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This retrospective study aimed to identify predictors for the development of palbociclib-induced neutropenia. This study retrospectively analysed 78 breast cancer patients who had received palbociclib at our hospital between January 2018 and May 2020. For the regression analysis of factors associated with palbociclib-induced neutropenia, variables were extracted manually from medical charts. The level of palbociclib-induced neutropenia was evaluated using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 5). Multivariate ordered logistic regression analysis was performed to identify predictors for the development of neutropenia. Optimal cut-off thresholds were determined using receiver operating characteristic (ROC) analysis. Values of P  < 0.05 (2-tailed) were considered significant. Significant factors identified included concomitant use of statin (odds ratio [OR] = 0.104, 95% confidence interval [CI] = 0.018–0.598; P  = 0.011) and body mass index (BMI) (OR = 1.118, 95% CI = 1.007–1.241; P  = 0.037). ROC analysis revealed that neutropenia (grade 4) was more likely to occur with a BMI ≥ 22.3 kg/m 2 . In conclusion, no concomitant use of statins and high BMI were identified as significant predictors for the development of palbociclib-induced neutropenia.

Recently, aldehyde dehydrogenase (ALDH) 1 has been identified as a reliable marker for breast cancer stem cells. The aim of our study was to investigate the clinicopathological characteristics of breast cancers with ALDH1+ cancer stem cells. In addition, the distribution of ALDH1+ tumor cells was compared on a cell‐by‐cell basis with that of estrogen receptor (ER)+, Ki67+, or human epidermal growth factor receptor type 2 (HER2)+ tumor cells by means of double immunohistochemical staining. Immunohistochemical staining of ALDH1 was applied to 203 primary breast cancers, and the results were compared with various clinicopathological characteristics of breast cancers including tumor size, histological grade, lymph node metastases, lymphovascular invasion, ER, progesterone receptor, HER2, Ki67, and topoisomerase 2A as well as prognosis. Immunohistochemical double staining of ALDH1 and ER, Ki67, or HER2 was also carried out to investigate their distribution. Of the 203 breast cancers, 21 (10%) were found to be ALDH1+, and these cancers were significantly more likely to be ER− (P = 0.004), progesterone receptor− (P = 0.025), HER2+ (P = 0.001), Ki67+ (P < 0.001), and topoisomerase 2A+ tumors (P = 0.012). Immunohistochemical double staining studies showed that ALDH1+ tumor cells were more likely to be ER−, Ki67−, and HER2+ tumor cells. Patients with ALDH1 (score 3+) tumors showed a tendency (P = 0.056) toward a worse prognosis than did those with ALDH1− tumors. Breast cancers with ALDH1+ cancer stem cells posses biologically aggressive phenotypes that tend to have a poor prognosis, and ALDH1+ cancer stem cells are characterized by ER−, Ki67−, and HER2+. (Cancer Sci 2009; 100: 1062–1068)

Androgen deprivation therapy and aromatase inhibitors are known to cause a decrease in bone mineral density and an increase in fractures. Patients receiving these treatments have been shown to have a fracture risk equal to or greater than that of patients with osteoporosis with prevalent fractures. This manual was created to prevent fractures in patients with cancer treatment-induced bone loss with high fracture risks who cannot be treated under the current Japanese guideline for the prevention and treatment of osteoporosis. This manual recommends drug treatment for patients with BMD − 2.0 ≤ T score < − 1.5 with the family history of hip fracture or 15% or more 10-year probability of major osteoporotic fractures by FRAX®; or in patients with BMD T score < − 2.0. It is important to verify whether the use of this manual can reduce fractures and improve the quality of life of patients with cancer treatment-induced bone loss by prospective studies.

