ABSTRACT
BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.
Subject(s)
Neoplasms , Humans , Male , Female , Adolescent , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Prospective Studies , Neoplasms/therapy , Immunotherapy, Adoptive , Treatment OutcomeABSTRACT
The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCRαß genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαß and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCRαß-CD8 γδT cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-γ against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαß-CD8 transduced γδT cells (TCRαß-CD8 γδT cells) were intravenously injected. Growth inhibition of KK-LC-1+ , HLA-B15+ lung cancer cells was confirmed in mice with injection of the TCRαß-CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαß-CD8 γδT cells injection. These results suggested that apoptosis of Fas-positive TCRαß-CD8 γδT cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells.
Subject(s)
Antigens, Neoplasm/immunology , Lung Neoplasms/etiology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Animals , Cell Line, Tumor , Cytokines/metabolism , Disease Models, Animal , Humans , Immunomodulation , Immunotherapy, Adoptive , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Lymphocytes, Tumor-Infiltrating/pathology , Mice, Transgenic , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Transduction, Genetic , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND/AIM: In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cell vaccination in combination with standard therapies in terms of the survival of patients with advanced or recurrent endometrial and cervical cancers of the uterus. PATIENTS AND METHODS: A total of 187 patients with advanced or recurrent uterine cancer were enrolled in this study. The correlation between overall survival and various clinical factors was examined by univariate and multivariate analyses. RESULTS: Univariate analysis revealed that the prognosis was improved in uterine cancer patients who received immune-cell therapy without prior chemotherapy or without distant metastasis. Multivariate analysis demonstrated that the absence of prior chemotherapy for endometrial cancer and liver/lung metastasis of cervical cancer are indications for immune-cell therapy. CONCLUSION: Survival benefit in uterine cancer patients could be potentially obtained by a combination of immune-cell therapy with other therapies.
Subject(s)
Endometrial Neoplasms/pathology , Uterine Cervical Neoplasms/pathology , Uterine Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Cell- and Tissue-Based Therapy/methods , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/pathology , Prognosis , Retrospective Studies , T-Lymphocytes/pathology , Treatment Outcome , Uterus/pathologyABSTRACT
BACKGROUND/AIM: We aimed to investigate the efficacy of immune-cell therapy in terms of the survival of patients with neuroendocrine carcinoma of the uterine cervix (NECC), which lacks standardized therapeutic approaches. PATIENTS AND METHODS: We identified 17 patients who were diagnosed as having NECC and treated with immune-cell therapy. The clinical characteristics of these patients were extracted from their records and their overall survival was measured. RESULTS: Of the 17 patients, two patients with early-stage NECC without recurrence and three patients with less than four treatments were excluded. The median survival times from the time of diagnosis and from the initial administration of immune-cell therapy were 49.7 and 24.4 months, respectively. The overall survival rates at 1, 2, and 5 years were 63.6%, 38.2%, and 25.5%, respectively. Long-term survival was observed in the patients with distant metastases. CONCLUSION: The preliminary results of this retrospective study suggested the potential efficacy of immune-cell therapy for NECC.
Subject(s)
Carcinoma, Neuroendocrine/immunology , Carcinoma, Neuroendocrine/therapy , Cervix Uteri/pathology , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/therapy , Adult , Carcinoma, Neuroendocrine/pathology , Cell- and Tissue-Based Therapy/methods , Female , Humans , Immunotherapy, Adoptive/methods , Middle Aged , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging/methods , Prognosis , Uterine Cervical Neoplasms/pathologyABSTRACT
BACKGROUND/AIM: Chemoimmunotherapy is a promising treatment for various malignant diseases. In this study, we examined whether first-line chemoimmunotherapy using adoptive immune-cell therapy was effective for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The therapeutic efficacy and safety of the standard first-line chemoimmunotherapy with adoptive αß T cell therapy and bevacizumab were assessed using thirty-two patients with mCRC in our hospital. Immunological status after this chemoimmunotherapy was also evaluated. RESULTS: The response and disease control rates were 68.8% and 87.5%, respectively. Further, median progression-free and overall survival were 14.2 and 35.3 months. Immunotherapy-associated toxicity was minimal. Significant decrease in the change of monocyte number (p=0.006) and increase in the change of rate of lymphocyte-to-monocyte ratio (p=0.039) were seen in the complete response group. CONCLUSION: First-line chemoimmunotherapy with adoptive αß T cell therapy may be useful for mCRC.
