Publications by authors named "Yuichi Takiguchi"

181 Publications

Risk factors for skeletal-related events in non-small cell lung cancer patients treated with bone-modifying agents.

Support Care Cancer 2021 Jan 6. Epub 2021 Jan 6.

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Purpose: The risk factors for skeletal-related events (SREs) among non-small cell lung cancer (NSCLC) patients during treatment with bone-modifying agents (BMAs) are not yet well-understood.

Methods: The medical records of 238 consecutive NSCLC patients treated with BMAs, including zoledronic acid and denosumab, at the Chiba University Hospital from 2012 to 2016 were reviewed in the present study. SREs were defined as either pathologic fractures, spinal cord compression, the need for bone irradiation or surgery, or hypercalcemia. The risk factors for earlier occurrence of the first SRE from the time of the first bone metastasis diagnosis after the initiation of BMA treatment were identified.

Results: Of the 238 included patients, 92% (n = 220) had a performance status (PS) of 0-2 at diagnosis of bone metastasis. Forty-eight (20%) patients developed at least one SRE. The most common first SRE was the need for bone irradiation surgery (n = 27, 56%). Significant risk factors included poor PS (hazard ratio [HR]: 4.36; p = .024), male sex (HR: 2.17; p = .022), and the use of zoledronic acid (HR: 1.91; p = .032). The overall survival (OS) from the first bone metastasis diagnosis was 394 days (95% confidence interval [CI]: 331-465). The OS of patients with PS 3 and 4 at the diagnosis of bone metastasis (median: 36 days; 95% CI: 13-50) was significantly (p < 0.0001) shorter than that of patients with PS 0-2 (median: 411 days; 95% CI: 354-558) (HR: 4.53; 95% CI: 2.62-7.35).

Conclusions: Careful observation is needed for patients with the identified risk factors, which include poor PS and male sex, despite the BMA treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-020-05880-5DOI Listing
January 2021

Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer.

Cancer Med 2021 01 14;10(2):626-633. Epub 2020 Dec 14.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan.

Cisplatin-based chemoradiotherapy is considered standard treatment for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study examined two regimens of chemotherapy in concurrent chemoradiation. Eligible patients with unresectable, radically irradible LA-NSCLC were randomized to either the SP (S-1 and cisplatin) or DP (docetaxel and cisplatin) arms with concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival (OS) rate at 2 years (the 2-year OS rate). From May 2011 to August 2014, 110 patients were enrolled. Of 106 eligible patients, the 2-year OS rates were 79% (95% CI: 66%-88%) and 69% (95% CI: 55%-80%) the SP and DP arms, respectively. The median progression-free survival was 11.6 months for the SP arm and 19.9 months for the DP arm, while the median survival time was 55.2 months for the SP arm and 50.8 months for the DP arm. Grade 3/4 leukopenia were more frequent in DP arm. The incidences of febrile neutropenia and pneumonitis tended to be higher in DP arm. There were no treatment-related deaths in either arm. The primary endpoint was met in both arms. The SP arm as a future reference regimen will be chosen due to fewer toxicities and better OS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877366PMC
January 2021

Colonoscopic evaluation of diarrhea/colitis occurring as an immune-related adverse event.

Jpn J Clin Oncol 2021 Mar;51(3):363-370

Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objective: Diarrhea is often observed as an immune-related adverse event. In this study, we conducted a retrospective review of the severity of diarrhea, its treatment and the endoscopic findings in patients developing diarrhea as an immune-related adverse event.

Methods: From August 2015 to June 2019, a total of 369 patients received treatment with immune checkpoint inhibitors at our hospital. For this study, development of grade 2 or more diarrhea in these patients was defined as an immune-related adverse event. We analyzed the histopathological severity of the bowel lesions according to the Nancy histological index for ulcerative colitis.

Results: Of the 369 patients, 27 (7.3%) developed diarrhea as an immune-related adverse event. Of these 27 patients, 18 received steroid treatment. Colonoscopy was performed in 17 patients and culture of the feces in 18. The tests revealed evidence of bacterial colitis (Aeromonas hydrophila) in two patients. The Nancy histological index was 4, 3, 2, 1 and 0 in two, three, two, two and seven patients, respectively. No findings on colonoscopy were observed in 7 of the 17 patients (41%) who underwent colonoscopy, and most of these patients recovered without steroid treatment. Patients with lower values of the Nancy histological index tended to show better responses to steroid treatment.

