Poor Result Reporting Rate in Cell Therapy Trials Registered at ClinicalTrials.gov.

As research associates in clinical experiments, we have an obligation to disclose clinical methodologies and findings in full transparency in ethics. However, inadequate disclosure in results reporting clinical trials registered on ClinicalTrials.gov has been revealed, with approximately half the trial results not being reported in an applicable manner. Our recent study in clinical trials of regenerative medicine for four kinds of neurological diseases revealed that the rate of result reporting to ClinicalTrials.gov is inadequate for gene and cell therapy (CT) trials. In this path, further curiosity emerged to see what the findings would be if the analysis was conducted for trials in all disease areas, and outcomes if gene therapy (GT) and CT were distinguished in terms. In this study, the scope of analysis was further expanded to include all disease areas, and the drug classification from the AdisInsight database was used for modality classification, with biologic drug trials classified as controls, CT, ex vivo GT, and in vivo GT. To begin, among all interventional clinical trials with registration in the ClinicalTrials.gov registry and with a primary completion between 2010 and 2019, we created a total of 5539 datasets corresponding to trials classified as GT and CT, while biologics (BLG) as controls in the AdisInsight drug classification. The status of reported results of these trials was identified by surveying posting status of ClinicalTrials.gov and publication in journals (PubMed), respectively. Based on the obtained dataset, multivariate analysis was performed on the data on the reporting rate of clinical trial results, aggregated by sponsor, phase, status, and modality (CT, ex vivo GT, in vivo GT, and BLG), respectively. The result shows that CT was identified as an independent factor restraining result reporting ratio in both ClinicalTrials.gov and total disclosures, whereas ex vivo GT as boosting result reporting ratio. Since the result reporting rate of CT results was notably poor, we discussed the causes and solutions in this regard.

A Pilot Study on Result Reporting Rates from Clinical Trials of Regenerative Medicine.

Sharing the methods and results of clinical trials with full transparency is an ethical obligation for those involved in clinical research. In this regard, ClinicalTrials.gov requires reporting of results to the registry within 1 year of completion of the trial. However, a poor result reporting rate has been pointed out, with approximately half the trial results not been reported. It has been suggested that one of the reasons behind this could be the influence of sponsors who conduct the clinical trials. In the course of our previous trend analysis on regenerative medicine for stroke (STR) using ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) portal site as data sources, we suspected whether the results of gene and/or cell therapy trials are poorly reported. For this reason, a multivariate analysis using data from ClinicalTrials.gov was performed to identify the factors suppressing the result reporting rate, expanding our study to four different kinds of neurological diseases and regenerative medicine as a treatment modality when small-molecule compounds and biologics were set up as controls, in addition to the sponsor type factor. As a result, we found gene and/or cell therapy (therapeutic modality) in addition to STR (disease area), trials completed in 2005-2007, and clinical phases II and IV as independent factors that suppressed the rate of reporting results to ClinicalTrials.gov. On the other hand, big pharmaceutical companies were identified as a factor that increased the reporting result rate to ClinicalTrials.gov. When we applied result reporting publications through PubMed as an index, our study data revealed that the following factors were not identified as the cause for a decrease in the reporting result rate: STR (as disease area), trials completed between 2005 and 2007, and gene/cell therapy (as treatment modality). In this context, our findings indicate that gene/cell therapy has led to the suppression of the result reporting rate to ClinicalTrials.gov. This confirmed our initial suspicion of the low result reporting rate of gene/cell therapy trials. We believe that further studies are required to elucidate the factors affecting the result reporting rate from the perspective of disease area and treatment modality. Impact Statement Several studies have addressed the poor result reporting rate of clinical trials, which still remains an issue. Regenerative medicine holds great promise for the future and the process of its practical application is expected to be challenging. Although having a limited disease area and small sample size, to the best of our knowledge, this is the first study to point out insufficient result reporting of clinical trials of regenerative medicine from the perspective of treatment modality. This report highlights an issue for discussing the path toward its translation through an overview of various factors in comparison with conventional treatment modalities.

Structural characterization of hemicellulose released from corn cob in continuous flow type hydrothermal reactor.

