Background: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A, B and human interleukin-2. The amino acid sequence of E7777 is the same as that of denileukin ...diftitox, approved in the USA for treatment of persistent or recurrent CD25-positive cutaneous T-cell lymphoma in 1999, but the purity of E7777 is improved and then it has an increased percentage of active protein monomer species. Since the specific bioactivity of E7777 is 1.5-2 times higher than that of the prior less purified form, a phase 1 study of E7777 was conducted in Japanese patients (pts) with peripheral and cutaneous T-cell lymphoma (PTCL and CTCL). The maximum tolerated and recommended dose of E7777 was 9 μg/kg/day for 5 consecutive days per 21-day cycle. E7777 was well tolerated and preliminary, but clinically meaningful antitumor activity was observed (Ohmachi, et al.: Cancer Sci 2018). Therefore, a subsequent phase 2 study of E7777 was conducted.
Methods: This multicenter, single-arm phase 2 study assessed the efficacy, safety, pharmacokinetics (PK) and immunogenicity (IM) of E7777 in pts with relapsed or refractory PTCL and CTCL. E7777 was administered by IV infusion over 60 min for 5 consecutive days of every 21-day cycle (up to 8 cycles) at dose of 9 μg/kg/day with premedication including systemic steroid. Primary endpoint was objective response rate (ORR) by the independent review assessment. Thirty-five patients were required to detect the lower limit of 2-sided 95% confidence interval (CI) to exceed the 5% threshold in ORR, with the expected ORR of 25% with a statistical power of 90%. Efficacy was evaluated based on integrated criteria of IWG2007 (Cheson, et al,: JCO 2007) for nodal/ex-nodal disease by CT or PET/CT assessment and ISCL2011 (Olsen, et al.: JCO 2011) for cutaneous and blood disease assessment, in both PTCL and CTCL. Tumor CD25 expression level (%) in archival tumor samples from all pts was examined by immunohistochemistry.
Results: As of 26 Apr 2019, a total of 37 pts were enrolled. Based on the central pathological review, 17 pts had PTCL PTCL-not otherwise specified (NOS), n=13; angioimmunoblastic T-cell lymphoma, n=3; anaplastic large cell lymphoma-ALK negative, n=1, 19 pts had CTCL mycosis fungoides, n=12; Sézary syndrome, n=2; primary cutaneous CD30+ T-cell lymphoproliferative disorder, n=2; primary cutaneous γδ T-cell lymphoma, n=1; primary cutaneous aggresive epidermotropic CD8+ cytotoxic T-cell lymphoma, n=1; PTCL-NOS, n=1 and 1 pt had the other disease (extranodal NK/T cell lymphoma, nasal type). The median age was 65 years (range 27-82), and the median number of prior chemotherapy regimens (excluding PUVA, interferon, etretinate) was 2 (range 1-10). Among the 36 pts with PTCL and CTCL, the ORR as assessed by the independent review was 36% (13/36 pts: 95%CI, 21%-54%), including 1 pt with complete response. The ORR were 41% (7/17 pts: 95%CI, 18%-67%) in PTCL and 31% (6/19 pts: 95%CI, 13%-57%) in CTCL, respectively. Responses were observed regardless of the level of CD25 expression in lymphoma cells. With a median follow-up time of 26.3 months, the median progression-free survival (mPFS) of all 36 pts with PTCL and CTCL was 3.1 months (95% CI, 1.9-6.0). The mPFS were 2.1 months (95% CI, 1.1-4.5) in PTCL and 4.2 months (95% CI, 2.6-NE) in CTCL, respectively. Among all 37 treated pts, the common adverse events (AEs) in any grade were AST increased (89%), ALT increased (87%), hypoalbuminemia (70%), lymphopenia (70%), pyrexia (51%), γ-GTP increased (46%), constipation (38%), thrombocytopenia (35%) and malaise (32%). The common Grade 3 or higher AEs were ALT increased (57%), lymphopenia (57%) and AST increased (43%). The common serious AEs considered related to study drug were ALT increased (14%), AST increased (14%) and capillary leak syndrome (11%). One pt died from rhabdomyolysis, which was considered as treatment related. PK and IM data will be presented.
Conclusions: The primary endpoint of the study was met with greater lower limit of 2-sided 95% CI in ORR than the predefined 5% threshold. The study results indicated the promising efficacy and acceptable safety profile of E7777 at the dose of 9 μg/kg/day in Japanese pts with relapsed or refractory PTCL and CTCL, regardless of the level of tumor CD25 expression. The common AEs were manageable, but ALT/AST increased, hypoalbuminemia and capillary leak syndrome should be carefully managed during the treatment.