Conclusions: To avoid unnecessary steroid administration, colonoscopic evaluation is essential in patients receiving treatment with immune checkpoint inhibitors who present with diarrhea as an immune-related adverse event. In addition, the endoscopic findings could be useful to predict the response to steroid treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jjco/hyaa203DOI Listing
March 2021

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

Cancer Sci 2021 Jan 30;112(1):388-396. Epub 2020 Nov 30.

Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-sayama, Japan.

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780021PMC
January 2021

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

JAMA Oncol 2020 Dec;6(12):1931-1938

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach.

Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.

Design, Setting, And Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan.

Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations.

Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations.

Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months.

Conclusions And Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP.

Trial Registration: UMIN Identifier: UMIN000016794.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.4643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563669PMC
December 2020

Treatment Rationale and Design of a Phase III Study of Afatinib or Chemotherapy in Patients with Non-small-cell Lung Cancer Harboring Sensitizing Uncommon Epidermal Growth Factor Receptor Mutations (ACHILLES/TORG1834).

Clin Lung Cancer 2020 11 21;21(6):e592-e596. Epub 2020 May 21.

Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.

We describe the treatment rationale and design of our randomized phase III study, the ACHILLES trial (Japan Registry of Clinical Trials: jRCTs031180175). The aim of this study is to investigate the superiority of afatinib over chemotherapy as first-line treatment in patients with advanced nonsquamous non-small-cell lung cancer with sensitizing uncommon or compound epidermal growth factor receptor (EGFR) mutations, with the exception of de novo T790M mutations and exon 20 insertions. Eligible patients will be randomized at a 1:2 ratio to receive either chemotherapy or afatinib until disease progression or unacceptable toxicity. Patients in the chemotherapy arm will receive pemetrexed 500 mg/m + cisplatin 75 mg/m or carboplatin area under the curve (AUC) 5 or 6 every 3 weeks × 4 cycles, followed by pemetrexed 500 mg/m every 3 weeks. In the afatinib arm, investigators will choose the starting dose of afatinib (30 mg or 40 mg orally daily). The primary endpoint is progression-free survival. A total of 106 patients will be enrolled in this trial over a 30-month registration period with a 15-month follow-up. Enrollment began in March 2019. The results of this trial will establish the superiority of afatinib over chemotherapy in a cohort with a large variety of EGFR mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2020.05.011DOI Listing
November 2020

Key prognostic factors for EGFR-mutated non-adenocarcinoma lung cancer patients in the Japanese Joint Committee of Lung Cancer Registry Database.

Lung Cancer 2020 08 18;146:236-243. Epub 2020 Jun 18.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Introduction: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-adenocarcinoma (ADC) non-small cell lung cancer patients is not well established. Herein, we investigated key prognostic factors influencing the efficacy of EGFR-TKIs in these patients.

Methods: A total of 12,320 lung cancer patients pathologically diagnosed in 2012 at teaching hospitals in Japan were retrospectively selected. The follow-up survey was closed in 2016.

Results: EGFR-mutated non-ADC patients were more prone to malignant pleural effusion (MPE) and distant metastasis than ADC patients (P = 0.071 and 0.022, respectively). EGFR-mutated ADC patients were likely to have a longer median overall survival (OS) than non-ADC patients [hazard ratio (HR) 1.3 (95 % CI, 0.97-1.8, P = 0.072)-29.5 months (95 % CI, 27.9-31.1 months) versus 19.5 months (95 % CI, 10.8-28.2 months) (P = 0.068)]. There was no significant difference in median OS between EGFR-positive ADC and non-ADC patients receiving treatment with first-generation EGFR-TKI. Among EGFR-positive non-ADC patients, the median OS was significantly longer for patients receiving EGFR-TKI treatment than for those who did not [HR 4.5 (95 % CI, 2.1-9.8, P < 0.001)-25.5 months (95 % CI, 8.1-42.9 months) versus 7.5 months (95 % CI, 3.4-11.6 months) (P < 0.001)]. While there was no significant difference in the median OS for ADC patients with either 19 del or L858R mutations, the median OS was significantly longer for EGFR-mutated non-ADC patients with 19 del than for those with L858R mutation (HR 3.2 [95 % CI, 1.5-6.9, P = 0.004]; it was not reached for 19 del and was 15.5 months for L858R [95 % CI, 6.6-24.4 months], P = 0.002).

