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1.
Cancer Drug Resist ; 4(3): 559-572, 2021.
Article in English | MEDLINE | ID: mdl-35582309

ABSTRACT

Pancreatic cancer is one of the most aggressive diseases among solid tumors. Most patients are diagnosed with advanced or metastatic disease and are characterized by poor chemosensitivity. Therefore, earlier diagnosis and novel therapeutic possibilities for pancreatic cancer patients are urgently needed. Liquid biopsy is an emerging technology that allows the noninvasive sampling of tumor material. Nowadays, liquid biopsy has shown promising results as diagnostic, prognostic and predictive biomarkers, but it has not yet been universally adopted into regular use by clinicians. In this review, we describe different components of liquid biopsy, especially circulating tumor cells, circulating tumor DNA and exosomes and their potential clinical utility for pancreatic cancer patients.

2.
Int J Mol Sci ; 23(8)2022 Apr 08.
Article in English | MEDLINE | ID: mdl-35456940

ABSTRACT

Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific drugs challenging. Indeed, KRAS was considered 'undruggable'. KRASG12C is the most commonly mutated variant of KRAS in non-small cell lung cancer. Currently, the achievements obtained with covalent inhibitors of this variant have given the possibility to assess the best therapeutic approach to KRAS-driven tumors. Mutation-related biochemical assets and the tissue of origin are expected to influence responses to treatment. Further attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising. Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Colonic Neoplasms , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/genetics , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Humans , Lung Neoplasms/genetics , Mutation , Proto-Oncogene Proteins p21(ras)/genetics
3.
Cancers (Basel) ; 14(8)2022 Apr 16.
Article in English | MEDLINE | ID: mdl-35454926

ABSTRACT

INTRODUCTION: BRAF mutation involved 2-4% of lung adenocarcinoma. Differences in clinicopathologic features and patient outcome exist between V600E and non-V600E BRAF mutated NSCLC. Thus, we sought to assess the frequency and clinical relevance of BRAF mutations in a real-life population of advanced-NSCLC, investigating the potential prognostic significance of distinct genetic alterations. MATERIALS AND METHODS: The present multicenter Italian retrospective study involved advanced BRAF mutant NSCLC. Complete clinicopathologic data were evaluated for BRAF V600E and non-V600E patients. RESULTS: A total of 44 BRAFmut NSCLC patients were included (V600E, n = 23; non-V600E, n = 21). No significant differences in survival outcome and treatment response were documented, according to V600E vs. non-V600E mutations, although a trend towards prolonged PFS was observed in the V600E subgroup (median PFS = 11.3 vs. 6.0 months in non-V600E). In the overall population, ECOG PS and age significantly impacted on OS, while bone lesions were associated with shorter PFS. Compared to immunotherapy, first-line chemotherapy was associated with longer OS in the overall population, and especially in the BRAF V600E subtype. CONCLUSIONS: Here, we report on real-life data from a retrospective cohort of advanced-NSCLC harboring BRAF alterations. Our study offers relevant clues on survival outcome, therapeutic response, and clinicopathologic correlations of BRAF-mutant NSCLC.

