Survival after Lung Metastasectomy from Urothelial Carcinoma: A Multi-Institutional Database Study.

BACKGROUND/OBJECTIVES: The efficacy of lung metastasectomy in patients with urothelial carcinoma remains inconclusive, as there is only limited evidence from small studies. In this study, we aimed to assess the prognostic outcomes of excising pulmonary metastases from urothelial carcinoma. METHODS: In this study, we utilized data from the Metastatic Lung Tumor Study Group of Japan database, a multi-institutional prospective database of pulmonary metastasectomies. We examined the data of patients who had undergone pulmonary metastasectomy for urothelial carcinoma between 1985 and 2021. Exclusion criteria included insufficient clinical information and follow-up of <3 months. RESULTS: The study cohort comprised 100 patients (63 bladder cancer, 37 renal pelvic and ureteral cancer), with a median follow-up of 34 months. There were 70 male and 30 female patients of average age 66.5 ± 10.4 years at lung metastasectomy. The median interval from treatment of the primary lesion to metastasectomy was 19 months and the maximum tumor diameter was 21 ± 15 mm. Three- and five-year overall survival rates were 69% and 59%, respectively. Three- and five-year disease-free survival rates were 56% and 46%, respectively. Multivariate analysis identified larger tumor diameter (hazard ratio: 1.62, 95% confidence interval: 1.21-2.17) and distant metastases at the time of treatment of the primary cancer (hazard ratio: 4.23; 95% confidence interval: 1.54-11.6) as significant adverse prognostic factors for overall survival. CONCLUSIONS: To our knowledge, this is the largest published case series of pulmonary resection for metastatic urothelial carcinoma, providing benchmark data for the assessment of long-term outcomes of this rare entity.

Machine learning models from computed tomography to diagnose thymic epithelial tumors requiring combined resection.

Background: Minimally invasive approaches have been a standard choice of surgery for noninvasive thymic epithelial tumors (TETs), but we sometimes experience cases requiring combined resection of adjacent structures. We develop and validate machine learning models to predict combined resection based on preoperative contrast-enhanced computed tomography (CT). Methods: This study included 212 patients with TETs (140 in the training cohort and 72 in the validation cohort) who underwent radical surgery. Radiomics features were extracted from contrast-enhanced CT and predicted with five feature selection methods and seven machine learning models in nested cross validation. The clinical utility of the models was analyzed by a decision curve analysis (DCA). Results: Fifty-five patients in the training cohort and 28 in the validation cohort required combined resection. The classifiers random forest (RF), gradient boosting (GB), and eXtreme Gradient Boosting (XGB) indicated high predictive performance, with the XGB classifier based on features selected by GB performing the best, with an area under the curve (AUC) of 0.797. In the validation cohort, the classifier had an AUC of 0.817. The DCA showed the validity of the model with a threshold range of 15-72%. When restricted to combined pulmonary and pericardial resection, the respective AUCs were 0.736 and 0.674 for the training cohort and 0.806 and 0.924 for the validation cohort. Conclusions: The machine learning model based on preoperative CT images was able to diagnose TETs requiring combined resection with high accuracy. The DCA demonstrated a wide range of model validity and may aid in surgical approach selection.

Time to Incurable Recurrence for Patients Treated With Pulmonary Metastasectomy for Colorectal Cancer.

BACKGROUND: Probability of cure is important for patients with lung metastasis who must decide whether to undergo metastasectomy. Although progression-free survival (PFS) is thought to reflect this, it does not include curative effects by repeat metastasectomy. Thus, the authors developed a new indicator, time to incurable recurrence (TTIR), in which only incurable recurrence was set as an event that included death, with incurable recurrence defined as recurrence not treated by definitive local therapy (DLT), recurrence treated by DLT but with PFS maintained less than 2 years, or recurrence followed by re-recurrence. METHODS: This multi-institutional study included 339 patients who underwent lung metastasectomy for colorectal cancer between 1990 and 2008. RESULTS: Among the 339 patients, 191 experienced recurrence, 77 received DLT for recurrence, 38 had a PFS of 2 years or longer after the treatment, and 33 had maintained a PFS at the last follow-up date. The patients had PFS ranging from 39 to 212 months (median, 101 months). The 5-year OS, PFS, and TTIR rates were respectively 63.4%, 42.2%, and 51.9%. The TTIR curve was similar to the OS curve 7 years after the initial metastasectomy. The difference between TTIR and PFS at 7 years was 9.7%, indicating probability of cure by repeat DLT. Multivariable analysis showed different prognostic factors among OS, PFS, and TTIR. CONCLUSION: At the initial metastasectomy, TTIR may reflect probability of a cure, including cure by repeat DLT, and can be used to analyze prognostic factors associated with cure.