Discussion: EGFR-mutated non-ADC patients were more prone to MPE and distant metastasis. Both ADC and EGFR del19-positive non-ADC patients can benefit from EGFR-TKI treatment, whereas EGFR L858R-positive non-ADC patients might require different therapeutic options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.06.015DOI Listing
August 2020

Survival and prognostic factors in elderly patients receiving second-line chemotherapy for relapsed small-cell lung cancer: Results from the Japanese Joint Committee of Lung Cancer Registry.

Lung Cancer 2020 08 6;146:160-164. Epub 2020 Jun 6.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objectives: Most patients with small-cell lung cancer (SCLC) experience relapse because of the emergence of drug-resistant tumor cells. Therefore, second-line therapy is subsequently required to prolong their survival. However, it is unclear whether second-line chemotherapy can provide a survival benefit to elderly patients with relapsed SCLC. Therefore, this study aimed to evaluate survival and identify prognostic factors in an elderly population.

Materials And Methods: Based on a nationwide registry database of patients with SCLC (the Japanese Joint Committee of Lung Cancer Registry), we retrospectively reviewed medical records of patients aged ≥ 75 years with relapsed SCLC who subsequently received second-line chemotherapy. Survival time since the initiation of second-line chemotherapy was evaluated.

Results: Among 731 patients aged ≥ 75 years with SCLC who were accumulated by the nationwide registry database, this study included 228 patients, comprising 190 men and 38 women with a median age of 78 years. The number of patients with performance status (PS) of 0-1 and 2-4 was 196 and 32, respectively. The overall survival (OS) and 1-year survival rates were 7.5 months and 24 %, respectively. A multivariate analysis identified PS, clinical stage at the time of starting first-line therapy, and the interval from the start of first-line therapy to that of second-line therapy as independent prognostic factors.

Conclusion: This study with the nationwide registry database showed that among the relapsed elderly SCLC patients who received second-line chemotherapy, a substantial OS may be expected in patients with good PS, at an early clinical stage at the time of starting first-line therapy, and with a longer interval from the start of first-line therapy to that of second-line chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.05.038DOI Listing
August 2020

Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer.

J Clin Oncol 2020 07 14;38(19):2187-2196. Epub 2020 May 14.

Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Purpose: To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC).

Patients And Methods: We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m, day 1) plus cisplatin (75 mg/m, day 1) or vinorelbine (25 mg/m, days 1 and 8) plus cisplatin (80 mg/m, day 1) with stratification by sex, age, pathologic stage, mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients.

Result: Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had -sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% 0.3%, respectively), neutropenia (81.1% 22.7%, respectively), and anemia (9.3% 2.8%, respectively). One treatment-related death occurred in each arm.

Conclusion: Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02674DOI Listing
July 2020

A Japanese lung cancer registry study on demographics and treatment modalities in medically treated patients.

Cancer Sci 2020 May 25;111(5):1685-1691. Epub 2020 Mar 25.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

This study provides the benchmark statistics on medically treated patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in Japan. Demographic background, treatment, and prognosis were obtained from patients with lung cancer pathologically diagnosed in 2012, who received nonsurgical treatment. Descriptive statistics and their associations with survival were analyzed. In total, 12 320 patients were registered from 314 institutions in Japan. The median age was 70 years, and 73% of the patients were male. The number (%) of stages I, II, III, and IV diseases were 468 (3.8%), 421 (3.4%), 3260 (26.5%), and 8171 (66.3%), respectively. NSCLC and SCLC accounted for 9872 (80.1%) and 2353 (19.1%) patients, respectively. Thoracic radiotherapy-based therapy, chemotherapy, and palliative care alone were administered to 2572 (20.9%), 7790 (63.2%), and 1952 (15.8%) patients, respectively. Clinical TNM stage was one of the strongest prognostic factors with the 3-year survival rates of 62.9%, 47.3%, 40.0%, 27.8%, 37.5%, 26.5%, and 18.2% for stages IA, IB, IIA, IIB, IIIA, IIIB, and IV, respectively. Among 6158 patients with NSCLC treated with chemotherapy, the 3-year survival rate was 33.4% in patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) at some point in their clinical course, whereas it was 17.4% in patients who did not. The 3-year survival rate of SCLC was only 15.9%. In conclusion, approximately two-thirds of the patients were diagnosed as stage IV at the initial diagnosis. Use of EGFR-TKIs significantly improved the survival of patients with NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226207PMC
May 2020

Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer.

Lung Cancer 2020 01 28;139:195-199. Epub 2019 Nov 28.

Thoracic Center, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan. Electronic address:

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018).

Methods: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018.

Results: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib).

