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Introduction: Chemoimmunotherapy is widely used as the first-line management of advanced non-small cell lung cancer (NSCLC) in clinical settings. However, predictive factors associated with the development of immune-related adverse events (irAEs) and prognostic factors for NSCLC patients undergoing chemoimmunotherapy remains largely unexplored. Therefore, in this study, we aimed to evaluate predictive factors for irAE development and prognostic factors associated with chemoimmunotherapy in NSCLC patients., Methods: This study enrolled 199 patients with advanced and recurrent NSCLC who underwent chemoimmunotherapy across eight institutions in Nagano prefecture from December 2018 to January 2023. We examined predictive factors associated with irAE development and prognostic factors associated with overall survival (OS)., Results: Among the patients, 106 experienced irAEs, while 93 patients did not. A total of 44 (22.1%) patients developed multiple irAEs. High serum albumin levels (Alb >3.5 g/dL) emerged as an independent predictive factor associated with irAE development in logistic regression analysis (odds ratio; 2.35, 95% confidence interval 1.27-4.34, p = 0.007). Furthermore, the development of multiple irAEs (p = 0.016), lower lactate dehydrogenase level (<223 U/L, p = 0.002), and decreased neutrophil-to-lymphocyte ratio (<3, p = 0.049) were identified as independent favorable prognostic factors associated with OS in multivariate Cox hazard analyses., Conclusion: The study results suggest that high serum Alb is a predictive factor for irAE development and that the presence of multiple irAEs is a favorable prognostic indicator for NSCLC patients undergoing chemoimmunotherapy., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death-ligand 1 (PD-L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD-L1 expression who received MONO or COMB as a first-line treatment. Here, we report updated data and evaluate the long-term outcomes., Methods: We performed a retrospective multicenter study of 298 patients with NSCLC and high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff., Results: In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0-1). At the prolonged data cutoff, the median follow-up was 20.2 (range: 0.1-41.4) months. The median progression-free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow-up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO., Conclusions: COMB may be effective as a first-line treatment for NSCLC with high PD-L1 expression in a selected subset of patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known about the efficacy of EGFR-TKI rechallenge after resistance to first-line (1L) osimertinib. This study aimed to assess the efficacy and safety of EGFR-TKI rechallenge therapy after resistance to 1L osimertinib in a Japanese clinical setting., Methods: Between April 2018 and August 2022, 26 patients who progressed after treatment with 1L osimertinib and received EGFR-TKI rechallenge were included in this multicenter retrospective analysis. Patients in whom 1L osimertinib was discontinued owing to toxicity and had subsequent disease progression were also included in the analysis., Results: Overall, the objective response rate for rechallenge therapy was 23.1%. The disease control rate was 53.9%, and the median progression-free survival (PFS) was 3.4 months. Patients who discontinued 1L osimertinib for toxicity had a higher response rate (42.9% vs. 15.8%) and longer PFS than those who discontinued it due to disease progression (median: 11.4 vs. 2.7 months, P = 0.001). Three patients (11.5%) developed rechallenge therapy-associated pneumonitis, two of which were grade ≥3., Conclusions: Rechallenge with EGFR-TKI after 1L osimertinib resistance showed limited clinical efficacy. However, it could be considered as a subsequent salvage therapeutic option for patients in whom 1L osimertinib was discontinued owing to toxicity., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Combination therapy of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies and platinum-based chemotherapy has been widely used as a first-line treatment for patients with unresectable advanced non-small cell lung cancer (NSCLC) in clinical settings; however, prognostic biomarkers associated with survival outcomes have not been sufficiently investigated., Methods: We enrolled 147 previously untreated patients with advanced NSCLC who were treated with a combination therapy of anti-PD-1/-PD-L1 antibodies and platinum-based chemotherapy at eight institutions in Nagano Prefecture between December 2018 and April 2023. We evaluated the prognostic value of the geriatric nutritional risk index (GNRI), a systemic inflammatory nutritional biomarker calculated from body weight and serum albumin level, for patients with NSCLC treated with a combination therapy of anti-PD-1/-PD-L1 antibodies and platinum-based chemotherapy., Results: The cutoff value of the GNRI was set at 92. The high GNRI and low GNRI groups included 88 and 59 patients, respectively. The median follow-up period was 15.9 months. The overall survival (OS) in the high GNRI group was significantly longer than that in the low GNRI group (27.9 vs. 15.6 months, p = 0.015). Multivariate analysis revealed that a high GNRI was an independently favorable prognostic predictor for OS (hazard ratio, 1.73; 95% confidence interval, 1.06-2.86; p = 0.031)., Conclusion: The present study demonstrates that the GNRI is a useful prognostic predictor in patients with NSCLC treated with a combination therapy of anti-PD-1/-PD-L1 antibodies and platinum-based chemotherapy in clinical settings., (© 2024 S. Karger AG, Basel.)

