Alcohol consumption and breast cancer prognosis after breast cancer diagnosis: a systematic review and meta­analysis of the Japanese Breast Cancer Society Clinical Practice Guideline, 2022 edition.

Alcohol consumption is internationally recognized as one of the compelling risk factors for breast cancer, but it does not necessarily correlate with the prognosis of breast cancer patients. Alcohol consumption in breast cancer patients was addressed in the 2022 Breast Cancer Clinical Practice Guidelines. A systematic review and meta-analysis of epidemiological studies on alcohol consumption and breast cancer recurrence, breast cancer-related mortality, all-cause mortality, and cardiovascular disease mortality in breast cancer patients was performed. The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant publications reporting cohort or case-control studies published until March 2021. A total of 33 studies (32 cohort studies and 1 case-control study) met the eligibility criteria; 4638 cases of recurrence, 12,209 cases of breast cancer-specific mortality, and 21,945 cases of all-cause mortality were observed. With regard to breast cancer recurrence, 7 studies assessed pre-diagnosis alcohol consumption (relative risk (RR) 1.02, 95% confidence interval (95% CI) 0.77-1.37, p = 0.88) and 3 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.85-1.10, p = 0.57), and no significant increase or decrease in risk was observed. With regard to breast cancer-related mortality, 19 studies assessed pre-diagnosis alcohol consumption (RR 1.02, 95% CI 0.93-1.11, p = 0.69), 9 studies assessed post-diagnosis alcohol consumption (RR 0.96, 95% CI 0.77-1.19, p = 0.70), and no significant increase or decrease in risk was observed. With regard to all-cause mortality, 18 studies assessed pre-diagnosis alcohol consumption (RR 0.90, 95% CI 0.82-0.99, p = 0.02), 8 studies assessed post-diagnosis alcohol consumption (RR 0.88, 95% CI 0.74-1.02, p = 0.08), and pre-diagnosis alcohol consumption was associated with a significantly decreased risk. With regard to cardiovascular disease mortality and alcohol consumption, 2 studies assessed it, and the RRwas 0.47 (95% CI 0.28-0.79, p = 0.005), showing that alcohol consumption was associated with a significantly decreased risk. The limitations of this study are that drinking status was mainly based on a questionnaire survey, which is somewhat inaccurate and has many confounding factors, and the cut-off value for the maximum alcohol intake in many studies was low, and it is possible that the actual intake was only an appropriate amount. In many countries, a standard drinking amount is set, and wise decisions are required.

[Neoadjuvant Epirubicin-Cyclophosphamide Therapy followed by Nab-Paclitaxel in Patients with Operable Breast Cancer-A Single-Center Phase â ¡ Trial].

Clinical studies have confirmed that nab-paclitaxel(nab-PTX)therapy is effective and safe in patients with metastatic breast cancer. Neoadjuvant chemotherapy(NAC) with nab-PTX has resulted in a pathological complete response (pCR) rate of 29% in all cases and 58% in HER2-positive cases. However, these data were obtained from an overseas study, and the effectiveness and safety of NAC with nab-PTX remain unclear in Japan. Thus, the present study was conducted to investigate these aspects. In patients with T1-3, N0-2, M0 breast cancer, 4 cycles of 260 mg/m2 nab-PTX were administered every 3 weeks after 4 cycles of EC therapy(100 mg/m2 of epirubicin and 600 mg/m2 of cyclophosphamide)as NAC. In HER2- positive patients, trastuzumab was used in combination with nab-PTX. Overall, 14 patients were registered between October 2014 and October 2018. One patient who had requested for another drug after providing informed consent was excluded, and the remaining 13 patients were analyzed. The primary endpoint was pCR rate. The median age of the subjects was 57 years, and the median tumor diameter was 35 mm. There were 7 cases of Stage Ⅱ disease and 6 cases of Stage Ⅲ disease. As for tumor subtype, there were 7 cases of Luminal-type, 2 cases of Luminal- HER2-type, 4 cases of HER2-type, and no triple negative-type tumors(the cut-off values for estrogen receptor [ER] and progesterone receptor were both 1%). The objective response rate to NAC was 77%(10/13 cases), and no PD was observed. The pCR rate was 54%(7/13 cases): 2 patients had Luminal-type tumors, 1 had a Luminal-HER2-type tumor, and 4 had HER2-type tumors. Predictive factors for pCR were ER negativity and HER2 positivity. Common adverse events of chemotherapy were hair loss, pain, malaise, anemia, dysgeusia, constipation, itchiness, and numbness, but their severity was modest, and they were manageable. This study suggests the efficacy and safety of nab-PTX after EC therapy in Japanese patients with operable breast cancer.