Conclusions: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2019.11.025DOI Listing
January 2020

Relationship between the immune microenvironment of different locations in a primary tumour and clinical outcomes of oesophageal squamous cell carcinoma.

Br J Cancer 2020 02 25;122(3):413-420. Epub 2019 Nov 25.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.

Background: Tumour microenvironments can differ according to intratumoural locations. We investigated the immune status at different locations in primary tumours and its clinical significance in oesophageal squamous cell carcinoma (ESCC).

Methods: The number of CD8 tumour-infiltrating immune cells (TIICs) and PD-1 TIICs, and PD-L1 expression on tumour cells (PD-L1) were immunohistochemically examined in the surface (Surf), centre (Cent) and invasive front (Inv) of tumours surgically resected from 192 patients with ESCC.

Results: The PD-L1 rate was lower in Inv than in Cent (12.0% vs. 18.2%, P = 0.012), although the numbers of CD8 TIICs and PD-1 TIICs were comparable among intratumoural locations. High numbers of CD8 and PD-1 TIICs and positive PD-L1 were related to better overall survival (OS) only in Surf and Cent (CD8: P = 0.012 in Surf, 0.018 in Cent, and 0.165 in Inv; PD-1: P = 0.028 in Surf, 0.021 in Cent, and 0.208 in Inv; and PD-L1: 0.044 in Surf, 0.026 in Cent, and 0.718 in Inv). Positive PD-L1 in Surf and/or Cent but not in Inv demonstrated a strong tendency toward better OS (P = 0.053).

Conclusions: Immune microenvironments according to the intratumoural location have different effects on the survival of patients with ESCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-019-0622-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000821PMC
February 2020

Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017.

Mol Clin Oncol 2019 Oct 23;11(4):349-353. Epub 2019 Jul 23.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa 240-8555, Japan.

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20-30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92-133 days], and the median number of ZA administrations was 4 (range, 2-41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156-264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/mco.2019.1903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713944PMC
October 2019

Resveratrol Targets Urokinase-Type Plasminogen Activator Receptor Expression to Overcome Cetuximab-Resistance in Oral Squamous Cell Carcinoma.

Sci Rep 2019 08 21;9(1):12179. Epub 2019 Aug 21.

Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Drug resistance to anti-cancer agents is a major concern regarding the successful treatment of malignant tumors. Recent studies have suggested that acquired resistance to anti-epidermal growth factor receptor (EGFR) therapies such as cetuximab are in part caused by genetic alterations in patients with oral squamous cell carcinoma (OSCC). However, the molecular mechanisms employed by other complementary pathways that govern resistance remain unclear. In the current study, we performed gene expression profiling combined with extensive molecular validation to explore alternative mechanisms driving cetuximab-resistance in OSCC cells. Among the genes identified, we discovered that a urokinase-type plasminogen activator receptor (uPAR)/integrin β1/Src/FAK signal circuit converges to regulate ERK1/2 phosphorylation and this pathway drives cetuximab-resistance in the absence of EGFR overexpression or acquired EGFR activating mutations. Notably, the polyphenolic phytoalexin resveratrol, inhibited uPAR expression and consequently the signaling molecules ERK1/2 downstream of EGFR thus revealing additive effects on promoting OSCC cetuximab-sensitivity in vitro and in vivo. The current findings indicate that uPAR expression plays a critical role in acquired cetuximab resistance of OSCC and that combination therapy with resveratrol may provide an attractive means for treating these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-48717-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704133PMC
August 2019

Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia.

Respir Investig 2019 Nov 1;57(6):512-533. Epub 2019 Aug 1.

Department of Radiation Oncology, National Cancer Center Hospital, Japan.

Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.resinv.2019.06.001DOI Listing
November 2019

Simultaneous chylous ascites and chylothorax during ramucirumab plus docetaxel chemotherapy in a patient with non-small lung cell cancer.

Int Cancer Conf J 2019 Jul 25;8(3):114-117. Epub 2019 Feb 25.

1Department of Medical Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670 Japan.