Hydrothermal reaction is known to be one of the most efficient procedures to extract hemicelluloses from lignocellulosic biomass. We investigated the molecular structure of xylooligosaccharides released from corn cob in a continuous flow type hydrothermal reactor designed in our group. The fraction precipitable from the extract with four volumes of ethanol was examined by 1H-NMR spectroscopy and MALDI-TOF MS before and after enzymatic treatment with different purified enzymes. The released water-soluble hemicellulose was found to correspond to a mixture of wide degree of polymerization range of acetylarabinoglucuronoxylan fragments (further as corn cob xylan abbreviated CX). Analysis of enzymatic hydrolyzates of CX with an acetylxylan esterase, GH3 ß-xylosidase, GH10 and GH11 xylanases revealed that the main chain contains unsubstituted regions mixed with regions of xylopyranosyl residues partially acetylated and occasionally substituted by 4-O-methyl-d-glucuronic acid and arabinofuranose esterified with ferulic or coumaric acid. Single 2- and 3-O-acetylation was accompanied by 2,3-di-O-acetylation and 3-O-acetylation of Xylp residues substituted with MeGlcA. Most of the non-esterified arabinofuranose side residues were lost during the hydrodynamic process. Despite reduced branching, the acetylation and ferulic acid modification of pentose residues contribute to high yields and high solubility of the extracted CX. It is also shown that different enzyme treatments of CX may lead to various types of xylooligosaccharides of different biomedical potential.

Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.

OBJECTIVE: To evaluate the efficacy and safety of fentanyl 1 day patch in opioid-naïve patients with non-cancer chronic pain insufficiently relieved by non-opioid analgesics. RESEARCH DESIGN AND METHODS: Two phase III placebo-controlled, double-blind, group-comparison, randomized withdrawal studies were conducted in patients with osteoarthritis and/or low back pain (N01 study) and post-herpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain (N02) in Japan. Both studies consisted of period I (10-29 days of titration, fentanyl 12.5-50.0 µg/h) and period II (12 weeks double-blind). CLINICAL TRIAL REGISTRATION: N01, NCT01008618; N02, NCT01008553 MAIN OUTCOME MEASURES: The primary endpoint was the number of days until study discontinuation due to insufficient pain relief in period II, and secondary endpoints included pain scored on visual analog scale (VAS), subject's overall assessment, the number of rescue dose, brief pain inventory short form score, score on short-form 36-item health survey version 2.0, physician's overall assessment, and assessment of adverse events. RESULTS: Of the 218 (N01) and 258 (N02) subjects who entered period I, 150 and 163 subjects entered period II, respectively. In the N01 study, the between-group difference was significant in the VAS score (95% CI: 7.3 [1.1, 13.5] mm, P = 0.0215) but not in the primary endpoint (P = 0.0846, log-rank test). In the N02 study, both primary efficacy (P = 0.0003) and VAS (8.7 [2.4, 15.0] mm, P = 0.0071) results showed that fentanyl was more effective than placebo. The major adverse events were nervous system and gastrointestinal disorders typically associated with opioid analgesic use. The incidence of adverse events in the fentanyl group was 68.5% to 85.7%. CONCLUSIONS: Although the primary efficacy results showed significant effects of fentanyl in the N02 but not the N01 study, overall results showed that fentanyl 1 day patch is effective and well tolerated.

Assessment of transposed ovarian movement: how much of a safety margin should be added during pelvic radiotherapy?

The purpose of this study was to analyze transposed ovarian movement. Data from 27 patients who underwent ovarian transposition after surgical treatment for uterine cancer were retrospectively analyzed. Computed tomography (CT) images including transposed ovaries were superimposed on other CT images acquired at different times, and were matched on bony structures. Differences in ovarian position between the CT images were measured. The planning organ at risk volume (PRV) margins were calculated from the formula of the 90% reference intervals (RIs) and the 95% RI, which were defined as mean ± 1.65 standard deviation (SD) and mean ± 1.96 SD, respectively. The 90% RI in the cranial, caudal, anterior, posterior, left and right directions were 1.5, 1.5, 1.4, 1.0, 1.7 and 0.9 cm, respectively. The 95% RI in the corresponding directions were 1.5, 2.0, 1.7, 1.2, 1.9 and 1.2 cm, respectively. These data suggest that bilateral ovaries need a PRV margin of ∼2 cm in all directions. The present study suggests that a transposed ovary needs the same PRV margin as a normal ovary (∼2 cm). Even after transposition, ovaries should be kept away from the radiation field to take into consideration the degree of ovarian movement.

Extra tyrosine in the carbohydrate-binding module of Irpex lacteus Xyn10B enhances its cellulose-binding ability.