Background: Combination immunotherapy (immune checkpoint inhibitors and cytotoxic anticancer agents) is widely used as first-line treatment for advanced non-small cell lung cancer (NSCLC). However, the therapeutic effect of combination immunotherapy has not been fully investigated. C-reactive protein, performance status, lactate dehydrogenase, albumin, and derived neutrophil-to-lymphocyte ratio (C-PLAN) are useful biomarkers for predicting the prognosis of NSCLC; however, there are no reports examining the C-PLAN index, which combines these five factors in a single prognostic factor., Methods: We retrospectively collected data from 178 patients with previously untreated advanced NSCLC who received combination immunotherapy at multicenter institutions in Nagano Prefecture between December 2018 and April 2022. We investigated the utility of the C-PLAN index as a prognostic factor using Cox regression analysis and correlated it with survival., Results: The good and poor C-PLAN index groups included 85 and 93 patients, respectively. The good C-PLAN index group had a longer median progression-free survival (PFS) (10.7 vs. 6.0 months; p = 0.022) and overall survival (OS) (25.3 vs. 16.5 months; p = 0.003) than the poor C-PLAN index group. The C-PLAN index was an independent favorable prognostic factor that correlated with PFS and OS in multivariate analysis. The good C-PLAN index group had a higher proportion of never-smokers (16.5 vs. 4.3%; p = 0.007) and stage III disease/postoperative recurrence (32.9 vs. 15.1%; p = 0.005) than the poor C-PLAN index group., Conclusion: The C-PLAN index is a useful prognostic factor for patients with previously untreated advanced NSCLC undergoing combination immunotherapy., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: Combination immunotherapy is widely used in clinical practice as the first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, predictive factors associated with long-term response to combination immunotherapy have not been well investigated. Herein, we compared the clinical findings, including systemic inflammatory nutritional biomarkers, between responders and nonresponders to combination immunotherapy. In addition, we investigated the predictive factors associated with long-term response to combination immunotherapy., Methods: This study included a total of 112 previously untreated advanced NSCLC patients who received combination immunotherapy at eight institutions in Nagano prefecture between December 2018 and April 2021. The responders were defined as those who achieved progression-free survival for 9 months or longer with combined immunotherapy. We evaluated predictive factors associated with long-term response, and the favorable prognostic predictors associated with overall survival (OS) using statistical analyses., Results: The responder and nonresponder groups included 54 and 58 patients, respectively. Compared with the nonresponder group, the responder group had significantly younger age (p = 0.046), higher prognostic nutritional index (44.8 vs. 40.7, p = 0.010), lower C-reactive protein/albumin ratio (CAR) (0.17 vs. 0.67, p = 0.001), and a higher rate of complete plus partial response (83.3% vs. 34.5%, p &lt; 0.001). The area under the curve and optimal cut-off value for CAR were 0.691 and 0.215, respectively. The CAR and best objective response were identified as independent favorable prognostic predictors associated with OS in the multivariate analyses., Conclusion: The CAR and best objective response were suggested to be useful predictors of long-term response in NSCLC patients who received combination immunotherapy., (© 2023 S. Karger AG, Basel.)