A 69-year-old woman was diagnosed as having non-small cell lung cancer (adenocarcinoma, T1aN3M1b). She had no history of surgery or abdominal trauma. She was treated with ramucirumab (10 mg/kg) plus docetaxel (60 mg/m) intravenously (RAM + DTX) every 3 weeks. Although an enhanced CT examination showed a partial tumor response after eight courses of RAM + DTX, she gradually began to experience abdominal fullness with severe peripheral pitching edema. Her body weight increased by 18 kg in 2 months and RAM + DTX chemotherapy was discontinued. An enhanced CT examination showed a large amount of ascites and pleural effusion, with no obstructions of the central vein or lymphatic ducts. The ascites were white and milky in appearance and contained 527 mg/dL of triglyceride. In addition, her pleural effusion was also white and milky in appearance. No further increases in ascites and pleural effusion were observed thereafter. Four months after her last RAM + DTX chemotherapy, she continued to exhibit a partial response and no increases in ascites or pleural effusion were present. The chylous effusion might have been caused by the RAM + DTX chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13691-019-00366-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545190PMC
July 2019

Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202).

Jpn J Clin Oncol 2019 Aug;49(8):749-754

Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo.

Background: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine.

Methods: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL).

Results: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen.

Conclusions: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jjco/hyz064DOI Listing
August 2019

AMPK activation induced in pemetrexed-treated cells is associated with development of drug resistance independently of target enzyme expression.

Mol Oncol 2019 06 15;13(6):1419-1432. Epub 2019 May 15.

Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Japan.

Pemetrexed (PEM) inhibits DNA and RNA synthesis and is currently one of the first-line agents for mesothelioma. PEM suppresses the activities of several enzymes involved in purine and pyrimidine synthesis, and elevated activity of these enzymes in tumors is often linked with resistance to PEM. The agent also stimulates AMP-activated protein kinase (AMPK) and consequently influences the mammalian target of rapamycin complex 1 (mTORC1) pathways. Nevertheless, it remains unclear whether PEM resistance is linked to the AMPK or mTORC1 pathways. Here, we established two independent PEM-resistant mesothelioma cell lines in which expression of the PEM-target enzymes was not elevated, and found that levels of phosphorylated AMPK and p70S6K and, to a lesser extent, levels of phosphorylated AKT and p53, were increased in these cells as compared with the respective parent cells. PEM stimulation also augmented phosphorylation of AMPK, p70S6K, AKT and p53 in most cases. An AMPK activator increased phosphorylation and PEM resistance in parental cells, and the inhibitor decreased the resistance of PEM-resistant cells. In contrast, inhibitors for p70S6K and AKT did not influence PEM resistance; furthermore, increased levels of endogenous p53 did not affect PEM sensitivity. These data collectively indicate that constitutive activation of AMPK is associated with PEM resistance, and that this is unconnected with elevated DNA and RNA synthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547620PMC
June 2019

A Repeated Biopsy by EBUS-TBNA Contributed to the Selection of an Appropriate Therapeutic Regimen for a Lung Cancer Patient.

J Bronchology Interv Pulmonol 2019 Apr;26(2):129-131

Departments of General Thoracic Surgery.

Since the development of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for lung cancer treatment, the need for a rebiopsy has increased. To select an appropriate therapeutic regimen, the genetic alterations in cancerous tissue should be determined. A rebiopsy plays an important role in the treatment of patients with diseases that are refractory to the previous generation of EGFR tyrosine kinase inhibitors. Cell-free DNA-based exploration is useful for determining the cause of treatment resistance in cases in which a rebiopsy is difficult; however, this method cannot detect histologic changes (a mechanism of resistance), which may lead to the selection of nonoptimum therapeutic agents. We herein report a case in which EGFR mutation-positive (exon 19 deletion) lung cancer was successfully treated with an appropriate chemotherapeutic regimen after disease progression. The regimen was selected based on the precise evaluation of a rebiopsy specimen, which determined the histologic type and detected a gene mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/LBR.0000000000000571DOI Listing
April 2019

Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line treatment for stage IV squamous non-small cell lung cancer: A phase 1b and randomized, open-label, multicenter, phase 2 trial in Japan.

Lung Cancer 2019 03 16;129:55-62. Epub 2019 Jan 16.

Thoracic Center, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan. Electronic address:

Objectives: This open-label, multicenter, phase 1b/2 study assessed necitumumab plus gemcitabine and cisplatin (GC + N) in patients with previously untreated squamous non-small cell lung cancer in Japan.

Materials And Methods: The phase 1b part determined the gemcitabine dose for the phase 2 part, in which patients were randomized 1:1 to GC + N or gemcitabine and cisplatin (GC) (gemcitabine 1250 mg/m on days 1 and 8; cisplatin 75 mg/m on day 1 of maximum four 3-week cycles; nectimumab 800 mg on days 1 and 8 of a 3-week cycle continued until progressive disease or unacceptable toxicity). The primary endpoint of the phase 2 part was overall survival.

