Studies about the biology, treatment pattern, and treatment outcome of metastatic/recurrent neuroendocrine tumor (NET) have been few.
We enrolled patients with metastatic/recurrent NET diagnosed ...between January 1996 and July 2007 and retrospectively analyzed.
A total of 103 patients were evaluated. Twenty-six patients (25.2%) had pancreatic NET, 27 (26.2%) had gastrointestinal NET, 2 (1.9%) had lung NET, 28 (27.2%) had NET from other sites, and 20 (19.4%) had NET from unknown origin. The liver was the most common metastatic site (68.9%). Thirty-four patients had grade 1 disease, 1 (1.0%) had grade 2 disease, 15 (14.6%) had grade 3 disease, 9 (8.7%) had large cell disease, and 7 (6.8%) had small cell disease.Sixty-six patients received systemic treatment (interferon, somatostatin analogues or chemotherapy), 64 patients received local treatment (TACE, radiofrequency ablation, metastasectomy, etc.). Thirty-six patients received both systemic and local treatments.Median overall survival (OS) was 29.0 months (95% confidence interval, 25.0-33.0) in the 103 patients. OS was significantly influenced by grade (p = .001). OS was 43.0, 23.0, and 29.0 months in patients who received local treatment only, systemic treatment only, and both treatments, respectively (p = .245). The median time-to-progression (TTP) was 6.0 months. Overall response rate was 34.0% and disease-control rate was 64.2%. TTP was influenced by the presence of liver metastasis (p = .011).
OS of metastatic/recurrent NET was different according to tumor grade. TTP was different according to metastasis site. Therefore, development of optimal treatment strategy based on the characteristics of NET is warranted.
Cadmium is a well known human and animal carcinogen and is a ubiquitous contaminant in the environment. Although the carcinogenic mechanism of cadmium is a multifactorial process, oxidative DNA ...damage is believed to be of prime importance. In particular, cadmium suppresses the capacity of cells to repair oxidative DNA damage. In this study, cadmium treatment led to a significant increase in γ-ray-induced 8-oxoguanine (8-oxoG) formation. Western blotting and semiquantitative reverse transcription-PCR revealed that cadmium treatment caused a decrease in the expression level of human OGG1 (8-oxoguanine-DNA glycosylase-1; hOGG1) in human fibroblast GM00637 and HeLa S3 cells. In addition, the cadmium-mediated decrease in hOGG1 transcription was the result of decreased binding of the transcription factor Sp1 to the hOGG1 promoter. Finally, we show that an increase in the functional hOGG1 expression level could inhibit the cadmium-mediated increase in γ-ray-induced 8-oxoG accumulation as well as in γ-radiation-induced mutation frequency at the HPRT (hypoxanthine-guanine phosphoribosyltransferase) gene locus. These results suggest that cadmium attenuates removal of γ-ray-induced 8-oxoG adducts, which in turn increases the mutation frequency, and that this effect might, at least in part, result from suppression of hOGG1 transcription via inactivation of Sp1 as a result of cadmium treatment.
NTRK1 gene fusions, the targets of multikinase inhibitors, are promising therapeutic targets for colorectal cancer (CRC). However, screening methods for detecting NTRK1 gene fusions in CRC tissues ...have not been reported. In this study, we investigated the potential use of immunohistochemistry (IHC) for detecting NTRK1 gene fusions. We performed and compared IHC with fluorescence in situ hybridization (FISH) in 80 CRC patients. TrkA immunostaining was observed to be both membranous and cytoplasmic and was scored semiquantitatively using staining intensity and proportions. The tumors were observed to be NTRK1 gene fusion-positive when ≥20 out of 100 nuclei in FISH. A significant correlation between the IHC and FISH results for determination of the NTRK1 gene fusions was observed. We measured the cytoplasmic TrkA expression, which showed an area under the receiver operating characteristic (ROC) curve of 0.926 (range: 0.864-0.987, 95% CI, P=.001). By choosing 4.5 (sum of the intensity and proportion scores of cytoplasmic TrkA expression) as the cut-off value for the positive and negative NTRK1 gene fusion groups, the sensitivity and specificity for predicting lymph node metastasis were 100 and 83.8%, respectively (P=.001). Specifically, high cytoplasmic TrkA expression (sum of intensity and proportion scores >4) was associated with the presence of NTRK1 gene fusions (P<.0001, r=0.528). Taken together, our data showed that IHC for TrkA can be used as an efficient screening method for detecting NTRK1 gene fusions in CRC.