Subject(s)
Colorectal Neoplasms/immunology , Colorectal Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Female , Fluorouracil/therapeutic use , Humans , Immunotherapy/methods , Lymphocytes/drug effects , Lymphocytes/immunology , Male , Middle Aged , Monocytes/drug effects , Monocytes/immunology , Progression-Free SurvivalABSTRACT
BACKGROUND AIMS: Activated γδT cells have been shown to exhibit cytotoxicity against tumor cells. However, the efficacy of γδT cell immunotherapy for a large number of patients with solid tumors remains unclear. In this study, we examined the efficacy of γδT cell immunotherapy using in vitro-activated γδT lymphocytes in combination with standard therapies in terms of the survival of patients with solid tumors, and determined prognostic factor for γδT cell immunotherapy. METHODS: 131 patients enrolled in this study received γδT cell immunotherapy with or without standard therapies. Their overall survival was analyzed by the Kaplan-Meier with log-rank test and Cox regression methods. Immunological analysis was performed by flow cytometry (FCM) before and after six cycles of γδT cell immunotherapy. RESULTS: Multivariable analysis revealed that patients who showed stable disease (SD) and partial response (PR) to γδT cell immunotherapy showed better prognosis than those with a progressive disease (PD) (P = 0.0269, hazard ratio [HR], 0.410, 95% confidence interval [CI], 0.190-0.901). Furthermore, when immunological parameters were examined by FCM, the high Vγ9/γδT ratio (i.e., the high purity of the Vγ9 cells within the adoptively transferred γδT cells) before treatment was found to be a good prognostic factor for γδT cell immunotherapy (P = 0.0142, HR, 0.328, 95% CI, 0.125-0.801). No serious adverse events were reported during γδT cell immunotherapy. CONCLUSION: Thus, γδT cell immunotherapy might extend the survival of patients with solid tumors.
Subject(s)
Immunotherapy/methods , Neoplasms/therapy , T-Lymphocytes/transplantation , Adult , Aged , Aged, 80 and over , Female , Flow Cytometry , Humans , Immunotherapy, Adoptive , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasms/immunology , Neoplasms/mortality , Prognosis , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Retrospective Studies , T-Lymphocytes/immunology , Treatment OutcomeABSTRACT
Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen (CTA) and predominant target for cancer immunotherapy. Our previous study indicated that KK-LC-1 was expressed in 82% of gastric cancers, and also in 79% of early stage of gastric cancers, with a correlation to Helicobacter pylori (H. pylori) infection. In addition, we found that KK-LC-1 was occasionally expressed at non-tumour sites of stomachs carrying tumours. Here, we investigated the characteristics of KK-LC-1 expression at non-tumour sites and the clinical utility of these phenomena. The gene expression of KK-LC-1 was detected at the non-tumour sites including pyloric glands. The most detectable corpus/gland subset had a KK-LC-1 expression rate of 77% in the pyloric gland of the lower corpus where H. pylori preferentially exists. KK-LC-1 expression rates were 67% or 32% with or without intestinal metaplasia, which also induced by H. pylori, respectively. Consequently, KK-LC-1 would be detected at the pre-cancerous condition of the stomach, and may be a useful marker to predict gastric cancer.