Results: In the phase 2 part, 181 patients received GC + N (N = 90) or GC (N = 91). Overall survival was significantly improved with GC + N versus GC (median, 14.9 months vs 10.8 months; hazard ratio [HR] = 0.66, 95% CI: 0.47 - 0.93, p = 0.0161). Improvements were also observed in progression-free survival (median, 4.2 months vs 4.0 months; HR = 0.56; p = 0.0004) and objective response rate (51% vs 21%; p < 0.0001). Survival was also significantly prolonged with GC + N versus GC for patients with epidermal growth factor receptor-positive tumors. Grade ≥3 treatment-emergent adverse events at ≥5% higher incidence with GC + N than GC were neutrophil count decreased (42% vs 35%), febrile neutropenia (12% vs 3%), decreased appetite (11% vs 4%), and dermatitis acneiform (6% vs 0%).

Conclusion: GC + N is well tolerated and has significant and clinically meaningful treatment benefit in the first-line treatment of patients with squamous non-small cell lung cancer in Japan. Clinicaltrials.gov identifier: NCT01763788.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2019.01.005DOI Listing
March 2019

Growth suppression of human oral cancer cells by candidate agents for cetuximab-side effects.

Exp Cell Res 2019 03 25;376(2):210-220. Epub 2019 Jan 25.

Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8- 1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.

Cetuximab, an inhibitor of the epidermal growth factor receptor that is used widely to treat human cancers including oral squamous cell carcinoma (OSCC), has characteristic side effects of skin rash and hypomagnesemia. However, the mechanisms of and therapeutic agents for skin rashes and hypomagnesemia are still poorly understood. Our gene expression profiling analyses showed that cetuximab activates the p38 MAPK pathways in human skin cells (human keratinocyte cell line [HaCaT]) and inhibits c-Fos-related signals in human embryonic kidney cells (HEK293). We found that while the p38 inhibitor SB203580 inhibited the expression of p38 MAPK targets in HaCaT cells, flavagline reactivated c-Fos-related factors in HEK293 cells. It is noteworthy that, in addition to not interfering with the effect of cetuximab by both compounds, flavagline has additive effect for OSCC growth inhibition in vivo. Collectively, our results indicate that combination of cetuximab and these potential therapeutic agents for cetuximab-related toxicities could be a promising therapeutic strategy for patients with OSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yexcr.2019.01.016DOI Listing
March 2019

Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site.

J Clin Oncol 2019 03 17;37(7):570-579. Epub 2019 Jan 17.

1 Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Purpose: Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP.

Patients And Methods: Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate.

Results: One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types.

Conclusion: Site-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.00771DOI Listing
March 2019

Long-Term Prognosis of Patients with Obscure Gastrointestinal Bleeding: A Retrospective Cohort Study.

Digestion 2019 11;100(1):37-44. Epub 2019 Jan 11.

Department of Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Aims: We evaluated the long-term prognosis of patients with obscure gastrointestinal bleeding (OGIB) who underwent capsule endoscopy (CE).

Methods: In our hospital, 429 patients underwent CE between November 2007 and March 2012. Among them, 259 patients underwent CE as the first examination for OGIB and were then followed at 77 clinics and hospitals. The clinical characteristics were investigated, including age, gender, overt/occult bleeding, the use of antithrombotic drugs and NSAIDs, complications (liver cirrhosis and hemodialysis), and CE. We asked the medical institutions for their survival data as of August 2017 (> 5 years after CE).

Results: The prognoses of 240 patients (92.6%) were analyzed. The average follow-up period was 55.7 (1-115) months. During the follow-up period, 57 patients (23.8%) died and the survival rates were 90.5% at 1 year, 81.7% at 3 years, and 74.7% at 5 years. Age 65 years or older and liver cirrhosis were predictive factors for a poor prognosis. Rebleeding occurred in 42 patients (17.9%) and small bowel cancer and gastrointestinal stromal tumor were found at 12 and 21 months after CE, respectively.

Conclusions: Patients with OGIB showed a poor prognosis, especially those who were elderly or who had liver cirrhosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000493854DOI Listing
December 2019

[Dawn of Cancer Clinical Sequencing in Chiba University Hospital].

Gan To Kagaku Ryoho 2018 Oct;45(10):1463-1465

Dept. of Frontier Surgery, Graduate School of Medicine, Chiba University.

