Exploring Predictive Risk Factors of Infusion Reactions with First Pertuzumab Administration in HER2-positive Breast Cancer Patients: A Single Institution Experience.

Introduction: Pertuzumab and trastuzumab are monoclonal antibodies used for treating HER2-positive breast cancer. These anti-HER2 antibodies may induce infusion reactions (IR), mainly upon first administration. We investigated factors predicting IR in the initial pertuzumab treatment for HER2-positive breast cancer. Methods: We retrospectively reviewed the medical records of 57 patients who first received pertuzumab-containing treatment in our hospital from January 2014 to February 2021. The frequency of IR during or immediately after pertuzumab administration was examined. We also analyzed patient characteristics that may represent possible risk factors for IR. Results: The incidence rate of IR was 44% (25/57). Red blood cell count (P < 0.001), hemoglobin (Hb) concentration (P = 0.0011), and hematocrit (P < 0.001) immediately before pertuzumab administration were significantly lower in patients with IR than in those without. In patients with IR, erythrocyte levels immediately before pertuzumab treatment were significantly lower than baseline when having received anthracycline-containing chemotherapy within three months. Logistic regression analysis showed that a decrease in Hb levels was a significant risk factor for IR (log odds ratio = -17). According to the receiver-operating characteristic analysis, a 10% decrease in Hb after anthracycline-containing treatment was the best cut-off value for predicting IR (sensitivity: 88%; specificity: 77%; area under the curve: 0.87). Conclusions: Our study showed a higher incidence of IR after pertuzumab treatment than in clinical trials. There was a strong association between IR occurrence and erythrocyte levels lower than baseline in the group that received anthracycline-containing chemotherapy immediately before.

Subcutaneous axillary primary epithelioid hemangioendothelioma: report of a rare case.

BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare and slow-growing malignant vascular neoplasm composed of epithelioid endothelial cells within a distinctive myxohyaline stroma. It most commonly involves somatic soft tissue, lungs, liver and bone. Herein, we describe a case of EHE arising in the axillary region. CASE PRESENTATION: A 61-year-old man was under observation for multiple hepatic hemangiomas. Fluorodeoxyglucose-positron emission tomography/computed tomography showed specific uptake in a right axillary tumor. The patient was referred to our department for further investigation of the axillary tumor. An elastic-soft and poorly mobile tumor was palpable in the right axilla. Contrast-enhanced computed tomography showed a right axillary tumor and enlarged hepatic hemangiomas. In addition, multiple nodules in both lungs, a left renal angiomyolipoma, and left adrenal adenoma were revealed. Ultrasonography showed masses in both lobes of the thyroid gland, and a 30-mm lobulated hypoechoic mass in the axilla with well-defined and rough borders, showing internal heterogeneity. Fine-needle aspiration cytology was performed on the thyroid and axillary tumors: the thyroid tumor was class V, raising suspicion of papillary thyroid cancer (PTC); the left superior internal jugular node was class V, raising suspicion of metastasis of PTC; and the axillary tumor was class III, raising suspicion of a mesenchymal tumor with few epithelioid cells. The multiple lung nodules were diagnosed as metastatic tumors derived from thyroid cancer. We diagnosed these diseases as PTC of T1b(m)N1bM1(lung) Stage IVB and a right axillary tumor of unclear origin. However, it was assumed to be a primary mesenchymal tumor or a lymph node metastasis from lung cancer or occult breast cancer. We performed total thyroidectomy, left cervical lymph node dissection, and right axillary tumor excision. Histopathologic examination revealed the thyroid tumor as a PTC and the axillary tumor as an EHE. The EHE showed nuclear atypia, necrosis and high mitotic figures. Hence, it was considered to be a high-risk EHE. CONCLUSIONS: We experienced a rare primary subcutaneous axillary EHE with metastatic thyroid cancer in the lung. Since our case was classified as a high-risk EHE, a close follow-up would be appropriate.

Impact of body mass index on short-term outcomes after differentiated thyroid cancer surgery: a nationwide inpatient database study in Japan.

