Somatic mutations introduced into the epidermal growth factor receptor (EGFR) gene in non‐small‐cell lung cancer (NSCLC) are important factors to determine therapeutic responses to gefitinib. The ...current diagnostic test measures the overall EGFR mutation status of the cancer tissue, and may ignore the presence of non‐mutated, gefitinib‐unresponsive cancer cells. Twenty‐one NSCLC patients with EGFR mutations were recruited for the study. All patients were treated with gefitinib after surgical treatment. Fifty to sixty areas of NSCLC tumors were sampled from each tissue, and their EGFR mutation states were determined by a primer extension assay. This assay discriminates between EGFR mutation‐positive and ‐negative cancer cells within a single tumor tissue. Fifteen tissues consisted only of cells with EGFR mutations, but the remaining six tissues contained both mutated and non‐mutated cells. Time to disease progression and overall survival after gefitinib treatment were significantly shorter in those patients with EGFR heterogeneity (P = 0.009 and P = 0.003, respectively). A considerable proportion of NSCLC contains a heterogeneous population of both EGFR mutated and non‐mutated cancer cells, resulting in a reduced response to gefitinib. The intratumor genetic heterogeneity of a target molecule such as EGFR would be an important factor to consider when treating patients with molecular target agents. (Cancer Sci 2008; 99: 929–935)
Background We retrospectively compared the oncologic outcome after segmentectomy versus lobectomy in patients with clinical (c-) T1a N0 M0 non-small cell lung cancer (NSCLC) detected as a part-solid ...ground-glass nodule or purely solid nodule on thin-section computed tomography. Methods From 1997 to 2010, 312 patients with c-T1a N0 M0 NSCLC were determined to require a surgical approach categorized as segmentectomy or lobectomy. Preoperatively available data were collected using logistic regression analysis, and propensity matching was performed. Factors affecting local-regional recurrence were assessed by Cox proportional hazards regression analysis and Kaplan-Meier estimates. Results The 5-year and 10-year overall survival rates for the 80 patients who underwent segmentectomy were 97.5% and 83.5%, respectively, compared with 87.75% and 75.0%, respectively, for the 232 patients who underwent lobectomy ( p = 0.019). Local-regional recurrence as the first relapse site was found in 3 the 80 segmentectomies (3.8%) of and in 15 of the 232 lobectomies (6.5%). The difference in local-regional recurrence-free survival in patients undergoing segmentectomy compared with lobectomy was not significant ( p = 0.304). In 69 propensity score-matched pairs, there was no significant difference in the overall survival ( p = 0.442) or local-regional recurrence-free survival ( p = 0.717) between the two groups. Multivariate analysis using the Cox proportional hazards regression model identified lymphatic invasion as the only independent factor predicting local-regional recurrence (relative risk, 10.764; 95% confidence interval, 2.98 to 57.68). Conclusions Our results suggest that the oncologic outcome of segmentectomy vs lobectomy is similar in this cohort of c-T1a N0 M0 NSCLC patients. These results will be validated by large-scale, prospective, randomized trials.
Examination of somatic epidermal growth factor receptor (EGFR) mutations is now a diagnostic routine for treatment of cancer using EGFR tyrosine kinase inhibitors (EGFR-TKI). Circulating tumor DNA is ...a promising target for noninvasive diagnostics. We evaluated its utility by quantitatively detecting activating and resistant mutations, which were measured with BEAMing (beads, emulsion, amplification, and magnetics).
Twenty-three patients with lung cancer with progressive disease after EGFR-TKI treatment and 21 patients who had never been treated with EGFR-TKIs were studied. Their primary tumors were confirmed to have activating mutations. In the plasma DNA of each patient, the activating mutation found in the corresponding primary tumor and the T790M resistance mutation were quantified by BEAMing.
In 32 of 44 patients, activating mutations were detected in the plasma DNA 72.7%; 95% confidence interval (CI), 58.0%-83.6%. The T790M mutation was detected in 10 of 23 patients in the first group (43.5%; 95% CI, 25.6%-53.4%). The ratio of T790M to activating mutations ranged from 13.3% to 94.0%. The peak of the distribution of the mutation allele fraction in the plasma DNA was in the 0.1% to 1% range.