Lessons Learned
Oraxol, a novel oral formulation of paclitaxel, displayed modest efficacy as second‐line chemotherapy for gastric cancer.
Considering its favorable toxicity profiles, further studies ...are warranted in various solid tumors including gastric cancer.
Background.
Oraxol consists of paclitaxel and HM30181A, a P‐glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM‐OXL‐201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second‐line chemotherapy for metastatic or recurrent gastric cancer (GC).
Methods.
In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m2 per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated.
Results.
In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m2. In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression‐free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug‐related adverse events (grade ≥3) were neutropenia and diarrhea.
Conclusion.
Oraxol exhibited modest efficacy and favorable toxicity profiles as second‐line chemotherapy for GC.
摘要
背景. Oraxol由紫杉醇和HM30181A(一种P糖蛋白抑制剂,可增加紫杉醇的口服生物利用度)组成。本项I期/II期研究(HM‐OXL‐201)旨在确定Oraxol的最大耐受剂量(MTD)和II期推荐研究剂量(RP2D)。此外,我们还对Oraxol用于转移性或复发性胃癌(GC)二线化疗的有效性和安全性进行了研究。
方法. 在I期研究阶段,紫杉醇经口服给药且剂量逐渐提升(90、120和150 mg/m2/天),HM30181A按固定剂量给药(15 mg/天)。Oraxol每周期给药6次(第1、2、8、9、15和16天),每4周为一周期。在II期研究阶段评价Oraxol的有效性和安全性。
结果. I期研究阶段未能确定MTD。依据毒性和药代动力学数据,确定口服紫杉醇的RP2D为150 mg/m2。在II期研究阶段,4/43例患者(9.3%)达到部分缓解。中位无进展生存和总生存分别为2.6个月和10.7个月。毒性特征谱良好,最常见的药物相关不良事件(≥ 3级)为中性粒细胞减少症和腹泻。
结论. Oraxol用于胃癌二线化疗时表现出一定的有效性和良好的毒性特征谱。The Oncologist 2015;20:896–897
Background
The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of ...fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.
Methods
Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m
2
in a 2-h infusion) on day 1, and then leucovorin (200 mg/m
2
in a 2-h infusion) and 5-FU (a 400 mg/m
2
bolus, followed by 600 mg/m
2
in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m
2
in a 2-h infusion) on day 1, and then leucovorin (400 mg/m
2
in a 2-h infusion) and 5-FU (a 400 mg/m
2
bolus, followed by 2400 mg/m
2
in a 46-h continuous infusion) on day 1.
Results
A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months 95 % confidence interval (CI), 1.7–2.5 and 5.6 months (95 % CI, 4.7–6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.
Conclusions
The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.
Growing concerns about unpredictable influenza pandemics require a broadly protective vaccine against diverse influenza strains. One of the promising approaches was a T cell‐based vaccine, but the ...narrow breadth of T‐cell immunity due to the immunodominance hierarchy established by previous influenza infection and efficacy against only mild challenge condition are important hurdles to overcome. To model T‐cell immunodominance hierarchy in humans in an experimental setting, influenza‐primed C57BL/6 mice were chosen and boosted with a mixture of vaccinia recombinants, individually expressing consensus sequences from avian, swine, and human isolates of influenza internal proteins. As determined by IFN‐γ ELISPOT and polyfunctional cytokine secretion, the vaccinia recombinants of influenza expanded the breadth of T‐cell responses to include subdominant and even minor epitopes. Vaccine groups were successfully protected against 100 LD50 challenges with PR/8/34 and highly pathogenic avian influenza H5N1, which contained the identical dominant NP366 epitope. Interestingly, in challenge with pandemic A/Cal/04/2009 containing mutations in the dominant epitope, only the group vaccinated with rVV‐NP + PA showed improved protection. Taken together, a vaccinia‐based influenza vaccine expressing conserved internal proteins improved the breadth of influenza‐specific T‐cell immunity and provided heterosubtypic protection against immunologically close as well as distant influenza strains.