Introduction: Recent studies have shown worse post-operative outcomes following several surgeries in underweight or obese patients. However, the association between body mass index (BMI) and short-term outcomes following thyroid cancer surgery remains unclear because of the small number of patients, deficits in background data known as risk factors (e.g. cancer stage, operative procedure, intraoperative device use and hospital volume) and categorisation of BMI. Methods: We identified patients who underwent thyroidectomy for differentiated thyroid cancer from July 2010 to March 2017 using a Japanese nationwide inpatient database. We used restricted cubic spline (RCS) analyses to investigate potential non-linear associations between BMI (without categorisation) and outcomes: post-operative complications (local and general), duration of anaesthesia, post-operative length of hospital stay and hospitalisation costs. The analyses were adjusted for demographic and clinical backgrounds including the above-stated factors. We also performed multivariable regression analyses for the outcomes with categorisation of BMI. Results: Among 59,671 eligible patients, the median BMI was 22.9 kg/m2 (interquartile range (IQR), 20.7-25.6 kg/m2). In total, 3860 patients (6.5%) had local complications and 787 patients (1.3%) had general complications. Although there were no significant associations with local complications, such as bleeding, recurrent laryngeal nerve paralysis and surgical site infection, the occurrence of general complications was significantly associated with higher BMI. BMI showed a linear association with the duration of anaesthesia and U-shaped associations with post-operative length of stay and hospitalisation costs. The lowest points of the U-shaped curves occurred at a BMI of approximately 24 kg/m2. The multivariate regression analyses showed consistent results with the RCS analyses. Discussion/conclusion: Whereas RCS analyses revealed no significant associations between BMI and post-operative local complications, obesity was significantly associated with the occurrence of general complications. The linear association between BMI and duration of anaesthesia corresponds to previous studies. Although post-operative length of stay and total hospitalisation costs demonstrated U-shaped associations, the slight differences would not be clinically important. Even if surgeons must pay attention to general complications in obese patients undergoing thyroid cancer surgery as well as other surgeries, underweight and overweight patients can undergo thyroidectomy as safely as patients with normal BMI.

Circulating Tumor DNA Harboring the BRAFV600E Mutation May Predict Poor Outcomes of Primary Papillary Thyroid Cancer Patients.

Background: The significance of circulating tumor DNA (ctDNA) in primary papillary thyroid cancer (PTC) is yet to be well established. This study aimed to clarify whether ctDNA carrying the BRAFV600E mutation in plasma from primary PTC patients before and after surgery can predict outcomes. Methods: Twenty-two primary PTC patients without distant metastasis, who underwent surgical resection at the University of Tokyo Hospital, were eligible for this study. Genomic DNA of the primary tumor was extracted from formalin-fixed and paraffin-embedded specimens, and the BRAFV600E mutation was detected by droplet digital polymerase chain reaction (ddPCR). Pre- and postsurgery ctDNAs were extracted from matched plasma samples obtained from 22 patients and analyzed for the BRAFV600E mutation using ddPCR. Results: The BRAFV600E mutation was detected in 16 of 22 (73%) primary tumors. Five of 16 (31%) cases carrying the BRAFV600E mutation in their tumors showed the identical mutation in presurgery plasma. Extrathyroidal extension of the primary tumor correlated significantly with the BRAFV600E mutation in presurgery ctDNA (p = 0.025). In the five patients carrying the BRAFV600E mutation in presurgery ctDNA, the fractional abundance of the BRAFV600E alleles to the total BRAF alleles in the primary tumor was significantly higher than that in the 11 patients without mutated BRAF in presurgery ctDNA (mean, 34% vs. 17%) (p < 0.01). Moreover, one patient with the mutated BRAFV600E in the primary tumor showed the identical mutation not in presurgery ctDNA but in postsurgery ctDNA. This patient had regional lymph node recurrence six months after surgery. Conclusions: Presurgery ctDNA with the BRAFV600E mutation was detected in 31% of cases with primary PTCs carrying the identical mutation. Detection of the BRAFV600E mutation in presurgery plasma can provide information on the increased fractional abundance of the mutated BRAFV600E alleles and local progression of the primary tumor. Furthermore, the fractional abundance of the mutated BRAFV600E in postsurgery ctDNA might predict PTC recurrence.

