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LESSONS LEARNED: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen. BACKGROUND: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m2 for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS). RESULTS: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period. CONCLUSION: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Humanos , Japão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Paclitaxel/uso terapêuticoRESUMO
Gemcitabine is widely accepted as the standard treatment for pancreatic cancer, but it can cause unpredictable side effects. Acute respiratory distress syndrome is a rare complication with gemcitabine, but is sometimes fatal. We describe a cured case of acute, severe gemcitabine-induced pulmonary toxicity. The patient was a 76-year-old man with pancreatic cancer who was receiving adjuvant gemcitabine chemotherapy after surgery. The patient received gemcitabine 1,000 mg/m2 on days 1, 8, and 15 for three 4-week cycles, with intervals of 1 week. He developed severe general fatigue on day 1 of the third cycle. Computed tomography showed diffuse ground-glass opacity with pleural effusion. There was no increase in ß-D-glucan, and cytomegalovirus antigenemia assays were negative. No bacteria or acid-fast bacilli were found. The number of eosinophils in bronchoalveolar lavage fluid was increased. Considering these data, we diagnosed eosinophilic pneumonia induced by gemcitabine. The patient was immediately treated with a steroid and neutrophil elastase inhibitor under respiratory supportive therapy. After 4 weeks, his pulmonary symptoms were markedly improved. Physicians should be cognizant of the possible association of serious pulmonary toxicity with gemcitabine treatment. A delay in diagnosis and treatment could lead to a fatal outcome.
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Antimetabólitos Antineoplásicos/efeitos adversos , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Eosinofilia Pulmonar/induzido quimicamente , Idoso , Desoxicitidina/efeitos adversos , Humanos , Masculino , Neoplasias Pancreáticas/complicações , Prognóstico , Eosinofilia Pulmonar/tratamento farmacológico , Tomografia Computadorizada por Raios X , GencitabinaRESUMO
BACKGROUND: Etoposide plus cisplatin (EP) combined with concurrent accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard treatment strategy for unresectable limited-disease (LD) small cell lung cancer (SCLC), which has remained unchanged for over two decades. Based on a previous study that confirmed the non-inferiority of amrubicin (AMR) plus cisplatin (AP) when compared with EP for extensive-disease (ED) SCLC, we have previously conducted a phase I study assessing AP with concurrent TRT (2 Gy/time, once daily, 50 Gy in total) for LD-SCLC therapy. Our findings revealed that AP with concurrent TRT could prolong overall survival to 39.5 months with manageable toxicities. Therefore, we plan to conduct a phase I study to investigate and determine the effect of AP combined with AHTRT, recommended dose (RD), maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) of AP in patients with LD-SCLC. METHODS: Treatment-naive patients with LD-SCLC, age between 20 and 75 years, who had a performance status of 0 or 1 and adequate organ functions will be enrolled. For chemotherapy, cisplatin 60 mg/m2 /day (day 1) and AMR (day 1 to 3) will be administered with AHTRT (1.5 Gy/time, twice daily, 45 Gy in total). The initial AMR dose is set to 25 mg/m2 /day. RD and MTD will be determined by evaluating toxicities. DISCUSSION: Based on our previous study, the initial dose of AMR 25 mg/m2 is expected to be tolerated and acceptable. Here, we aim to determine whether treatment with AP and concurrent AHTRT would be an optimal choice with manageable toxicities for LD-SCLC.
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Quimiorradioterapia , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Adulto , Idoso , Antraciclinas , Quimiorradioterapia/efeitos adversos , Cisplatino/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Etoposídeo , Humanos , Neoplasias Pulmonares/terapia , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/terapia , Adulto JovemRESUMO
A 54-year-old man was admitted to Saga University hospital with dyspnea on effort and a sensation of pressure in the chest. Chest CT images showed a low-density mass in the mediastinum surrounding the carina and left hilus, causing narrowing of both the left pulmonary artery and left main bronchus. The pathological findings from a surgical biopsy showed markedly fibrotic tissue with lymphocytes and plasmacytes, and we diagnosed idiopathic fibrosing mediastinitis, stage II. Oral glucocorticoid treatment of 30 mg/day prednisolone reduced the mass and improved the narrowing of the left pulmonary artery and left main bronchus. The patient was given low-dosage glucocorticoids as maintenance treatment. Previous reports indicated that idiopathic fibrosing mediastinitis with severe tissue fibrosis is difficult to control with glucocorticoid monotherapy. Here, we report a case of idiopathic fibrosing mediastinitis that was effectively treated with glucocorticoids.