The xylanase (Xyn10B) that strongly adsorbs on microcrystalline cellulose was isolated from Driselase. The Xyn10B contains a Carbohydrate-binding module family 1 (CBM1) (IrpCBMXyn10B) at N-terminus. The canonical essential aromatic residues required for cellulose binding were conserved in IrpCBMXyn10B; however, its adsorption ability was markedly higher than that typically observed for the CBM1 of an endoglucanase from Trametes hirsuta (ThCBMEG1). An analysis of the CBM-GFP fusion proteins revealed that the binding capacity to cellulose (7.8 µmol/g) and distribution coefficient (2.0 L/µmol) of IrpCBMXyn10B-GFP were twofold higher than those of ThCBMEG1-GFP (3.4 µmol/g and 1.2 L/µmol, respectively), used as a reference structure. Besides the canonical aromatic residues (W24-Y50-Y51) of typical CBM1-containing proteins, IrpCBMXyn10B had an additional aromatic residue (Y52). The mutation of Y52 to Ser (IrpCBMY52S-GFP) reduced these adsorption parameters to 4.4 µmol/g and 1.5 L/µmol, which were similar to those of ThCBMEG1-GFP. These results indicate that Y52 plays a crucial role in strong cellulose binding.

Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: A multicenter collaborative study.

Paclitaxel/carboplatin chemotherapy for cancer (TC therapy) exhibits neurotoxicity and causes peripheral neuropathy at a high frequency, which is difficult to cope with. In this study, we investigated the efficacy of Goshajinkigan, a traditional Japanese herbal medicine, for TC therapy-induced peripheral neuropathy. The subjects included in our study were patients with ovarian or endometrial cancer who underwent TC therapy and developed peripheral neuropathy. The patients were randomly divided into Group A, comprising of 14 patients (vitamin B12 treatment), and Group B, comprising of 15 patients (vitamin B12 + Goshajinkigan treatment). The observation period was 6 weeks following treatment initiation, and the evaluation items were as follows: i) the current perception threshold (CPT value) of the peripheral nerve, ii) visual analogue scale for numbness, iii) National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade of neurotoxicity, and iv) a questionnaire on the subjective symptoms of peripheral neuropathy (functional assessment of cancer therapy-taxane). These were compared between the groups and no significant differences were noted in any item. However, CTCAE grade 3 neurotoxicity developed in 2 patients (14.3%) after 6 weeks of administration in Group A, whereas no neurotoxicity was observed in Group B. When the change in the frequency of abnormal CPT ratio at 6 weeks of administration from that before treatment was compared between the groups, the frequency of abnormal value was significantly lower in Group B than in Group A (p<0.05). This suggests that Goshajinkigan inhibits the progression of peripheral neuropathy.

Fertility-sparing treatment using medroxyprogesterone acetate for endometrial carcinoma.

The purpose of this study was to present the results of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC), and to clarify patient characteristics by investigating patient background factors. A total of 59 patients with EC, who received MPA as fertility-sparing therapy at two institutions over a 21-year period between 1987 and 2008, were studied retrospectively. Patients were administered oral MPA at 400-600 mg/day for 16-24 weeks as long as they responded. Endometrial tissue was assessed twice, at 8-12 weeks (during treatment) and shortly after treatment. The overall complete response (CR) rate was 71%. A total of 22 (52%) of 42 responders later developed relapse. A total of 19 cases became pregnant, and 25 infants were born. Eighty percent of recurrences occurred within 2 years. For stages I a and I b- II a (FIGO, 1988), initial CR rates were 80.0 and 42.9%, respectively (p<0.01), demonstrating a significant difference. Total hysterectomy was performed for 26 patients (44%) due to recurrence or failure to respond to the initial treatment. Among these 26 patients, postoperative stages were more advanced in 10 patients (38%). The grade advanced (became more poorly differentiated) postoperatively in 2 patients (8%). Premenopausal females with EC can be treated successfully with MPA, however patients should be informed of the risks and limitations of this conservative treatment.

Significance of matrix metalloproteinase-7 [correction of matrix metalloproteinase-2], -11 and tissue inhibitor of metalloproteinase-1 expression in normal, hyperplastic and neoplastic endometrium.