Backgrounds: The PACIFIC trial established durvalumab consolidation therapy after concurrent chemoradiotherapy (CCRT) as the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the predictive factors of durvalumab efficacy in this population. This study aimed to validate the predictive use of inflammation-related parameters in patients with LA-NSCLC treated with CCRT plus durvalumab., Methods: We recruited 76 LA-NSCLC patients who received CCRT followed by durvalumab from 10 Japanese institutions. The neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), and prognostic nutrition index (PNI) were measured before (pre-treatment) and 2 months after (post-treatment) durvalumab induction. Cox proportional hazards analysis was used to examine prognostic factors associated with progression-free survival (PFS) after durvalumab therapy., Results: The median follow-up time was 17 (range, 3.3-35.8) months. The median PFS and overall survival (OS) times were 26.1 and 33.7 months, respectively. Durvalumab was discontinued in 47 (61.8%) patients, with non-infectious pneumonitis being the most common reason. Post-treatment CAR (cutoff, 0.2) was a significant stratifying factor in survival comparison (<0.2 vs. ≥ 0.2, median PFS, not-reached vs. 9.6 months. Log-rank, p = 0.002). Multivariate analysis with a Cox proportional hazards model showed that post-treatment CAR was an independent prognostic factor for PFS (hazard ratio, 3.16, p = 0.003)., Conclusions: This study suggests that post-treatment CAR has predictive value for LA-NSCLC patients treated with CCRT plus durvalumab consolidation therapy., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: In the LUX-Lung 3 and LUX-Lung 6 trials, afatinib improved overall survival in previously untreated patients with EGFR 19del mutated non-small cell lung cancer (NSCLC) compared to chemotherapy. The appropriate management of adverse events and dose reduction of afatinib are important for EGFR-positive NSCLC patients. We conducted a retrospective and observational study of patients treated with first-line afatinib for EGFR-positive NSCLC in Nagano prefecture, Japan, focusing on efficacy and toxicities., Methods: We retrospectively collected the medical records of NSCLC patients initially treated with afatinib between May 2014 and March 2018., Results: A total of 62 patients with a median age of 67 years and a median body surface area (BSA) of 1.57 m 2 were included. The overall response rate was 87.7% and median progression-free survival (PFS) was 15.7 months. The median PFS was similar between standard initial dose (40 mg) and reduced initial doses (30 and 20 mg) (15.7 vs. 14.2 months; P = 0.978). The frequency of dose reduction and the discontinuation rate in the 40 mg daily dose group was higher in patients with BSA < 1.58 m 2 (100%) compared to BSA ≥ 1.58 m 2 (68.2%) (P = 0.014). The frequency of diarrhea was higher in patients with BSA < 1.58 m 2 (93.5%) compared to BSA ≥ 1.58 m 2 (71.0%) (P = 0.02)., Conclusion: In real-world clinical practice, first-line afatinib was well managed and was equally as effective as in previous clinical trials of EGFR-positive NSCLC. BSA is considered a predictive marker for appropriate afatinib dose reduction., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Afatinib has been available in Japan for the treatment of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) since May 2014. We conducted an observational study in patients treated with afatinib in Nagano prefecture, focusing on response and associated toxicities., Methods: We analyzed the clinical records of NSCLC patients treated with afatinib between May 2014 and February 2015., Results: The records of a total of 73 patients (27 men, 46 women) with a median age of 69 years (range: 42-85 years) were analyzed. Afatinib was administered to 11 patients as a first-line therapy, but it was predominantly administered as a fifth-line or beyond therapy (32 cases, 43.8%). The overall response rates for afatinib as a first-line therapy and beyond second-line therapy were 80% (95% confidence interval [CI]: 55.2-100.0%) and 27.1% (95% CI: 14.5-39.7%), respectively. The main toxicities grade >3 included diarrhea (8.2%), skin rash (6.8%), nausea (6.8%), and appetite loss (6.8%). A low body surface area (BSA) (<1.5m 2 ) was significantly associated with a higher frequency of diarrhea grade >2, compared with a higher BSA (≥ 1.5m 2 ). Forty-eight patients (63.0%) were treated without a dose reduction of afatinib., Conclusions: Although the survival benefit with afatinib remains unclear, our observational analysis demonstrated the feasibility of using afatinib for EGFR-mutated NSCLC in clinical practice. In particular, a relatively high level of drug delivery is possible. In addition, a lower BSA may be a predictor of diarrhea in patients treated with afatinib., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Our previous animal and preliminary human studies indicated that bronchoscopy-guided cooled radiofrequency ablation (RFA) for the lung is a safe and feasible procedure without major complications., Objectives: The present study was performed to evaluate the safety, effectiveness and feasibility of computed tomography (CT)-guided bronchoscopy cooled RFA in patients with medically inoperable non-small-cell lung cancer (NSCLC)., Methods: Patients with pathologically diagnosed NSCLC, who had no lymph node involvement or distant metastases (T1-2aN0M0) but were not surgical candidates because of comorbidities (e.g., synchronous multiple nodules, advanced age, cardiovascular disease, poor pulmonary function, etc.) were enrolled in the present study. The diagnosis and location between the nearest bronchus and target tumor were made by CT-guided bronchoscopy before the treatment. A total of 28 bronchoscopy-guided cooled RFA procedures were performed in 20 patients. After treatment, serial CT imaging was performed as follow-up., Results: Eleven lesions showed significant reductions in tumor size and 8 lesions showed stability, resulting in a local control rate of 82.6%. The median progression-free survival was 35 months (95% confidence interval: 22-45 months), and the 5-year overall survival was 61.5% (95% confidence interval: 36-87%). Three patients developed an acute ablation-related reaction (fever, chest pain) and required hospitalization but improved with conservative treatment. There were no other adverse events in the present study., Conclusions: CT-guided bronchoscopy cooled RFA is applicable for only highly selected subjects; however, our trial may be an alternative strategy, especially for disease local control in medically inoperable patients with stage I NSCLC.

