The positron emission tomography (PET) radioligand
F-THK5351 is now used to evaluate monoamine oxidase B expression in the reactive astrogliosis seen in various central nervous diseases. Traumatic ...brain injury (TBI) is known to induce reactive astrogliosis in the lesion site. This is a first report to examine the spatial and temporal changes in reactive astrogliosis as evaluated by
F-THK5351 after a severe TBI.
A 27-year-old man suffering from a severe TBI with multiple brain contusions was examined using
F-THK5351 PET/CT in the subacute and chronic phases after the injury. The first PET scan, performed 46 days after the TBI, showed intense uptake of
F-THK5351 in and around the brain contusions. The second PET scan, performed 271 days after the TBI, showed reduced uptake of
F-THK5351 at the original sites of the brain contusions and increased uptakes in the white matter surrounding the contusions and the corpus callosum. The patient exhibited sustained improvement of neuropsychological impairment between the two PET examinations and remarkable recovery from the severe TBI.
There were evident temporal and spatial changes in
F-THK5351 uptake in the traumatized brain between the two PET examinations. These changes may have been related to the remarkable neurological recovery in this patient. The degree and distribution of reactive astrogliosis detected by
F-THK5351 PET may be useful in assessing pathophysiology and predicting prognosis in TBI patients.
The liver is involved in the synthesis of serum proteins, regulation of metabolism and maintenance of homeostasis and provides a variety of opportunities for gene therapy. The enriched vasculature ...and blood circulation, fenestrated endothelium, abundant receptors on the plasma membranes of the liver cells, and effective transcription and translation machineries in the hepatocytes are some unique features that have been explored for delivery, and functional analysis, of genetic sequences in the liver. Both viral and non‐viral methods have been developed for effective gene delivery and liver‐based gene therapy. This review describes the fundamentals of gene delivery, and the preclinical and clinical progress that has been made toward gene therapy using the liver as a target.
To establish a prognostic formula that distinguishes non-hypervascular hepatic nodules (NHNs) with higher aggressiveness from less hazardous one.
Seventy-three NHNs were detected in gadolinium ...ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging (Gd-EOB-DTPA-MRI) study and confirmed to change 2 mm or more in size and/or to gain hypervascularity. All images were interpreted independently by an experienced, board-certified abdominal radiologist and hepatologist; both knew that the patients were at risk for hepatocellular carcinoma development but were blinded to the clinical information. A formula predicting NHN destiny was developed using a generalized estimating equation model with thirteen explanatory variables: age, gender, background liver diseases, Child-Pugh class, NHN diameter, T1-weighted imaging/T2-weighted imaging detectability, fat deposition, lower signal intensity in arterial phase, lower signal intensity in equilibrium phase, α-fetoprotein, des-γ-carboxy prothrombin, α-fetoprotein-L3, and coexistence of classical hepatocellular carcinoma. The accuracy of the formula was validated in bootstrap samples that were created by resampling of 1000 iterations.
During a median follow-up period of 504 d, 73 NHNs with a median diameter of 9 mm (interquartile range: 8-12 mm) grew or shrank by 68.5% (fifty nodules) or 20.5% (fifteen nodules), respectively, whereas hypervascularity developed in 38.4% (twenty eight nodules). In the fifteen shrank nodules, twelve nodules disappeared, while 11.0% (eight nodules) were stable in size but acquired vascularity. A generalized estimating equation analysis selected five explanatories from the thirteen variables as significant factors to predict NHN progression. The estimated regression coefficients were 0.36 for age, 6.51 for lower signal intensity in arterial phase, 8.70 or 6.03 for positivity of hepatitis B virus or hepatitis C virus, 9.37 for des-γ-carboxy prothrombin, and -4.05 for fat deposition. A formula incorporating the five coefficients revealed sensitivity, specificity, and accuracy of 88.0%, 86.7%, and 87.7% in the formulating cohort, whereas these of 87.2% ± 5.7%, 83.8% ± 13.6%, and 87.3% ± 4.5% in the bootstrap samples.
These data suggest that the formula helps Gd-EOB-DTPA-MRI detect a trend toward hepatocyte transformation by predicting NHN destiny.
To validate a 'drug score' that stratifies patients receiving immunotherapy based on concomitant medications (antibiotics/proton pump inhibitors/corticosteroids) in urothelial carcinoma (UC).
We ...assessed oncological outcomes according to the drug score in 242 patients with advanced UC treated with pembrolizumab.
The drug score classified patients into three risk groups with significantly different survivals. Heterogeneous treatment effect analyses showed that the primary cancer site (bladder UC BUC or upper-tract UC UTUC) significantly affected the prognostic capability of the drug score; it significantly correlated with survivals in BUC, while there were no such correlations in UTUC.
A drug score was examined in advanced UC treated with pembrolizumab and was validated in BUC but not in UTUC.
Prognosis of patients with hepatocellular carcinoma (HCC) who undergo transcatheter intra-arterial therapies, including transcatheter arterial chemoembolization and transcatheter arterial infusion ...chemotherapy, is affected by many clinical factors including liver function and tumor progression. However, the effect of body composition such as skeletal muscle and visceral and subcutaneous adipose tissues (VAT and SAT, respectively) on the prognosis of these patients remains unclear. We investigated the prognostic value of body composition in HCC patients treated with transcatheter intra-arterial therapies.
