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Background While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy. Methods To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions. Results The study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF. Conclusions We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

Background Sodium channels located in the dorsal root ganglion, particularly Nav1.7 and Nav1.8, encoded by SCN9A and SCN10A , respectively, act as molecular gatekeepers for pain detection. Our aim was to determine the association between TIPN and SCN9A and SCN10A polymorphisms . Methods Three single nucleotide polymorphisms (SNPs) in SCN9A and two in SCN10A were investigated using whole-genome genotyping data from 186 Japanese breast or ovarian cancer patients classified into two groups as follows: cases that developed taxane-induced grade 2–3 neuropathy ( N  = 108) and controls ( N  = 78) with grade 0–1 neuropathy. Multiple logistic regression analyses were conducted to evaluate associations between TIPN and SNP genotypes. Results SCN9A- rs13017637 was a significant predictor of grade 2 or higher TIPN (odds ratio (OR) = 3.463; P  = 0.0050) after correction for multiple comparisons, and precision was improved when only breast cancer patients were included (OR 5.053, P  = 0.0029). Moreover, rs13017637 was a significant predictor of grade 2 or higher TIPN 1 year after treatment (OR 3.906, P  = 0.037), indicating its contribution to TIPN duration. Conclusion SCN9A rs13017637 was associated with the severity and duration of TIPN. These findings are highly exploratory and require replication and validation prior to any consideration of clinical use.

Mortality rate of maintenance hemodialysis patients is known to be high. Cardio-ankle vascular index (CAVI) is an index reflecting the proper stiffness of the arterial tree from the origin of the aorta to the ankle. We aimed to clarify the utility of CAVI as a predictor of mortality in hemodialysis patients. The roles of age and nutritional conditions on survival were also examined. We followed 242 patients undergoing hemodialysis for 6 consecutive years. Data from 209 patients (mean age was 60 ± 11 years) excluding those with ankle-brachial index <0.90 were then analyzed. CAVI and heart to ankle pulse wave velocity (haPWV) were measured using Vasera 1500. Thirty-eight hemodialysis patients who died during the 6-year period had higher age, cardiothoracic ratio (CTR), CAVI, and haPWV, and lower diastolic blood pressure, albumin, phosphate, and calcium phosphate product. The Kaplan-Meier curves for cumulative survival among the tertile groups showed that the mortality rate was higher in the highest tertile (T3) compared to T1/T2 for both CAVI and haPWV. Receiver operating characteristic (ROC) analysis revealed that CAVI had better discriminatory power for all-cause mortality compared to haPWV. In the Cox-proportional hazards analyses, 1 SD increase in both parameters contributed independently to all-cause mortality [CAVI: HR 1.595 (95% CI 1.108-2.297), haPWV: HR 1.695 (95% CI 1.185-2.425)], as well as age and CTR. Both parameters above the cut-offs estimated in the ROC analysis (CAVI ≥ 9.2, haPWV ≥ 8.9) also had independent contributions to mortality. Through the 6 consecutive years of follow-up in 209 HD patients, increased CAVI might represent a major modifiable risk factor for all-cause mortality. Further research is needed to examine whether CAVI-lowering interventions contribute to improved prognosis.

Background Locoregional recurrence (LRR) after mastectomy reduces the patient’s quality of life and survival. There is a consensus that postmastectomy radiotherapy (PMRT) helps establish locoregional control and reduces LRR in patients with ≥4 metastatic nodes. However, in patients with 1–3 metastatic nodes, the incidence of LRR and the role of PMRT have been the subject of substantial controversy. This study assessed the risk factors for LRR and the efficacy of PMRT in Japanese breast cancer patients with metastatic nodes. Methods This study analyzed 789 cases of invasive breast carcinoma with metastatic nodes from 1998 to 2008. We divided the study population into 4 groups: 1–3 positive nodes with/without chemotherapy and ≥4 positive nodes with/without chemotherapy. Risk factors for LRR were identified and the relationship between LRR and PMRT was analyzed. Results During the median follow-up of 59.6 months, 61 (7.7%) patients experienced LRR. In patients who received chemotherapy, independent LRR risk factors were high nuclear grade, severe lymphatic invasion, vascular invasion, and progesterone receptor-negative status in patients with 1–3 positive nodes, and severe lymphatic invasion and estrogen receptor-negative status in patients with ≥4 nodes. Although patients treated with PMRT had good outcomes, there was no significant difference, and PMRT did not significantly improve the outcome of the patients with all risk factors. Conclusions With systemic therapy and adequate dissection, PMRT by itself was of limited value in establishing locoregional control. The indication for PMRT in patients with 1–3 positive nodes remains controversial.