4.
JTO Clin Res Rep ; 3(2): 100278, 2022 Feb.
Article in English | MEDLINE | ID: mdl-35199053

ABSTRACT

INTRODUCTION: ALK tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced ALK-positive NSCLC. Nevertheless, drug resistance inevitably occurs. Here, we report a case of a patient with metastatic ALK-positive lung adenocarcinoma with an impressive resistance to sequential treatment with ALK TKIs mediated by YES1 and MYC amplification in a contest of epithelial-to-mesenchymal transition and high progressive chromosomal instability. METHODS: The patient received, after chemotherapy and 7 months of crizotinib, brigatinib and lorlatinib with no clinical benefit to both treatments. A study of resistance mechanisms was performed with whole exome sequencing on different biological samples; primary cell lines were established from pleural effusion after lorlatinib progression. RESULTS: At whole exome sequencing analysis, YES1 and MYC amplifications were observed both in the pericardial biopsy and the pleural effusion samples collected at brigatinib and lorlatinib progression, respectively. Increasing chromosomal instability from diagnostic biopsy to pleural effusion was also observed. The addition of dasatinib to brigatinib or lorlatinib restored the sensitivity in primary cell lines; data were confirmed also in H3122_ALK-positive model overexpressing both YES1 and MYC. CONCLUSIONS: In conclusion, YES1 and MYC amplifications are candidates to justify a rapid acquired resistance to crizotinib entailing primary brigatinib and lorlatinib resistance. In this context, a combination strategy of ALK TKI with dasatinib could be effective to overcome a rapid resistance.

5.
Interact Cardiovasc Thorac Surg ; 35(1)2022 Jun 15.
Article in English | MEDLINE | ID: mdl-35188192

ABSTRACT

OBJECTIVES: Lung cancer is increasingly diagnosed as a second cancer. Our goal was to analyse the characteristics and outcomes of early-stage resected lung adenocarcinomas in patients with previous cancers (PC) and correlations with adenocarcinoma subtypes. METHODS: We retrospectively reviewed data of patients radically operated on for stage I-II lung adenocarcinoma in 9 thoracic surgery departments between 2014 and 2017. Overall survival (OS) and time to disease relapse were evaluated between subgroups. RESULTS: We included 700 consecutive patients. PC were present in 260 (37.1%). Breast adenocarcinoma, lung cancer and prostate cancer were the most frequent (21.5%, 11.5% and 11.2%, respectively). No significant differences in OS were observed between the PC and non-PC groups (P = 0.378), with 31 and 75 deaths, respectively. Patients with PC had smaller tumours and were more likely to receive sublobar resection and to be operated on with a minimally invasive approach. Previous gastric cancer (P = 0.042) and synchronous PC (when diagnosed up to 6 months before lung adenocarcinoma; P = 0.044) were related, with a worse OS. Colon and breast adenocarcinomas and melanomas were significantly related to a lower incidence of high grade (solid or micropapillary, P = 0.0039, P = 0.005 and P = 0.028 respectively), whereas patients affected by a previous lymphoma had a higher incidence of a micropapillary pattern (P = 0.008). CONCLUSIONS: In patients with PC, we found smaller tumours more frequently treated with minimally invasive techniques and sublobar resection, probably due to a more careful follow-up. The impact on survival is not uniform and predictable; however, breast and colon cancers and melanoma showed a lower incidence of solid or micropapillary patterns whereas patients with lymphomas had a higher incidence of a micropapillary pattern.


Subject(s)
Adenocarcinoma of Lung , Adenocarcinoma , Lung Neoplasms , Adenocarcinoma/pathology , Adenocarcinoma of Lung/pathology , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/epidemiology , Lung Neoplasms/surgery , Male , Neoplasm Staging , Prognosis , Retrospective Studies
8.
Cancers (Basel) ; 13(21)2021 Oct 28.
Article in English | MEDLINE | ID: mdl-34771566

ABSTRACT

In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC.

9.
Curr Treat Options Oncol ; 22(11): 96, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34524570

ABSTRACT

OPINION STATEMENT: The quest for immunotherapy (IT) biomarkers is an element of highest clinical interest in both solid and hematologic tumors. In non-small-cell lung cancer (NSCLC) patients, besides PD-L1 expression evaluation with its intrinsic limitations, tissue and circulating parameters, likely portraying the tumor and its stromal/immune counterparts, have been proposed as potential predictors of IT responsiveness. STK11 mutations have been globally labeled as markers of IT resistance. After a thorough literature review, STK11 mutations condition the prognosis of NSCLC patients receiving ICI-containing regimens, implying a relevant biological and clinical significance. On the other hand, waiting for prospective and solid data, the putative negative predictive value of STK11 inactivation towards IT is sustained by less evidence. The physiologic regulation of multiple cellular pathways performed by STK11 likely explains the multifaceted modifications in tumor cells, stroma, and tumor immune microenvironment (TIME) observed in STK11 mutant lung cancer, particularly explored in the molecular subgroup of KRAS co-mutation. IT approaches available thus far in NSCLC, mainly represented by anti-PD-1/PD-L1 inhibitors, are not promising in the case of STK11 inactivation. Perceptive strategies aimed at modulating the TIME, regardless of STK11 status or specifically addressed to STK11-mutated cases, will hopefully provide valid therapeutic options to be adopted in the clinical practice.