The clinical efficacy and outcomes of gefitinib therapy as a first-line treatment for elderly patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations were analyzed retrospectively. We analyzed chemotherapy-naïve NSCLC patients aged 75 years or older who had EGFR mutations (exon 19 deletion mutation or L858R), who were initially treated with gefitinib (250 mg) once daily in Nagano Prefecture. A total of 55 patients (16 men, 39 women) with a median age of 81.1 years (range; 75-94 years) treated between April 2007 and July 2012 were analyzed. The overall response rate and disease control rate were 72.7 % (95 % confidence interval (CI); 59.5-82.9 %) and 92.7 % (95 % CI; 82.0-97.6 %), respectively. Median progression-free survival and overall survival from the start of gefitinib treatment were 13.8 months (95 % CI; 9.9-18.8 months) and 29.1 months (95 % CI; 22.4 months-not reached), respectively. Two-year survival rate was 59.5 % (95 % CI; 41.0-78.0 %). Major grade 3 toxicities were skin rash (1.8 %) and increased levels of aspartate aminotransferase or alanine aminotransferase (7.3 %). First-line treatment with gefitinib for elderly EGFR-mutated NSCLC patients was effective and well tolerated. The results suggest that first-line gefitinib should be considered as a preferable standard treatment in elderly patients with advanced NSCLC harboring EGFR mutations.

Introduction: Salvage treatment for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor in patients with non-small-cell lung cancer is a matter of clinical concern. Several retrospective reports have indicated the usefulness of epidermal growth factor receptor tyrosine kinase inhibitor readministration; however, there have been few prospective studies., Materials and Methods: This study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced or metastatic non-small-cell lung cancer who responded well to initial gefitinib treatment. The subjects received at least 1 regimen of cytotoxic chemotherapy after progressive disease with the initial gefitinib therapy. Gefitinib administration (250 mg/d, orally) was started after progressive disease with the previous chemotherapeutic regimen. The primary endpoint in the present study was the response rate., Results: Twenty patients were enrolled between April 2007 and May 2011. Three patients achieved partial response, and 6 showed stable disease. Thus, the overall response rate and disease control rate of gefitinib readministration were 15% (95% CI, 3.21-37.9) and 45% (95% CI, 23.1-68.5), respectively. Median progression-free survival and overall survival from the start of gefitinib readministration were 2.0 months (95% CI, 0.9-3.1 months) and 12.0 months (95% CI, 8.0-16.0 months), respectively., Conclusion: These results suggest that gefitinib readministration may be an option, albeit with a low response rate and short progression-free survival, for patients who responded well to initial gefitinib followed by systemic chemotherapy. These findings provide valuable information for the management of previous gefitinib responders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC)., Methods: The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40 mg/m(2) twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle., Results: In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90 mg/m(2) (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80 mg/m(2) of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8 % (90 % confidence interval (CI): 6.1-25.5 %), and the median progression-free and overall survival times were 4.5 months (95 % CI: 3.5-5.0) and 15.0 months (95 % CI: 9.5-20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9 % of the patients, thrombocytopenia in 5.1 % and nausea in 7.7 %., Conclusion: Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC.