Maruyama:Eisai: Honoraria, Research Funding. Ando:Eisai: Research Funding. Yamamoto:Chugai: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Novartis: Honoraria, Research Funding; Kyowa Kirin: Honoraria; Gilead Sciences: Research Funding; Otsuka: Honoraria; SymBio: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; AbbVie: Consultancy, Research Funding; ARIAD: Research Funding; Solasia Pharma: Research Funding; Janssen: Honoraria; MSD: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; Pfizer: Honoraria; Eisai: Consultancy, Honoraria, Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Kiyohara:Eisai: Research Funding. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria. Fukuhara:Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene Corporation: Honoraria, Research Funding; Zenyaku: Honoraria; Janssen Pharma: Honoraria; Eisai: Honoraria, Research Funding; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Mundi: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Tokura:Eisai: Consultancy, Honoraria. Kuroda:Eisai: Research Funding. Uchida:Eisai: Honoraria. Nakanishi:Eisai: Employment. Nakai:Eisai: Employment. Matsunaga:Eisai: Employment. Tobinai:HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Verastem: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; AbbVie: Research Funding; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding.
E7777 is investigational drug
Objective
Inter-ictal
18
F-2-fluoro-deoxy-
d
-glucose-positron emission tomography (FDG-PET) is widely used for preoperative evaluation to identify epileptogenic zones in patients with temporal lobe ...epilepsy. In this study, we combined statistical parametric mapping (SPM) with the asymmetry index and volume-of-interest (VOI) based extent analysis employing preoperative FDG-PET in unilateral mesial temporal lobe epilepsy (MTLE) patients. We also evaluated the detection utility of these techniques for automated identification of abnormalities in the unilateral hippocampal area later confirmed to be epileptogenic zones by surgical treatment and subsequent good seizure control.
Methods
FDG-PET scans of 17 patients (9 males, mean age 35 years, age range 16–60 years) were retrospectively analyzed. All patients had been preoperatively diagnosed with unilateral MTLE. The surgical outcomes of all patients were Engel class 1A or 1B with postoperative follow-up of 2 years. FDG-PET images were spatially normalized and smoothed. After two voxel-value adjustments, one employing the asymmetry index and the other global normalization, had been applied to the images separately, voxel-based statistical comparisons were performed with 20 controls. Peak analysis and extent analysis in the VOI in the parahippocampal gyrus were conducted for SPM. For the extent analysis, a receiver operating characteristic (ROC) curve was devised to calculate the area under the curve and to determine the optimal threshold of extent.
Results
The accuracy of the method employing the asymmetry index was better than that of the global normalization method for both the peak and the extent analysis. The ROC analysis results, for the extent analysis, yielded an area under the curve of 0.971, such that the accuracy and optimal extent threshold of judgment were 92 and 32.9%, respectively.
Conclusion
Statistical
z
-score mapping with the asymmetry index was more sensitive for detecting regional glucose hypometabolism and more accurate for identifying the side harboring the epileptogenic zone using inter-ictal FDG-PET in unilateral MTLE than
z
-score mapping with global normalization. Moreover, the automated determination of the side with the epileptogenic zone in unilateral MTLE showed improved accuracy when the combination of SPM with the asymmetry index and extent analysis was applied based on the VOI in the parahippocampal gyrus.
There has been no previous prospective study evaluating 3-month dual antiplatelet therapy (DAPT) after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in patients with acute coronary ...syndrome (ACS). The STOPDAPT trial is a prospective multi-center single-arm study evaluating 3-month DAPT duration in all-comer population after CoCr-EES implantation. Among 1525 study patients enrolled from 58 Japanese centers, the present study compared the 1-year clinical outcomes between ACS patients (N = 487) and stable coronary artery disease (CAD) patients (N = 1038). In the ACS group, 228 patients (47%) had unstable angina and 259 patients (53%) had myocardial infarction. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis (ST) and TIMI major/minor bleeding. Thienopyridine was discontinued within 4-month in 455 patients (94.0%) in the ACS group and 977 patients (94.3%) in the stable CAD group. Cumulative 1-year incidence of and the adjusted risk for the primary endpoint were not significantly different between the ACS and stable CAD groups (2.3% vs. 3.0%, P = 0.42, and HR 0.94, 95%CI 0.44-1.87, P = 0.87). In the 3-month landmark analysis, cumulative incidence of the primary endpoint was also not significantly different between the ACS and stable CAD groups (1.3% vs. 2.4%, P = 0.16). There was no definite/probable ST through 1-year in both groups. In the propensity matched analysis, the cumulative 1-year incidence of the primary endpoint were similar between the ACS and stable CAD groups (2.3% versus 2.1%, P = 0.82). In conclusion, stopping DAPT at 3 months after CoCr-EES implantation in patients with ACS including 47% of unstable angina was as safe as that in patients with stable CAD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cisplatin (CDDP) is an anticancer agent that is commonly used in hepatic arterial infusion (HAI) chemotherapy for hepatocellular carcinoma (HCC). This study aimed to clarify the safe and effective ...dose of CDDP in HAI for HCC. The hypervascular area was measured in 42 HCCs before and after HAI with CDDP. Serum platinum concentration was quantified in the peripheral and/or middle hepatic veins by atomic absorption spectrometry. The relation between the HCC response and CDDP dose was statistically analyzed. The multiple HCC nodules in an individual case generally demonstrated the same response to CDDP. The free‐platinum concentration stayed relatively constant in the hepatic vein during HAI followed by a rapid decline, while total‐platinum gradually increased then slowly disappeared over several days. After CDDP‐HAI, 15 HCCs shrunk and 27 HCCs grew. The reduction rate in the shrunken nodules was tended to be correlated with CDDP dose after standardization with the target liver volume. On the other hand, the growth rate of the enlarged HCCs was significantly correlated with CDDP dose after normalization with creatinine clearance. These data support a recommendation of CDDP‐HAI infusion where the amount of CDDP (mg) administered is less than patient creatinine clearance (mL/min/1.73 m2) upon an assumption of HCC doubling time of 90 days, and the targeted liver is smaller than 200 times the CDDP dose (mg). A further analysis is required to define appropriate injection speeds.