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Glucocorticoides/uso terapêutico , Mediastinite/tratamento farmacológico , Prednisolona/uso terapêutico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIM: Afatinib, a 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of non-small cell lung cancer (NSCLC), causes diarrhoea in over 90% of patients. The association of genetic background with diarrhoea is poorly understood. PATIENTS AND METHODS: We evaluated the roles of four single nucleotide polymorphisms (SNPs) in ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily G member 2 (ABCG2) genes-ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T, and ABCG2 421 C>A-on treatment-induced diarrhoea in 38 patients with NSCLC treated with afatinib. RESULTS: Diarrhoea occurred more frequently in patients with ABCB1 2677 T(A)/T(A) (14/16, 87.5%) than in patients with non-T(A)/T(A) alleles (8/22, 36.4%) (p=0.003). ABCB1 2677 T(A)/T(A) was significantly predictive of diarrhoea (p=0.002) by multivariable regression analysis. CONCLUSION: Afatinib-induced diarrhoea is associated with the SNP ABCB1 2677 T(A)/T(A).
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Afatinib/efeitos adversos , Antineoplásicos/efeitos adversos , Diarreia/etiologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/efeitos adversos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Diarreia/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Razão de Chances , Inibidores de Proteínas Quinases/uso terapêuticoAssuntos
Medula Óssea/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Biópsia por Agulha , Diagnóstico Diferencial , Feminino , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/diagnóstico , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: Immune-related adverse events (irAEs) should be anticipated with treatment by immune checkpoint inhibitors (ICIs). Although the relationship between irAEs and efficacy of ICI has been reported, it has not yet been clarified whether the benefit from ICI outweighs the low frequency of proceeding to subsequent therapies after discontinuation due to irAEs. METHODS: The study comprised 61 patients with non-small cell lung cancer who underwent treatment with ICIs (nivolumab or pembrolizumab monotherapy) at the Saga University Medical School Hospital from December 2015 to January 2018. Therapeutic effect and progression-free survival (PFS) were compared between the irAEs discontinuation group (AEg) and the group with discontinuation due to all causes other than irAEs (Non-AEg). RESULTS: A total of 30% patients(18/61) had therapy discontinued due to irAEs: 22.5% (9/40) with nivolumab and 42.9% (9/21) with pembrolizumab. The response rate was 50.0% in the AEg and 8.1% in the on-AEg (P = 0.001). The median PFS was significantly longer in the AEg (9.3 months; 95% CI 2.1-12.1) than in the non-AEg (1.9 months; 95% CI 0.9-3.6): HR 0.45 (95%CI 0.20-0.89; log-rank test P = 0.026). The prevalence of drug-induced interstitial lung disease (ILD) was 6.1% (3/49) in cases without interstitial pneumonia (IP) as the underlying disease, whereas it was 50% (6/12) in cases with IP (P = 0.001). CONCLUSION: Discontinuation of treatment with ICIs due to irAEs predict a good response to ICIs and favorable outcome since their anti-cancer effects continue even after discontinuation. However, the presence of IP as the underlying disease increases the risk of drug-related ILD onset.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Imunoterapia/efeitos adversos , Doenças Pulmonares Intersticiais/patologia , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Seguimentos , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Suspensão de TratamentoRESUMO
Paraneoplastic limbic encephalitis (PLE) is a rare neurologic disorder that can complicate various malignancies, including lung cancer. PLE is most frequently found the initial presentation of lung cancer. In this study, we reported the case of a 74-year-old Japanese woman who developed PLE after partial remission of small cell lung cancer (SCLC) by first-line systemic chemotherapy. Brain magnetic resonance imaging showed no metastatic tumor or cerebrovascular disease. Anti-glutamic acid decarboxylase (GAD) and anti-amphiphysin antibodies were detected in her serum. She was diagnosed as having PLE related to the recurrence of SCLC and received high-dose glucocorticoid, and sequentially systemic chemotherapy with amrubicin. Unfortunately, these treatments did not improve her disease progression and she died 4 months later. Although PLE rarely occurs at the time of SCLC recurrence, physicians should pay attention to PLE onset even after chemotherapy.