The major advantage of BEAMing is its ability to calculate the fraction of T790M-positive alleles from the alleles with activating mutations. This feature enables the detection of increases and decreases in the number of T790M mutations in cancer cells, regardless of normal cell DNA contamination, which may be useful for monitoring disease progression. Circulating tumor DNA could potentially be used as an alternative method for EGFR mutation detection.
At present, even when early-stage, small-sized non–small cell lung cancers are being increasingly detected, lesser resection has not become the treatment of choice. We sought to compare sublobar ...resection (segmentectomy or wedge resection) with lobar resection to test which one is the appropriate procedure for such lesions.
From 1992 to 2001, a nonrandomized study was performed in 3 institutes for patients with a peripheral cT1N0M0 non–small cell lung cancer of 2 cm or less who were able to tolerate a lobectomy. The results of the sublobar resection group enrolled preoperatively (n = 305) were compared with those of the lobar resection group (n = 262).
Except for distribution of tumor location, there were no significant differences in any variable, patient characteristics, curability, pathologic stage, morbidity, or recurrence rate. Median follow-up was more than 5 years. Disease-free and overall survivals were similar in both groups with 5-year survivals of 85.9% and 89.6% for the sublobar resection group and 83.4% and 89.1% for the lobar resection group, respectively. Multivariate analysis confirmed that the recurrence rate and prognosis associated with sublobar resection were not inferior to those obtained with lobar resection. Postoperative lung function was significantly better in patients who underwent sublobar resection.
Sublobar resection should be considered as an alternative for stage IA non–small cell lung cancers 2 cm or less, even in low-risk patients. These results could lay the foundation for starting randomized controlled trials anew, which would bring great changes of lung cancer surgery in this era of early detection of lung cancer.
The purpose of this study was to evaluate the natural course of the progression of pulmonary subsolid nodules (SSNs).
Eight facilities participated in this study. A total of 795 patients with 1229 ...SSNs were assessed for the frequency of invasive adenocarcinomas. SSNs were classified into three categories: pure ground-glass nodules (PGGNs), heterogeneous GGNs (HGGNs) (solid component detected only in lung windows), and part-solid nodules.
The mean prospective follow-up period was 4.3 ± 2.5 years. SSNs were classified at baseline as follows: 1046 PGGNs, 81 HGGNs, and 102 part-solid nodules. Among the 1046 PGGNs, 13 (1.2%) developed into HGGNs and 56 (5.4%) developed into part-solid nodules. Among the 81 HGGNs, 16 (19.8%) developed into part-solid nodules. Thus, the SSNs at the final follow-up were classified as follows: 977 PGGNs, 78 HGGNs, and 174 part-solid nodules. Of the 977 PGGNs, 35 were resected (nine minimally invasive adenocarcinomas MIAs, 21 adenocarcinomas in situ AIS, and five atypical adenomatous hyperplasias). Of the 78 HGGNs, seven were resected (five MIAs and two AIS). Of the 174 part-solid nodules, 49 were resected (12 invasive adenocarcinomas, 26 MIAs, 10 AIS, and one adenomatous hyperplasia). For the PGGNs, the mean period until their development into part-solid nodules was 3.8 ± 2.0 years, whereas the mean period for the HGGNs was 2.1 ± 2.3 years (p = 0.0004).
This study revealed the frequencies and periods of development from PGGNs and HGGNs into part-solid nodules. Invasive adenocarcinomas were diagnosed only among the part-solid nodules, corresponding to 1% of all 1229 SSNs.
IL-23 is a proinflammatory cytokine consisting of a p19 subunit and a p40 subunit that is shared with IL-12. IL-23 is overexpressed in and around tumor tissues, where it induces local inflammation ...and promotes tumor development. Many tumor cells produce large amounts of lactic acid by altering their glucose metabolism. In this study, we show that lactic acid secreted by tumor cells enhances the transcription of IL-23p19 and IL-23 production in monocytes/macrophages and in tumor-infiltrating immune cells that are stimulated with TLR2 and 4 ligands. DNA elements responsible for this enhancing activity of lactic acid were detected in a 2.7-kb 5'-flanking region of the human IL-23p19 gene. The effect of lactic acid was strictly regulated by extracellular pH. Furthermore, by inducing IL-23 overproduction, lactic acid facilitated the Ag-dependent secretion of proinflammatory cytokine IL-17 but not IFN-gamma by TLR ligand-stimulated mouse splenocytes. Interestingly, this effect was observed even in the absence of TLR ligand stimulation. These results suggest that rather than just being a terminal metabolite, lactic acid is a proinflammatory mediator that is secreted by tumor cells to activate the IL-23/IL-17 proinflammatory pathway but not the Th1 pathway. Targeting the lactic acid-induced proinflammatory response may be a useful approach for treating cancer.