Subject(s)
Antigens, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Stomach Neoplasms/genetics , Stomach/pathology , Antigens, Neoplasm/analysis , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Helicobacter Infections/complications , Helicobacter pylori/isolation & purification , Humans , Prognosis , Stomach Neoplasms/complications , Stomach Neoplasms/diagnosis , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND/AIM: Various types of chemoimmunotherapies for malignant tumors have been reported. However, there are few reports on hepatectomy after chemoimmunotherapy. We evaluated the safety and efficacy of hepatectomy for patients with stage IV colorectal liver metastases (CLM) after chemoimmunotherapy using activated αß T-cells. PATIENTS AND METHODS: From June 2012 to December 2016, five patients who underwent hepatectomy after receiving capecitabine and oxaliplatin (XELOX) plus bevacizumab and ex vivo-expanded αß T-lymphocytes as first-line chemoimmunotherapy were included. RESULTS: The median age of the five patients (two men, three women) was 61.4 (range=56-75) years. The surgical procedure was partial hepatectomy in two, laparoscopic partial hepatectomy in two, and one case of partial hepatectomy with subsegmentectomy. There was no postoperative complication of Clavien-Dindo grade 3A or higher. One patient had multiple lung metastases. CONCLUSION: Hepatectomy after chemoimmunotherapy using activated αß T-cells for CLM can be performed safely.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colorectal Neoplasms/therapy , Immunotherapy, Adoptive/methods , Liver Neoplasms/secondary , Liver Neoplasms/surgery , T-Lymphocyte Subsets/transplantation , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/administration & dosage , Bevacizumab/therapeutic use , Capecitabine , Combined Modality Therapy , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Fluorouracil/therapeutic use , Hepatectomy , Humans , Male , Middle Aged , Oxaloacetates , Treatment OutcomeABSTRACT
BACKGROUND: Adoptive immunotherapy for cancer has evolved through development of novel technologies for generating a large number of activated killer cells, such as αß T-cells, γδ T-cells, and natural killer cells. There has been no prospective trial of combination therapy involving adoptive immunotherapy and first-line chemotherapy for stage IV colorectal cancer. The present pilot study aimed to evaluate the safety and feasibility of combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer (COMVI study). PATIENTS AND METHODS: The COMVI study was a prospective, single-arm pilot trial. Therapy in each 21-day treatment cycle involved XELOX (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1-14), bevacizumab (7.5 mg/kg on day 1), and αß T-lymphocytes (over 5×109 on day 18) cultured ex vivo with an immobilized antibody to CD3 and interleukin-2. RESULTS: The study included six patients (two men and four women) between June 2013 and September 2014. The median patient age was 68 years (range=55-75 years). The overall response rate was 83.3% [complete response in two (33.3%); partial response in three (50.0%); stable disease in one (16.7%); no cases of progressive disease]. The tumor volume reduction rate was 53% (range=38.0-100%). The median progression-free and overall survival durations were 567 and 966 days, respectively. Most adverse events were mild-to-moderate in intensity, and no grade 4 adverse events occurred in the six patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study. CONCLUSION: Combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are needed to confirm the safety and efficacy of such chemoimmunotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , Colorectal Neoplasms/therapy , Combined Modality Therapy/methods , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , T-Lymphocyte Subsets/transplantation , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Capecitabine , Colorectal Neoplasms/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Female , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Humans , Immunotherapy, Adoptive/methods , Male , Middle Aged , Oxaloacetates , Pilot Projects , Prospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND/AIM: Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large numbers of αß and γδ T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αß T cells with chemotherapy for stage IV colorectal cancer (CRC). PATIENTS AND METHODS: Fifteen patients with advanced or recurrent CRC received XELOX + bevacizumab + ex vivo expanded αß T lymphocytes as a first-line chemoimmunotherapy. RESULTS: Median age of the 15 patients (4 men, 11 women) was 65 years (range=49-80). Median progression-free survival was 21.3 months. Response rate was 80% (complete response (CR)=26.7%, partial response (PR)=53.3%, stable disease (SD)=20% and progressive disease (PD)=0%). Most adverse events were mild to moderate regarding their intensity and immunotherapy-associated toxicity was minimal. CONCLUSION: Combination of adoptive αß T cell immunotherapy with chemotherapy for stage IV CRC is feasible and safe.
Subject(s)
Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/therapy , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Aged , Aged, 80 and over , Bevacizumab/administration & dosage , Capecitabine , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Combined Modality Therapy , Deoxycytidine/therapeutic use , Disease-Free Survival , Female , Fluorouracil/therapeutic use , Humans , Immunotherapy, Adoptive , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Oxaloacetates , Retrospective Studies , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/transplantation , Treatment OutcomeABSTRACT
We present a case of a human pulmonary dirofilariasis in a 59-year-old man. At the medical examination, a chest computed tomography (CT) revealed a mass, measuring 18 × 15 mm in diameter, with an irregular margin on the bottom of the right lower lobe. We could not neglect the possibility of a primary lung cancer, and therefore, a lung partial resection was performed under video-assisted thoracoscopic surgery. The intra-operative pathological findings revealed inflammatory granuloma with coagulation necrosis and no malignant cells. The permanent pathological examination showed occlusion of the peripheral pulmonary artery by worms and formation of a necrotic mass surrounded by reactive inflammation and hemorrhage. Human pulmonary dirofilariasis is an extremely rare zoonotic infection, and sometimes it is difficult to distinguish it from a primary lung cancer on radiographic findings.