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Epidermal growth factor receptor (EGFR) mutations in lung cancer enhance tyrosine kinase activity and increase sensitivity to the EGFR tyrosine kinase inhibitor, gefitinib. Mutation analysis of the EGFR gene is therefore indispensable for predicting gefitinib response. We investigated a CA-repeat polymorphism in the EGFR gene related to EGFR mutations. Because an increasing number of CA-repeats at intron 1 of the EGFR gene has been reported to reduce transcription activity, we examined the relationship between EGFR mutations and this CA-repeat polymorphism. EGFR mutations at exon 19 were closely associated with shorter CA-repeat length in the shorter allele, but this was not the case for EGFR mutations at exons 18 or 21. Increased intrinsic EGFR mRNA expression in non-cancerous lung tissues from lung adenocarcinoma patients was also significantly associated with shorter CA-repeat length. A higher frequency of EGFR mutations at exon 19 was associated with shorter CA-repeat length only in patients with high levels of EGFR mRNA expression. To determine the phenotypes of cells possessing shorter CA-repeats, an in vitro study using human bronchial epithelial cells with different CA-repeat lengths was performed; more rapid cell growth and activated EGF/EGFR signaling were found more often in the cells having both shorter CA-repeats and increased EGFR mRNA expression. These results suggest that CA-repeat length in the EGFR gene may be a genetic factor related to cancer in the case of EGFR mutations at exon 19. The mechanism likely involves enhanced intrinsic expression of EGFR mRNA and activated EGF/EGFR signaling that accompany shorter CA-repeats.
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Repetições de Dinucleotídeos/genética , Receptores ErbB/genética , Éxons/genética , Íntrons/genética , Neoplasias Pulmonares/genética , Mutação/genética , Polimorfismo Genético/genética , Adenocarcinoma/genética , Adenocarcinoma/secundário , Idoso , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Brônquios/citologia , Brônquios/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundário , Células Cultivadas , DNA de Neoplasias/genética , Células Epiteliais/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Derrame Pleural Maligno/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/secundárioRESUMO
A pilot study of irinotecan hydrochloride(CPT-11)and cisplatin(CDDP)combination chemotherapy had been performed for previously treated non-small cell lung cancer. CPT-11(60 mg/m(2))and CDDP(30 mg/m(2))were administered on days 1 and 15 every 28 days, and the combination chemotherapy was repeated up to 4 courses. The efficacy and safety of this pilot study based on outpatient therapy were evaluated. Eleven patients were entered, and the median number of courses was 3 courses. Severe adverse reactions(grade 3 or higher)were 33% for neutropenia, and 9.1% for leukopenia, anemia, diarrhea, fatigue, and vomiting. A case with grade 3 diarrhea needed hospital admission for a short period, and thereafter outpatient therapy could continue. The efficacy of this study was 73% of SD and 27% of PD, and MST was 358 days. These results suggest that this protocol could be carried out as outpatient therapy, and may contribute to prolonged survival time.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/efeitos adversos , Feminino , Humanos , Irinotecano , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Taxa de SobrevidaRESUMO
A 72-year-old Japanese woman was noted to have multiple cystic lung shadows and infiltrates on chest radiography and computed tomography (CT). She complained of dryness of the mouth and eyes, but she did not have respiratory symptoms, such as cough, sputum production, and dyspnea. Her laboratory findings showed high titers of anti-SSA/Ro and anti-SSB/La antibodies. Surgical lung biopsy was performed and demonstrated pathologic findings of amyloid light-chain deposition and bronchiolitis with lymphocytic infiltration. Taken altogether, she was diagnosed as Sjögren syndrome with bronchiolitis and pulmonary amyloidosis. Since then, she has been carefully followed up without treatment. After 6 years, the cystic lung lesions on CT gradually enlarged and increased in number, but she remained to have no respiratory symptoms and no manifestations of lymphoma. Here, we report a rare case of Sjögren syndrome complicated with cystic lung disease and pulmonary amyloidosis.
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Although mechanisms of acquired resistance to 1st and 3rd generation EGFR-TKI continue to be elucidated, there have been few clinical investigations into the mechanisms of acquired resistance to the 2nd generation EGFR-TKI afatinib. We analyzed data from 20 patients with advanced lung adenocarcinoma who acquired resistance to afatinib, including resistance during EGFR-TKI re-challenge. We examined EGFR T790M and C797S mutations, BRAF V600E mutation, and MET amplification with the MBP-QP method and with droplet digital PCR using ctDNA and re-biopsy samples obtained before and after afatinib treatment. Just before afatinib treatment, 15 of the 20 patients were T790M negative and five were positive. Among the T790M negative patients, 40.0% (6/15) became positive at the time of PD under afatinib. In patients positive for T790M, changes in T790M allele frequency were correlated with afatinib treatment efficacy. C797S was not detected in any patients just before afatinib treatment, but it appeared after treatment in three patients, although with very low allele frequency. Two of these three patients, although positive for both C797S and T790M, achieved PR to osimertinib. However, PFS of these patients was somewhat shorter than that of patients positive for T790M only. BRAF V600E was detected in one patient at PD under afatinib. MET amplification was not detected in this study. T790M is associated with acquired resistance to afatinib, as with 1st generation EGFR-TKI, but with somewhat lower frequency. The influence of C797S on resistance to afatinib is less than that of T790M, but C797S might cause shorter PFS under osimertinib.
