Examining the effectiveness of a deep learning-based computer-aided breast cancer detection system for breast ultrasound.

PURPOSE: This study aimed to evaluate the clinical usefulness of a deep learning-based computer-aided detection (CADe) system for breast ultrasound. METHODS: The set of 88 training images was expanded to 14,000 positive images and 50,000 negative images. The CADe system was trained to detect lesions in real- time using deep learning with an improved model of YOLOv3-tiny. Eighteen readers evaluated 52 test image sets with and without CADe. Jackknife alternative free-response receiver operating characteristic analysis was used to estimate the effectiveness of this system in improving lesion detection. RESULT: The area under the curve (AUC) for image sets was 0.7726 with CADe and 0.6304 without CADe, with a 0.1422 difference, indicating that with CADe was significantly higher than that without CADe (p < 0.0001). The sensitivity per case was higher with CADe (95.4%) than without CADe (83.7%). The specificity of suspected breast cancer cases with CADe (86.6%) was higher than that without CADe (65.7%). The number of false positives per case (FPC) was lower with CADe (0.22) than without CADe (0.43). CONCLUSION: The use of a deep learning-based CADe system for breast ultrasound by readers significantly improved their reading ability. This system is expected to contribute to highly accurate breast cancer screening and diagnosis.

Lack of impact of the ALDH2 rs671 variant on breast cancer development in Japanese BRCA1/2-mutation carriers.

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients.

Diagnostic performance of dedicated breast positron emission tomography.

BACKGROUND: Dedicated breast positron emission tomography (dbPET) has been developed for detecting smaller breast cancer. We investigated the diagnostic performance of dbPET in patients with known breast cancer. METHODS: Eighty-two preoperative patients with breast cancer were included in the study (84 tumours: 11 ductal carcinomas in situ [DCIS], 73 invasive cancers). They underwent mammography (MMG), ultrasonography (US), and contrast-enhanced breast magnetic resonance imaging (MRI) before whole-body PET/MRI (WBPET/MRI) and dbPET. We evaluated the sensitivity of all modalities, and the association between the maximum standard uptake value (SUVmax) level and histopathological features. RESULTS: The sensitivities of MMG, US, MRI, WBPET/MRI and dbPET for all tumours were 81.2% (65/80), 98.8% (83/84), 98.6% (73/74), 86.9% (73/84), and 89.2% (75/84), respectively. For 11 DCIS and 22 small invasive cancers (≤ 2 cm), the sensitivity of dbPET (84.9%) tended to be higher than that of WBPET/MRI (69.7%) (p = 0.095). Seven tumours were detected by dbPET only, but not by WBPET/MRI. Five tumours were detected by only WBPET/MRI because of the blind area of dbPET detector, requiring a wider field of view. After making the mat of dbPET detector thinner, all 22 scanned tumours were depicted. The higher SUVmax of dbPET was significantly related to the negative oestrogen receptor status, higher nuclear grade, and higher Ki67 (p < 0.001). CONCLUSIONS: The sensitivity of dbPET for early breast cancer was higher than that of WBPET/MRI. High SUVmax was related to aggressive features of tumours. Moreover, dbPET can be used for the diagnosis and oncological evaluation of breast cancer.

In vitro synthesis of mucin-type O-glycans using saccharide primers comprising GalNAc-Ser and GalNAc-Thr residues.

