858R (vs. E19 del, HR =1.57), and PIL grade 3 (vs. grade 0-2, HR =1.60-2.48) were poor prognostic factors for PFS (P<0.05 for all). CONCLUSIONS: Pre-existing PIL grade is an independent prognostic factor for predicting resistance to EGFR-TKIs in patients with EGFR-mutant advanced NSCLC. Higher PIL grade suggests higher risk of early progression.

Neoadjuvant EGFR-TKI Therapy for EGFR-Mutant NSCLC: A Systematic Review and Pooled Analysis of Five Prospective Clinical Trials.

PURPOSE: The role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) has not been clarified. A pooled analysis of prospective clinical trials was conducted to evaluate the efficacy and safety of neoadjuvant EGFR-TKI therapy. METHODS: The PubMed, Embase, Web of Science, and Cochrane Library databases, as well as meeting abstracts were searched for prospective clinical trials evaluating the efficacy and safety of neoadjuvant EGFR-TKI for treatment of EGFR-mutant NSCLC. The main outcomes included the objective response rate (ORR), downstaging rate, surgical resection rate (SRR), pathologic complete response (pCR) rate, progression-free survival (PFS), and adverse events. RESULTS: A total of five, phase II, prospective, clinical trials involving 124 patients with resectable or potentially resectable EGFR-mutant NSCLC treated with neoadjuvant erlotinib or gefitinib treatment were included in this pooled analysis. The median neoadjuvant medication time was 42 (range, 21-56) days and the median time of response evaluation was 45 (range, 42-56) days. The pooled ORR was 58.5% [95% confidence interval (CI), 45.5%-71.8%] and the surgical resection and complete resection (R0) rates were 79.9% (95% CI, 65.3%-94.5%) and 64.3% (95% CI, 43.8%-84.8%), respectively. In the stage IIIA subgroup (n = 68), the pooled ORR, SRR, and R0 rate were 51.4%, 72.9%, and 57.0%, respectively, while the downstaging and pCR rates were 14.0% and 0.0%, respectively. The pooled median PFS and overall survival were 13.2 and 41.9 months, respectively. Of the most common grade 3/4 adverse events in the overall group, the incidences of hepatotoxicity and skin rash were 5.3% and 14.7%, respectively. The most commonly reported postoperative complications were lung infection, arrhythmia, and pneumothorax. CONCLUSION: Neoadjuvant EGFR-TKI therapy provides a feasible treatment modality for patients with resectable or potentially resectable EGFR-mutant NSCLC, with satisfactory surgical outcomes and low toxicity. Although further phase III clinical trials are needed to confirm these findings, it is necessary to explore the feasibility of a more effective EGFR-TKI combination neoadjuvant therapy given the modest downgrade and pCR rates for EGFR-TKI alone.

Risk factors of atrial fibrillation occurring after radical surgery of esophageal carcinoma.

BACKGROUND: Atrial fibrillation (AF) is a common complication after radical surgery of esophageal cancer. The aim of this study was to explore AF risk factors after radical surgery of esophageal carcinoma. METHOD: The data of 335 patients with esophageal cancer who were admitted in our hospital from January 2014 to August 2016 for the first time were retrospectively analyzed. We retrieved the papers in some data banks using the search terms including English and Chinese search terms, and obtained 13 factors which were mentioned in more than 6 papers. The 13 factors including age, gender, history of smoking, history of hypertension, history of peripheral vascular disease, history of cardiac stents or angina pectoris, preoperative pulmonary infection, preoperative brain natriuretic peptide (BNP) level, preoperative left ventricular diastolic dysfunction, operative method, lesion location, intraoperative blood transfusion, adhesion between lymph nodes and pericardium, underwent univariate and multivariate analyses. RESULTS: Of the 335 patients with esophageal cancer, 48 had AF within one week after operation. Univariate analysis indicated that the age (OR: 4.89; CI: 2.53-9.47, P: 0.000), gender (OR: 2.26; CI: 1.17-4.37, P: 0.013), history of peripheral vascular disease (OR: 2.29; CI: 1.06-4.92, P: 0.030), history of cardiac stents or angina pectoris (OR: 27.30; CI: 12.44-59.91, P: 0.000), preoperative BNP level (OR: 27.13; CI: 10.97-67.06, P: 0.000), preoperative left ventricular diastolic dysfunction (OR: 2.22; CI: 1.19-4.14, P: 0.012), operative method (OR: 2.09; CI: 1.002-4.380, P: 0.046), intraoperative blood transfusion (OR: 20.24; CI: 8.39-48.82, P: 0.000), and adhesion between lymph nodes and pericardium were risk factors (OR: 2.05; CI: 1.08-3.87, P: 0.024). Furthermore, multivariate analysis displayed that advanced age (OR: 5.044; CI: 1.748-14.554, P: 0.003), male (OR: 6.161; CI: 2.143-17.715, P: 0.001), history of cardiac stents or angina pectoris (OR: 48.813; CI: 13.674-174.246, P: 0.000), preoperative BNP > 100 (OR: 41.515; CI: 9.380-183.732, P: 0.000), open surgery (OR: 3.357; CI: 1.026-10.983, P: 0.045), intraoperative blood transfusion (OR: 58.404; CI: 10.777-316.509, P: 0.000), and adhesion between lymph nodes and pericardium (OR: 3.954; CI: 1.364-11.459, P: 0.011) were risk factors which could increase the incidence of postoperative AF. CONCLUSION: We should pay attention to the above risk factors in order to reduce the incidence of postoperative AF.