Individual data meta-analysis for the study of survival after pulmonary metastasectomy in colorectal cancer patients: A history of resected liver metastases worsens the prognosis.

OBJECTIVES: To assess the impact of a history of liver metastases on survival in patients undergoing surgery for lung metastases from colorectal carcinoma. METHODS: We reviewed recent studies identified by searching MEDLINE and EMBASE using the Ovid interface, with the following search terms: lung metastasectomy, pulmonary metastasectomy, lung metastases and lung metastasis, supplemented by manual searching. Inclusion criteria were that the research concerned patients with lung metastases from colorectal cancer undergoing surgery with curative intent, and had been published between 2007 and 2014. Exclusion criteria were that the paper was a review, concerned surgical techniques themselves (without follow-up), and included patients treated non-surgically. Using Stata 14, we performed aggregate data and individual data meta-analysis using random-effect and Cox multilevel models respectively. RESULTS: We collected data on 3501 patients from 17 studies. The overall median survival was 43 months. In aggregate data meta-analysis, the hazard ratio for patients with previous liver metastases was 1.19 (95% CI 0.90-1.47), with low heterogeneity (I2 4.3%). In individual data meta-analysis, the hazard ratio for these patients was 1.37 (95% CI 1.14-1.64; p < 0.001). Multivariate analysis identified the following factors significantly affecting survival: tumour-infiltrated pulmonary lymph nodes (p < 0.001), type of resection (p = 0.005), margins (p < 0.001), carcinoembryonic antigen levels (p < 0.001), and number and size of lung metastases (both p < 0.001). CONCLUSIONS: A history of liver metastases is a negative prognostic factor for survival in patients with lung metastases from colorectal cancer. We registered the meta-analysis protocol in PROSPERO (CRD42015017838).

What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection?

PURPOSES: Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. METHODS: We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. RESULTS: A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. CONCLUSIONS: This study revealed eight risk factors for fatal AEIP.

Chylopericardium following thoracoscopic resection of a mediastinal cyst: A case report.

INTRODUCTION: Thoracic duct cysts are very rare, and diagnosis is often difficult. We report a rare case of chylopericardium following thoracic duct cyst resection. There are no established guidelines on the management of such cases. We reviewed the literature on postoperative complications after thoracic duct cyst resection, and conducted the first thorough review of the etiology and management of chylopericardium in surgical cases. PRESENTATION OF CASE: A 54-year-old male presented with cardiac tamponade due to chylopericardium. He had undergone resection of a thoracic duct cyst 2 years previously, which was complicated by postoperative chylothorax. Chyle accumulation resolved with conservative treatment. DISCUSSION: Chylothorax is a frequent complication following thoracic duct cyst resection, especially in cases where no intraoperative diagnosis is reached. Diagnosis may be difficult due to anomalous location of the cyst, as in our case. Chylopericardium is rarely reported, and may have occurred in our case because of prior pleurodesis. Chyle accumulation can reportedly be managed with diet restrictions in over half of reported cases, especially in cases of lung or mediastinal tumor resection. CONCLUSION: The most important points highlighted by this rare case of chylopericardium secondary to thoracic duct cyst resection are: 1) pedicles should be ligated in cyst resections, regardless of location; 2) careful assessment in the initial surgery may help identify the point of leakage; 3) low-fat diet is the first choice in the initial management of postoperative chylopericardium, but surgical repair may be considered in cases with no response after>2 weeks of conservative treatment.