This retrospective study was undertaken to identify predictors for the development of hypocalcaemia even with prophylactic administration of calcium and vitamin D, and to help guide future strategies to improve the safety, efficacy, and QOL of patients receiving denosumab. Between January 2016 and February 2020, a total of 327 advanced cancer patients at our hospital who were receiving denosumab were enrolled. Variables associated with the development of hypocalcaemia were extracted from the clinical records. The level of hypocalcaemia was evaluated using CTCAE version 5. Multivariate ordered logistic regression analysis was performed to identify predictors for the development of hypocalcaemia. Optimal cut off thresholds were determined using ROC analysis. Values of P  < 0.05 (2-tailed) were considered significant. 54 patients have developed hypocalcemia (≥ Grade 1). Significant factors identified included concomitant use of vonoprazan [odds ratio (OR) = 3.74, 95% confidence interval (CI) 1.14–12.26; P  = 0.030], dexamethasone (OR = 2.45, 95%CI 1.14–5.42; P  = 0.022), pre-treatment levels of serum calcium (OR = 0.27, 95%CI 0.13–0.54; P  < 0.001), ALP/100 (OR = 1.04, 95%CI 1.01–1.07; P  = 0.003), and haemoglobin (OR = 0.79, 95%CI 0.68–0.93; P  = 0.004). ROC curve analysis revealed that the threshold for pre-treatment levels of serum calcium was ≤ 9.3 mg/dL, ALP was ≥ 457 U/L, and haemoglobin was ≤ 10.4 g/dL. In conclusion, concomitant use of vonoprazan or dexamethasone, and pre-treatment levels of serum calcium (low), ALP (high) and haemoglobin (low) were identified as significant predictors for the development of denosumab-induced hypocalcaemia.

IntroductionAndrogen deprivation therapy (ADT) is widely used for the treatment of prostate cancer. ADT is associated with reduced bone density leading to an increased risk of osteoporotic fracture. The objective of this retrospective cohort study was to quantify fracture risk in men treated with ADT for prostate cancer in real-world practice in Japan.Materials and methodsData were extracted from the Japanese Medical Data Vision (MDV) database. Men initiating ADT for treatment of prostate cancer between April 2010 and March 2021 were identified and matched to a cohort of prostate cancer patients not taking ADT using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared between cohorts using a Cox cause-specific hazard model. Information was extracted on demographics, comorbidities and bone densitometry.Results30,561 men with PC starting ADT were matched to 30,561 men with prostate cancer not treated with ADT. Following ADT initiation, <5% of men underwent bone densitometry. Prescription of ADT was associated with an increased fracture risk compared to not taking ADT (adjusted hazard ratio: 1.63 [95% CI 1.52–1.75]).ConclusionADT is associated with a 1.6-fold increase in the risk of osteoporotic fracture in men with prostate cancer. Densitometry in this population is infrequent and monitoring urgently needs to be improved in order to implement effective fracture prevention.

IntroductionAromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients’ quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far.Materials and methodsPatients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months.ResultsAt 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6–10.1), 4.3% (95% CI 3.0–5.5), and 3.1% (95% CI 2.1–4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab.ConclusionTwice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.

The development of proteinuria restricts the dose of anti-angiogenic agents, thereby reducing their efficacy. Thus, this retrospective study was undertaken to identify predictive factors of the development of angiogenesis inhibitor-induced proteinuria, and to elucidate if there is a difference in the likelihood of proteinuria among anti-angiogenic agents or cancer types, to help guide future strategies to improve the safety, efficacy, and quality of life of patients receiving chemotherapy. Between April 2014 and February 2019, 124 cancer patients at our outpatient chemotherapy center who were receiving chemotherapy with bevacizumab, ramucirumab, or aflibercept were enrolled. Variables related to the development of proteinuria were extracted from the patients’ clinical records and used for regression analysis. The level of the proteinuria was evaluated based on CTCAE version 5. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of proteinuria. The Wilcoxon/Kruskal-Wallis test was used to identify significant differences between groups. Significant factors identified included systolic blood pressure (SBP) [odds ratio (OR) = 1.031, 95% confidence interval (CI) = 1.005–1.058; P  = 0.0197], number of cycles (OR = 1.049, 95% CI = 1.018–1.082; P  = 0.0019), and calcium channel blocker use (OR = 2.589, 95% CI = 1.090–6.146; P  = 0.0311). There was no difference among the three anti-angiogenic agents ( P  = 0.4969) or among cancer types ( P  = 0.2726) in the likelihood of proteinuria. In conclusion, SBP, number of cycles, and calcium channel blocker use were identified as significant predictors of the development of angiogenesis inhibitor-induced proteinuria. There was no difference among the three anti-angiogenic agents or among cancer types.

