Transitional dynamics in oncology clinical trials: evaluating the impact of Clinical Trials Act on cooperative groups.

OBJECTIVE: large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown. METHODS: a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023. RESULTS: the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects. CONCLUSION: the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act's enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process.

Results of the JRS-I LRA0401 and LRB0402 Japan Rhabdomyosarcoma Study Group trials for low-risk embryonal rhabdomyosarcoma.

BACKGROUND: Failure-free survival (FFS) rates of low-risk patients with rhabdomyosarcoma improved in Intergroup Rhabdomyosarcoma Study IV after the escalation of cyclophosphamide total dose to 26.4 g/m2. However, this dose may increase the risk of adverse events, including infertility, in some patients. The JRS-I LRA0401 and LRB0402 protocols aimed to reduce the cyclophosphamide dose to 9.6 g/m2 and 17.6 g/m2, respectively, without decreasing the FFS rates. METHODS: Subgroup-A patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 1.2 g/m2/cycle cyclophosphamide. Subgroup-B patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 2.2 g/m2/cycle cyclophosphamide, followed by six cycles (24 weeks) of vincristine and actinomycin D. Group II/III patients in both subgroups received radiotherapy. RESULTS: In subgroup A (n = 12), the 3-year FFS rate was 83% (95% confidence interval [CI], 48-96), and the 3-year overall survival (OS) rate was 100%. Only one isolated local recurrence was observed (8.3%). There were no unexpected grade-4 toxicities and no deaths. In subgroup B (n = 16), the 3-year FFS and OS rates were 88% (95% CI, 59-97) and 94% (95% CI, 63-99), respectively. There were no unexpected grade 4 toxicities and no deaths. CONCLUSIONS: Shorter duration therapy using vincristine, actinomycin D, and lower dose cyclophosphamide with or without radiotherapy for patients with low-risk subgroup A rhabdomyosarcoma (JRS-I LRA0401 protocol) and moderate reduction of cyclophosphamide dose for patients with low-risk subgroup B rhabdomyosarcoma (JRS-I LRB0402 protocol) did not compromise FFS.

Guidance regarding COVID-19 for survivors of childhood, adolescent, and young adult cancer: A statement from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19.

Larger Degree of Renal Function Decline in Chronic Kidney Disease Is a Favorable Factor for the Attenuation of eGFR Slope Worsening by SGLT2 Inhibitors: A Retrospective Observational Study.

INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2Is) have beneficial effects on the renal function of chronic kidney disease (CKD) patients, although the types of patients suitable for this treatment remain unclear. METHODS: A retrospective observational study was conducted on CKD patients who were treated with SGLT2I in our department from 2020 to 2023. The estimated glomerular filtration rate (eGFR) just before treatment was defined as the baseline and the difference between pre-and post-treatment eGFR slopes were used to compare the improvement of renal function. Logistic regression analysis was used to evaluate the independent factors for its improvement. RESULTS: A total of 128 patients were analyzed (mean age: 67.2 years; number of women: 28 [22%]). The mean eGFR was 42.1 mL/min/1.73 m2, and urine protein was 0.66 g/gCr. The eGFR slopes of patients with an eGFR <30 mL/min/1.73 m2 were improved significantly after treatment (-0.28 to -0.14 mL/min/1.73 m2/month, p < 0.001) but were worsened in patients with an eGFR ≥30 mL/min/1.73 m2. Logistic analysis for the improvement in eGFR slopes showed that women (odds ratio [OR], 5.63; 95% confidence interval [CI], 1.16-27.3; p = 0.03), use of mineralocorticoid receptor antagonists (OR, 11.79; 95% CI, 1.05-132.67; p = 0.012) and rapid decline of eGFR before treatment (OR, 12.8 per mL/min/1.73 m2/month decrease in eGFR; 95% CI, 3.32-49.40; p < 0.001) were significant independent variables. CONCLUSION: SGLT2Is may have beneficial effects, especially for rapid decliners of eGFR, including advanced CKD.

Relationship between the degree of property damage and changes in red blood cells, hematocrit, and hemoglobin among victims of the Noto Peninsula Earthquake.