Subject(s)
Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/pathology , Immunomodulation , Lung Neoplasms/etiology , Lung Neoplasms/pathology , Tumor Microenvironment/immunology , /genetics , Animals , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/therapy , Disease Management , Disease Susceptibility , Energy Metabolism , Gene Expression Regulation, Neoplastic , Humans , Immunomodulation/genetics , Immunotherapy , Lung Neoplasms/metabolism , Lung Neoplasms/therapy , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mutation , Prognosis , Signal Transduction , Treatment Outcome , Tumor Escape/genetics , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics
10.
Future Oncol ; 17(27): 3579-3584, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34155918

ABSTRACT

Background: Alpha-fetoprotein (AFP) is the only biomarker with proven prognostic value in advanced hepatocellular carcinoma. Preliminary data indicate crosstalk between AFP and VEGF signaling. Methods: The authors looked at 69 patients with advanced hepatocellular carcinoma who were previously tested for VEGFR2 expression, had available baseline AFP serum concentrations and were treated with sorafenib within clinical trials. Results: Shorter progression-free survival and overall survival were associated with increased AFP level and elevated VEGFR2 staining. At multivariate analysis of AFP level was the only independent prognostic factor for progression-free survival and overall survival. Conclusion: The authors' study confirms the adverse prognostic role of elevated baseline AFP and also suggests a possible role of AFP in primary resistance to sorafenib therapy.


Lay abstract Alpha-fetoprotein (AFP) is a plasma protein commonly used as a tumor marker for hepatocellular carcinoma. Sorafenib is a targeted therapy used to block the growth of cancer cells in several ways. It affects various proteins on the surface of cancer cells as well as targets inside the cell. Some of these targets are involved in tumor angiogenesis (growth of new blood vessels). In the present analysis, elevated AFP plasma levels before starting sorafenib therapy were correlated with inferior survival compared with patients with low AFP levels, thus suggesting a possible role of AFP in resistance to sorafenib therapy. Using a specific antibody, the authors also studied the expression on cancer cells of VEGFR2, which is a protein involved in angiogenesis and one of the targets of sorafenib. No correlation was found between AFP level and VEGFR2 expression. The underlying mechanisms involved in resistance to sorafenib therapy still need to be clarified and deserve further studies.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Sorafenib/therapeutic use , alpha-Fetoproteins/analysis , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/blood , Drug Resistance , Humans , Liver Neoplasms/blood , Prognosis
11.
Eur J Case Rep Intern Med ; 8(5): 002498, 2021.
Article in English | MEDLINE | ID: mdl-34123940

ABSTRACT

We report the case of a 46-year-old male patient who was referred for chest pain and bilateral pleural effusion. Despite treatment with antibiotics and steroids, the pleural effusion worsened over a few months until pulmonary function was halved. The CT scan showed bilateral pleural thickening with right basal opacity. Histology revealed extensive fibrotic tissue with focal collections of lymphocytes and giant cells without traces of asbestos bodies. Since no evidence of an infectious, embolic or occupational aetiology was found, this bilateral pleural effusion progressing to diffuse pleural thickening was diagnosed as cryptogenic fibrosing pleuritis, a rare pleural disease. LEARNING POINTS: Bilateral pleural effusion progressing to diffuse pleural thickening was diagnosed as cryptogenic fibrosing pleuritis, a rare pleural disease.Cryptogenic fibrosing pleuritis was treated with high-dose corticosteroids.The patient showed stable disease at 6-year follow-up.