The lithium storage capacity of an iron oxide‐based anode of porous carbon–Fe3O4 (i.e., PC–Fe3O4) was investigated by varying the initial current and mass density of the electrode to achieve a good ...utilization coefficient of the oxide. It was confirmed that these factors largely affected the capacity of PC–Fe3O4 and a certain mass density of the electrode was key to achieve a high area capacity (μAh cm−2). Moreover, the chemical and electrochemical lithiation of PC–Fe3O4 were related to the lithiation time and pressure and both were both systemically studied. After optimization, a new battery of PC–Fe3O4/LiNi0.59Co0.16Mn0.25O2 with a high area capacity of 748 μAh cm−2 (≈150 mAh g−1) and superior energy density of 483 Wh kg−1 (work voltage≈3.2 V) was developed. The battery showed reversible work ability in the rate window of 50–800 mA g−1, and also it could be charged/discharged for well over 1000 cycles with a capacity retention of 63.8 % under the high current value of 0.505 mA (current density, 50 mA g−1).
A pillar of stability: A study of the lithiation of an iron oxide‐based anode is performed, and a new battery is developed with porous carbon (PC)–Fe3O4/LiNi0.59Co0.16Mn0.25 architecture. The chemical and electrochemical lithiation of PC–Fe3O4 are related to the lithiation time and pressure and both are both systemically studied. The optimized battery exhibits a high energy density and stable cycling over 1000 cycles.
HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression ...or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification.
This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing.
Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 52% of 46 patients; all grade 1–2) and infusion reactions (20 43% of 46 patients; all grade 1–2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 43% of 86 patients; all grade 1–2 except for one patient) and infusion reactions (29 34% of 86 patients; all grade 1–2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0–48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths.
These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies.
Zymeworks.
Palbociclib is a specific inhibitor of CDK4/6 and has been shown to provide a survival benefit in hormone receptor-positive advanced breast cancer. TCGA database reported that about half of gastric ...cancers exhibit abnormalities in cell-cycle-related molecules, suggesting that gastric cancer is a good candidate for palbociclib treatment; however, the antitumor effects and predictive markers of palbociclib in gastric cancer remain incompletely described. Herein, the effect and predictive markers of palbociclib on gastric cancer cells were investigated. Our results reveal that palbociclib showed anti-proliferative effects by inducing G1 phase cell-cycle arrest and cellular senescence in some gastric cancer cells. Basal protein expression level of cyclin E showed an inverse correlation of cancer cell sensitivity to palbociclib. In addition, palbociclib enhanced the antitumor effect of 5-FU in vitro and in vivo by modulating thymidine synthase expression. These results suggest that cyclin E protein expression determines the anti-proliferative effect of palbociclib, and palbociclib acts synergistically with 5-FU in gastric cancer. These findings provide a rationale for future clinical trials of palbociclib and 5-FU combination-based chemotherapy in gastric cancer.
•The anti-proliferative effect of palbociclib on GC cell lines was determined.•Palbociclib suppressed proliferation by inducing G1 phase arrest and senescence.•The protein level of cyclin E negatively predicts sensitivity to palbociclib on GC.•5-FU plus palbociclib shows synergistic antitumor effects on GC cells.•Palbociclib reduced levels of thymidylate synthase-induced by 5-FU.
Bariatric surgery is relatively new in Korea, and studies comparing different bariatric procedures in Koreans are lacking. This study aimed to compare the clinical outcomes of laparoscopic adjustable ...gastric banding (LAGB), Roux-en-Y gastric bypass (RYGB), and sleeve gastrectomy (SG) for treating morbidly obese Korean adults.
In this multicenter retrospective cohort study, we reviewed the medical records of 261 obese patients who underwent different bariatric procedures. Clinical outcomes were measured in terms of weight loss and resolution of comorbidities, such as diabetes, hypertension, and dyslipidemia. Safety profiles for the procedures were also evaluated.
In terms of weight loss, the three procedures showed similar results at 18 months (weight loss in 52.1% for SG, 61.0% for LAGB, and 69.2% for RYGB). Remission of diabetes, hypertension, and dyslipidemia was more frequent in patients who underwent RYGB (65.9%, 63.6%, and 100% of patients, respectively). Safety profiles were similar among groups. Early complications occurred in 26 patients (9.9%) and late complications in 32 (12.3%). In the LAGB group, five bands (6.9%) were removed. Among all patients, one death (1/261=0.38%) occurred in the RYGB group due to aspiration pneumonia.
The three bariatric procedures were comparable in regards to weight-loss outcomes; nevertheless, RYGB showed a higher rate of comorbidity resolution. Bariatric surgery is effective and relatively safe; however, due to complications, some bands had to be removed in the LAGB group and a relatively high rate of reoperations was observed in the RYGB group.
PDF