Mucin-type O-glycosylation of serine or threonine residue in proteins is known to be one of the major post-translational modifications. In this study, two novel alkyl glycosides, Nα-lauryl-O-(2-acetamido-2-deoxy-α-d-galactopyranosyl)-l-serineamide (GalNAc-Ser-C12) and Nα-lauryl-O-(2-acetamido-2-deoxy-α-d-galactopyranosyl)-l-threonineamide (GalNAc-Thr-C12) were synthesized as saccharide primers to prime mucin-type O-glycan biosynthesis in cells. Upon incubating human gastric cancer MKN45 cells with the saccharide primers, 22 glycosylated products were obtained, and their structures were analyzed using liquid chromatography-mass spectrometry and enzyme digestion. The amounts of glycosylated products were dependent on the amino acid residues in the saccharide primers. For example, in vitro synthesis of T antigen (Galß1-3GalNAc), fucosyl-T (Fucα1-2Galß1-3GalNAc), and sialyl-T (NeuAcα2-3Galß1-3GalNAc) preferred a serine residue, whereas sialyl-Tn (NeuAcα2-6GalNAc) preferred a threonine residue. Furthermore, the glycosylated products derived from GalNAc-Ser/Thr-C12 and Gal-GalNAc-Ser/Thr-C12 using cell-free synthesis showed the same amino acid selectivity as those in the cell experiments. These results indicate that glycosyltransferases involved in the biosynthesis of mucin-type O-glycans distinguish amino acid residues conjugated to GalNAc. The saccharide primers developed in this study might be useful for comparing mucin-type oligosaccharides in cells and constructing oligosaccharide libraries to study cell function.

BRCAness as a prognostic indicator in patients with early breast cancer.

BRCAness is defined as a phenotypic copy of germline BRCA mutations, which describes presence of homologous recombination defects in sporadic cancers. We detected BRCAness by multiplex ligation-dependent probe amplification (MLPA) and explored whether BRCAness can be used as a predictor of prognosis. BRCAness status was classified for total 121 breast cancer patients. Forty-eight patients (39.7%) were identified as BRCAness positive. Tumors of BRCAness were more likely to be hormone receptors negative (95.8% vs. 50.7%, P < 0.001), nuclear grade III (76.1% vs. 48.4%, P = 0.001) and triple-negative breast cancer subtype (91.6% vs. 42.5%, P < 0.001). Five-year disease free survival (DFS) (54.0% vs. 88.0%, P < 0.001) and overall survival (OS) (76.3% vs. 93.1%, P = 0.002) were significantly lower in BRCAness patients. In neoadjuvant chemotherapy subgroup analysis, clinical response rate for taxane-based regimen was significantly lower in BRCAness patients (58.3% vs. 77.8%, P = 0.041). Cox regression multivariate analysis showed that BRCAness was the independent prognostic factor for DFS (HR 2.962, 95%CI 1.184-7.412, P = 0.020), but not for OS (HR 2.681, 95%CI 0.618-11.630, P = 0.188). BRCAness is associated with specific characteristics and may suggest resistance to taxane-based chemotherapy. BRCAness can be used as a negative prognostic indicator for breast cancer.

Innovative use of magnetic resonance imaging-guided focused ultrasound surgery for non-invasive breast cancer: a report of two cases.

OBJECTIVE: This report describes the first clinical experience with magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) using the ExAblate 2100 system for non-invasive breast cancer. METHODS: Two women with non-invasive breast cancer underwent MRgFUS treatment. One week after the MRgFUS treatment, US-guided vacuum-assisted biopsy was performed for the ablated lesions at the same time as breast-conserving surgery. RESULTS: The patients experienced good cosmetic outcomes and did not experience any severe adverse events, such as skin burns. Pathological examination of the surgical specimens revealed a few degenerated intraductal lesions around the breast biopsy markers. CONCLUSION: Performing MRgFUS with the new ExAblate 2100 system appears to be safe and feasible. The histopathological results revealed that adequate ultrasound energy in the appropriate location can induce tumor necrosis.

Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome.

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

The clinical impact of MRI screening for BRCA mutation carriers: the first report in Japan.