Recent improvement of survival prognosis after pulmonary metastasectomy and advanced chemotherapy for patients with colorectal cancer.

OBJECTIVES: New chemotherapeutic regimens (i.e. FOLFOX or FOLFIRI with molecular targeted drugs) have improved the prognosis of patients with unresectable or recurrent colorectal cancer. To estimate the prognostic impact of these chemotherapies, we examined the chronological change in survival rates of patients who underwent pulmonary metastasectomy for colorectal cancer metastasis. METHODS: Using a large database, we conducted a retrospective, multi-institutional study to collect data of 1223 eligible patients from 26 institutions who had undergone pulmonary metastasectomy with curative intent. We divided those patients who underwent metastasectomy in different time periods according to the major trend of chemotherapy regimens for recurrent colorectal cancer: those who underwent metastasectomy between 1990 and 1999 ( N = 451, Group A), between 2000 and 2004 ( N = 433, Group B) or between 2005 and 2007 ( N = 339, Group C). RESULTS: Five-year overall survival rates after metastasectomy were 45% in Group A, 56% in Group B and 66% in Group C ( P < 0.0001) whereas rates after metastasectomy plus chemotherapy were 32% in Group A, 47% in Group B and 70% in Group C ( P = 0.0059). The prognosis of patients who underwent both metastasectomy and chemotherapy in Group C was significantly better than that of the other two groups. Overall survival of patients who did not receive chemotherapy was not significantly different between the groups. CONCLUSION: Survival rates of patients after pulmonary metastasectomy for colorectal cancer metastasis who underwent chemotherapy have increased over the years. It implies that newer chemotherapy regimens might have had a positive impact on these patients.

Thoracoscopic surgery versus open surgery for lung metastases of colorectal cancer: a multi-institutional retrospective analysis using propensity score adjustment†.

OBJECTIVES: Thoracoscopic surgery for lung metastasectomy remains controversial. The study aimed at determining the efficacy of thoracoscopic surgery for lung metastasectomy. METHODS: This was a multi-institutional, retrospective study that included 1047 patients who underwent lung metastasectomy for colorectal cancer between 1999 and 2014. Prognostic factors of overall survival were compared between the thoracoscopic and open thoracotomy groups using the multivariate Cox proportional hazard model. The propensity score, calculated using the preoperative covariates, included the era of lung surgery as a covariate. A stepwise backward elimination method, with a probability level of 0.15, was used to select the most powerful sets of outcome predictors. The difference between the radiological tumour number and the resected tumour number (delta_num) was also evaluated. RESULTS: The c -statistics and the P -value of the Hosmer-Lemeshow Chi-square of the propensity score model were 0.7149 and 0.1579, respectively. After adjusting for the propensity score, the thoracoscopy group had a better survival rate than the open group (stratified log-rank test: P = 0.0353). After adjusting for the propensity score, the most powerful predictive model for overall survival was that which combined thoracoscopy [hazard ratio (HR): 0.468, 95% CI: 0.262-0.838, P = 0.011] and anatomical resection (HR: 1.49, 95% CI: 1.134-1.953, P = 0.004). Before adjusting for the propensity score, the delta_num was significantly greater in the open group than in the thoracoscopy group (thoracoscopy: 0.06, open: 0.33, P = 0.001); however, after adjustment, there was no difference in the delta_num (thoracoscopy: 0.04, open: 0.19, P = 0.114). CONCLUSIONS: Thoracoscopic metastasectomy showed better overall survival than the open approach in this analysis. The thoracoscopic approach may be an acceptable option for resection of pulmonary metastases in terms of tumour identification and survival outcome in the current era.

Surgical Intervention for Non-Small-Cell Lung Cancer Patients with Pleural Carcinomatosis: Results From the Japanese Lung Cancer Registry in 2004.