Comparison of outcomes after differentiated thyroid cancer surgery performed with and without energy devices: A population-based cohort study using a nationwide database in Japan.

BACKGROUND: The benefits of using energy devices (EDs) such as ultrasonic coagulating shears or electrothermal bipolar vessel sealing devices for thyroid cancer surgery have been evaluated only with limited data obtained from small samples. MATERIALS AND METHODS: Using a Japanese national inpatient database, we identified 59,394 patients with thyroid cancer who underwent thyroidectomy without EDs (without-ED group, n = 32,360) and with EDs (with-ED group, n = 26,764) from July 2010 to March 2017. One-to-one propensity score matching was performed to compare the occurrence of postoperative complications including recurrent laryngeal nerve paralysis and chyle leakage, duration of anesthesia, length of stay, total costs, in-hospital mortality rate between the two groups. We also performed multivariate regression analyses using a generalized estimating equation and multiple imputation as a sensitivity analysis. RESULTS: In the propensity-matched analysis involving 22,108 pairs, no significant differences were found in any postoperative complications (7.4% vs. 7.3%, p = 0.73), duration of anesthesia (217 min vs. 218 min, p = 0.54), length of stay (8.7 days vs. 8.2 days, p = 0.07) and in-hospital mortality rate (0.07% vs. 0.09%, p = 0.61). Compared with the without-ED group, the with-ED group showed a lower occurrence of postoperative recurrent laryngeal nerve paralysis (2.3% vs. 2.7%, p = 0.01) but a higher occurrence of postoperative chyle leakage (0.3% vs. 0.1%, p < 0.001) and total cost (US $7246 vs. US $6937, p < 0.001). The multivariate regression analysis showed compatible results with the propensity-matched analysis. CONCLUSION: In this large nationwide cohort of patients with thyroid cancer, no significant difference was detected in the proportions of any complications. The use of EDs was associated with a lower occurrence of postoperative recurrent laryngeal nerve paralysis but a higher occurrence of postoperative chylothorax and higher cost.

A case of primary breast angiosarcoma with multiple discontinuous small lesions.

BACKGROUND: Angiosarcoma of the breast is rare. It carries a poor prognosis because of its high risk of local recurrence and distant metastases. Presently, there are still no established systemic therapies. Thus, the main treatment strategy for breast angiosarcoma is complete resection. This underscores the importance of closely monitoring the spread of the tumor lesion, particularly for multifocal angiosarcoma, and to plan an optimal operative procedure. We herein present the successful surgical treatment of a rare case of multifocal primary breast angiosarcoma. CASE PRESENTATION: A 43-year-old woman visited our hospital with a growing lump on her right breast accompanied by pain. Clinical and radiological examinations revealed a well-circumscribed 40-mm-diameter tumor at the inner lower quadrant of her right breast. Histological examination of a needle biopsy specimen revealed angiosarcoma. Based on a precise evaluation of the tumor by contrast-enhanced MRI and contrast-enhanced CT scan, a wide local excision with sufficient margins was performed. In the resected specimen, three discontinuous small lesions of angiosarcoma were observed around the main tumor. Therefore, total mastectomy was additionally performed. Pathological examination revealed two other small nodules of angiosarcoma in the remnant right breast, which appeared to be close but not continuous to the defective part of the initial resection. Postoperative follow-up at 1 year showed no signs of recurrence or distant metastasis. Multifocal primary breast angiosarcoma is extremely rare with only two previous reports describing its multifocality. CONCLUSIONS: Owing to its rarity, a standardized surgical treatment for breast angiosarcoma remains controversial. Our case suggests that primary breast angiosarcoma may occasionally present with multifocal tumor. Thus, it is important to keep in mind the multifocality of breast angiosarcoma when assessing its spread by diagnostic imaging and when planning the surgical strategy.

Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody.