BACKGROUND: There is no consensus on the appropriate surveillance for high-risk women with breast cancer in Japan. We investigated their imaging features and pathological characteristics to build a proper surveillance system for asymptomatic high-risk individuals in the future. METHODS: We retrospectively reviewed 93 female (median age 43 years) BRCA1 and BRCA2 mutation carriers from our institutional clinical database from 2011 to 2017. The study population was composed of 112 breast cancers. Mammography and MRI were reviewed by examiners blinded to patients' clinical history. Final surgical or biopsy histopathology served as the reference standard in all the patients. RESULTS: Fifty-nine breast cancers met selection criteria; of these, 30 were BRCA1-associated tumors, and 29 were BRCA2-associated tumors. Invasive ductal carcinoma was the most prevalent type in both BRCA1 and BRCA2. There were statistically significant differences in phenotype, nuclear grade, and Ki-67 labeling index between BRCA1 and BRCA2 mutation carriers. Additionally, imaging findings on mammography and MRI were statistically different. Tumors in BRCA2 carriers demonstrated mammographic calcifications more frequently, while those in BRCA1 carriers demonstrated a mass or architectural distortion (P < 0.001). Enhancement pattern on MRI also significantly differed between the two subgroups (P = 0.006). The size of MRI-detected lesions was statistically smaller than the size of those detected by other modalities (P = 0.004). CONCLUSIONS: The imaging and histological characteristics of BRCA1/2 mutation carriers were consistent with other countries' studies. MRI-detected lesions were significantly smaller than lesions detected by non-MRI modality. All lesions in BRCA1 mutation carriers could be detected by MRI.

BRCA1/BRCA2 mutations in Japanese women with ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is considered a component of the clinical spectrum of breast cancer even in those with BRCA1/2 mutation. The aim of this study was to report the feature of DCIS raised in Japanese women with BRCA1/2 mutations. METHODS: A total of 325 Japanese women with breast cancer (BC) (with or without invasive cancer) were referred for genetic counseling and underwent genetic testing for mutations in the BRCA1 and BRCA2 genes in Showa University Hospital between December 2011 and August 2016. And 49 of them who were pathologically diagnosed as DCIS were included in this study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status. A Cox proportional hazards model is used to predictive value of parameters for Ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR). RESULTS: (a) Of 325 patients (with or without invasive cancer), 19.1% (62/325) tested positive for BRCA1/BRCA2 mutations. And 18.4% (9/49) was positive for BRCA1/BRCA2 mutations in DCIS, compared with 19.2% (53/276) in IDC (p = 1.000). Among BRCA mutations, 14.5% (9/62) had DCIS compared with nonmutations (15.2%, 40/263). Incidence of DCIS was 3.0% (1/33) of BRCA1 mutations and 27.5% (8/29) of BRCA2 mutation (p = 0.009). (b) Median age of diagnosis in BRCA mutation carriers was 39 years, compared with 46 years in noncarriers. Age, Family history (FH) of BC, FH of first or second BC and total number of relatives with BC diagnosis (DX) has significant difference between BRCA mutation carriers and noncarriers in univariate analysis. In a multivariate logistic model, total relatives with BC DX ≥ 2 (odds ratio [OR], 5.128; 95% confidence interval [CI], 1.266-20.763; p = 0.022), age at diagnosis ≤35 years (OR 0.149, 95% CI 0.023-0.954, p = 0.045) and ER+/HER2+ status (OR 5.034, 95% CI 1.092-23.210, p = 0.038) remained as independent significant predictors for BRCA mutation. Ki67 index (cut off by 14% or 30%) did not differ between BRCA mutation carriers and noncarriers (p = 0.459 and p = 0.651). (c) There was a significant difference in ER-positive tumors among BRCA2 carriers and noncarriers (p = 0.042). Subgroup analysis showed BRCA2 carriers tend to be of higher grade (Grade 2 and 3), more frequently ER+/PR+ (p = 0.041) and lower proliferation (Ki67 index) than noncarriers, whereas differences in nuclear grade and ki67 index were not found significantly in our study. (d) BRCA mutation was not associated with an increased risk of IBTR and CBTR. CONCLUSION: DCIS is equally as prevalent in patients who were BRCA mutation carriers as in high familial-risk women who were noncarriers, but occurs at earlier age. BRCA2 carriers have higher incidence in DCIS than that of BRCA1 carriers, and tend to be higher grade and more frequently ER positive and lower proliferation. Total relatives with BC DX ≥2, age at diagnosis ≤35 years and ER+/HER2+ might be independent predictors for BRCA mutation in Japanese women with DCIS and patients of these risk factors should be recommended to receive genetic counseling and BRCA testing.