INTRODUCTION: A subset of non-small-cell lung cancer (NSCLC) patients with malignant pleural effusion and/or malignant pleural nodules is now classified as stage IV and is generally considered a contraindication to surgery. However, several reports have demonstrated that the prognosis of patients with pleural carcinomatosis first detected at thoracotomy is relatively favorable. The aim of this study was to describe the results of surgical intervention in NSCLC patients with pleural carcinomatosis in Japan. METHODS: In 2010, the Japanese Joint Committee of Lung Cancer Registry conducted a nationwide registration of lung cancer patients who underwent surgery in 2004. Using this database, we performed a retrospective study focused on pleural carcinomatosis. We examined the clinicopathological features, the current status of therapy, and surgical outcomes in patients with pleural carcinomatosis. RESULTS: Among the 11,420 registered NSCLC patients, 329 (2.9%) patients had pleural carcinomatosis. The median survival time and 5-year survival rate of 313 patients without other metastatic disease were 34.0 months and 29.3%, respectively. Primary tumor resection was performed in 256 (81.8%) patients, and macroscopic complete resection was achieved in 152 (48.6%) patients, with 5-year survival rates of 33.1% and 37.1%, respectively. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (p < 0.001), best stage nodal status (p = 0.002), and the presence or absence of gross residual tumor (p = 0.013) were independent predictors of survival. CONCLUSION: In our surgical registry for NSCLC, patients with pleural carcinomatosis accounted for 2.9%, and macroscopic complete resection for them was associated with better survival.

Prognostic factors after pulmonary metastasectomy for colorectal cancer and rationale for determining surgical indications: a retrospective analysis.

OBJECTIVE: We aimed to identify prognostic factors after pulmonary metastasectomy for colorectal cancer and propose the clinical application of them. Furthermore, we endeavored to provide a rationale for pulmonary metastasesectomy. BACKGROUND: Several prognostic factors have been proposed, but clinical application of them remains unclear. Moreover, there is no theoretical evidence that pulmonary metastasectomy is indicated for colorectal cancer. METHODS: We retrospectively analyzed 1030 patients who underwent pulmonary metastasectomy for colorectal cancer from 1990 to 2008. Prognostic factors were identified and the relationship of recurrent sites after pulmonary resection to pulmonary tumor size was assessed. RESULTS: Overall 5-year survival was 53.5%. Median survival time was 69.5 months. Univariate analysis showed tumor number (P < 0.0001), tumor size (P < 0.0001), prethoracotomy serum carcinoembryonic antigen (CEA) level (P < 0.0001), lymph node involvement (P < 0.0001), and completeness of resection (P < 0.0001) to significantly influence survival. In multivariate analysis, all remained independent predictors of outcome. In patients whose recurrent sites extended downstream from the lung via hematogenous colorectal cancer spread, pulmonary tumor size was significantly larger than in those with recurrent sites confined to the lung and regions upstream from the lung. CONCLUSIONS: We should utilize these prognostic factors to detect patients who might benefit from surgery. Therefore, we should periodically follow up advanced colorectal cancer patients by chest computed tomography to detect small pulmonary metastases before serum CEA elevation. Metastases to the lung or organs upstream from the lung are regarded as semi-local for colorectal cancer. This concept provides a rationale for validating surgical indications for pulmonary metastases from colorectal cancer.

Changes in diagnostic strategies for hilar-type Castleman's disease: report of two cases.

Castleman's disease (CD) is rare and difficult to diagnose preoperatively. We report two similar cases of hyaline vascular type CD diagnosed preoperatively using different modalities. In the first case, a biopsy specimen taken during diagnostic thoracoscopy revealed lymphatic structure suggestive of CD. In the second case, endobronchial ultrasound-guided transbronchial needle aspiration enabled sampling of histological cores for histological diagnosis. In both cases, the final diagnosis was established by surgical resection.

Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer.