OBJECTIVES: The aim of this study was to assess the impact of the Noto Peninsula Earthquake on various hematologic parameters. We studied the relationships between the degree of property damage and changes in red blood cells (RBCs), hemoglobin (Hb), and hematocrit (Ht) among residents before and after the March 2007 Noto Peninsula Earthquake. METHODS: A total of 5,563 residents of Wajima City who were not receiving oral treatment for anemia and who had received basic health screenings for fiscal years (FYs) 2006 and 2007, before and after the earthquake. We analyzed changes in their RBCs, Hb, and Ht levels by gender, age, body mass index (BMI), level of property damage, and evaluation standards. RESULTS: RBCs, Hb, and Ht for FY2007 showed a trend of decreasing values compared to FY2006 in both male and female subjects. RBCs and Hb significantly decreased in females aged between 65 and 74 years who experienced total property damage, and Ht significantly increased for those younger than 65 years who experienced the same level of damage. In addition, significant differences by degree of property damage and FY2007/FY2006 ratio were seen only among subjects with a BMI ratio <1. Furthermore, we found a significant relationship between reduction of RBCs or Hb and increasing age in females; however, no significant relationship to property damage was found. No significant relationships were found for males. CONCLUSIONS: A significant association between property damage and changes in RBCs, Hb, and Ht was not found in this population of residents who experienced the Noto Peninsula Earthquake.

Pilot study to estimate the safety and effectiveness of hydroxyurea and methotrexate recurrent langerhans cell histiocytosis (LCH-HU-pilot).

METHODS AND ANALYSIS: This study was a non-blinded, multicenter, single-arm study. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH. In this study, all patients received hydroxyurea, and if the treatment response was unsatisfactory, methotrexate was added. The duration of treatment was 48 weeks. The primary endpoint was the rate of non-active disease achievement, which was 24 weeks after initiating hydroxyurea administration. No active disease is defined as the resolution of all the signs and symptoms related to LCH.

Investigation of fiducial marker recognition possibility by water equivalent length in real-time tracking radiotherapy.

Real-time tumor tracking radiotherapy (RTRT) systems typically use fiducial markers implanted near the tumor to track the target using X-ray fluoroscopy. Template pattern matching, used in tracking, is often used to automatically localize the fiducial markers. In radiotherapy of the liver, the thickness of the body that can recognize the fiducial markers must be clinically assessed. The purpose of this study was to quantify the recognition of fiducial markers according to body thickness in stereotactic body radiotherapy of the liver using clinical images obtained using SyncTraX FX4. The recognition scores of fiducial markers were examined in relation to water equivalent length (WEL), tube current, and each flat panel detector. The relationship between the contrast ratio of the fiducial marker and the background and the WEL was also investigated. The average recognition score was found to be less than 20 when the WEL was greater than 25 cm. The probability of successful tracking of image recognition was mostly smaller than 0.8 when the WEL was over 30 cm. The relationship between WEL and tube current did not significantly differ between 100 and 140 mA, but there was a significant difference (p < 0.05) for all other combinations. To ensure tracking of fiducial markers during SBRT, if the WEL representing body thickness is longer than 25 cm, the X-ray fluoroscopy arrangement should be determined based on the WEL.

[New parameters "average flow" and "acceleration wave": comparison with current parameters in the flow volume curve].

AIM: The flow volume curve is an essential test method for diagnosis and treatment of the respiratory diseases. However, this curve depends on patient's continuous effort toward optimal expiration and it has been reported that differences in this effort may possibly result in error in flow speed. To overcome the potential error, we devised the "average flow" and the "acceleration wave" that comprehends the overall data of the expiration flow speed, and have done comparative analysis with the current parameters. METHODS: The average flow is derived by taking the integration from the beginning of the expiration to the end, and divides the integrated value by the number of data counts. Additionally, the acceleration wave is derived by taking the second degree derivative of the flow volume curve. RESULTS: The average flow showed strong correlation among healthy male and healthy female V50, obstructive index and criteria for COPD severity patients. Also, we were able to obtain the maximum acceleration from the acceleration wave. Significantly, this value showed strong correlation with the COPD patient's peak flow and average flow/peak flow. CONCLUSIONS: If the ratio of the average flow and the peak flow is below a fixed criterion, it is an obstructive lung disease, if it is above, it is possible to detect restrictive lung disease. Since the maximum acceleration rate of the acceleration wave is derived by the start of the expiration nearly up to 100 ml, it is especially possible to detect minute changes of the flow speed in large respiratory tract.

Structural changes in renal arterioles are closely associated with central hemodynamic parameters in patients with renal disease.

Although central hemodynamics are known to be closely associated with microvascular damage, their association with lesions in the small renal arteries has not yet been fully clarified. We focused on arterioles in renal biopsy specimens and analyzed whether their structural changes were associated with noninvasive vascular function parameters, including central blood pressure (BP) and brachial-ankle pulse wave velocity (baPWV). Forty-four nondiabetic patients (18-50 years of age) with preserved renal function underwent renal biopsy. Wall thickening of arterioles was analyzed based on the media/diameter ratio, and hyalinosis was analyzed by semiquantitative grading. Associations of these indexes (arteriolar wall remodeling grade index (RG index) and arteriolar hyalinosis index (Hyl index)) with clinical variables were analyzed. Multiple regression analyses demonstrated that the RG index was significantly associated with central systolic BP (ß = 0.97, p = 0.009), serum cystatin C-based estimated glomerular filtration rate (ß = -0.36, p = 0.04), and high-density lipoprotein cholesterol levels (ß = -0.37, p = 0.02). The Hyl index was significantly associated with baPWV (ß = 0.75, p = 0.01). Our results indicate that aortic stiffness and abnormal central hemodynamics are closely associated with renal microvascular damage in young to middle-aged, nondiabetic kidney disease patients with preserved renal function.