Effects of Dynamin-related Protein 1 Regulated Mitochondrial Dynamic Changes on Invasion and Metastasis of Lung Cancer Cells.

Objective: Mitochondrial imbalance of division and fusion will lead to uncontrolled cell growth. This study investigated the effects of mitochondrial dynamics regulated by dynamin-related protein 1 (Drp1) on the invasion and metastasis of lung cancer cells at the cellular level. Methods: Lentivirus-mediated RNAi and gene overexpression vectors containing shDrp1 and Lv-Drp1 were transfected into lung adenocarcinoma cell lines 95D and A549, respectively. An MTT assay was used to assess cell viability and a cell clone assay was used to evaluate the tumorigenic ability of lentivirus-infected cells. Cell invasion and wound healing assays were used to assess cell invasiveness and the migration rate after lentivirus infection. Annexin V-APC staining was used to determine the cell apoptosis rate. Results: In 95D cells, when the Drp1 gene is overexpressed (OE) the proliferation rate and apoptosis rate were significantly higher than those in the control group (NCOE) (P < 0. 05). There was no significant difference in clone number, invasion rate, and migration rate between the two groups (P > 0. 05). The proliferation rate and clone number in the shDrp1 infected 95D cell group (KD) were significantly lower than those in the control group (NCKD) (P < 0. 05). There was no difference in apoptosis rate, invasion rate, and migration rate between h (P > 0.05). In A549 cells, unlike in 95D cells, the invasion rate of the KD group was 25% lower than that of the NCKD group (P < 0.05). After 8 hours, the cell migration rates of the two groups were basically the same, but after 24 hours, the migration rate of the KD group was 10% lower than that of the NCKD group (P < 0.05). Compared with the NCOE group, the migration rate of the OE group increased significantly (P < 0.05). Conclusion: Mitochondrial Drp1 is associated with the proliferation, invasion, and metastasis of lung adenocarcinoma cells. Inhibition of Drp1 expression may contribute to anti-tumor therapy for lung cancer.

Durable Clinical Response to Pyrotinib After Resistance to Prior Anti-HER2 Therapy for HER2-Positive Advanced Gastric Cancer: A Case Report.

Background: Patients with advanced gastric cancer, especially the HER2-positive type, have a poor prognosis; there is a paucity of effective anti-HER2 drug therapies in patients who develop resistance to trastuzumab. Case presentation: We report the case of a 36-year-old male with HER2-positive gastric cancer with lung and liver metastases. The patient responded after treatment with trastuzumab combined with chemotherapy and attained a progression-free survival (PFS) of 17 months. Subsequently, the patient received apatinib that selectively inhibits the VEGFR2 and obtained an evident tumor response and a PFS of 8 months. When the disease progressed again, the regimen containing lapatinib failed. Then, the patient received treatment with nivolumab. However, he presented with hyper-progressive disease (HPD). Finally, he received a combination of capecitabine and pyrotinib, an irreversible dual TKI, acting on HER2 and EGFR. The tumor shrank markedly with this combination therapy. The mechanism of both HPD due to immunotherapy and the resistance to trastuzumab and lapatinib were investigated in this case. Loss of phosphatase and tensin homolog (PTEN) and new mutations of BRCA1 and KRAS were detected after resistance to trastuzumab and lapatinib. Conclusions: For patients with HER2-positive advanced gastric cancer who have developed resistance to trastuzumab, pyrotinib is a promising new agent, which can be used as salvage therapy.

Chest Wall Toxicity After Stereotactic Body Radiation Therapy: A Pooled Analysis of 57 Studies.

PURPOSE: The significance of clinical and dosimetric risk factors in relation to chest wall (CW) injury after stereotactic body radiation therapy (SBRT) for lung tumors were analyzed through a meta-analysis of 57 published studies. METHODS AND MATERIALS: Studies related to CW injury after lung SBRT were obtained through searching PubMed, Embase, and Cochrane electronic databases. An estimate of the incidence of CW pain (CWP) or rib fracture (RF) was derived using a Bayesian hierarchical model. Linear regression analysis was performed to assess the relationship between CWP or RF and clinical or dosimetric factors. RESULTS: A total of 57 studies incorporating 5985 cases reporting clinical data on CW injury after SBRT were analyzed. The overall CWP and RF rates by Bayesian hierarchical modeling were 11.0% (95% confidence interval [CI], 8.0-14.4) and 6.3% (95% CI, 3.7-9.7), respectively. The rates of grade ≥2 and grade ≥3 CWP were 6.2% (95% CI, 3.88-8.93) and 1.2% (95% CI, 0.48-2.12), respectively. Sex was significantly correlated with RF (P < .001), with female patients having a greater risk of RF than male patients (hazard ratio = 0.59; 95% CI, 0.46-0.76). No correlation was found between RF, grade ≥2 CWP, or grade ≥3 CWP, with the clinical and dosimetric factors of age, tumor size, origin of lung tumor, gross tumor volume, planning target volume, fractional dose, number of fractions, or biologically effective dose. However, tumor to CW distance (<16-25 mm), body mass index, maximum dose (Dmax) of 0.5 to 5 cm3, and the volume of CW or ribs receiving >30 Gy were significantly associated with CWP and RF. CONCLUSIONS: The overall rates of RF and grade ≥2 CWP after thoracic SBRT are relatively low. Sex, tumor to CW distance, maximum dose, and the radiation exposure of the CW or ribs are factors associated with the risk of CW toxicity after SBRT.