System for Monitoring Progress in a Mixing and Grinding Machine Using Sound Signal Processing.

In this paper we present a system for monitoring progress in a mixing and grinding machine via the signal processing of sound emitted by the machine. Our low-cost, low-maintenance system may improve automatic machines and the industrial Internet of Things. We used the Pumpkin Pi board and Raspberry Pi, which are low-cost hardware devices, for recording sounds via a microphone and analyzing the sound signals, respectively. Sound data obtained at regular intervals were compressed. The estimated power spectral density (PSD) values calculated from the sound signals were related to the status of the material during mixing and grinding. We examined the correlation between the PSD obtained by the STFT and the particle distributions in detail. We found that PSD values had both repeatability and a strong relation with the particle distributions that were created by the mixing and grinding machine, although the relation between the PSD and the particle size distributions was not merely linear. We used the PSD values to estimate the progress remotely during the operation of the machine.

Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells.

BACKGROUND: Combined endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor has been indicated to improve not only progression-free survival, but also overall survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, resistance to this combination therapy inevitably develops. How to manage this resistant breast cancer is one of the most important clinical issues. To investigate the mechanisms of action responsible for resistance, we developed breast cancer cells resistant to CDK4/6 inhibitors, and analyzed their biological characteristics and sensitivity to different anticancer agents. METHODS: HR-positive, HER2-negative MCF-7 and KPL-1 breast cancer cells were cultivated in palbociclib (PAL) or abemaciclib (ABE)-added culture medium for over 5 months, and we successfully developed PAL- or ABE-resistant cells. The effects of PAL or ABE on the cell growth, basal RB expression, RB phosphorylation, cell cycle and cell senescence were compared between resistant and parental cells. Effects of the other CDK4/6 inhibitor, different chemotherapeutic agents and estrogen on the cell growth were also examined. The expression levels of cyclin D1, CDK2, CDK4, CDK6, cyclin E1 and estrogen receptor (ER)-ɑ were measured using RT-PCR. RESULTS: Long-term exposure to up to 200 nM PAL or ABE resulted in the development of PAL- or ABE-resistant MCF-7 or KPL-1 breast cancer cells. Basal expression levels of RB in both resistant cells were down-regulated. Inhibitory effects of either PAL or ABE on RB phosphorylation were reduced in both resistant cells. Accordingly, G1-S cell cycle retardation and cell senescence induced by either inhibitor were also attenuated in both resistant cells. Both resistant cells were cross-resistant to the other CDK4/6 inhibitor but almost as equally sensitive to different chemotherapeutic agents (5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin and eribulin) as the parental cells. The mRNA expression level of CDK6 significantly increased in the resistant MCF-7 cells and that of Rb1 significantly decreased in the resistant KPL-1 cells. Although both resistant cells were less sensitive to estrogen than the parental cells, the expression levels of ER-ɑ did not significantly change in either. CONCLUSIONS: Our study suggests that acquired resistance to PAL or ABE confers cross-resistance to the other CDK4/6 inhibitor but not to chemotherapeutic agents in HR-positive, HER2-negative breast cancer cells. Down-regulation of basal RB expression and normalized RB phosphorylation reduced by CDK4/6 inhibitors may be responsible for the attenuated anti-cell growth effects of the inhibitors.

Anti-cell growth and anti-cancer stem cell activity of the CDK4/6 inhibitor palbociclib in breast cancer cells.

BACKGROUND: A cyclin-dependent kinase (CDK) 4/6 inhibitor, palbociclib, has been used to treat patients with estrogen receptor (ER)-positive (+) and human epidermal growth factor receptor (HER) 2-negative (-) advanced breast cancer. To investigate the mechanisms underlying the antitumor activity of palbociclib, we conducted a preclinical study on the anti-cell growth and anti-cancer stem cell (CSC) activity of palbociclib in breast cancer cells. METHODS: The effects of palbociclib on Rb phosphorylation, cell growth, cell cycle progression, apoptosis, cell senescence and the proportion of CSCs were investigated in five human breast cancer cell lines of different subtypes. To investigate the mechanisms of the anti-CSC activity of palbociclib, small-interfering RNAs for CDK4 and/or CDK6 were used. Palbociclib dose-dependently reduced Rb phosphorylation and cell growth in association with G1-S cell cycle blockade and the induction of cell senescence, but without increased apoptosis, in all breast cancer cell lines. RESULTS: The anti-cell growth activity of palbociclib widely differed among the cell lines. Palbociclib also dose-dependently reduced the CSC proportion measured by three different assays in four of five cell lines. The inhibition of CDK4 expression, but not CDK6 expression, reduced the increased proportion of putative CSCs induced by estradiol in ER (+)/HER2 (-) cell lines. CONCLUSIONS: These results suggest that palbociclib exhibits significant anti-cell growth and anti-CSC activity in not only ER (+) breast cancer cell lines but also ER (-) cell lines. CDK4 inhibition induced by palbociclib may be responsible for its anti-CSC activity.

