Characteristics of Anticancer Drugs Approved Under the Accelerated Approval Program in the US: Success or Failure in Converting to Regular Approval.

BACKGROUND: Accelerated approval (AA) program expedites access to promising drugs for life-threatening conditions, particularly in oncology. However, challenges arise from the trade-off between faster access and the certainty of clinical benefits. We examined the differences between the indications for successful conversion of AA to regular approval (RA) and those withdrawn from the perspective of whether the confirmatory trial was appropriately designed and conducted to verify the efficacy estimated in the pivotal trial for AA (AA trial). METHODS: All the anticancer drugs approved by the United States (US) Food and Drug Administration (FDA) between January 2016 and December 2019 were identified on the FDA website. From these, we selected drugs granted AA for solid tumors based on single-arm trials. We compared the characteristics of the AA and confirmatory trials between products that were successfully converted to RA and those that were withdrawn. RESULTS: Twenty-four AA indications were identified, of which 11 were converted to RA and 6 were withdrawn. The magnitude of the objective response rate (ORR) in both the AA and confirmatory trials was not a factor that clearly determined the conversion or withdrawal of AA. However, if the experimental arm did not achieve a certain level of ORR over the control arm in the confirmatory trial, it was thought to increase the uncertainty of successful conversion to RA. CONCLUSION: A relatively high ORR compared with that of the control arm in the confirmatory trial, after AA, is important for successfully obtaining RA.

Clinical features and oncological outcomes of bladder cancer microsatellite instability.

OBJECTIVES: Excellent anticancer effect for solid tumors with microsatellite instability (MSI)-high by anti-PD-1 antibody has been reported. In this study, we investigated the clinical impact of MSI status in bladder cancer. METHODS: This study included 205 Japanese patients who underwent transurethral resection for bladder cancer between 2005 and 2021. The prevalence rates of microsatellite stable (MSS), MSI-low (MSI-L), and MSI-high (MSI-H) were determined using molecular testing. We examined the association of MSI status (MSS versus MSI-L/H) with clinicopathological characteristics and oncological outcomes. RESULTS: MSI-L/H tumors were associated with higher T-category in non-muscle invasive bladder cancer (NMIBC). Additionally, MSI-L/H tumors were associated with a higher risk of intravesical recurrence in NMIBC patients treated with intravesical bacillus Calmette-Guérin (BCG) but not with non-BCG therapy. CONCLUSIONS: This study suggested that the MSI status might serve as a predictive marker for intravesical recurrence after BCG intravesical therapy in NMIBC and highlighted an unmet need for an alternative treatment in patients with MSI-L/H tumors.

Response rate of anticancer drugs approved by the Food and Drug Administration based on a single-arm trial.

BACKGROUND: In recent years, an increasing number of anticancer drugs have been approved based on the results of a single-arm trial (SAT). The magnitude of the objective response rate (ORR) in SATs is important for regulatory decisions, but there has been no clear guidance specifying the degree of ORR for approval. METHODS: All anticancer drugs approved by the US Food and Drug Administration (FDA) between January 2016 and December 2019 were identified through the FDA website. From these, we selected drugs approved for solid tumors based on SATs. For each indication, one regimen was selected from the standard-of-care as the best comparison therapy (BCT), which was defined as the latest regimen for the same tumor and treatment line. We compared the ORR of the investigated product with that of the BCT. RESULTS: Of the 31 solid tumor indications identified, we selected BCT for 28. In 23 of the 28 indications (82.1%), the ORR of the investigated product exceeded that of the BCT, and in 16 of these (69.6%), the lower limit of the 95% confidence interval (CI) of the ORR of the investigated product exceeded the point estimate of the BCT ORR. For seven products, the lower limit of the 95% CI was below the point estimate of the BCT ORR, with differences ranging from 1.0% to 3.4%. CONCLUSION: The lower limit of a 95% CI of the ORR of a new drug in an SAT exceeding the point estimate of the BCT ORR could be an important factor in obtaining regulatory approval.

Evaluation of particulate 137Cs discharge from a mountainous forested catchment using reservoir sediments and sinking particles.