Synergistic cytotoxic effects of recombinant human adenovirus p53 and radiation at various time points in A549 lung adenocarcinoma cells.

The aim of this study was to evaluate the effects of recombinant human adenovirus p53 (rAd-p53; Gendicine) transfection and radiation at various time points following transfection. Cytotoxic effects and p53 protein expression levels were analyzed. rAd-p53 containing the human wild-type p53 gene was introduced into the human lung adenocarcinoma cell line A549, and cells were irradiated with a single dose of 6 MeV 4 Gy ß rays. According to the time interval between rAd-p53 transfection and radiotherapy (RT), A549-transfected rAd-p53 cells were divided into 5 groups: radiation administered immediately after transfection (0 h-RT) group, after 3 h group (3 h-RT), after 6 h group (6 h-RT), after 24 h group (24 h-RT) and after 48 h group (48 h-RT). Cells with rAd-p53 transfection alone (Ad-p53) and with empty adenovirus (Ad) were included as the two control groups. Following 72 h of transfection, cell viability and growth were analyzed using MTT assays and flow cytometry, and p53 protein expression was analyzed using western blot analysis. From 0 h-RT to 48 h-RT, cell viability gradually decreased, while percentage of apoptotic cells and p53 protein expression gradually increased. The cell viability suppression rates in the 6 h-RT, 24 h-RT and 48 h-RT groups were 56.7±5.4, 60.8±6.0 and 68.9±6.6, respectively, which were significantly greater compared to that of the Ad-p53 (40.8±4.7), 0 h-RT (45.0±3.5) and 3 h-RT groups (47.0±4.3). No statistically significant differences were observed in the cell viability suppression rates among the 6 h-RT, 24 h-RT and 48 h-RT groups (P>0.05). Similar changes were observed in the percentage of apoptotic cells. The p53 protein expression level in the 6 h-RT group (0.856±0.092) was higher compared to that in the 3 h-RT group (0.643±0.089) (t=2.882; P=0.045), but not significantly different from that of the 24 h-RT group (1.193±0.202). The cell viability suppression rate and percentage of apoptotic cells was positively correlated with p53 protein expression in the A549 cells (P<0.05). Radiation may inhibit or damage p53 protein expression at the early stage of rAd-p53 transfection. To sensitize tumor cells to irradiation and achieve maximal cytotoxic effects, it is recommended to conduct RT at least 6 h following transfection with rAd-p53.

Altered expression of mitochondrial cytochrome c oxidase I and NADH dehydrogenase 4 transcripts associated with gastric tumorigenesis and tumor dedifferentiation.

This study aimed to detect the expression of mitochondrial mRNA in normal and cancerous gastric tissues and discuss their association with clinicopathological characteristics. Semi-quantitative reverse-transcription PCR was used to analyze mitochondrial transcripts in 42 cases of matched cancerous and normal gastric tissues. Expression of these genes was then statistically analyzed to determine the correlation with the clinicopathological characteristics from the patients. Transcripts of cytochrome c oxidase I (CO I) and NADH dehydrogenase 4 (ND4) were highly expressed in gastric cancer tissues compared to normal gastric tissues (P=0.005 and P=0.001, respectively). The expression levels of CO I and ND4 were higher in the diffused type of gastric cancer than in the intestinal type (P=0.024 and P=0.0002, respectively). Elevated expression of CO I and ND4 were associated with gastric tumorigenesis and tumor dedifferentiation ex vivo.

EGFR and KRAS mutations and altered c-Met gene copy numbers in primary non-small cell lung cancer and associated stage N2 lymph node-metastasis.

This study aimed to detect mutations in EGFR and KRAS and alterations of c-Met gene copy number (GCN) changes in primary and lymph node-metastatic NSCLCs. The data showed the concordant rate of EGFR genotype in primary and stage N2 lymph node-metastatic tumors was 95.45%. c-Met GCN in stage N2 lymph nodes was significantly higher than that of the primary tumors (P=0.038). The results suggest both primary and lymph-node metastases have relatively consistent EGFR mutations and EGFR mutations are not relevant to changes in c-Met GCN. c-Met GCN was increased significantly in EGFR TKI-naive patients with lymph node-metastatic tumors.