Genome medicine has been attractingmuch of attention in Japan. The combination of molecular targetingdrug s and somatic mutations has been developed for cancer treatment, which was introduced clinically with evidence by cancer type. Several cancer somatic mutations can be identified in a single test inexpensively using next-generation sequencing(NGS). Drug approval not based on organs but on cancer genome analysis has been practiced mainly in the United States, and is also being implemented in Japan. However, cancer treatment strategies using molecular targeting drugs and the associated diagnosis are limited in each type of cancer. Furthermore, the benefit of NGS, which is an improved and inexpensive technique, is still insignificant in Japan. However, the clinical biobank system was initiated in 2011 to prepare the era of cancer genome medicine in our department. The quality of biological samples was strictly controlled by the standardized sampling procedures, which can be used by the researchers accordingto their convenience. Furthermore, the cooperative research involvingcommercial corporations has been started.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2018

Intracardiac Tumors With Extracardiac Extension Diagnosed by Endoscopic Ultrasound With Bronchoscope-Guided Fine-Needle Aspiration.

Ann Thorac Surg 2019 01 15;107(1):e5-e7. Epub 2018 Jun 15.

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Obtaining biopsy specimens for pathologic diagnosis of primary cardiac tumors is challenging because of their anatomic location and the risk of tumor embolization. Due to the difficulty of histologic diagnosis and limited treatment strategies, it is not uncommon for patients to be treated based on radiologic findings alone. However, a firm pathologic diagnosis may permit more appropriate treatment selection, especially for those with primary cardiac lymphoma. Endoscopic ultrasound with bronchoscope-guided fine-needle aspiration is a minimally invasive modality for sampling mediastinal lymph nodes and mediastinal lesions adjacent to the esophagus. In this case report we present 2 patients with cardiac tumors that were successfully and safely diagnosed by endoscopic ultrasound with bronchoscope-guided fine-needle aspiration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2018.05.046DOI Listing
January 2019

A Randomized Phase III Study Comparing Carboplatin With Nab-Paclitaxel Versus Docetaxel for Elderly Patients With Squamous-Cell Lung Cancer: Study Protocol.

Clin Lung Cancer 2018 09 19;19(5):e711-e715. Epub 2018 May 19.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Background: Treatment with carboplatin (CBDCA) with weekly paclitaxel (PTX) has shown survival benefits compared with vinorelbine or gemcitabine in elderly patients with non-small-cell carcinoma (NSCLC). Docetaxel (DOC), however, remains a standard treatment in NSCLC. The 130-nm albumin-bound formulation of PTX (nab-PTX) has shown activity in NSCLC. Treatment with CBDCA with weekly nab-PTX showed significantly higher efficacy than CBDCA with PTX in patients with squamous histology and significantly increased overall survival (OS) in patients aged 70 years and older.

Patients And Methods: This randomized, multicenter, phase III trial (UMIN000019843) was designed to compare the efficacy and safety of CBDCA with nab-PTX with DOC in patients aged 70 years and older with advanced squamous NSCLC. Elderly patients who have received no previous chemotherapy for advanced/metastatic squamous NSCLC with Eastern Cooperative Oncology Group performance status of 0 or 1 will be randomized 1:1 to DOC (60 mg/m intravenous [I.V.] on day 1) or CBDCA (area under the blood concentration time curve 6 on day 1) with nab-PTX (100 mg/m I.V. on days 1, 8, and 15) of each 21-day cycle. The primary end point is OS. Recruitment began in December 2015 and planned enrollment is 250 patients.

Conclusion: If OS is greater in patients treated with CBDCA with nab-PTX than with DOC, this study will provide a new standard of care for elderly patients with squamous NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2018.05.005DOI Listing
September 2018

Prognostic impact of presumed breast or ovarian cancer among patients with unfavorable-subset cancer of unknown primary site.

BMC Cancer 2018 02 13;18(1):176. Epub 2018 Feb 13.

Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: The clinical utility and prognostic impact of presumed primary breast or ovarian cancer among patients with an unfavorable subset of cancer of unknown primary site (CUP) remains unclear. We aimed to evaluate the clinical relevance of the presumed primary site of CUP and the clinical outcome of site-specific therapy based on such presumptions.

Methods: Patients referred to our center who were diagnosed with unfavorable-subset CUP and treated between April 2007 and March 2015 were enrolled in this study. Data were collected retrospectively from the hospital database and electronic medical records. Presumptive primary breast or ovarian cancer was based on histological and immunohistochemical analyses and metastatic patterns. The outcomes of patients with unfavorable-subset CUP with a putative primary site in the breast or ovary (P-CUP) and of patients with unfavorable-subset CUP, but without P-CUP (U-CUP), were assessed.