CD1d- and PJA2-related immune microenvironment differs between invasive breast carcinomas with and without a micropapillary feature.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is characterized by its unique morphology and frequent nodal metastasis. However, the mechanism for development of this unique subtype has not been clearly elucidated. The aim of this study was to obtain a better understanding of IMPC. METHODS: Using representative cases of mixed IMPC, mRNA expression in the micropapillary area and usual invasive area was compared. Then, immunohistochemical analyses for 294 cases (76 invasive carcinomas with a micropapillary feature [ICMF] and 218 invasive carcinomas without a micropapillary feature [ICNMF]) were conducted. Clinicopathological analyses were also studied. RESULTS: DNA microarray analyses for mixed IMPC showed that BC-1514 (C21orf118) was commonly upregulated in the micropapillary area. CAMK2N1, CD1d, PJA2, RPL5, SAMD13, TCF4, and TXNIP were commonly downregulated in the micropapillary area. Immunohistochemically, we confirmed that BC-1514 was more upregulated in ICMF than in ICNMF. CD1d and PJA2 were more downregulated in ICMF than ICNMF. All patients with cases of PJA2 overexpression survived without cancer recurrence during the follow-up period, although the differences for disease-free (p = 0.153) or overall survival (p = 0.272) were not significant. CONCLUSIONS: The CD1d- and PJA2-related tumour microenvironment might be crucial for IMPC. Further study of the immune microenvironment and micropapillary features is warranted.

Comprehensive immunohistochemical analyses on expression levels of hedgehog signaling molecules in breast cancers.

BACKGROUND: The hedgehog (Hh) signaling pathway plays important roles in cell proliferation, malignant progression, invasion and metastasis, and the expansion of cancer stem cells (CSCs). Comprehensive immunohistochemical (IHC) analyses have not yet been conducted on the expression levels of Hh signaling molecules in breast cancer tissues. METHODS: A total of 204 patients with invasive breast cancer treated in our institute were study subjects. IHC analyses on the expression levels of the Hh signaling molecules, sonic Hh (SHH), PTCH1, GLI1, GLI2, and GLI3 and the CSC-related factor, SOX2, were investigated. RESULTS: Positive correlations were observed among all of the Hh signaling molecules tested. SOX2 expression correlated with the expression levels of all Hh signaling molecules. SHH expression positively correlated with tumor size, the Ki-67 labeling index, histological grade, estrogen receptor negativity, progesterone receptor negativity, and HER2 positivity. GLI1 expression positively correlated with the histological grade. GLI2 expression positively correlated with the histological grade, Ki-67 labeling index, and HER2 positivity. Univariate analyses revealed that a younger age, larger tumor size, positive lymph node metastasis, higher histological grade, positive lymphatic invasion, and higher Ki-67 labeling index were related to poor relapse-free survival (RFS). The positivity of all Hh signaling molecules and SOX2 did not correlate with poor RFS. A multivariate analysis revealed that positive lymphatic invasion and a younger age were independent worse prognostic factors for RFS. CONCLUSIONS: This comprehensive analysis demonstrated for the first time that SHH, GLI1, and GLI2 expression levels positively correlated with the malignant phenotypes of tumor cells.

Anti-cell growth and anti-cancer stem cell activities of the non-canonical hedgehog inhibitor GANT61 in triple-negative breast cancer cells.