Background Treatment-related infertility is one of the important quality-of-life issues in young breast cancer (YBC) patients. Although existing guidelines recommend supporting fertility preservation (FP) of YBC, the perceptions of reproductive specialists (RS) has not been evaluated. We investigated the perceptions and needs of RS with regard to FP of YBC patients. Methods A cross-sectional survey was sent to 423 certified RS registered to the Japan Society for Reproductive Medicine to self-evaluate their perceptions and needs regarding FP in YBC patients. Results Two hundred RS (47 %) responded to the survey. 99 % responded that RS should be engaged in FP of YBC patients. 88 % responded that they would like to treat YBC patients, while 46 % responded that cancer treatment is more important than childbirth, even when the patient is recurrence-free 5 years after primary treatment. Respondents affiliated to private clinics were more likely to accept both fertilized and unfertilized egg preservation than those affiliated with academic or general hospitals. 70 % responded that they were anxious about treating breast cancer patients: concerns regarding a greater or unknown risk of recurrence (66 %), insufficient knowledge about breast cancer (47 %), and lack of a patient’s spouse/partner (24 %) were identified as major barriers in supporting FP for YBC patients. Conclusions RS recognize the need for FP in YBC patients and are willing to participate in their care. Affiliation of RS was related to a positive attitude to egg preservation. Various concerns regarding FP among RS indicate the need for evidence that supports the safety of FP, inter-disciplinary communication, and practice guidelines.

The present study investigated fibrotic foci (FFs), the grading system for lymph vessel tumor emboli (LVTEs), and the histological characteristics of nodal metastatic tumors that were significantly associated with the outcomes of 115 patients with invasive ductal carcinoma (IDC) who had received neoadjuvant chemotherapy. We compared the outcome predictive power of FFs, the grading system for LVTEs, and the histological characteristics of metastatic tumors in lymph nodes with the well‐known clinicopathological characteristics of tumor recurrence and tumor‐related death in multivariate analyses. The presence of FFs, as assessed by a biopsy performed before neoadjuvant chemotherapy, significantly increased the hazard rates (HRs) for tumor‐related death in all the cases and in cases with nodal metastasis. The grading system for LVTEs, which was assessed using surgical specimens obtained after neoadjuvant chemotherapy, was significantly associated with increasing hazard rates (HRs) for tumor recurrence and tumor‐related death in all the cases and in cases with nodal metastasis. Moderate to severe stroma in nodal metastatic tumors and five or more mitotic figures in nodal metastatic tumors were significantly associated with elevated HRs for tumor recurrence and tumor‐related death among all the cases. These results indicated that FFs, the grading system for LVTEs, and the histological characteristics of tumor cells in lymph nodes play important roles in predicting the tumor progression of IDCs of the breast in patients treated with neoadjuvant chemotherapy. (Cancer Sci 2009; 100: 1823–1833)

The purpose of this study was to determine whether p53 protein expression in tumor stromal fibroblasts assessed immunohistochemically by the Allred score system is significantly associated with nodal metastasis by invasive ductal carcinoma (IDC), and significantly associated with the outcome of 1042 IDC patients according to adjuvant therapy status, UICC pTNM stage, and triple‐negative IDC status, in multivariate analyses with well‐known clinicopathological factors. The Allred scores for p53 expression in tumor stromal fibroblasts were significantly associated with the number of nodal metastases, and Allred scores of 4–8 for p53 in tumor stromal fibroblasts significantly increased the hazard rate for distant organ metastasis or for tumor death in the triple‐negative IDC patients, and the UICC pTNM stage I, II, and III patients. The results indicated that p53 protein expression in tumor stromal fibroblasts is closely associated with the number of nodal metastases and the outcome of IDC patients. (Cancer Sci 2009; 00: 000–000)

Background In JCOG0306 trial, a phase II study to examine the efficacy of neoadjuvant chemotherapy followed by radiation therapy (NAC-RT) to primary breast cancer, pathological complete response (pCR) was evaluated from specimens of the representative cross-section including the tumor center that had been accurately marked [representative specimen (RS) method]. In this ancillary study, we examined if the RS method was comparable to the conventional total specimen (TS) method, which is widely employed in Japan, to identify the pCR group showing excellent prognosis. Methods We obtained long-term follow-up data of 103 patients enrolled in JCOG0306 trial. As histological therapeutic effect, pCR (ypT0 and ypT0/is) and quasi-pCR [QpCR, ypT0/is plus Grade 2b (only a few remaining invasive cancer cells)] were evaluated with RS and TS methods. Concordance of pCR between these two methods and associations of the pCR with prognosis were examined. Results ypT0, ypT0/is, and QpCR were observed in 28 (27.2%), 39 (37.9%), and 45 (43.7%) patients with RS method, whereas these were 20 (19.4%), 25 (24.3%) and 40 (38.9%) with TS method, respectively. Between RS and TS methods, concordance proportions of ypT0 and ypTis were 92.2% and 86.4%, respectively. Risk of recurrence of ypT0/is group was lower than that of non-ypT0/is group (HR 0.408, 95% CI [0.175–0.946], P  = 0.037) and risk of death of ypT0/is group was lower than that of non-ypT0/is group (HR 0.251, 95% CI [0.073–0.857], P  = 0.027). The ypT0 and ypT0/is groups with RS method showed excellent prognosis similarly with those with TS method, and RS method was able to differentiate the OS and RFS between pCR and non-pCR than TS method significantly even if pCR was classified ypT0 or ypT0/is. With TS method, QpCR criteria stratified patients into the better and worse prognosis groupsmore clearly than pCR criteria of ypT0 or ypT0/is. Conclusions RS method was comparable to TS method for the evaluation of pCR in the patients who received NAC-RT to primary breast cancer provided the tumor center was accurately marked. As pCR criteria with RS method, ypT0/is appeared more appropriate than ypT0.

Background Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes. Methods In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses. Results We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort. Conclusion We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine. Trial registration The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w .