12.
Tumori ; : 3008916211018515, 2021 May 26.
Article in English | MEDLINE | ID: mdl-34039110

ABSTRACT

OBJECTIVE: To evaluate the influence of lung adenocarcinoma second predominant pattern on the maximal standard uptake value (SUVmax) and its prognostic effect in different histologic groups. METHODS: We retrospectively collected surgically resected pathologic stage I and II lung adenocarcinoma from nine European institutions. Only patients who underwent preoperative PET-CT and with available information regarding SUVmax of T (SUVmaxT) and N1 (SUVmaxN1) component were included. RESULTS: We enrolled 344 patients with lung adenocarcinoma. SUVmaxT did not show any significant relation according to the second predominant pattern (p = 0.139); this relationship remained nonsignificant in patients with similar predominant pattern. SUVmaxT influenced the disease-free survival in the whole cohort (p = 0.002) and in low- and intermediate-grade predominant pattern groups (p = 0.040 and p = 0.008, respectively). In the high-grade predominant pattern cohort and in the pathologic N1 cases, SUVmaxT lost its prognostic power. SUVmaxN1 did not show any significant correlation with predominant and second predominant patterns and did not have any prognostic impact on DFS. CONCLUSIONS: SUVmaxT is influenced only by the adenocarcinoma predominant pattern, but not by second predominant pattern. Concurrently, in high-grade predominant pattern and pN1 group the prognostic power of SUVmaxT becomes nonsignificant.

13.
Front Oncol ; 11: 642190, 2021.
Article in English | MEDLINE | ID: mdl-33981604

ABSTRACT

Introduction: Small cell lung cancer (SCLC) transformation represents a mechanism of resistance to osimertinib in EGFR-mutated lung adenocarcinoma, which dramatically impacts patients' prognosis due to high refractoriness to conventional treatments. Case Description: We present the case of a patient who developed a SCLC phenotypic transformation as resistance mechanism to second-line osimertinib for T790M-positive EGFR-mutated NSCLC. Our patient received platinum-etoposide doublet following SCLC switch and achieved a modest clinical benefit which lasted 4 months. NGS and IHC analyses for p53 and Rb were performed on subsequent liver biopsies, revealing baseline TP53 mutation and complete absence of p53 and Rb expression. Primary cell cultures were established following a liver biopsy at the time of SCLC transformation, and drug sensitivity assays showed meaningful cell growth inhibition when osimertinib was added to platinum-etoposide compared with control (p < 0.05). A review of the current literature regarding SCLC transformation after failure of osimertinib was performed. Conclusions: Based on retrospective data available to date, platinum-etoposide chemotherapy is the preferred treatment choice in the occurrence of SCLC transformation after osimertinib failure. The extension of osimertinib in combination with chemotherapy in the occurrence of SCLC transformation as resistance mechanism to osimertinib is a matter of debate. The combination of osimertinib and platinum-etoposide was effective in inhibiting cell growth in our primary cell cultures. Clinical studies are needed to further explore this combination in the occurrence of SCLC transformation as a resistance mechanism to osimertinib.