Biased agonism is a paradigm that may explain the selective activation of a signaling pathway via a GPCR that activates multiple signals. The autoantibody-induced inactivation of the calcium-sensing receptor (CaSR) causes acquired hypocalciuric hypercalcemia (AHH). Here, we describe an instructive case of AHH in which severe hypercalcemia was accompanied by an increased CaSR antibody titer. These autoantibodies operated as biased allosteric modulators of CaSR by targeting its Venus flytrap domain near the Ca2+-binding site. A positive allosteric modulator of CaSR, cinacalcet, which targets its transmembrane domain, overcame this autoantibody effect and successfully corrected the hypercalcemia in this patient. Hence, this is the first study to our knowledge that identifies the interaction site of a disease-causing GPCR autoantibody working as its biased allosteric modulator and demonstrates that cinacalcet can correct the AHH autoantibody effects both in vitro and in our AHH patient. Our observations provide potentially new insights into how biased agonism works and how to design a biased allosteric modulator of a GPCR. Our observations also indicate that the diagnosis of AHH is important because the severity of hypercalcemia may become fatal if the autoantibody titer increases. Calcimimetics may serve as good treatment options for some patients with severe AHH.

A multicenter, observational study of metastatic breast cancer patients who were treated with eribulin mesylate or taxane-based regimens.

AIM: This multicenter, observational study aimed to investigate the survival benefit of eribulin as well as that of taxane-based regimens in Japanese patients with metastatic breast cancer (MBC) in a real-world setting. METHODS: This study enrolled women with MBC who received eribulin or taxane-based regimens with or without bevacizumab in routine clinical practice from July 2011 to March 2014. Patients were followed until September 2015. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), post-progression survival (PPS) and adverse events. Efficacy findings were adjusted according to demographics. RESULTS: In total, 216 patients receiving eribulin monotherapy (n = 101), taxane monotherapy (n = 73) or taxane plus bevacizumab (n = 42) were followed for a median time of 15.4 months. Median OS, PFS and PPS were 22.3, 8.1 and 14 months in the eribulin monotherapy group; 13.2, 3.6 and 7.6 months in the taxane monotherapy group; and 12.9, 5.7 and 6.3 months, in the taxane plus bevacizumab group, respectively. The incidence of neutropenia was 67.3, 41.1 and 16.7%, and the incidence of grade 4 neutropenia was 1.0, 8.2 and 7.1% in the eribulin monotherapy, taxane monotherapy and taxane plus bevacizumab groups, respectively. One patient (1.0%) discontinued eribulin and 18 patients (15.7%) discontinued taxane-based regimens because of adverse events. CONCLUSION: In Japanese MBC patients in a real-world setting, eribulin showed a survival benefit and tolerability similar to that in previous reports.

Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Breast cancer remains a common malignancy in women, but the take-up for breast cancer screening programs in Japan is still low, possibly due to its perceived inconvenience. TFF1 and TFF3 are expressed in both breast cancer tissue and normal breast. Serum trefoil proteins were reported as cancer screening markers for gastric, prostate, lung, pancreatic cancer and cholangio carcinoma. The purpose of this study was to examine whether serum trefoil proteins could be screening biomarkers for breast cancer. Serum trefoil proteins in 94 breast cancer patients and 84 health check females were measured by ELISA. Serum TFF1 and TFF3 were significantly higher and serum TFF2 was significantly lower in breast cancer patients. Area under the curve of receiver operating characteristic of TFF1, TFF2, and TFF3 was 0.69, 0.83, and. 0.72, respectively. AUC of the combination of TFF1, TFF2, and TFF3 was 0.96. Immunohistochemically, TFF1 expression was positive in 56.5% and TFF3 was positive in 73.9% of breast cancers, while TFF2 was negative in all tumors. Serum TFF1 had positive correlation with expression of TFF1 in breast cancer tissue. Serum concentrations of TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Post-mastectomy radiation therapy in breast cancer with 1-3 involved lymph nodes: the Pros.

In 2014, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reported that post-mastectomy radiation therapy (PMRT) for breast cancer patients with 1-3 cancer-positive lymph nodes is associated with a survival benefit. However, it is not known whether this applies to Japanese patients in daily clinical practice, because this conclusion was based on the results of older, western trials. Therefore, we studied the differences between PMRT results in western breast cancer patients and current practice in Japanese patients. Although we identified three differences, they do not appear to strongly impact the results of EBCTCG. We conclude that Japanese breast cancer patients with 1-3 positive lymph nodes should receive PMRT in daily clinical practice.

Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial-mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re-undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple-negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus-labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E-box-binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT-MET dynamics that could affect the development of triple-negative breast cancer.

Virtual Touch tissue quantification cannot assess breast cancer lesions except for ductal carcinomas in situ and small invasive cancers: a retrospective study.

BACKGROUND: Virtual Touch tissue quantification (VTTQ) is a promising new technology that quantitatively determines the stiffness of tissue. However, the clinical impact of this device on the assessment of breast cancer is unclear. METHODS: This study aimed to review the ultrasound records of patients with breast lesions where VTTQ was used to assess 123 normal breast tissues, 18 benign tumors, and 117 histopathologically confirmed breast cancers in a total of 129 patients. To determine the VTTQ value, a 5×5 mm region of interest was placed in the center of the area of interest, and the target lesion was measured at least three times by VTTQ. RESULTS: Seventy-six percent of the malignant lesions could not be assessed using VTTQ. Among the malignant lesions, ductal carcinomas in situ (DCIS) and invasive breast cancers smaller than 1.6 cm tended to be 'measurable.' Only 17 and 1% of benign breast lesions and areas of normal breast tissue, respectively, were considered to be 'unmeasurable' (P<0.001). CONCLUSIONS: A breast lesion that could not be quantitatively assessed by VTTQ was suspicious for malignancy. By contrast, DCIS lesions and small invasive breast cancers tended to be 'measurable.' These findings indicate that VTTQ may be a useful application for assessing breast tumors.

A case of breast cancer in the axillary tail of Spence - enhanced magnetic resonance imaging and positron emission tomography for diagnostic differentiation and preoperative treatment decision.

BACKGROUND: The management of cancer in the axillary area depends on the etiology of the tumor. CASE REPORT: A 37-year-old woman presented with a 2 cm mass in the axillary fossa. Core needle biopsy revealed adenocarcinoma. There were no abnormal breast findings on physical examination, mammography, or ultrasonography. However, enhanced magnetic resonance imaging (MRI) and positron emission tomography (PET) showed a segmentally-distributed, abnormal area in the upper-outer quadrant, continuous with the axillary mass. Samples of this area obtained by vacuum-assisted biopsy showed intraductal carcinoma. These findings indicated that the axillary lesion was a part of primary breast cancer originating from the axillary tail. Based on these results, the patient underwent total mastectomy with sentinel lymph node biopsy. Pathological examination of the specimen showed invasive ductal carcinoma accompanied by intraductal carcinoma extending up to 8.5 cm. Our case suggests that enhanced MRI and PET can provide useful preoperative information for the management of axillary breast lesions.

BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization.

The breast cancer susceptibility gene (BRCA2) is localized mainly in the nucleus where it plays an important role in DNA damage repair. Some BRCA2 protein is also present in the centrosome. Here, we demonstrate that BRCA2 interacts with plectin, a cytoskeletal cross-linker protein, and that this interaction controls the position of the centrosome. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin B (CDK1/CycB) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of HeLa cells by adding activated CDK1/CycB kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. Plectin has six homologous ankyrin-like repeat domains (termed PLEC M1-M6). Using a pull-down assay, we found that GST-PLEC M1 and a GST-C-terminal region fusion protein (which comprised PLEC M6, along with an adjacent vimentin site) interacted with BRCA2. Since each PLEC module exhibits high homology to the others, the possibility of all six domains participating in this interaction was indicated. Moreover, when PLEC M1 was overexpressed in HeLa cells, it competed with endogenous plectin and inhibited the BRCA2-plectin interaction. This inhibitory effect resulted in dissociation of the centrosomes from the nucleus and increased the rate of micronuclei formation which may lead to carcinogenesis. In addition, when either BRCA2 or plectin was suppressed by the appropriate siRNA, a similar change in centrosomal positioning was observed. We suggest that the BRCA2-plectin interaction plays an important role in the regulation of centrosome localization and also that displacement of the centrosome may result in genomic instability and cancer development.