This study retrospectively evaluated 100 HCC patients treated with transcatheter intra-arterial therapies between 2005 and 2015. Areas of skeletal muscle, VAT, and SAT were measured on computed tomography images at third lumbar vertebra level and normalized by the height squared to calculate the skeletal muscle index, VAT index, and SAT index (SATI). The visceral to subcutaneous adipose tissue area ratio was also calculated. Overall survival (OS) was compared between high- and low-index groups for each body composition. Furthermore, prognostic significance was assessed by univariate and multivariate analyses using Cox proportional hazards models.
Among the body composition indexes, only SATI could significantly differentiate OS (
=0.012). Multivariate analysis showed that SATI (low- vs. high-SATI: HR, 2.065; 95% CI, 1.187-3.593;
=0.010), serum albumin (<3.5 vs. ≥3.5 g/dL; HR, 2.007; 95% CI, 1.037-3.886;
=0.039), serum alpha-fetoprotein (<20 vs. ≥20 ng/mL; HR, 0.311; 95% CI, 0.179-0.540;
<0.001), and Modified Response Evaluation Criteria in Solid Tumors assessment (complete response+partial response+stable disease vs. progressive disease; HR, 0.392; 95% CI, 0.221-0.696;
=0.001) were indicated as independent prognostic factors for OS.
High SAT volume is associated with better survival outcomes in HCC patients treated with transcatheter intra-arterial therapies. Elucidation of the mechanisms regulating SAT volume may offer a new therapeutic strategy for these patients.
This study sought to evaluate the diagnostic accuracy of coronary binary in-stent restenosis (ISR) with angiography using 64-slice multislice computed tomography coronary angiography (CTCA) compared ...with invasive coronary angiography (ICA).
A noninvasive detection of ISR would result in an easier and safer way to conduct patient follow-up.
We performed CTCA in 81 patients after stent implantation, and 125 stented lesions were scanned. Two sets of images were reconstructed with different types of convolution kernels. On CTCA, neointimal proliferation was visually evaluated according to luminal contrast attenuation inside the stent. Lesions were graded as follows: grade 1, none or slight neointimal proliferation; grade 2, neointimal proliferation with no significant stenosis (<50%); grade 3, neointimal proliferation with moderate stenosis (> or =50%); and grade 4, neointimal proliferation with severe stenosis (> or =75%). Grades 3 and 4 were considered binary ISR. The diagnostic accuracy of CTCA compared with ICA was evaluated.
By ICA, 24 ISRs were diagnosed. Sensitivity, specificity, positive predictive value, and negative predictive value were 92%, 81%, 54%, and 98% for the overall population, whereas values were 91%, 93%, 77%, and 98% when excluding unassessable segments (15 segments, 12%). For assessable segments, CTCA correctly diagnosed 20 of the 22 ISRs detected by ICA. Six lesions without ISR were overestimated as ISR by CTCA. As the grade of neointimal proliferation by CTCA increases, the median value of percent diameter stenosis increased linearly.
Binary ISR can be excluded with high probability by CTCA, with a moderate rate of false-positive results.
A 56-year-old Japanese man with liver cirrhosis (LC) due to hepatitis C virus was admitted to our hospital for radiofrequency ablation of residual tumor following lusutrombopag administration. ...Laboratory tests revealed thrombocytopenia and leukopenia. The patient’s LC was managed, and he was classified as Child–Pugh A. After admission, lusutrombopag was administered for 7 days. The platelet count increased to over 50,000/mm
3
after 7–14 days and returned to previous levels 50 days after administration. Leukocyte and erythrocyte counts also increased in response to the treatment and stayed elevated for over 120 days. Lusutrombopag acts selectively on human thrombopoietin (TPO) receptors and activates signaling pathways that promote the proliferation and differentiation of bone marrow progenitor cells into megakaryocytes, consequently increasing the blood platelet count. However, the patient treated with lusutrombopag in our case study showed increased blood leukocyte and erythrocyte counts as well. Given that TPO receptors are reportedly expressed in not only megakaryocyte progenitor cells but also hematopoietic progenitors, lusutrombopag may potentially improve pancytopenia caused by LC and can be used for the recovery of blood counts before other treatments.
Diagnostic imaging of hepatic lymphoma Abe, Hiroyuki; Kamimura, Kenya; Kawai, Hirokazu ...
Clinics and research in hepatology and gastroenterology,
09/2015, Letnik:
39, Številka:
4
Journal Article
Recenzirano
Summary Hepatic lymphoma is a rare disease with poor prognosis because of delayed diagnosis. The disease comprises primary, metastatic, and intravascular hepatic lymphomas. The pathological ...characteristics of lymphomas differ contributing to difficulty in early diagnosis. Early diagnosis and appropriate treatment result in improved prognosis; therefore, diagnostic radiology and its development with various contrast agents are critical for improving disease outcomes. Herein, we review hepatic lymphomas and summarize the results of imaging studies in correlation with pathological characteristics. The information provided will help physicians in early diagnosis and thereby improving prognosis.
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
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