As histone deacetylase inhibitors (HDACIs) have limited efficacy against solid tumors, we investigated whether and how oxidative stress is involved in sensitivity to HDACIs to develop a novel therapeutic option of HDACIs treatment. We first tested whether a reduction of the antioxidant glutathione (GSH) by glutamine deprivation affects sensitivity to a commercially available HDACI vorinostat and reactive oxygen species (ROS) accumulation. Next we investigated the relationship between a glutamate-cystine transporter xCT and the efficacy of vorinostat using siRNA of xCT and bioinformatic analyses. Finally, we verified the combinatory effects of vorinostat and the xCT inhibitor salazosulfapyridine (SASP) on ROS accumulation, cell death induction, and colony formation. Glutamine deprivation increased vorinostat-mediated cell death with ROS accumulation. Genetic ablation of xCT improved the efficacy of vorinostat, consistent with the results of public data analyses demonstrating that xCT expressions positively correlate with insensitivity to HDACIs in many types of cancer cell lines. Vorinostat caused ROS accumulation when combined with SASP, possibly resulting in synergistic ferroptosis. Our study provides a novel mechanistic insight into the mechanism underlying sensitivity to HDACIs involving xCT, suggesting xCT to be a promising predictive marker of HDACIs and rationalizing combinatory therapy of HDACIs with xCT inhibitors to induce ferroptosis.

Activation of AMP-Activated Protein Kinase Reduces Hyperglycemia-Induced Mitochondrial Reactive Oxygen Species Production and Promotes Mitochondrial Biogenesis in Human Umbilical Vein Endothelial Cells Daisuke Kukidome , Takeshi Nishikawa , Kazuhiro Sonoda , Koujiro Imoto , Kazuo Fujisawa , Miyuki Yano , Hiroyuki Motoshima , Tetsuya Taguchi , Takeshi Matsumura and Eiichi Araki Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan Address correspondence and reprint requests to Takeshi Nishikawa, MD, PhD, Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Email: takeshi{at}kaiju.medic.kumamoto-u.ac.jp Abstract We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator–activated response-γ coactivator-1α (PGC-1α) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPKα1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1α completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative–AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1α pathway. AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside AMPK, AMP-activated protein kinase GAPDH, glyceraldehyde-3-phosphate dehydrogenase HUVEC, human umbilical vein endothelial cell MnSOD, manganese superoxide dismutase mtROS, mitochondrial reactive oxygen species mtTFA, mitochondrial DNA transcription factor A NRF, nuclear respiratory factor PGC-1α, peroxisome proliferator–activated response-γ coactivator-1α ROS, reactive oxygen species TBS, Tris-buffered saline UCP, uncoupling protein Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 12, 2005. Received July 25, 2005. DIABETES

Predictive value and accuracy of the acute pain trajectory were compared with those of pain intensity at 1 day after the surgery for pain prevalence at 6 months after the surgery. Female patients scheduled for breast cancer surgery were eligible for this study. Patients were questioned about pain intensity daily during the 7 days after surgery. Presence of pain, its location, and intensity as well as the Japanese version of the quality of the recovery-40 (QOR-40) were determined in an interview prior to and at 6 months after the surgery. Acute pain trajectory was determined by a group-based trajectory modeling analysis that was based on the pain intensity at 1-7 days after surgery. Predictive value of the acute pain trajectory for the presence of pain at 6 months after the surgery was assessed by a logistic regression model. The predictive value was compared with pain intensity at 1 day after the surgery. A total of 123 participants completed the 6-month follow-up. The three-cluster model (mild, moderate, and severe pain) was considered to be the most statistically appropriate model for the acute pain trajectory. After 6 months, 51.2% and 8.9% of participants reported pain and severe pain, respectively. Presence of pain at 6 months after the surgery was associated with poor recovery. The severe pain cluster was significantly associated with the presence of pain at 6 months after the surgery (adjusted odds ratio, 9.40; <0.001 vs mild pain cluster). Classification of patients according to the acute pain trajectory, when compared with the classification according to pain intensity at 1 day after the surgery, made it possible to predict with better precision those patients who will develop persistent postsurgical pain.