Functional Outcomes and Social Attainment in Asian/Pacific Islander Childhood Cancer Survivors in the United States: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: Given the relatively small population of Asians or Pacific Islanders (API) in the United States, studies describing long-term outcomes in API survivors of childhood cancer are limited. This study compared functional outcomes between API versus non-Hispanic White (NHW) survivors. METHODS: This study included 203 API 5-year survivors [age at follow-up: 29.2 (SD = 6.3) years] and 12,186 NHW survivors [age at follow-up 31.5 (SD = 7.3) years] from the Childhood Cancer Survivor Study. Self-reported functional outcomes of neurocognitive function, emotional distress, quality of life, and social attainment were compared between the two groups using multivariable regression, adjusted for sex, age at diagnosis and evaluation, cancer diagnosis, and neurotoxic treatment. RESULTS: No statistically significant race/ethnicity-based differences were identified in neurocognitive and emotional measures. API survivors reported, on average, less bodily pain than NHW survivors [mean 54.11 (SD = 8.98) vs. 51.32 (SD = 10.12); P < 0.001]. NHW survivors were less likely to have attained at least a college degree than API survivors [OR = 0.50; 95% confidence interval (CI) = 0.34-0.73]. API survivors were more likely than NHW survivors to be never-married (OR = 2.83; 95% CI = 1.93-4.13) and to live dependently (OR = 3.10; 95% CI = 2.02-4.74). Older age (>45 years), brain tumor diagnosis, and higher cranial radiation dose were associated with poorer functional outcomes in API survivors (all, P < 0.05). CONCLUSIONS: We observed differences in social attainment between API and NHW survivors, although statistically significant differences in neurocognitive and emotional outcomes were not identified. IMPACT: Future studies should evaluate whether racial/ethnic differences in environmental and sociocultural factors may have differential effects on health and functional outcomes.

Effect of herbal medicine Juzentaihoto on hepatic and intestinal heat shock gene expression requires intestinal microflora in mouse.

AIM: To evaluate the role of intestinal microflora in the effects of multi-herbal medicine on gene expression in the gut and liver. METHODS: The multi-herbal medicine Juzentaihoto (JTX) was administered to five germ-free mice and regular mice for 2 wk. Among the results of the comprehensive gene chip analysis of the intestine and liver, we featured heat shock proteins (HSPs) 70 and 105 because their gene expression changed only in the presence of microflora. Real-time RT-PCR was performed to confirm the expression levels of these HSP genes. To determine whether JTX acts directly on the HSP genes, sodium arsenite (SA) was used to induce the heat shock proteins directly. To examine the change of the intestinal microflora with administration of JTX, the terminal restriction fragment polymorphism (T-RFLP) method was used. To identify the changed bacteria, DNA sequencing was performed. RESULTS: Heat shock protein gene expression, documented by gene chip and real-time RT-PCR, changed with the administration of JTX in the regular mice but not in the germ-free mice. JTX did not suppress the direct induction of the HSPs by SA. T-RFLP suggested that JTX decreased unculturable bacteria and increased Lactobacillus johnsoni. These data suggested that JTX changed the intestinal microflora which, in turn, changed HSP gene expression. CONCLUSION: Intestinal microflora affects multi-herbal product JTX on the gene expression in the gut and liver.

Effect of visual biofeedback to acquire supraglottic swallow in healthy individuals: a randomized-controlled trial.

The aim of this study is to evaluate the effect of visual biofeedback therapy in acquiring supraglottic swallow (SGS) in a randomized-controlled trial with healthy individuals. Eighteen individuals (mean age, 26 years) who could not close or keep closed the vocal folds before and during the swallow in SGS were allocated randomly to either a visual biofeedback group (eight individuals) or a nonbiofeedback group (10 individuals). A videoendoscope was inserted intranasally and an SGS exercise, using 4 ml of green-colored water, was performed 30 times per day up to 5 days. When the participant failed to perform SGS, the result was provided only to the participants in the visual biofeedback group. The median length of time until acquiring SGS was 1.5 days in the visual biofeedback group and 3.5 days in the nonbiofeedback group (P=0.040). We concluded that visual biofeedback effectively enabled participants to acquire SGS earlier.

Changes of shear-wave velocity by interferon-based therapy in chronic hepatitis C.