An excess dose of cisplatin in hepatic arterial infusion chemotherapy for hepatocellular carcinoma may enhance rapid tumor growth in case of resistance to cisplatin. A relationship between cisplatin dose and a tumor growth rate suggests that cisplatin (mg) should not be applied more than creatinine clearance (mL/min/1.73 m2) especially when it is not clear whether a target of HCC is sensitive or resistant to cisplatin, and the targeted liver volume should be smaller than 200 times of the CDDP dose (mg).
To determine whether an active intervention is beneficial for the survival of elderly patients with hepatocellular carcinoma (HCC).
The survival of 740 patients who received various treatments for ...HCC between 1983 and 2011 was compared among different age groups using Cox regression analysis. Therapeutic options were principally selected according to the clinical practice guidelines for HCC from the Japanese Society of Hepatology. The treatment most likely to achieve regional control capability was chosen, as far as possible, in the following order: resection, radiofrequency ablation, percutaneous ethanol injection, transcatheter arterial chemoembolization, transarterial oily chemoembolization, hepatic arterial infusion chemotherapy, systemic chemotherapy including molecular targeting, or best supportive care. Each treatment was used alone, or in combination, with a clinical goal of striking the best balance between functional hepatic reserve and the volume of the targeted area, irrespective of their age. The percent survival to life expectancy was calculated based on a Japanese national population survey.
The median ages of the subjects during each 5-year period from 1986 were 61, 64, 67, 68 and 71 years and increased significantly with time (P < 0.0001). The Child-Pugh score was comparable among younger (59 years of age or younger), middle-aged (60-79 years of age), and older (80 years of age or older) groups (P = 0.34), whereas the tumor-node-metastasis stage tended to be more advanced in the younger group (P = 0.060). Advanced disease was significantly more frequent in the younger group compared with the middle-aged group (P = 0.010), whereas there was no difference between the middle-aged and elderly groups (P = 0.75). The median survival times were 2593, 2011, 1643, 1278 and 1195 d for 49 years of age or younger, 50-59 years of age, 60-69 years of age, 70-79 years of age, or 80 years of age or older age groups, respectively, whereas the median percent survival to life expectancy were 13.9%, 21.9%, 24.7%, 25.7% and 37.6% for each group, respectively. The impact of age on actual survival time was significant (P = 0.020) with a hazard ratio of 1.021, suggesting that a 10-year-older patient has a 1.23-fold higher risk for death, and the overall survival was the worst in the oldest group. On the other hand, when the survival benefit was evaluated on the basis of percent survival to life expectancy, age was again found to be a significant explanatory factor (P = 0.022); however, the oldest group showed the best survival among the five different age groups. The youngest group revealed the worst outcomes in this analysis, and the hazard ratio of the oldest against the youngest was 0.35 for death. The survival trends did not differ substantially between the survival time and percent survival to life expectancy, when survival was compared overall or among various therapeutic interventions.
These results suggest that a therapeutic approach for HCC should not be restricted due to patient age.
Sorafenib (SOR) is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC). Therefore, the management of side effects is essential for the longer period of ...continuous medication. Among the various side effects, hand-foot syndrome (HFS) is the most common, occurring in 30%-50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms.
To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB), which was reported to improve peripheral blood flow, on the prevention of the symptom was examined by monitoring its occurrence and the peripheral blood flow.