ABSTRACT
Clinical evaluation of micrometastases in the lymph nodes of lung cancer patients is not currently recommended in guidelines because of several different results concerning their prevalence and prognostic implications. However, a recent large, prospective, multicenter clinical study has shown a significant prognostic impact of micrometasteses in the lymph nodes of patients with resectable lung cancer; therefore, the clinical significance of micrometastases as predictive markers of recurrence and prognosis has begun to be clarified. From the viewpoint of surgery for lung cancer, sentinel node navigation surgery, segmentectomy, and individualized therapies such as adjuvant chemotherapy are expected to be developed. In the near future, standardization and improvement of the efficiency of diagnostic procedures will be necessary in common clinical practice. Recently, minimal residual cancer cell research, such as circulating tumor cells in the peripheral blood and disseminated tumor cells in the bone marrow, has made good progress. As research in this field continues, it is expected that the mechanism of metastasis and novel therapeutic strategies targeting minimal residual cancer cells will become better understood.
Subject(s)
Lung Neoplasms/diagnosis , Lymphatic Metastasis/pathology , Neoplasm Micrometastasis/pathology , Humans , Lung Neoplasms/surgery , PrognosisABSTRACT
It is not easy to induce cytotoxic T lymphocytes (CTLs) against cancer in in vitro culture. Regulatory T cells (Tregs) are considered to play a pivotal role in tumor immune escape. In this study, we analyzed the distribution of Tregs among tumor-infiltrating lymphocytes (TILs), regional lymph node lymphocytes (RLNLs) and peripheral blood lymphocytes (PBLs) in patients with lung cancer, and analyzed the effect of Tregs on the induction of CTLs in vitro. A total of 84 patients with non-small cell lung cancer underwent surgery between January 2003 and December 2004. The TILs, RLNLs and PBLs from these patients were subjected to a comparison analysis. The proportion of CD4(+)CD25(+)Foxp3(+) cells in these lymphocytes was determined by flow cytometry. The effects of Tregs on the induction of CTLs was analyzed by the depletion of Tregs in mixed lymphocyte-tumor cell culture (MLTC). The average proportions of Tregs in the TILs, RLNLs and PBLs were 10.4±9.5, 4.4±2.4 and 2.8±2.1%, respectively. The proportion of Tregs in the RLNLs was significantly higher than that in the PBLs (P<0.001); furthermore, TILs contained a larger number of Tregs than RLNLs (P=0.034). These Tregs substantially suppressed the induction of CTLs against autologous tumor cells. The depletion of Tregs in the MLTC resulted in the successful induction of CTLs. Tregs were found at a higher frequency in the TILs and RLNLs than in the PBLs in lung cancer patients. Since Tregs inhibited the induction of CTLs, the depletion of Tregs may represent a new therapeutic strategy for lung cancer patients.
ABSTRACT
PURPOSE: MHC antigens and adhesion molecules, such as the intracellular adhesion molecule (ICAM-I), play an important role in cellular immune response. We examined the expression patterns of these molecules in both primary and metastatic esophageal carcinoma cells from the same patient and evaluated the cellular immune responses against these cells. MATERIALS AND METHODS: In the esophageal cancer patient (H122), tumor cell lines were established from primary and subcutaneous metastatic lesions. We compared the expression of cell surface molecules on the metastatic tumor cell line (H122SC) with that on the primary tumor cell line (H122ESO) using flow cytometry. Moreover, we analyzed the differences in cellular immune responses against these cell lines, which expressed similar levels of the Tara antigen, using the Tara antigen-specific CTL clone. RESULTS: H122SC ICAM-1 expression was significantly lower in H122ESO, and the Tara antigen-specific CTL clone produced lower levels of TNF in response to H122SC than H122ESO. ICAM-1 transfection into the H122SC rendered these cells as sensitive to the CTL clone as the H122ESO. CONCLUSION: The metastatic tumor cells displayed lower regulated ICAM-1 expression levels and were less sensitive to specific CTLs. ICAM-1 downregulation may be one mechanism by which tumor cells escape immunologic surveillance.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/metabolism , Immunity, Cellular , Intercellular Adhesion Molecule-1/metabolism , T-Lymphocytes, Cytotoxic/metabolism , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Down-Regulation , Esophageal Neoplasms/immunology , Esophageal Neoplasms/pathology , Flow Cytometry , Humans , Male , Microfilament Proteins/metabolism , Middle Aged , Tumor Necrosis Factors/metabolismABSTRACT