AIM: To evaluate the changes of shear-wave velocity (Vs) by acoustic radiation force impulse after treatment in chronic hepatitis C. METHODS: Eighty-seven patients with chronic hepatitis C were consecutively treated with combinations of interferon (IFN) plus ribavirin (RBV). Vs value (m/s) was measured with acoustic radiation force impulse before treatment, at end of treatment (EOT), 1 year after EOT, and 2 years after EOT. RESULTS: In patients with a sustained virological response (SVR) (n = 41), Vs significantly decreased at EOT [1.19 (1.07-1.37), P = 0.0004], 1 year after EOT [1.10 (1.00-1.22), P = 0.0001], and 2 years after EOT [1.05 (0.95-1.16), P < 0.0001] compared with baseline [1.27 (1.11-1.49)]. In patients with a relapse (n = 26), Vs did not significantly decrease at EOT [1.23 (1.12-1.55)], 1 year after EOT [1.20 (1.12-1.80)], and 2 years after EOT [1.41 (1.08-2.01)] compared with baseline [1.39 (1.15-1.57)]. In patients with a nonvirological response (n = 20), Vs did not significantly decrease at EOT [1.64 (1.43-2.06)], 1 year after EOT [1.66 (1.30-1.95)], and 2 years after EOT [1.61 (1.36-2.37)] compared with baseline [1.80 (1.54-2.01)]. Among genotype 1 patients, baseline Vs was significantly lower in SVR patients [1.28 (1.04-1.40)] than in non-SVR patients [1.56 (1.20-1.83)] (P = 0.0142). CONCLUSION: Reduction of Vs values was shown in SVR patients after IFN-plus-RBV therapy by acoustic radiation force impulse.

Reduction of liver stiffness by antiviral therapy in chronic hepatitis B.

BACKGROUND: Liver stiffness (LS) has been reported to correlate with fibrosis stage (F). The correlation between LS and fibrosis stage and the reduction of LS by antiviral therapy were examined in patients with hepatitis B infection. METHODS: LS was measured by FibroScan in 212 patients infected with hepatitis B virus. Liver biopsies were done in 51 patients. Changes of LS were assessed in 29 patients treated with nucleotide or nucleoside analogs and 52 patients without antiviral therapy. RESULTS: LS was significantly correlated with fibrosis stage (ρ = 0.686, P < 0.0001). The optimal cut-off values of LS were 7.1 kPa for F ≥ 2, 10.7 kPa for F ≥ 3, and 16.0 kPa for F4. LS was significantly reduced by antiviral therapy, from 12.9 (range 6.2-17.9) kPa to 6.6 (4.4-10.3) kPa measured at an interval of 512 (range 366-728) days (P < 0.0001). Eleven of 19 (58%) patients with baseline fibrosis stages of F3-4 deduced from LS had 2-point or greater reductions of deduced stage at the last LS measurement. The change ratio of hyaluronic acid (P = 0.0390) was associated with a 2-point or greater reduction of deduced fibrosis stage. Without antiviral therapy, LS tended to increase, increasing from 6.1 (range 3.9-8.5) kPa to 6.3 (range 4.4-9.7) kPa at an interval of 422 (range 358-709) days (P = 0.0682). CONCLUSIONS: LS was significantly correlated with fibrosis stage in patients with chronic hepatitis B. The reduction of LS by antiviral therapy was significantly correlated with the reduction of hyaluronic acid. Thus, we conclude that LS can be useful to assess the progression and regression of liver fibrosis stage noninvasively.

A new index for non-invasive assessment of liver fibrosis.

AIM: To construct and evaluate a new non-invasive fibrosis index for assessment of the stage of liver fibrosis. METHODS: A new fibrosis index (Fibro-Stiffness index) was developed in 165 of 285 patients with chronic hepatitis C, and was validated in the other 120 patients where liver biopsy was performed. Its usefulness was compared with liver stiffness (LS) measured by FibroScan, the aminotransferase-to-platelet ratio index, the Forns index and the FibroIndex. RESULTS: The Fibro-Stiffness index consists of LS, platelet count and prothrombin time. The values of the Fibro-Stiffness index differed significantly between neighboring fibrosis stages except F0-F1. The area under the receiver operating characteristics curves of the Fibro-Stiffness index for prediction of F ≥ 2 (0.90), F ≥ 3 (0.90) and F = 4 (0.92) in the estimation group and those for F ≥ 3 (0.93) and F = 4 (0.97) in the validation group were the highest among the 5 methods examined. The accuracy of the Fibro-Stiffness index had highest values for F ≥ 2, F ≥ 3 and F = 4 in both the estimation and validation groups. The diagnostic performance for F = 4 was improved by a combination of the Fibro-Stiffness index with serum hyaluronic acid level. CONCLUSION: The Fibro-Stiffness index was constructed and validated. It showed superior diagnostic performance to other indices for F ≥ 2, 3 and 4.