BACKGROUND: Matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) are key factors in the degradation of extracellular matrix and basement membranes. This study aimed to examine the expressions of MMP-7 and -11 and TIMP-1 in normal, hyperplastic and neoplastic endometrium and their correlation to clinicopathologic factors. PATIENTS AND METHODS: Tissue samples of 40 normal endometria, 20 endometrial hyperplasias and 120 endometrial endometrioid adenocarcinomas were used for the study. Immunohistochemical staining for MMP-7 and -11 and TIMP-1 protein was performed on formalin-fixed and paraffin-embedded tissue samples. These expressions were represented as incidence of expression. RESULTS: MMP-7 was highly expressed in the glands of the basal and functional layers during the proliferative and menstrual phases. MMP-11 expression in the gland of the basal layer and the stroma of the functional layer fluctuated during the menstrual cycle. TIMP-1 was highly expressed in the late secretory and menstrual phases. MMP-7 was expressed at significantly higher levels in endometrial hyperplasia than normal endometrium, whereas MMP-11 was expressed at lower levels. In endometrial adenocarcinoma, MMP-7, MMP-11 and TIMP-1 were expressed at the same levels as in hyperplasia. MMP-7 expression in endometrial carcinoma was correlated with myometrial invasion and estrogen receptor expression. The expression of MMP-7 in the adjacent stroma was associated with a poor prognosis. CONCLUSION: MMP-7, MMP-11 and TIMP-1 expression may be regulated by the menstrual cycle, and related to the degradation and remodeling of the normal endometrium. MMP-7 expression might be a prognostic factor in endometrial carcinoma.

Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma: Kitasato Gynecologic Radiation Oncology Group (KGROG 0501).

In order to evaluate the safety and efficacy of chemoradiotherapy using nedaplatin for locally advanced uterine cervical carcinoma in Japanese patients, we have started a single-institute phase II trial. Eligibility criteria include: (i) pathologically proven squamous cell carcinoma or adenocarcinoma, (ii) clinical FIGO stage Ib, IIa, or IIb with bulky tumor (> 40 mm) or pelvic lymph node swelling, or (iii) clinical FIGO stage IIIa, IIIb and IVa, (iv) no para-aortic lymph node swelling. A combination of external beam radiation and high dose rate intracavitary irradiation is given. Nedaplatin (30 mg/m2) is intravenously infused on a weekly basis for five times. The primary endpoint is 3-year overall survival, and the secondary endpoints are tumor response, 2-year overall survival, 3-year progression-free survival, acute adverse events, protocol treatment compliance, and late adverse events. We plan to recruit 45 patients within 3 years.

High expression of skp2 correlates with poor prognosis in endometrial endometrioid adenocarcinoma.

PURPOSE: Skp2 interacts with the degradation of cyclin-dependent kinase inhibitor p27. This study aimed to investigate the correlation of skp2 expression with the expression of p27 and other cell cycle regulators, and clinicopathological parameters in endometrial endometrioid adenocarcinoma. METHODS: Tissue samples of 136 endometrioid adenocarcinomas, in addition to 20 endometrial hyperplasias and 20 normal endometria, were immunohistochemically stained for skp2. The expression was represented as a labeling index (LI), which indicates the percentage of positive nuclei. RESULTS: Skp2 staining was localized in the nuclei of the glandular cells of the proliferative phase endometrium, and endometrial hyperplasia and carcinoma cells. Skp2 expression was increased significantly in those of higher histological grade. The high level of skp2 expression was significantly correlated with the presence of lymph node metastasis and lymph-vascular space involvement. The LI of skp2 in endometrial carcinoma was significantly correlated with that of p27, Ki-67, cdk2, cyclin A, cyclin D1, cyclin E, p53 and PTEN. The high level of skp2 expression (LI> or =20%) was significantly correlated with the patients' poor survival. CONCLUSIONS: The skp2 level might have increased due to p27 accumulation and may be a good indicator of proliferative activity and poor prognosis.

Cytologic scoring of endometrioid adenocarcinoma of the endometrium.