Results: A total of 780 patients were referred to our hospital with malignancy of unknown origin. Of these, 409 patients were diagnosed with CUP and 344 patients with unfavorable-subset CUP. Following clinicopathological examination, 40 (11.6%) of the 344 patients had P-CUP and the remaining 303 (88.3%) patients had U-CUP. In total, 136 patients received chemotherapy (22 with P-CUP and 114 with U-CUP). Among the 22 patients with P-CUP, three received hormonal therapy for breast cancer, and 19 received chemotherapy based on the presumed primary organ (breast, 4; ovaries, 15). Conventional platinum-based chemotherapy was administered to 105 patients with U-CUP and non-platinum drug treatment to nine patients. The objective response rates were 61.1% (95% confidence interval [CI]: 38.6-83.6) and 41.1% (95% CI: 31.8-50.4) for patients with P-CUP and U-CUP, respectively. The median overall survival durations were 50.0 months and 16.9 months (log-rank: P = 0.002) for patients with P-CUP and U-CUP, respectively. P-CUP was identified as an independent predictor of good prognosis according to multivariate analysis.

Conclusions: Patients with P-CUP had higher response rates and a better prognosis compared with patients with U-CUP. It might thus be reasonable to classify this subset as a new category of CUP with a favorable prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-018-4092-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809895PMC
February 2018

Inhibition of Gli leads to antitumor growth and enhancement of cisplatin-induced cytotoxicity in large cell neuroendocrine carcinoma of the lung.

Oncol Rep 2018 Mar 3;39(3):1148-1154. Epub 2018 Jan 3.

Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a highly aggressive tumor without established standard treatment. The Hedgehog (Hh) signal, which is critical in embryogenesis, is known to play important roles in maintaining a malignant phenotype in various cancers. The present study explored the possibility of targeting the Hh signal in the treatment of LCNEC by suppressing Hh downstream molecules, Smoothened (Smo) and GLI family zinc finger 1/2 (Gli1/2), in 3 human LCNEC cell lines. Smo inhibitor, BMS-833923, and Gli inhibitor, GANT61, downregulated Gli1 and 2, resulting in the suppression of the cell viability of the 3 cell lines as assessed using an MTT assay. The downregulation of Gli1 and/or Gli2 using siRNA for each gene also led to cell growth inhibition in the 3 cell lines. The downregulation of Gli1/2 made the cells more sensitive to cisplatin, resulting in increased apoptosis. These findings suggest that the Hh signaling pathway may be a candidate target for the treatment of LCNEC of the lung.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/or.2018.6183DOI Listing
March 2018

Augmented expression of cardiac ankyrin repeat protein is induced by pemetrexed and a possible marker for the pemetrexed resistance in mesothelioma cells.

Cancer Cell Int 2017 11;17:120. Epub 2017 Dec 11.

Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba, 260-8717 Japan.

Background: Pemetrexed (PEM) is an anti-cancer agent targeting DNA and RNA synthesis, and clinically in use for mesothelioma and non-small cell lung carcinoma. A mechanism of resistance to PEM is associated with elevated activities of several enzymes involved in nucleic acid metabolism.

Methods: We established two kinds of PEM-resistant mesothelioma cells which did not show any increase of the relevant enzyme activities. We screened genes enhanced in the PEM-resistant cells with a microarray analysis and confirmed the expression levels with Western blot analysis. A possible involvement of the candidates in the PEM-resistance was examined with a WST assay after knocking down the expression with si-RNA. We also analyzed a mechanism of the up-regulated expression with agents influencing AMP-activated protein kinase (AMPK) and p53.

Results: We found that expression of cardiac ankyrin repeat protein (CARP) was elevated in the PEM-resistant cells with a microarray and Western blot analysis. Down-regulation of CARP expression with si-RNA did not however influence the PEM resistance. Parent and PEM-resistant cells treated with PEM increased expression of CARP, AMPK, p53 and histone H2AX. The CARP up-regulation was however irrelevant to the genotypes and not induced by an AMPK activator. Augmented p53 levels with nutlin-3a, an inhibitor for p53 degradation, and DNA damages were not always associated with the enhanced CARP expression.

Conclusions: These data collectively suggest that up-regulated CARP expression is a potential marker for development of PEM-resistance in mesothelioma and that the PEM-mediated enhanced expression is not directly linked with immediate cellular responses to PEM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12935-017-0493-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725641PMC
December 2017