14.
Mol Biol Rep ; 48(4): 3485-3494, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33856606

ABSTRACT

Benign metastasizing leiomyoma (BML) is a rare disease characterized by extrauterine benign leiomyomatosis in patients with a previous or concomitant history of uterine leiomyoma. Currently, there are no specific criteria to predict the metastasizing ability of the uterine leiomyoma and the risk of malignant degeneration of pulmonary BML, and these are the aims of this study. We analyzed 10 uterine (three leiomyomas, four leiomyomas that gave rise to lung BML, three healthy tissues) and 11 pulmonary tissue samples (eight lung BML, three healthy tissues). Interestingly, one of the BML lesions exceptionally evolved into a leiomyosarcoma (case 2). Uterine leiomyoma microvascular density (MVD) was higher in the patients with uterine leiomyomas that gave rise to lung BML, reaching a peak in case 2. Strong positivity for the estrogen (ER) and progesterone (PR) receptors and a low proliferation index (Ki67 < 1%) were discovered both in patients with uterine leiomyoma and in patients with BML. Interestingly, in case 2, the last dedifferentiated leiomyosarcoma showed a weaker ER and PR positivity with a higher proliferation index (Ki67:30%). Regarding the uterine miRNA-126, a trend toward a hypo-expression between uterine leiomyoma and uterine leiomyoma that gave rise to lung BML was discovered, reaching the lowest level in case 2. Considering the pulmonary samples, we observed a higher miRNA-221 and a lower miRNA-126 expression in the leiomyosarcoma. We tried to better elucidate the biological behaviour of this rare disease. The analysis of the miRNA-221 and miRNA-126 could offer new diagnostic, prognostic and therapeutic perspectives.


Subject(s)
Biomarkers, Tumor/genetics , Leiomyoma/genetics , Lung Neoplasms/genetics , MicroRNAs/genetics , Uterine Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Female , Humans , Leiomyoma/metabolism , Leiomyoma/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/secondary , MicroRNAs/metabolism , Middle Aged , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism
15.
Clin Lung Cancer ; 22(5): 473-477, 2021 09.
Article in English | MEDLINE | ID: mdl-33762169

ABSTRACT

BACKGROUND: Alectinib is a potent anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) which is currently used in the first-line setting of advanced ALK+ non-small cell lung cancer (NSCLC). Despite favorable results in the metastatic setting, the activity of alectinib in locally-advanced ALK+ NSCLC as a neoadjuvant treatment remains to be assessed. We report the case of a patient with stage IIIA ALK+ NSCLC (cT2aN2) who received alectinib as neoadjuvant treatment, achieving major pathological response (MPR) at pathologic examination. Hence we present the treatment rationale and study design of a phase II, open-label, single-arm, multicenter clinical trial (ALNEO study, EUDRACT number 2020-003432-25). MATERIALS AND METHODS: Patients with potentially resectable stage III ALK+ NSCLC (any T with N2, T4N0-1) will be registered to receive oral alectinib 600 mg twice daily for 2 cycles of 4 weeks each (8 weeks totally) during the neoadjuvant phase. After definitive surgery, patients will enter in the adjuvant setting, during which they will receive alectinib 600 mg twice daily for 24 cycles (96 weeks). The primary endpoint is MPR, defined as ≤10% residual viable tumor cells histologically detected in the resected primary tumor and all resected lymph nodes after surgery. Secondary endpoints include pathological complete response, objective response, event-free survival, disease-free survival, overall survival, adverse events. CONCLUSIONS: Our case report supports the feasibility of alectinib as neoadjuvant treatment. ALNEO study will further explore the activity and safety of this novel treatment strategy.


Subject(s)
Carbazoles/pharmacology , Carbazoles/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Neoadjuvant Therapy , Patient Safety , Piperidines/pharmacology , Piperidines/therapeutic use , Adolescent , Adult , Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung/surgery , Female , Humans , Male , Middle Aged , Young Adult
16.
Tumori ; 108(1): 86-92, 2022 Feb.
Article in English | MEDLINE | ID: mdl-33730957