BACKGROUND: Endometrial carcinoma is one of the most frequent malignancies in the female genital tract, and its incidence has been increasing in Japan. Histologic grade is an important factor for organizing treatment strategies, including hormone therapy, and for predicting the prognosis of the patient. The objective of this study was to evaluate the applicability and usefulness of cytologic scoring in assessing the morphologic differentiation of endometrioid adenocarcinomas of the endometrium using endometrial smears. METHODS: Sixty-four endometrial cytologic samples of endometrioid adenocarcinomas of the endometrium were used in this study. All patients underwent endometrial cytology before hysterectomy, and the diagnosis was confirmed by histologic examination of the extirpated uterus. Each cytologic specimen was scored according to a scoring system established by the authors. The cytologic grade based on those estimated scores was compared with the histologic grade and clinicopathologic parameters, respectively. RESULTS: The cytologic grade (CG) was correlated positively with the histologic grade. A high cytologic score was correlated with p53 mutation and myometrial invasion and was correlated negatively with estrogen receptor and progesterone receptor status. The concordance rates of cytologic grade with well differentiated (Grade 1), moderately differentiated (Grade 2), and poorly differentiated (Grade 3) histologic grades were 83.3% (35 of 42 tumors), 9.1% (1 of 11 tumors), and 100% (11 of 11 tumors), respectively. The total concordance rate was 73.4% (47 of 64 tumors). The best cut-off value for distinguishing histologic Grade 1 from the others was a cytologic score of 17, representing a sensitivity of 83% and a specificity of 81%. For distinguishing histologic Grade 3 from the others, the best cut-off value was a cytologic score of 20, representing a sensitivity of 100% and a specificity of 83%. CONCLUSIONS: The cytologic scoring system studied for endometrioid adenocarcinoma was useful for predicting histologic grade and tumor malignant potential.

Aspiration cytology of malignant fibrous histiocytoma after radiation therapy for carcinoma of the uterine cervix: a case report.

BACKGROUND: Cytologic reports on malignant fibrous histiocytoma (MFH) following radiation therapy for carcinoma of the uterine cervix are very rare. CASE: A 59-year-old woman presented with slowly increasing pain in the left hip joint. Eight years earlier, she had received radiotherapy at a dosage of 5,000 cGy to the whole pelvis for carcinoma of the uterine cervix. An osteolytic lesion of the pelvic bone was revealed on computed tomography, and a hard tumor was palpable in the left pelvic cavity. Fine needle aspiration (FNA) of the tumor via the left vaginal wall obtained 0.5 mL of yellow fluid consisting of markedly anaplastic and pleomorphic giant cells. Frequent multinucleation and mitoses were observed, although no atypical spindle cells were observed. Immunocytochemistry disclosed vimentin reactivity. An open biopsy of the tumor revealed the histologic and immunohistochemical features of MFH arising in the pelvic cavity. CONCLUSION: FNA of the pelvic lesion via the vaginal wall revealed an MFH in the radiation therapy field. This is one of the few reports dealing with FNA cytology of a postradiation sarcoma in the pelvic cavity.

Variation in synergistic activity by flavone and its related compounds on the increased susceptibility of various strains of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics.

We found that some flavonoids had a weak antibacterial effect on methicillin-resistant Staphylococcus aureus (MRSA), but that at sub-MIC concentrations they greatly increased the susceptibility of these strains to beta-lactam antibiotics. Flavone showed diverse synergistic effects on the susceptibility of MRSA to beta-lactam antibiotics. The variation of the synergistic effects of the flavones to increase the susceptibility of strains of MRSA to beta-lactam antibiotics coincided with their varying effects on growth-inhibition of these strains. Based on these findings, we have proposed a model for the mechanisms of high resistance of MRSA to beta-lactams and the massive reduction in the beta-lactams MIC caused by flavones.

Clinicopathologic relevance of asymptomatic endometrial carcinoma.

OBJECTIVE: To assess whether screening asymptomatic women is significant for early detection of endometrial carcinoma. STUDY DESIGN: We compared the clinicopathologic findings and prognoses of 21 asymptomatic patients with 427 symptomatic patients with endometrial carcinoma. RESULTS: The incidence of asymptomatic endometrial carcinoma was 4.7%. Nineteen of 21 asymptomatic patients with endometrial carcinoma were found by cytologic screening for endometrial cancer. There was a statistical difference in the histopathology and depth of myometrial invasion between the asymptomatic and symptomatic groups. However, no statistical differences were found in tumor grade, lymph node metastasis, adnexal metastasis, cervical invasion, peritoneal cytology, surgical stage and patient age. Univariate analysis showed that the presence or absence of symptoms was not related to survival. CONCLUSION: The detection of asymptomatic endometrial carcinoma is not related to a reduced mortality rate. Screening asymptomatic women for endometrial carcinoma is not recommended.