The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells

Introduction

Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.

Methods

The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT- and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.

Results

mRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-β-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.

Conclusions

Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT- and ER-positive breast cancer cells.     

A case of primary malignant lymphoma of the duodenum successfully treated with dose escalating chemotherapy

A 65-year-old woman with diabetes mellitus was hospitalized for heart failure and anemia in August 2001, and recovered with conservative treatment. An endoscopic examination revealed an ulcerative mass located in the duodenal bulb to the 2nd portion. Abdominal CT scan demonstrated tumor involvement in the pancreas head. The diagnosis of a diffuse large B-cell lymphoma, clinical stage IIE, was made by endoscopic biopsy. Although surgical resection of the localized intestinal tumor would have been a common choice for initial treatment, polychemotherapy was selected; the patient had diabetes mellitus and preferred polychemotherapy to surgical operation. Because of bulky intestinal mass, transmural disease and sensitive histological type, standard-dose chemotherapy was considered to include a high risk of intestinal perforation. We performed dose-escalating chemotherapy: A half dose of THP-COP (pirarubicin, cyclophosphamide, vincristine) was given at the start in October 2001, 60% THP-COP as the next cycle, 80% THP-COP as the 3rd cycle and thereafter. Without serious complications of the intestine, she received a total of 6 cycles of chemotherapy and subsequent involved field radiation. There has been no evidence of recurrence of disease 14 months from the start of chemotherapy. When conditions make surgical treatment difficult, dose-escalating chemotherapy in a treatment cycle may be considered as an alternative.     

Hypercalcemia Associated with the Ectopic Expression of 25-hydroxyvitamin D3-1α-hydroxylase in Diffuse Large B-cell Lymphoma

An 82-year-old man was transferred to our hospital due to impaired consciousness. His albumin-corrected calcium level was 14.2 mg/dL, intact parathyroid hormone (PTH) and PTH-related protein levels were reduced, and his 1,25-dihydroxyvitamin D [1,25(OH)₂VitD] level was elevated at 71.5 pg/mL. Computed tomography revealed masses on the bilateral ribs. The mass on the rib was biopsied and diagnosed as diffuse large B-cell lymphoma (DLBCL). Immunostaining of the biopsy sample with the anti-CYP27B1 antibody revealed the ectopic expression of 1α-hydroxylase in the lesion. We herein report a rare case of hypercalcemia induced by the overproduction of 1,25(OH)₂VitD in DLBCL ectopically expressing 1α-hydroxylase.     

A case of primary small cell neuroendocrine carcinoma of the uterus

Neuroendocrine carcinoma of the uterine endometrium is extremely rare and found in <1% of all primary endometrial carcinomas. We report a case of neuroendocrine carcinoma of the endometrium detected in a 65-year-old woman and focus our attention on the main imaging features. The low apparent diffusion coefficient value and high maximum standardized uptake value for neuroendocrine cancer serve to distinguish this cancer from endometrial cancer.     

Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE‐1 (phase 2) Japanese cohort

Chimeric antigen receptor (CAR) T cells targeting B‐cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE‐1 study of ciltacabtagene autoleucel (cilta‐cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), patients received a single cilta‐cel infusion at a target dose of 0.75 × 10⁶ (range, 0.5–1.0 × 10⁶CAR‐positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta‐cel. Thirteen patients underwent apheresis, nine of whom received cilta‐cel infusion. Eight patients who received cilta‐cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below‐target dose of cilta‐cel also achieved a best response of VGPR. MRD negativity (10⁻⁵ threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta‐cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR‐T cell neurotoxicity was reported. A positive benefit/risk profile for cilta‐cel was established for heavily pretreated Japanese patients with relapsed or refractory MM.     

Incidence of thromboembolic complications in hospitalized COVID-19 patients in a medical ward in Japan: A single-center retrospective and prospective observational study

Background:A high incidence of thromboembolic complications is one of the hallmarks of COVID-19. However, there may be a difference in the incidence of thromboembolic complications between Asian and Western people. In addition, few prospective studies have been conducted to determine the incidence of thromboembolic complications in hospitalized COVID-19 patients in medical wards in Japan.Methods:A single-center retrospective and prospective cohort study was conducted to determine the incidence of thromboembolic complications in symptomatic COVID-19 patients in a medical ward in a Japanese hospital. All 1116 consecutive COVID-19 patients who were admitted to our hospital from November 1, 2020, to October 26, 2021, were included. The primary outcome was any thromboembolic complications, which included venous thromboembolism, myocardial infarction, ischemic stroke, and other arterial embolisms.Results:The median patient age was 50 (IQR, 37–61), 402 (36.0%) were women, 1005 (90.1%) were Japanese, the median body mass index was 24.1 (IQR, 21.6–27.2), and 43 (3.9%) had Padua scores of at least 4 points at admission. Regarding the severity of COVID-19, 543 (48.7%), 315 (28.2%), 204 (18.3%), and 54 (4.8%) patients had mild, moderate, severe, and critical COVID-19, respectively. Nine patients (0.8%) died, and 47 patients (4.2%) were transferred to other hospitals for intensive care. The primary outcome occurred in only 5 patients (0.5%; 95% CI, 0.1–0.8) and consisted of 3 ischemic strokes, 2 limb ischemia events, and one asymptomatic pulmonary embolism. Even in the 204 patients with severe COVID-19, the prevalence of thromboembolic complications was only 2.5% (95% CI, 0.3–4.6).Conclusion:Thromboembolic complications of COVID-19 are rare even in severe cases in a medical ward in a Japanese hospital. Further studies are needed to identify severe COVID-19 patients with a higher risk for thromboembolic complications in Japan.     