BACKGROUND: Triple-negative breast cancer (TNBC) exhibits biologically aggressive behavior and has a poor prognosis. Novel molecular targeting agents are needed to control TNBC. Recent studies revealed that the non-canonical hedgehog (Hh) signaling pathway plays important roles in the regulation of cancer stem cells (CSCs) in breast cancer. Therefore, the anti-cell growth and anti-CSC effects of the non-canonical Hh inhibitor GANT61 were investigated in TNBC cells. METHODS: The effects of GANT61 on cell growth, cell cycle progression, apoptosis, and the proportion of CSCs were investigated in three TNBC cell lines. Four ER-positive breast cancer cell lines were also used for comparisons. The expression levels of effector molecules in the Hh pathway: glioma-associated oncogene (GLI) 1 and GLI2, were measured. The combined effects of GANT61 and paclitaxel on anti-cell growth and anti-CSC activities were also investigated. RESULTS: Basal expression levels of GLI1 and GLI2 were significantly higher in TNBC cells than in ER-positive breast cancer cells. GANT61 dose-dependently decreased cell growth in association with G1-S cell cycle retardation and increased apoptosis. GANT61 significantly decreased the CSC proportion in all TNBC cell lines. Paclitaxel decreased cell growth, but not the CSC proportion. Combined treatments of GANT61 and paclitaxel more than additively enhanced anti-cell growth and/or anti-CSC activities. CONCLUSIONS: The non-canonical Hh inhibitor GANT61 decreased not only cell growth, but also the CSC population in TNBC cells. GANT61 enhanced the anti-cell growth activity of paclitaxel in these cells. These results suggest for the first time that GANT61 has potential as a therapeutic agent in the treatment of patients with TNBC.

Anti-cancer stem cell activity of a hedgehog inhibitor GANT61 in estrogen receptor-positive breast cancer cells.

Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)-positive breast cancer cells. It has been suggested that the non-canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER-positive breast cancer cells. We studied anti-CSC activity of a non-canonical Hh inhibitor GANT61 in ER-positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER-positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti-cell growth and anti-CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER-positive cell lines. E2 increased the expression levels of glioma-associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1-S cell cycle retardation and increased apoptosis. GANT61 decreased the E2-induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2-induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti-cell growth and/or anti-CSC activities in some ER-positive cell lines. In conclusion, the non-canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER-positive breast cancer cells. GANT61 enhanced anti-cell growth and/or anti-CSC activities of antiestrogens in ER-positive cell lines.

A case of adenomatous goiter involving diffuse, acute, and painful thyroid enlargement after fine-needle aspiration cytology.

The patient was a 44-year-old woman who exhibited a diffuse goiter during health screening. Her medical history did not include any significant medication-based treatment. An echographic examination detected a solid cystic tumor, which measured 21 × 14 × 10 mm, in her right thyroid lobe; however, she displayed normal thyroid function. After fine-needle aspiration cytology had been performed with a 22 G injection needle, the patient immediately complained of compression and pain extending from the front of her neck to her lower chin, which was not accompanied by dyspnea. A second echographic examination revealed diffuse and edematous enlargement and increased internal blood flow in the bilateral thyroid lobes as well as a thyroid nodule. We immediately iced the patient's neck and administered 125 mg methylprednisolone via an intravenous infusion. Within one hour, her symptoms had markedly improved, but acute pain remained. Thus, we continued the steroid (prednisone) treatment, but the dose was gradually reduced from 10 mg/day to 5 mg/day at 1 week after the patient's symptoms disappeared. The mechanism responsible for the patient's condition remains unclear.

[A pilot study of the reduced effects of adverse events caused by oral morphine and oxycodone after rotating to fentanyl patch in patients with metastatic breast cancer].

BACKGROUND: It has been confirmed by several clinical trials that the fentanyl patch causes less adverse events than sustained-release oral morphine, and after rotation. However, there has been no evidence comparing the fentanyl patch with controlled-release oral oxycodone in terms of adverse events. PURPOSE: We prospectively investigated the reduced effects of adverse events caused by sustained-release oral morphine and controlled-release oxycodone after rotating to the fentanyl patch in patients with metastatic breast cancer. METHOD: Metastatic breast cancer patients requiring sustained-release oral morphine or controlled-release oral oxycodone(n=9, 2 taking oral morphine, 7 taking oral oxycodone, mean age, 57. 5 years)were recruited. Those experiencing adverse events from oral morphine or oral oxycodone were administered a fentanyl patch. RESULTS: The pain score was reduced significantly at the 4th week. The fentanyl patch was associated with significantly less nausea, vomiting, constipation, sleepiness and dizziness over the study period. CONCLUSION: This study suggested that the fentanyl patch can reduce adverse events caused by sustained-release oral morphine as well as controlled-release oral oxycodone.