Cystic apocrine ductal carcinoma in situ with increased EGFR expression, trisomy 7, and associated focal invasion.

A 71-year-old woman was admitted to our hospital with a lump in her right breast. Mammography revealed an internal high-density mass in the lower right breast, which was larger than it was 2 years ago. Considering the findings from ultrasonography, computed tomography, and cytology, an intracystic carcinoma could not be ruled out. The patient underwent excisional biopsy, which revealed an apocrine ductal carcinoma in situ (ADCIS) with focal invasive apocrine carcinoma (IAC). The diagnosis was based on morphology and immunohistochemistry (IHC), which was negative for the estrogen and progesterone receptors, and positive for the androgen receptor. Expression of the human epidermal growth factor receptor 2 and the epidermal growth factor receptor (EGFR) received an immunohistochemical score of 2+. Trisomy of chromosome 7, including multiple CEP 7 and EGFR signals, was observed in ADCIS by fluorescence in situ hybridization (FISH). IAC exhibited similar results for IHC and FISH. This is the first reported case showing trisomy 7 resulting in EGFR copy number gain and increased EGFR expression in ADCIS.

A case of Miller Fisher syndrome during preoperative chemotherapy for breast cancer.

A 53-year-old woman with breast cancer received FEC treatment (5FU: 500 mg/m(2), epirubicin: 100 mg/m(2), and cyclophosphamide: 500 mg/m(2)) every 3 weeks as preoperative chemotherapy. Fifteen days after her third cycle of FEC, she developed a cold. Diplopia occurred 4 days after developing the cold, and progressive paresthesia of the hands and weakness of the limbs occurred. She had ophthalmoplegia, ataxia, and are flexia and was diagnosed with Miller Fisher Syndrome (MFS). The cause of MFS during chemotherapy is believed to be caused by an immunological response to infection, or drug neurotoxicity. In our case, since the patient underwent an antecedent upper respiratory infection in the period of myelosuppression, her MFS was probably induced by the immunoreaction associated with this infection. Our patient underwent intravenous immunoglobulin therapy. After initiation of the treatment, her neurological symptoms improved, then, she received a fourth cycle of FEC and her remaining neurological symptoms did not worsen. Thus, we report a rare case of MFS developed in immunosuppression by chemotherapy and remind physicians of the alarming triad of MFS symptoms.

Decreased level of phosphatidylcholine (16:0/20:4) in multiple myeloma cells compared to plasma cells: a single-cell MALDI-IMS approach.

Lipid metabolic changes under diseased conditions, particularly in solid tumors, are attracting increased attention. However, in non-solid tumors, including most hematopoietic tumors, lipid analyses are scarce. Multiple myeloma (MM) is a plasma cell disorder arising from bone marrow, and the lipid status of MM cells has not been reported yet. In this study, we analyzed flow cytometry-sorted single MM cells and normal plasma cells (NPCs) using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), a two-dimensional label-free mass spectrometry technique for biomolecular analysis, to obtain specific lipid information. We isolated 1.31-5.77% of MM cells and 0.03-0.24% of NPCs using fluorescence-activated cell sorting (FACS). Analysis of purified cells using MALDI-IMS at the single-cell level revealed that the peak intensity and ion signals of phosphatidylcholine [PC (16:0/20:4) + H](+) at m/z 782.5 were significantly decreased in MM cells compared to NPCs. By examining particular cell populations rather than cell mixtures, our method can become a suitable tool for the analysis of rare cell populations at the single-cell level and advance the understanding of MM progression.