Preparation of Collagen/Hydroxyapatite Composites Using the Alternate Immersion Method and Evaluation of the Cranial Bone-Forming Capability of Composites Complexed with Acidic Gelatin and b-FGF

Bone-substitute materials are essential in dental implantology. We prepared collagen (Col)/hydroxyapatite (Hap)/acidic gelatin (AG)/basic fibroblast growth factor (b-FGF) constructs with enhanced bone-forming capability. The Col/Hap apatite composites were prepared by immersing Col sponges alternately in calcium and phosphate ion solutions five times, for 20 and 60 min, respectively. Then, the sponges were heated to 56 °C for 48 h. Scanning electron microscopy/energy-dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction analyses showed that the Col/Hap composites contained poorly crystalline Hap precipitates on the Col matrix. Col/Hap composite granules were infiltrated by AG, freeze-dried, and immersed in b-FGF solution. The wet quaternary constructs were implanted in rat cranial bone defects for 8 weeks, followed by soft X-ray measurements and histological analysis. Animal studies have shown that the constructs moderately increase bone formation in cranial bone defects. We found that an alternate immersion time of 20 min led to the greatest bone formation (p < 0.05). Constructs placed inside defects slightly extend the preexisting bone from the defect edges and lead to the formation of small island-like bones inside the defect, followed by disappearance of the constructs. The combined use of Col, Hap, AG, and b-FGF might bring about novel bone-forming biomaterials.     

Mirizzi Syndrome Type IV Successfully Treated with Peroral Single-operator Cholangioscopy-guided Electrohydraulic Lithotripsy: A Case Report with Literature Review

A 76-year-old man presented with liver dysfunction and intrahepatic bile duct dilatation. Imaging studies showed two large stones that had become impacted in the common hepatic duct, which was fused with the gallbladder. The patient was diagnosed with Mirizzi syndrome type IV. Hepaticojejunostomy and stone removal failed due to dense gallbladder adhesions involving the right hepatic artery. The bile flow was temporarily restored; however, the patient experienced cholangitis 16 months later. The stones were extracted via peroral single-operator cholangioscopy (SOC)-guided electrohydraulic lithotripsy. This is the first case in which stones were completely removed by SOC-guided treatment in a patient with Mirizzi syndrome type IV.     

Contrast Enhancement of the Normal Infundibular Recess Using Heavily T2-weighted 3D FLAIR

Purpose: The purpose of the present study was to evaluate contrast enhancement of the infundibular recess in the normal state using heavily T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) (HT2-FLAIR).Methods: Twenty-six patients were retrospectively recruited. We subjectively assessed overall contrast enhancement of the infundibular recess between postcontrast, 4-hour (4-h) delayed postcontrast, and precontrast HT2-FLAIR images. We also objectively conducted chronological and spatial comparisons by measuring the signal intensity (SI) ratio (SIR). Chronological comparisons were performed by comparing SI of the infundibular recess/SI of the midbrain (SIR_IR-MB). Spatial comparisons were conducted by comparing SI on postcontrast HT2-FLAIR/SI on precontrast HT2-FLAIR (SIR_Post-Pre) of the infundibular recess with that of other cerebrospinal fluid (CSF) spaces, including the superior part of the third ventricle, lateral ventricles, fourth ventricle, and interpeduncular cistern.Results: In the subjective analysis, all cases showed contrast enhancement of the infundibular recess on both postcontrast and 4-h delayed postcontrast HT2-FLAIR, and showed weaker contrast enhancement of the infundibular recess on 4-h delayed postcontrast HT2-FLAIR than on postcontrast HT2-FLAIR. In the objective analysis, SIR_IR-MB was the highest on postcontrast images, followed by 4-h delayed postcontrast images. SIR_Post-Pre was significantly higher in the infundibular recess than in the other CSF spaces.Conclusion: The present results demonstrated that the infundibular recess was enhanced on HT2-FLAIR after an intravenous gadolinium injection. The infundibular recess may be a potential source of the leakage of intravenously administered gadolinium into the CSF.