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Afatinib/farmacologia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Acrilamidas , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Antineoplásicos/uso terapêutico , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/isolamento & purificação , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Frequência do Gene , Humanos , Biópsia Líquida , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Reação em Cadeia da Polimerase , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Despite treatment, pulmonary nocardiosis, which is a rare opportunistic disease caused by Nocardia species, has poor clinical outcomes including recurrence and death. Currently, the treatment regimen and duration for pulmonary nocardiosis are not fully understood. The present study aimed to clarify the factors related to the clinical outcome of pulmonary nocardiosis. METHODS: The medical records of 24 patients with pulmonary nocardiosis were retrospectively reviewed. The patients were divided into two groups based on the outcomes within 2 years: patients with controlled disease (n = 14) and patients who developed recurrence or died (n = 10). RESULTS: Nocardia was identified by 16S ribosomal RNA sequencing in 17 patients (70.8%) and by conventional biochemical test in five patients (20.8%). The patients' characteristics, clinical findings, radiological features, and treatment history were not different between the two groups. Compared with patients who developed recurrence or died, those with controlled disease had significantly longer total duration of treatment with antibiotics, especially trimethoprim/sulfamethoxazole (67.5 ± 111.6 days vs. 9.0 ± 6.5 days; p = 0.01). Pancytopenia was the most frequent adverse effect of trimethoprim/sulfamethoxazole. CONCLUSIONS: Longer duration of trimethoprim/sulfamethoxazole treatment was significantly associated with better outcomes of pulmonary nocardiosis. In such cases, antibiotics, especially trimethoprim/sulfamethoxazole, should be administered for more than 3 months.
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Antibacterianos/administração & dosagem , Nocardiose/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nocardia/genética , Nocardia/isolamento & purificação , Nocardiose/microbiologia , Pancitopenia/induzido quimicamente , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Combinação Trimetoprima e Sulfametoxazol/efeitos adversosRESUMO
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare disease that shows hypoxia with severe pulmonary hypertension related to malignant tumor. Diagnosis is difficult due to rapid clinical progression and the need to demonstrate pathological findings from lung biopsy. A 64-year-old woman visited our hospital with hypoxia and pulmonary hypertension. Diffuse granular shadows in the centrilobular area and ground-glass shadows in both lungs and left ovarian tumor were found on radiological imaging. PTTM was suspected, but pulmonary artery blood aspiration by right cardiac catheter failed to detect cancer cells. We could not obtain lung or ovary biopsies because of hypoxia or pulmonary hypertension. The patient died due to respiratory failure. Signet ring cell carcinoma of unknown primary, PTTM, and Krukenberg tumor were diagnosed on autopsy. Since early diagnosis facilitates adequate treatment, physicians should not miss the opportunity for biopsy in cases of suspected PTTM.
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We report a case of initial lung adenocarcinoma in which transformation to small cell lung carcinoma (SCLC) was observed after acquired resistance to the 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and alternating treatment between chemotherapy and osimertinib was effective. A 61-year-old woman with EGFR mutation positive stage IV lung adenocarcinoma was administered 1st generation EGFR-TKI for 8 months as the first line therapy, then chemotherapy and 2nd generation EGFR-TKI after progressive disease (PD). Four years after initial diagnosis, EGFR T790M was detected in a metastatic lesion of the right thoracic wall and osimertinib was prescribed. Although partial response (PR) was achieved, a new metastatic lesion appeared in the right pleurum near the diaphragm, in which SCLC characteristics were observed with elevation of pro-gastrin-releasing peptide (pro-GRP) at the time of PD under osimertinib. Osimertinib was discontinued and carboplatin plus irinotecan chemotherapy was chosen as the next treatment, leading to PR after 2 cycles. Subsequently, the right thoracic wall tumor harboring T790M and the right pleural tumor near the diaphragm showing transformation to SCLC exhibited opposite responses to therapy alternating between osimertinib and chemotherapy. It is concluded that extended disease control can be achieved by combining appropriate treatments according to the mechanisms of resistance inferred from precise genetic and pathological examination in real time.