Aberrant methylation of promoter CpG that causes silencing of tumor suppressor genes (TSGs) may play a key role in the carcinogenesis of many cancer types. RASSF1A, regarded as a TSG, has been extensively studied in lung cancer and other malignant tumors, whereas RASGRF2 has only been reported to possibly play a role in the pathogenesis of pancreatic cancer cell lines. The aims of our study were to i) determine the methylation profile of RASGRF2 and ii) compare the methylation profiles of RASGRF2 with RASSF1A in lung cancer. We examined RASGRF2 expression by reverse transcription PCR and aberrant methylation of RASGRF2 by methylation-specific PCR in lung cancer cell lines. Loss of RASGRF2 expression was presented in 36% lung cancer cell lines while aberrant methylation of RASGRF2 was present in 30% (3/10) non-small cell lung cancer (NSCLC) cell lines and in 25% (1/4) small cell lung cancer (SCLC) cell lines. The concordance between loss of expression and aberrant methylation of RASGRF2 was 86% (12/14). RASGRF2 expression was restored after treatment with the demethylating agent, 5-aza-2'-deoxycytidine in all four cell lines tested that downregulated RASGRF2 expression. Among primary NSCLC, RASGRF2 and RASSF1A methylation was observed in 34% (39/114) and 39% (44/114) of cases respectively, while it was observed in only 7% (4/57) and none of the corresponding non-malignant lung tissue. There is no correlation between RASGRF2 and RASSF1A methylation status. Both RASGRF2 and RASSF1A methylation did not associate with clinical characteristics. Frequent methylation and silencing of RASGRF2 in tumor cells may play an important role, different from that of RASSF1A, in the carcinogenesis of NSCLC.

Spontaneous regression of bone metastasis from renal cell carcinoma; a case report.

BACKGROUND: Spontaneous regression of metastatic renal cell carcinoma is rarely observed. CASE PRESENTATION: Metastatic renal cell carcinoma was identified in a 70-year-old male using computed tomography-guided percutaneous needle biopsy. Two months after the diagnosis, a partial resection of the sternal bone was performed. Pathological examination revealed granulated tissue with bleeding and necrosis but no carcinogenic cells. CONCLUSION: We report a pathologically identified case in which a sternal bone metastasis that was noticed two years after radical nephrectomy regressed completely and spontaneously.

Aberrant methylation: common in thymic carcinomas, rare in thymomas.

Thymic carcinoma, which is a rare epithelial neoplasm of the thymus gland, is different from thymoma in its clinical and pathological features. To clarify the mechanism underlying the aggressive behavior of thymic carcinoma, we examined the clinicopathologic features, aberrant methylation patterns of the tumor suppressor genes, and epidermal growth factor receptor (EGFRs) mutation in both thymic carcinomas and thymomas. Clinical data of 11 thymic cancers and 13 thymomas were reviewed. Resected samples of 5 thymic cancers and 6 thymomas selected from 24 cases were used for methylation and mutation studies. Positive tumor markers were more frequent in thymic cancers than in thymomas (p=0.0233), and the methylation index, which reflects the overall methylation pattern, was significantly higher in thymic carcinomas (p=0.0053). No tumors showed a mutation of EGFR, KRAS, and HER2. Thymic carcinoma is distinct from thymoma not only with respect to clinicopathological features, but also aberrant methylation patterns of the tumor suppressor genes.

Phase I study of vinorelbine plus gemcitabine as third-line chemotherapy for refractory non-small cell lung cancer.

For non-small cell lung cancer (NSCLC), which is refractory for both platinum-based chemotherapy and docetaxel, no standard regimen has yet been established. We conducted a phase I study of a combination of vinorelbine and gemcitabine as third-line chemotherapy for refractory NSCLC to determine both the maximum tolerated dose (MTD) and the recommended dose (RD). Twenty patients with NSCLC refractory for both platinum and docetaxel were enrolled, and all patients were eligible for this phase I study. Cohorts of three to seven patients received vinorelbine at doses ranging from 20 to 25 mg/m(2), and gemcitabine at doses ranging from 600 to 1000 mg/m(2), on days 1 and 8 every 3 weeks. The dose-limiting toxicities were treatment delay, serum gammaGTP elevation, diarrhea and cerebral infarction, which were resolved without serious sequela, and there was no treatment-related death. The MTD was vinorelbine at 25 mg/m(2) and gemcitabine at 1000 mg/m(2) and the RD was vinorelbine at 25 mg/m(2) and gemcitabine at 800 mg/m(2). The median overall survival time was 6.8 months for all 20 patients eligible. As third-line chemotherapy, the combination of vinorelbine and gemcitabine was feasible and promising for NSCLC which is refractory for both platinum and docetaxel.