ABSTRACT

Radiomics has emerged as a noninvasive tool endowed with the potential to intercept tumor characteristics thereby predicting clinical outcome. In a recent study on resected non-small cell lung cancer (NSCLC), we identified highly prognostic computed tomography (CT) -derived radiomic features (RFs), which in turn were able to discriminate hot from cold tumor immune microenvironment (TIME). We aimed at validating a radiomic model capable of dissecting specific TIME profiles bearing prognostic power in resected NSCLC. The validation cohort included 31 radically resected NSCLCs clinicopathologically matched with the training set (n = 69). TIME was classified in hot and cold according to a multiparametric immunohistochemical analysis involving PD-L1 score and incidence of immune effector phenotypes among tumor infiltrating lymphocytes (TILs). High- throughput radiomic features (n = 841) extracted from CT images were correlated to TIME parameters to ultimately define prognostic classes. We confirmed PD-1 to CD8 ratio as best predictor of clinical outcome among TIME characteristics. Significantly prolonged overall survival (OS) was observed in patients carrying hot (median OS not reached) vs cold (median OS 22 months; hazard ratio 0.28, 95% confidence interval 0.09 -0.82; p = 0.015) immune background, thus validating the prognostic impact of these two TIME categories in resected NSCLC. Importantly, in the validation setting, three out of eight previously identified RFs sharply distinguishing hot from cold TIME were endorsed. Among signature-related RFs, Wavelet-HHH_gldm_HighGrayLevelEmphasis highly performed as descriptor of hot immune contexture (area under the receiver operating characteristic curve 0.94, 95% confidence interval 0.81 -1.00; p = 0.01). Based on our findings, Radiomics may decipher specific TIME profiles providing a noninvasive prognostic approach in resected NSCLC and an exploitable predictive strategy in advanced cases.


Subject(s)
B7-H1 Antigen/genetics , CD8 Antigens/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Tumor Microenvironment/genetics , Aged , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Disease-Free Survival , Female , Humans , Lung/diagnostic imaging , Lung/metabolism , Lung/pathology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Male , Neoplasm Staging , Prognosis , Tomography, X-Ray Computed , Tumor Microenvironment/immunology
17.
Anticancer Drugs ; 32(7): 758-762, 2021 08 01.
Article in English | MEDLINE | ID: mdl-33675607

ABSTRACT

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) used both as the first-line treatment of EGFR-mutated non-small cell lung cancer patients and in second-line after T790M-positive disease progression to first- or second-generation TKIs. Unfortunately, patients unavoidably experience disease progression to osimertinib and the current research is focused on resistance mechanisms and the relative therapeutic strategy. We report the case of a patient with advanced EGFR-mutated (exon 19 deletion and T790M-positive) non-small cell lung cancer who developed disease progression to osimertinib characterized by the loss of T790M concurrently with the emergence of G724S EGFR mutation, which was tackled by subsequent afatinib treatment. Next-generation sequencing molecular study of rebiopsy at time of progression to osimertinib revealed the persistence of EGFR exon 19 deletion, loss of T790M with a new G724S EGFR mutation; other concomitant mechanisms were excluded. Retrospective analysis of cell-free DNA revealed the emergence of G724S EGFR mutation four months before the radiologically-proven disease progression. The patient, after chemotherapy, was treated with afatinib with clinical and radiological benefit. Our case report contributes to increase the knowledge on acquired resistance mechanisms to osimertinib treatment, and it shows, for the first time, the efficacy of afatinib in the case of T790M loss and emergence of G724S EGFR mutation.


Subject(s)
Afatinib/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Acrylamides/therapeutic use , Aniline Compounds/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Exons , Humans , Lung Neoplasms/genetics , Male , Middle Aged
18.
J Surg Oncol ; 123(2): 560-569, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33169397