INTRODUCTION: This study was performed to determine the incidence rates of resistance factors, i.e., high-level hepatocyte growth factor (HGF) expression, epidermal growth factor receptor (EGFR) T790M secondary mutation, and MET amplification, in tumors with intrinsic and acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant lung cancer. METHODS: Ninety-seven specimens from 93 EGFR mutant lung cancer patients (23 tumors with acquired resistance from 20 patients, 45 tumors with intrinsic resistance from 44 patients [nonresponders], 29 sensitive tumors from 29 patients) from 11 institutes in Japan were analyzed. HGF expression, EGFR T790M secondary mutation, and MET amplification were determined by immunohistochemistry, cycleave real-time polymerase chain reaction, and fluorescence in situ hybridization, respectively. RESULTS: High-level HGF expression, EGFR T790M secondary mutation, and MET amplification were detected in 61, 52, and 9% of tumors with acquired resistance, respectively. High-level HGF expression was detected in 29% of tumors with intrinsic resistance (nonresponders), whereas EGFR T790M secondary mutation and MET amplification were detected in 0 and 4%, respectively. HGF expression was significantly higher in tumors with acquired resistance than in sensitive tumors (p < 0.001, Student's t test). Fifty percent of tumors with acquired resistance showed simultaneous HGF expression with EGFR T790M secondary mutation and MET amplification. CONCLUSIONS: High-level HGF expression was detected more frequently than EGFR T790M secondary mutation or MET amplification in tumors with intrinsic and acquired EGFR-TKI resistance in EGFR mutant lung cancer in Japanese patients. These observations provide a rationale for targeting HGF in EGFR-TKI resistance in EGFR mutant lung cancer.
Subject(s)
Carcinoma/genetics , ErbB Receptors/genetics , Hepatocyte Growth Factor/genetics , Lung Neoplasms/genetics , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma/drug therapy , Drug Resistance, Neoplasm/genetics , Erlotinib Hydrochloride , Gefitinib , Gene Amplification , Humans , Japan , Lung Neoplasms/drug therapy , Male , Middle Aged , Mutation , Proto-Oncogene Proteins c-met/genetics , Quinazolines/therapeutic useABSTRACT
This study evaluated 325 patients who had undergone pleural lavage cytology (PLC) immediately after thoracotomy following a complete resection for non-small cell lung cancer (NSCLC) between 2004 and 2008. The number of patients with negative and positive findings in PLC was 309 and 13, respectively. The proportion of T1 in the PLC-positive group was significantly smaller than that of the PLC-negative group. The pathologic examinations revealed that the parietal pleural invasion was significantly more severe in the PLC-positive group than in the PLC-negative group. Pathologic lymphovascular invasion was also significantly more prominent in the PLC-positive group than in the PLC-negative group. The 5-year survival rate after surgery in the PLC-positive group and PLC-negative group was 54.7% and 79.0%, respectively. The positive finding in PLC showed a tendency of an unfavorable prognosis for NSCLC patents following complete resection. Further clinical studies will be necessary to evaluate the efficacy of adjuvant therapy for PLC-positive patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung/surgery , Lung Neoplasms/surgery , Pleura/pathology , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/pathology , Lymph Nodes/pathology , Male , Neoplasm Invasiveness , Postoperative Period , Retrospective Studies , Therapeutic Irrigation , ThoracotomyABSTRACT
The incidence of multiple primary lung adenocarcinoma (MPLA) is increasing, and it is important to distinguish MPLA from intrapulmonary metastasis (IPM) in order to determine the therapeutic strategy. However, there is no reliable method to differentiate between the two. The purpose of this study was to distinguish MPLA from IPM based on the gene status of EGFR and K-ras and the morphological Noguchi classification system. Sixty-eight tumors from 34 cases of clinical MPLA were evaluated. Of them, 11 cases (32.4%) were diagnosed as biological MPLA (bMPLA) by EGFR/K-ras mutation analyses, and 12 cases (35.3%) by morphological analysis. In all, 23 of the 34 cases (67.6%) were diagnosed as bMPLA. The remaining 11 cases were diagnosed as biological IPM (bIPM). The 5-year survival rates of bMPLA and bIPM were 90.9% and 63.6%, respectively (p=0.04). These findings suggest that the combination method including gene mutation and morphological analysis can guide treatment decisions and that there is a need for systemic chemotherapy, and surveillance monitoring.