The time and size dependencies of particulate 137Cs concentrations in a reservoir were investigated to evaluate the dynamics of 137Cs pollution from a mountainous forested catchment. Sediment and sinking particle samples were collected using a vibracorer and a sediment trap at the Ogaki Dam Reservoir in Fukushima, which is located in the heavily contaminated area that formed as a result of the Fukushima Dai-ichi Nuclear Power Plant accident of 2011. The inventory of 137Cs discharged into the reservoir during the post-accident period (965 days) was estimated to be approximately 3.0 × 1012-3.9 × 1012 Bq, which is equivalent to 1.1%-1.4% of the initial estimated catchment inventory. The particulate 137Cs concentration showed a decline with time, but the exponent value between the specific surface area and the 137Cs concentration for the fine-sized (<63 µm) particle fraction remained almost constant from the immediate aftermath of the accident. These quantitative findings obtained by reconstructing the contamination history of particulate 137Cs in reservoir sediments and sinking particles have important implications for the evaluation of 137Cs dynamics in mountainous forested catchments.

Evaluation of particulate 137Cs discharge from a mountainous forested catchment using reservoir sediments and sinking particles.

The time and size dependencies of particulate 137Cs concentrations in a reservoir were investigated to evaluate the dynamics of 137Cs pollution from a mountainous forested catchment. Sediment and sinking particle samples were collected using a vibracorer and a sediment trap at the Ogaki Dam Reservoir in Fukushima, which is located in the heavily contaminated area that formed as a result of the Fukushima Dai-ichi Nuclear Power Plant accident of 2011. The inventory of 137Cs discharged into the reservoir during the post-accident period (965 days) was estimated to be approximately 3.0 × 1012-3.9 × 1012 Bq, which is equivalent to 1.1%-1.4% of the initial estimated catchment inventory. The particulate 137Cs concentration showed a decline with time, but the exponent value between the specific surface area and the 137Cs concentration for the fine-sized (<63 µm) particle fraction remained almost constant from the immediate aftermath of the accident. These quantitative findings obtained by reconstructing the contamination history of particulate 137Cs in reservoir sediments and sinking particles have important implications for the evaluation of 137Cs dynamics in mountainous forested catchments.

Predicting the long-term (137)Cs distribution in Fukushima after the Fukushima Dai-ichi nuclear power plant accident: a parameter sensitivity analysis.

Radioactive materials deposited on the land surface of Fukushima Prefecture from the Fukushima Dai-ichi Nuclear Power Plant explosion is a crucial issue for a number of reasons, including external and internal radiation exposure and impacts on agricultural environments and aquatic biota. Predicting the future distribution of radioactive materials and their fates is therefore indispensable for evaluation and comparison of the effectiveness of remediation options regarding human health and the environment. Cesium-137, the main radionuclide to be focused on, is well known to adsorb to clay-rich soils; therefore its primary transportation mechanism is in the form of soil erosion on the land surface and transport of sediment-sorbed contaminants in the water system. In this study, we applied the Soil and Cesium Transport model, which we have developed, to predict a long-term cesium distribution in the Fukushima area, based on the Universal Soil Loss Equation and simple sediment discharge formulas. The model consists of calculation schemes of soil erosion, transportation and deposition, as well as cesium transport and its future distribution. Since not all the actual data on parameters is available, a number of sensitivity analyses were conducted here to find the range of the output results due to the uncertainties of parameters. The preliminary calculation indicated that a large amount of total soil loss remained in slope, and the residual sediment was transported to rivers, deposited in rivers and lakes, or transported farther downstream to the river mouths. Most of the sediment deposited in rivers and lakes consists of sand. On the other hand, most of the silt and clay portions transported to river were transported downstream to the river mouths. The rate of sediment deposition in the Abukuma River basin was three times as high as those of the other 13 river basins. This may be due to the larger catchment area and more moderate channel slope of the Abukuma River basin than those of the other rivers. Annual sediment outflows from the Abukuma River and the total from the other 13 river basins were calculated as 3.2 × 10(4)-3.1 × 10(5) and 3.4 × 10(4)-2.1 × 10(5)ty(-1), respectively. The values vary between calculation cases because of the critical shear stress, the rainfall factor, and other differences. On the other hand, contributions of those parameters were relatively small for (137)Cs concentration within transported soil. This indicates that the total amount of (137)Cs outflow into the ocean would mainly be controlled by the amount of soil erosion and transport and the total amount of (137)Cs concentration remaining within the basin. Outflows of (137)Cs from the Abukuma River and the total from the other 13 river basins during the first year after the accident were calculated to be 2.3 × 10(11)-3.7 × 10(12) and 4.6 × 10(11)-6.5 × 10(12)Bqy(-1), respectively. The former results were compared with the field investigation results, and the order of magnitude was matched between the two, but the value of the investigation result was beyond the upper limit of model prediction.