Purpose: There is as yet no optimal treatment regimen for patients with epidermal growth factor receptor (EGFR) gene wild-type non-small-cell lung cancer (NSCLC) that has progressed despite cytotoxic chemotherapy. This trial was performed to evaluate the efficacy and toxicity of erlotinib, a tyrosine kinase inhibitor of EGFR, in Japanese patients with EGFR wild-type tumors., Methods: Patients with stage III/IV or postoperative recurrence of NSCLC whose tumors have wild-type EGFR were eligible. Erlotinib (150 mg/day) was administered until disease progression or unacceptable toxicity occurred. The primary end point was disease control rate (DCR)., Results: Thirty-one patients (23 men and 8 women; median age, 71 years; range, 31-89) were enrolled between January 2008 and June 2011. Twenty-one had adenocarcinoma, nine had squamous cell carcinoma, and one had large cell carcinoma. Ten, nine, eight, and four patients showed performance status 0, 1, 2, and 3, respectively. Erlotinib was administered following the median 3.1 regimens of cytotoxic chemotherapies. One patient achieved complete response, four showed partial response, and eight had stable disease. Thus, response rate was 17.2%, and DCR was 44.8%. Skin rash was the most common side effect (80.6%). Two patients developed interstitial lung disease. Nevertheless, all of these events were reversible, and there were no treatment-related deaths. The median progression-free survival and survival times were 2.1 and 7.7 months, respectively., Conclusion: Erlotinib might be an alternative option for patients resistant to cytotoxic chemotherapy even in those with EGFR wild-type NSCLC.

To elucidate the function of MAS-related GPCR, member D (MRGD) in cancers, we investigated the in vitro and in vivo oncogenic function of MRGD using murine fibroblast cell line NIH3T3 in which MRGD is stably expressed. The expression pattern of MRGD in clinical samples was also analyzed. We found that overexpression of MRGD in NIH3T3 induced focus formation and multi-cellular spheroid formation, and promoted tumors in nude mice. In other words, overexpression of MRGD in NIH3T3 induced the loss of contact inhibition, anchorage-independent growth and in vivo tumorigenesis. Furthermore, it was found that the ligand of MRGD, beta-alanine, enhanced spheroid formation in MRGD-expressing NIH3T3 cells. From investigation of clinical cancer tissues, we found high expression of MRGD in several lung cancers by immunohistochemistry as well as real time PCR. Based on these results, MRGD could be involved in tumorigenesis and could also be a novel anticancer drug target.

Background: Pulmonary pleomorphic carcinoma is a very rare pulmonary malignant tumor which has various clinical manifestations and a poor prognosis., Case: A 74-year-old man presented with fever and weight loss of more than 10kg during 2 months from April 200X. Chest CT showed a nodule in the right upper lobe, and supraclavicular and mediastinal lymphadenopathy. Positron emission tomography (PET) comfirmed 18Ffluorodeoxyglucose accumulation in the sites. A left supraclavicular node biopsy demonstrated pulmonary pleomorphic carcinoma. The tumors responded well to gemcitabine plus docetaxel combination chemotherapy. This symptoms disappeared and the response continued for 1 year after 6 cycles of chemotherapy., Conclusion: We report a case of pulmonary pleomorphic carcinoma presenting with fever, which showed a marked response to chemotherapy.

A 76-year-old man with squamous cell lung cancer underwent right lower lobectomy in November, 2005. He was diagnosed with pT2N0M0, stage I B, and tegafur/uracil (UFT) was administered. On July, 2007, right hilar lymphadenopathy was detected and considered to be a recurrence. UFT was discontinued, and gemcitabine (GEM) and docetaxel (DOC) combination chemotherapy was initiated on August 21. He began to complain of fatigue, palpitation and dizziness since the fifth day of the administration, and anemia (hemoglobin: Hb 8.7 g/dL) was detected on the fifteenth day. On the twenty-second day of the administration, he was admitted to our hospital because of aggravation of anemia (Hb 6.5 g/dL). His anemia was diagnosed as immune hemolytic anemia based on the laboratory findings including a positive Coombs' test. He showed improvement with prednisolone therapy. The anemia was considered to be drug-induced. This case was extremely rare, and there are no reports on immune hemolytic anemia related to GEM and/or DOC.

Based on 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid[2-(cyclohexanecarbonylamino)benzothiazol-6-yl]amide (1), which shows selective cytotoxicity against tumorigenic cell lines, 2,6-dichloro-N-[2-(cyclopropanecarbonylamino)benzothiazol-6-yl]benzamide (13b) was designed and synthesized as a biologically stable derivative containing no nitro group. The highly potent derivative 13b exhibited excellent in vivo inhibitory effect on tumor growth.