The amino-acid balance in cancer patients often differs from that in healthy individuals, because of metabolic changes. This study investigated the use of plasma amino-acid profiles as a novel marker ...for screening non-small-cell lung cancer (NSCLC) patients.
The amino-acid concentrations in venous blood samples from pre-treatment NSCLC patients (n = 141), and age-matched, gender-matched, and smoking status-matched controls (n = 423), were measured using liquid chromatography and mass spectrometry. The resultant study data set was subjected to multiple logistic regression analysis to identify amino acids related with NSCLC and construct the criteria for discriminating NSCLC patients from controls. A test data set derived from 162 patients and 3,917 controls was used to validate the stability of the constructed criteria.
The plasma amino-acid profiles significantly differed between the NSCLC patients and the controls. The obtained model (including alanine, valine, isoleucine, histidine, tryptophan and ornithine concentrations) performed well, with an area under the curve of the receiver-operator characteristic curve (ROC_AUC) of >0.8, and allowed NSCLC patients and controls to be discriminated regardless of disease stage or histological type.
This study shows that plasma amino acid profiling will be a potential screening tool for NSCLC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The usefulness of residual tumor resection after epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment remains unclear. We describe two patients who underwent residual tumor ...resection after responding to EGFR-TKIs for advanced non-small cell lung cancer (NSCLC) harboring EGFR gene mutations, along with a review of the literature.
The patient in Case 1 was a 72-year-old female non-smoker who was initially diagnosed with T2aN2M0, stage IIIA adenocarcinoma harboring an EGFR exon 21 L858R mutation. After 8 months of gefitinib therapy, a marked radiologic response was noted, and right upper lobectomy with systemic lymph node dissection was performed. The patient developed brain metastasis despite continuous gefitinib therapy. The patient in Case 2 was a 68-year-old female non-smoker who was initially diagnosed with T3N2M0, stage IIIA adenocarcinoma and an extensive pulmonary thromboembolism. After 3 months of therapy with afatinib and anticoagulants, a marked radiologic response and symptom relief were achieved. We then performed right bilobectomy with systemic lymph node dissection. She developed bone metastasis despite postoperative afatinib therapy.
The timing and validity of salvage surgery for residual lesions remain unclear when TKIs are offered as first-line therapy to patients with advanced NSCLC. In our two cases, surgery was performed without any complications. Surgical resection of the residual tumor might contribute to good local control. The accumulation of more clinical data is needed to further investigate the role of surgery in patients with advanced NSCLC harboring EGFR gene mutations.
Objectives
Accurate histological diagnosis and molecular testing using a sufficient tumor sample of advanced lung cancer, especially non-small cell lung cancer (NSCLC), are crucial for precision ...medicine. The aim of this study was to assess the feasibility and safety of surgical biopsy for intrathoracic lesions, and, in addition, overall survival after surgical biopsy.
Methods
One hundred-one patients who underwent surgical biopsy for intrathoracic lesions of lung cancer at our hospital between 2011 and 2019 were retrospectively reviewed. Their clinical and pathologic records were reviewed. In addition to evaluating the oncologic safety of the surgical biopsy, the overall survival based on the biopsy results was estimated.
Results
The total number of surgical sites of the 101 patients was 131, and common biopsy sites were the lungs (82, 62.6%) followed by hilar/mediastinal lymph nodes (27, 20.6%). There were 13 postoperative complications (12.9%) without surgery-related deaths. The median time from surgical biopsy to the initiation of treatment was 27 days. Appropriate amounts of specimens for diagnosis and molecular testing were obtained from all patients (100%). When limited to treatment-naïve patients with stage IV adenocarcinoma, patients treated with tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) based on molecular testing had a better prognosis.
Conclusions
Surgical biopsy for intrathoracic lesions of lung cancer may be a safe and effective method to make a definitive diagnosis, including companion diagnostics for advancing precision therapy in selected patients with inoperable advanced NSCLC.
Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant ...chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC.
Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis.
Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001).
This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.
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