Aberrant methylation of FBN2 in human non-small cell lung cancer.

FBN2, a large modular extracellular matrix glycoprotein, is known to be a key component of human elastic fiber. A loss of FBN2 expression due to promoter methylation was recently identified in pancreatic cancer. We examined FBN2 expression by reverse transcription PCR and aberrant methylation of FBN2 by methylation specific PCR in lung cancer cell lines. Aberrant methylation of FBN2 was present in 55% (6 of 11) of non-small cell lung cancer (NSCLC) cell lines, but it absent in small cell lung cancer cell lines. The concordance between loss of expression and aberrant methylation of FBN2 was 88% (14 of 16) in the cell lines. FBN2 expression was restored after treatment with the demethylating agent, 5-aza-2'-deoxycytidine in all six cell lines tested that lacked FBN2 expression. Among primary NSCLC, 49% (62/126) of cases had FBN2 methylation, but only 7% (5/69) of the corresponding nonmalignant lung tissues had it. Although FBN2 methylation was detected even in patients with early stage disease, it occurred frequently in large tumors (p=0.022), with nodal metastasis (p=0.037), or with advanced stages of NSCLC (p=0.014). Methylation and silencing of FBN2 in tumor cells may play an important role in carcinogenesis, invasion, and metastasis of NSCLC.

Multimodality therapy and significance of serum CYFRA21-1 for thymic carcinoma.

Thymic carcinoma is a rare mediastinal neoplasm with a poor prognosis due to delayed diagnosis and highly malignant behavior. To evaluate 7 serum tumor markers and the outcome of treatment, 11 stage III-IVb thymic carcinomas undergoing multimodality treatment were reviewed. High levels of serum CYFRA21-1 were detected in 5 patients (45%) and correlated with the progression of disease. Of the patients, 6 underwent surgery. The median survival time was 38.4 months, and the 5-year survival rate was 15.6%. The metastatic stage (IVb) and treatment without resection were significantly associated with poorer overall survival (p=0.0034 and p=0.0041, respectively). Our data demonstrated that serum CYFRA21-1 may represent a potential new biomarker in thymic carcinoma. Stage may provide a basis for prognosis in stage III-IVb thymic carcinoma, and resection is one of the most important parts of multimodality treatment for advanced thymic carcinoma. Effective neoadjuvant treatment is therefore essential.

Tumor-draining lymph nodes of primary lung cancer patients: a potent source of tumor-specific killer cells and dendritic cells.

BACKGROUND: The tumor-draining lymph node tissue (TDLT) of lung cancer patients generated killer cells specific to autologous tumor cells when cultured with low dose IL-2. This production of killer cells lasted as long as 2 months after the initiation of the culture (productive phase). Even after this productive phase, TDLT supported the generation of the killer cells when these were co-cultured with peripheral blood lymphocytes (PBL) from the same patients. We tried to analyze the mechanisms of this production of killer cells from TDLT. MATERIALS AND METHODS: TDLT, tumor tissues as well as PBL were obtained from primary lung cancer patients and cultured in vitro. Cell growth, cell surface markers and specific cytotoxic activity of the lymphocytes were examined. RESULTS: The majority of the cells from TDLT or TDLT+ PBL co-culture (TDL-Pb) were CD3-positive T cells (89-99%) and a 51Cr-releasing assay showed that these cells had a stronger cytotoxic activity against autologous tumor cells than cells from PBL cultured with IL-2. Their activity against allogeneic MHC incompatible target cells was not, however, elevated. Cytotoxic activity against autologous tumor cells was blocked by anti-HLA class 1 (52.0%), class 11 (47.9%) and CD8 (46.8%) antibodies, but not by anti-CD56 antibody. The treatment of TDLT with anti-CD8, CD4, CD80 and CD83 all together completely abrogated the ability of TDLT to generate killer cells, with one of these antibodies it did so partially, while treatment with anti-CD56 antibody failed to do so at all. CONCLUSION: These results collectively suggest that TDLT contains tumor antigen-pulsed DCs as well as precursors of specific killer T cells and gives rise to the generation of killer cells when cultured in a low dose of IL-2.