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The clinical utility of plasma DNA for detecting cancer-specific mutations has rapidly achieved recognition, but reliability has not been established because of relatively low mutation-detection rates compared with those from tissue re-biopsy. To address this shortcoming we examined efficiency, in terms of mutation detection, of an automated DNA extraction system that uses cellulose magnetic beads. A fully automated, highly sensitive point-mutation-detection method, mutation-biased PCR and quenching probe (MBP-QP) system, was used for this study. Plasma DNA was extracted from 61 plasma samples collected from patients with advanced non-small cell lung cancer. Extraction was performed manually with 200 µl plasma (200-M) by using a silica membrane spin column system or an automated system using 200 µl (200-A) or 1000 µl (1000-A) plasma. Median DNA yield quantified by real-time PCR was 4.4, 4.5, and 17.3 ng with the three methods, respectively. Sensitivity for detecting epidermal growth factor receptor (EGFR) L858R point mutation was 36.6%, 58.5%, and 77.5%, and specificity was 93.3%, 100%, and 96.7%, respectively. Concordance rates were 60.6%, 76.1%, and 85.7%. The size distribution of plasma DNA with automated extraction was bimodal with modes at about 170 bp and 5 Kb, and plasma DNA of both sizes included tumor-derived DNA. In this report, we demonstrate that automated DNA extraction using cellulose magnetic beads can improve mutation-detection rates with plasma DNA in association with two overall sizes of DNA fragments recovered by this DNA isolation system. Examining the biological characteristics of these fragments will be the subject of further investigation.
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BACKGROUND/AIM: The purpose of this study was to consider appropriate application of liquid and re-biopsy through analysis of current status in practice. PATIENTS AND METHODS: We performed a retrospective analysis of 22 patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who exhibited 1st/2nd generation EGFR-tyrosine kinase inhibitors resistance. The cobas® method was used to detect T790M with re-biopsy and the mutation-biased PCR and quenched probe method was used with liquid biopsy. RESULTS: T790M detection rate was 52% with re-biopsy and 58% with liquid biopsy. The concordance between tissue and plasma was 58%. One patient who was T790M-positive with liquid biopsy showed heterogeneity among metastatic lesions in terms of osimertinib efficacy, as revealed by T790M detection with re-biopsy. CONCLUSION: Liquid biopsy reflects the whole body, whereas re-biopsy is useful for spatial diagnosis. Considering these characteristics, a combination of liquid and re-biopsy contribute to enhanced treatment.
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Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Biomarcadores Tumorais/sangue , Biópsia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Biópsia Líquida , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Estudos RetrospectivosRESUMO
Liquid biopsy with circulating free DNA (cfDNA) is a recommended alternative method of re-biopsy. Quality control with cfDNA is indispensable for precise examinations, and it is desirable to achieve high-quality cfDNA separation. We investigated two issues: the influence of pre-analytical procedures on cfDNA analysis performed as a routine procedure in a standard clinical laboratory, and the extent of deterioration of cfDNA quality due to long-term storage. Comparisons among blood collection tube types, storage temperatures, and periods of blood separation were performed in terms of cfDNA quantification, cfDNA size distribution, and detection of EGFR mutations. Quality of cfDNA was better with collection tubes containing 3.2% sodium citrate than with those containing EDTA 2K, and was maintained with storage at 4° C for up to 72 h after blood collection, equivalent to results with cell-stabilizing blood collection tubes. Analysis of cfDNA stored for 7 years showed that samples with low allele frequency (AF) deteriorated more readily than samples with high AF. Despite the same storage period and extraction method, AF of plasma stored for 7 years was remarkably lower than that of cfDNA. However, deterioration due to long-term plasma storage was overcome by changing the DNA extraction method from a silica membrane spin column to a cellulose magnetic beads system. These results can guide the establishment of standardized pre-analytical procedures for liquid biopsy with cfDNA.
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A 76-year-old asymptomatic man was found to have a mass in the right lower lung field. Although the presence of a mucinous component in the majority of the tumor was shown by magnetic resonance imaging, the presence of cancer cells was suspected by contrast enhancement on computed tomography (CT) and based on the partial accumulation in the marginal regions of the tumor on fluorodeoxyglucose-positron emission tomography (FDG-PET). A transbronchial lung biopsy was non-diagnostic, but resection of the mass resulted in a diagnosis of colloid adenocarcinoma. The findings from combined contrast CT and FDG-PET may raise the suspicion of colloid adenocarcinoma and prompt the consideration of surgical resection.
Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma Mucinoso/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Adenocarcinoma de Pulmão/cirurgia , Adenocarcinoma Mucinoso/cirurgia , Idoso , Doenças Assintomáticas , Meios de Contraste , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/cirurgia , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X/métodosRESUMO
OBJECTIVES: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m2) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL-1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation. RESULTS: In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m2, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2-85.9%), median progression-free survival was 11.8 months (60% CI, 10.6-16.2 months; 95% CI, 8.2-20.8 months), and median overall survival was not reached. CONCLUSION: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.