A total of 25 patients were enrolled in this study. In all, eight patients developed HFS, and all cases showed a significant decrease in the peripheral blood flow. DBB contributed to an increase in the flow (
= 0.009) and significantly decreased occurrence of HFS (
= 0.005) than control. Multivariable analysis showed that the ingestion of DBB is a significant independent contributor to HFS-free survival period (
= 0.035).
The mechanism of SOR-induced HFS involves a decrease in the peripheral blood flow, and the ingestion of DBB effectively prevents the development of the syndrome by maintaining the flow.
Purpose
The purpose of this study was to determine the adequate circumferential resection margin (CRM) for abdomino-peranal (intersphincteric) resection (ISR) that would prevent the relapse of rectal ...cancers.
Methods
The records of 41 cases that underwent curative ISR for rectal cancer were retrospectively reviewed. The relapse-free survival rates and overall survival rates were evaluated and correlated with the maximum depth of the inner muscularis layer reached during ISR (i.e., the radial margin RM and distal margin DM). Cases were divided into three groups based on the sizes of the RM and DM: (1) group A (RM >2 mm and DM >1.5 cm), (2) group B (RM >2 mm or DM >1.5 cm but not both), and (3) group C (RM <2 mm and DM <1.5 cm).
Results
The relapse-free survival rates of the cases in group C were lower than those in the cases of group A or group B (p = 0.002 and 0.037, respectively). The resection margins required to prevent rectal cancer relapse were >2 mm for the RM and >1.5 cm for the DM. For these margins, the intersphincteric space had to be entered (i.e., between the internal and external anal sphincters).
Conclusion
It is critical to enter the intersphincteric space to ensure an adequate CRM (RM >2 mm and DM >1.5 cm) for preventing rectal cancer recurrence after ISR.
The Japan Society for Occupational Health (JSOH) recommends the Occupational Exposure Limits (OELs) as reference values for preventing adverse health effects on workers caused by occupational ...exposure to chemical substances, continuous or intermittent noise, impulsive or impact noise, heat stress, cold stress, whole-body vibration, hand-arm vibration and time-varying electric, magnetic and electromagnetic fields and ultraviolet and ionizing radiation.
There is no standard therapeutic procedure for the hepatocellular carcinoma (HCC) in patients with poor hepatic reserve function. With the approval of newly developed chemotherapeutic agent of ...miriplatin, we have firstly conducted the phase I study of CDDP powder (DDP-H) and miriplatin combination therapy and reported its safety and efficacy for treating unresectable HCC in such cases. To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for the combination of transarterial oily chemoembolization (TOCE) and transarterial chemotherapy (TAC) using miriplatin and DDP-H for treating unresectable hepatocellular carcinoma (HCC).
Transarterial chemotherapy using DDP-H was performed through the proper hepatic artery targeting the HCC nodules by increasing the dose of DDP-H (35-65 mg/m(2)) followed by targeting the HCC nodules by transarterial oily chemoembolization with miriplatin.
A total of nine patients were enrolled in this study and no DLT was observed with any dose of DDP-H in all cases in whom 80 mg (median, 18-120) miriplatin was administered. An anti-tumour efficacy rating for partial response was obtained in one patient, while a total of four patients (among eight evaluated) showed stable disease response, leading to 62.5% of disease control rate. The pharmacokinetic results showed no further increase in plasma platinum concentration following miriplatin administration.
Our results suggest that a combination of DDP-H and miriplatin can be safely administered up to their respective MTD for treating HCC.
This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003541).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To establish a formula to guide appropriate embolization volume for postprocedural platelet gain following partial splenic arterial embolization (PSE) for hypersplenism.
The hepatic volume (Vh) and ...splenic volume (Vsp) were measured by using 2-mm-thick computed tomography images before and after PSE in 20 patients with various chronic liver diseases. A formula was derived from the relationship between the platelet count increase ratio (dPlt%) and the organ volumes, which was then evaluated in another cohort.
After an embolization of a median of 72.1% of the spleen (interquartile range, 38.2%-93.8%), the dPlt% was 67.7% ± 40.0 and significantly correlated with the increasing ratio of Vh to Vsp (P = .019, ρ = 0.52). Because the difference in Vh/Vsp ratio after PSE was significantly correlated with the spleen embolization ratio (eVsp%; P = .0003, ρ = 0.72), the estimated dPlt% could be derived from the Vh/Vsp ratio before PSE and the eVsp%. The estimated dPlt% was significantly correlated with the actual dPlt% (P = .0003, ρ = 0.72). When the formula was evaluated in another cohort of 14 cases, another strict correlation was observed (P < .0001, ρ = 0.92).
These data suggest that platelet count after PSE can be predicted before the procedure by using the Vh/Vsp ratio and the anticipated spleen embolization volume. The use of such a prediction can prevent too much or too little embolization, thereby leading to an improvement in the risk/return trade-off in PSE.
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