ABSTRACT

BACKGROUND AND OBJECTIVES: Adenocarcinoma patterns could be grouped based on clinical behaviors: low- (lepidic), intermediate- (papillary or acinar), and high-grade (micropapillary and solid). We analyzed the impact of the second predominant pattern (SPP) on disease-free survival (DFS). METHODS: We retrospectively collected data of surgically resected stage I and II adenocarcinoma. SELECTION CRITERIA: anatomical resection with lymphadenectomy and pathological N0. Pure adenocarcinomas and mucinous subtypes were excluded. Recurrence rate and factors affecting DFS were analyzed according to the SPP focusing on intermediate-grade predominant pattern adenocarcinomas. RESULTS: Among 270 patients, 55% were male. The mean age was 68.3 years. SPP pattern appeared as follows: lepidic 43.0%, papillary 23.0%, solid 14.4%, acinar 11.9%, and micropapillary 7.8%. The recurrence rate was 21.5% and 5-year DFS was 71.1%. No difference in DFS was found according to SPP (p = .522). In patients with high-grade SPP, the percentage of SPP, age, and tumor size significantly influenced DFS (p = .016). In patients with lepidic SPP, size, male gender, and lymph-node sampling (p = .005; p = .014; p = .038, respectively) significantly influenced DFS. CONCLUSIONS: The impact of SPP on DFS is not homogeneous in a subset of patients with the intermediate-grade predominant patterns. The influence of high-grade SPP on DFS is related to its proportion in the tumor.


Subject(s)
Adenocarcinoma of Lung/pathology , Adenocarcinoma, Papillary/pathology , Carcinoma, Acinar Cell/pathology , Databases, Factual , Lung Neoplasms/pathology , Neoplasm Recurrence, Local/pathology , Adenocarcinoma of Lung/surgery , Adenocarcinoma, Papillary/surgery , Aged , Carcinoma, Acinar Cell/surgery , Europe , Female , Follow-Up Studies , Humans , Lung Neoplasms/surgery , Male , Neoplasm Recurrence, Local/surgery , Prognosis , Retrospective Studies , Survival Rate
19.
Oncol Lett ; 20(5): 194, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32952663

ABSTRACT

Thromboembolic events are frequent in patients with cancer, commonly involving the venous and pulmonary circulation. The arterial system is rarely implicated in embolism and, when involved, a cardiogenic origin should always be excluded. In the present study, a case of a patient who developed multiple embolic events concomitantly with the diagnosis of locally-advanced non-small cell lung cancer with high expression levels of programmed death-ligand 1 (PD-L1) in >50% of tumor cells is reported. A cardiac defect interpreted as a patent foramen ovale required low molecular weight heparin administration. Despite the anti-coagulant therapy, before first-line anticancer treatment with pembrolizumab immunotherapy could be administered due to high PD-L1 expression levels, a new hospitalization was required due to the onset of novel ischemic manifestation. New transthoracic and transesophageal echocardiography revealed a previously misdiagnosed vegetation of the mitral valve that caused systemic embolization. The lack of any sign of infection led to the diagnosis of a non-bacterial thrombotic endocarditis (NBTE), whose embolic sprouting gave rise to the widespread ischemic events. No active anticancer treatment was feasible due to the rapid progression of the disease. NBTE can evolve quickly, eventually preventing any chance of treatment targeting the primary cause, which in the present study was lung cancer. If NBTE can be correctly diagnosed sooner then there may be the potential for anticancer therapy that does not worsen the hypercoagulability state, thus improving cancer-associated survival.

20.
Immunotherapy ; 2020 Jul 28.
Article in English | MEDLINE | ID: mdl-32723023

ABSTRACT

Background: The abscopal effect consists of distant metastases response after local treatment based on systemic immune stimulation. It is a rare event observed in many tumors, especially with radiotherapy and immunotherapy. Clinical case: We report the long-term abscopal effect in a metastatic renal cell carcinoma patient with lung metastasectomy, after hypofractionated radiotherapy on lymph node metastasis. The patient was pretreated with pazopanib, which was discontinued early owing to toxicity before radiotherapy. Methodology: Immunohistological analyses of the primary tumor and metastases were performed. Discussion: We supposed that radiotherapy, and maybe tyrosine kinase inhibitors, could act as immune-primers for abscopal effect modifying the immune tumor microenvironment. Conclusion: Future studies are needed to optimize the combination of radiotherapy with systemic therapy for better long-term tumor control in selected patients.

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