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Palbociclib is a first-in-class potent oral inhibitor of cyclin-dependent kinase (CDK)4/6 that was approved in the USA in 2015 and in Japan in 2017. Next-generation abemaciclib was approved in the USA and Japan in 2018. The use of palbociclib results in a high frequency of bone marrow suppression, whereas abemaciclib induces a low frequency of bone marrow suppression, but a high incidence of diarrhea. However, the most appropriate uses for these CDK4/6 inhibitors remain unclear. In this study, we analyzed the efficacy and side-effects associated with the use of palbociclib at our hospital and examined the suitability of palbociclib or abemaciclib. Among 35 patients who used palbociclib at our hospital from December, 2017 to December, 2018, the mean age was 39-83 years. The patients receiving treatment with palbociclib with a combination of drugs included 20 patients (57%) receiving fulvestrant, 8 patients (23%) receiving letrozole, and 7 patients (20%) receiving fulvestrant + LH-RH (leuprorelin). Fourteen patients (40%) had a history of receiving chemotherapy, and 21 patients (60%) had no history of receiving chemotherapy. The number of prior treatment regimens was 0-11 (mean, 2.9). The initial dose of palbociclib was 125 mg for 29 patients (83%) and 100 mg for 6 patients (17%). Partial response, stable disease and progressive disease were achieved in 6 (17%), 19 cases (54%) and 10 cases (29%), respectively. Leukocytopenia was observed in 24 cases, neutropenia was observed in 26 cases, anemia was observed in 13 cases, thrombocytopenia was observed in 15 cases, fatigue was observed in 3 cases and itchy skin was observed in 1 case. When the number of neutrophils prior to palbociclib introduction was <3,000, neutropenia of grade 3 or higher was observed in all cases following palbociclib introduction. Thus, in order to avoid grade 3 or higher neutropenia and to maintain relative dose intensity, abemaciclib treatment may be considered for cases with neutrophils of <3,000 prior to the introduction of a CDK4/6 inhibitor.

HOPX is involved in multiple organ development and acts as a tumor suppressor in various cancers. Epigenetic silencing of HOPX via its promoter methylation has been shown frequent and cancer-specific in human cancers. The proliferation of thyroid cancer cells and cancer progression are strongly influenced by epigenetic alterations as well as genetic changes. Papillary thyroid cancer (PTC) comprises the vast majority of thyroid cancers and exhibits slow progression. However, ~10% of patients still show disease recurrence and refractoriness to treatment. Accordingly, it is important approach to research epigenetic mechanisms in PTC progression to find useful biomarkers. Here, we aimed to seek into the roles and clinical impact of epigenetic silencing of HOPX in PTC.The promoter methylation of HOPX was observed in five of six human thyroid cancer cell lines. Down-regulation of HOPX was seen in three cell lines including PTC line K1, and demethylating agents restored HOPX expression. The promoter methylation was observed with high sensitivity and specificity in human PTC tissues. HOPX promoter methylation independently predicted disease recurrence in PTC patients. Epigenetic silencing of HOPX was associated with Ki-67 expression. Of note, HOPX promoter methylation was dramatically associated with worse prognosis especially in patients with stage I PTC. Forced HOPX expression suppressed cell proliferation, invasive activities, and anchorage-independent growth in vitro. HOPX promoter methylation is frequent and cancer-specific event, leading to aggressive phenotype in PTC. Epigenetic silencing of HOPX may be a clue to tackle cancer progression and have clinical impact as a novel biomarker in PTC.

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Background CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. Methods Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. Results (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively). Conclusion Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.