Subject(s)
Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , Genes, erbB-1 , Genes, ras , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Mutation , Neoplasms, Multiple Primary/diagnosis , Neoplasms, Multiple Primary/genetics , Adenocarcinoma/secondary , Aged , Aged, 80 and over , Diagnosis, Differential , ErbB Receptors/genetics , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/secondary , Male , Middle AgedABSTRACT
This study aims to investigate the therapeutic and prognostic implications of esophageal cancer in patients with other primary cancer. Between April 1992 and December 2008, in 83 patients underwent surgery for esophageal cancer at our department. Among them, 24 patients (28.9%) had medical history of additional primary cancer. There were 16 metachronous cancers and 8 synchronous cancers. Six patients had antecedent other primary cancers, and subsequent primary cancers developed in 10 patients. The other primary cancers included head and neck cancer in 8 patients, gastric cancer in 8, lung cancer in 6, colorectal cancer in 3, and other cancer in 3. The patients with other primary cancers were both heavy smokers and heavy drinkers in comparison to those without other primary cancers. The post-operative 5-year survival rate in patients with subsequent cancers, antecedent cancers, and synchronous cancers were 100%, 70.0%, and 46.9%. The 5-year survival rate was 33.4% in patients without other primary cancers. A high incidence of multiple primary cancers was observed in patients with esophageal carcinoma but the prognosis of these patients with metachronous cancers are better than that of patient with synchronous cancers and patients without other primary cancers. Post-operative follow up is considered to be necessary for early detection of multiple occurrences of carcinoma, especially in the upper aerodigestive tract.
Subject(s)
Esophageal Neoplasms/mortality , Neoplasms, Multiple Primary/mortality , Aged , Esophageal Neoplasms/surgery , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Survival RateABSTRACT
PURPOSE: This study investigated the preoperative serum levels of CYFRA 21-1 and CEA as prognostic factors in patients with stage I non-small cell lung cancer. SUBJECTS: This study evaluated 341 patients who had undergone a complete resection for stage I NSCLC between 2002 and 2008. RESULTS: The patients included 193 males and 148 females. The mean age of the patients was 69.2 years (range: 19-88). The histological types included 264 adenocarcinomas, 56 squamous cell carcinomas, 11 large cell carcinomas, and 10 other types of carcinoma. A pneumonectomy was performed in 2 patients, a bilobectomy in 7, a lobectomy in 255, a segmentectomy in 46, and partial resection of the lung in 31 patients. The positive rates for CYFRA 21-1 in the adenocarcinoma and squamous cell carcinoma patients were 33.3% and 76.8%, respectively. The positive rates for CEA in adenocarcinoma and squamous cell carcinoma patients were 23.8% and 26.8%, respectively. The 5-year survival rate after surgery in the normal CYFRA 21-1 group and the high CYFRA 21-1 groups were 92.8% and 75.4%, respectively, in the patients with stage I NSCLC. There was a significant difference between the 2 groups (p<0.0001). The 5-year survival rate according to the serum level of CEA in the patients with stage I NSCLC were 88.3% for the normal group and 76.3% for the high group. In a multivariate analysis using the variables found to be significant prognostic factors in univariate analysis, a high CYFRA 21-1 level was found to be a significant independent prognostic factor (95% confidence interval 1.213-5.442, p=0.014). CONCLUSION: A high preoperative CYFRA 21-1 level was a significant independent prognostic factor in patients with stage I NSCLC. The patients with a high CYFRA 21-1 level should carefully followed-up to rule out occult metastasis. Further clinical studies will be necessary to evaluate the efficacy of adjuvant therapy for the patients selected according to this criterion.
Subject(s)
Antigens, Neoplasm/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/diagnosis , Keratin-19/metabolism , Lung Neoplasms/diagnosis , Receptors, Cell Surface/metabolism , Adult , Aged , Aged, 80 and over , Antigens, Neoplasm/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/physiopathology , Disease Progression , Female , Humans , Keratin-19/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Lung Neoplasms/physiopathology , Male , Middle Aged , Neoplasm Staging , Preoperative Care , Prognosis , Receptors, Cell Surface/genetics , Survival AnalysisABSTRACT
PURPOSE: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (EGFR-TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR-TKI in adenocarcinoma of the lung. PATIENTS AND METHODS: Forty-three patients who were treated with EGFR-TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups. RESULT: Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p=0.045). The S group had better response rate (p=0.006) and longer progression-free survival (PFS; p=0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p=0.063), and significant longer PFS (p=0.012) than the W group. CONCLUSION: A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR-TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR-TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study.