Embryonic stem cells deficient in I beta1,6-N-acetylglucosaminyltransferase exhibit reduced expression of embryoglycan and the loss of a Lewis X antigen, 4C9.

Embryoglycan is a class of branched high-molecular-weight poly-N-acetyllactosamines characteristically expressed in early embryonic cells and has been shown to be involved in the intercellular adhesion of early embryonic cells in vitro. Branching of poly-N-acetyllactosamine chains is performed by beta1,6-N-acetylglucosaminylation of the galactosyl residue. We previously knocked out the gene encoding I beta1, 6-N-acetylglucosaminyltransferase (IGnT), and the resultant deficient mice were born without any abnormality, although the mice exhibited various deficits in later life. In the present investigation, we produced embryonic stem (ES) cells from IGnT-deficient embryos. The mutant ES cells exhibited a reduced capability in embryoglycan synthesis. Thus, IGnT is a major enzyme involved in the branching of poly-N-acetyllactosamine chains in embryoglycan. Since ES cells are equivalent to multipotential cells of the embryonic ectoderm in early postimplantation embryos, this result indicates that an abundance of embryoglycan in these cells is not essential for normal embryogenesis. The IGnT-deficient ES cells continued to express SSEA-1, but lacked the expression of 4C9 antigen, although the epitope of 4C9 antigen was confirmed to be Lewis X by a transfection experiment. The result establishes the distinct nature of 4C9 antigenicity, which requires either Lewis X epitope on I-branch or clustering of Lewis X epitope, best accomplished by poly-N-acetyllactosamine branching. Alpha6-integrin was newly identified as a carrier of embryoglycan. The IGnT-deficient ES cells adhered to dishes coated with laminin, which is a ligand for alpha6-integrin, significantly less than wild-type ES cells, raising the possibility that embryoglycan in ES cells enhances alpha6-integrin-dependent adhesion in vitro.

alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine, a heparin-binding growth factor.

Midkine is a heparin-binding growth factor that promotes the growth, survival, migration and differentiation of various target cells. So far, receptor-type protein tyrosine phosphatase zeta, low-density-lipoprotein-receptor-related protein and anaplastic lymphoma kinase have been identified as receptors for midkine. We found beta1 integrin in midkine-binding proteins from 13-day-old mouse embryos. beta1-Integrin bound to a midkine-agarose column and was eluted mostly with EDTA. Further study revealed that the alpha-subunits capable of binding to midkine were alpha4 and alpha6. Purified alpha4beta1- and alpha6beta1-integrins bound midkine. Anti-alpha4 antibody inhibited the midkine-dependent migration of osteoblastic cells, and anti-alpha6 antibody inhibited the midkine-dependent neurite outgrowth of embryonic neurons. After midkine treatment, tyrosine phosphorylation of paxillin, an integrin-associated molecule, was transiently increased in osteoblastic cells. Therefore, we concluded that alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine. We observed that the low-density-lipoprotein-receptor-related-protein-6 ectodomain was immunoprecipitated with alpha6beta1-integrin and alpha4beta1-integrin. The low-density-lipoprotein-receptor-related-protein-6 ectodomain was also immunoprecipitated with receptor-type protein tyrosine phosphatase zeta. alpha4beta1- and alpha6beta1-Integrins are expected to co-operate with other midkine receptors, possibly in a multimolecular complex that contains other midkine receptors.