Palmitic acid, verified by lipid profiling using secondary ion mass spectrometry, demonstrates anti-multiple myeloma activity.

Recent studies indicate that lipid metabolic changes affect the survival of multiple myeloma (MM) cells. Time-of-flight secondary ion mass spectrometry (TOF-SIMS), an imaging mass spectrometry technique, is used to visualize the subcellular distribution of biomolecules including lipids. We therefore applied this method to human clinical specimens to analyze the membrane fatty acid composition and determine candidate molecules for MM therapies. We isolated MM cells and normal plasma cells (PCs) from bone marrow aspirates of MM patients and healthy volunteers, respectively, and these separated cells were analyzed by TOF-SIMS. Multiple ions including fatty acids were detected and their ion counts were estimated. In MM cells, the mean intensity of palmitic acid was significantly lower than the mean intensity in PCs. In a cell death assay, palmitic acid reduced U266 cell viability dose-dependently at doses between 50 and 1000 µM. The percentage of apoptotic cells increased from 24h after palmitic acid administration. In contrast, palmitic acid had no effect on the viability of normal peripheral blood mononuclear cells (PBMCs). The results of this study indicated that palmitic acid is a potential candidate for novel therapeutic agents that specifically attack MM cells.

Single-cell time-of-flight secondary ion mass spectrometry reveals that human breast cancer stem cells have significantly lower content of palmitoleic acid compared to their counterpart non-stem cancer cells.

Lipids comprise the primary component of cell membranes. Imaging mass spectrometry is increasingly being used to visualize membranous lipids in clinical specimens, and it has revealed that abnormal lipid metabolism is related to the development of diseases. To characterize cell populations which are rare and sparsely localized in tissues, we conducted time-of-flight secondary ion mass spectrometry (TOF-SIMS) analyses of individual cells sorted by fluorescence activated cell sorting (FACS) and applied the method to analyze breast cancer stem cells (CSCs). TOF-SIMS analyses visualized phosphoric acids and four fatty acid (FA) species in the sorted CD45(-)/CD44(+)/CD24(-) CSCs, and these ions are suspected to have originated from membranous phospholipids as they were uniformly detected from the locus where the cells attached. Integrated ion intensity of palmitoleic acids [FA(16:1)] normalized by phosphoric acid signals were decreased significantly in CSCs as compared to that of CD45(-)/CD44(-)/CD24(+) non-stem cancer cells (NSCCs). This finding was supported by liquid chromatography coupled electrospray ionization-tandem mass spectrometry analysis, which revealed phosphatidylcholine (PC)(16:0/16:1) to be less abundant and PC(16:0/16:0) to be more abundant in CSCs as compared to NSCCs. Therefore, our novel method successfully provided lipid composition analysis of individual cells classified by the expression of a complex combination of cell-surface markers. The lipid compositions of CSCs originating from the heterogeneous cellular populations of clinical specimens were successfully characterized by this method.

Accumulated phosphatidylcholine (16:0/16:1) in human colorectal cancer; possible involvement of LPCAT4.

The identification of cancer biomarkers is critical for target-linked cancer therapy. The overall level of phosphatidylcholine (PC) is elevated in colorectal cancer (CRC). To investigate which species of PC is overexpressed in colorectal cancer, an imaging mass spectrometry was performed using a panel of non-neoplastic mucosal and CRC tissues. In the present study, we identified a novel biomarker, PC(16:0/16:1), in CRC using imaging mass spectrometry. Specifically, elevated levels of PC(16:0/16:1) expression were observed in the more advanced stage of CRC. Our data further showed that PC(16:0/16:1) was specifically localized in the cancer region when examined using imaging mass spectrometry. Notably, because the ratio of PC(16:0/16:1) to lyso-PC(16:0) was higher in CRC, we postulated that lyso-PC acyltransferase (LPCAT) activity is elevated in CRC. In an in vitro analysis, we showed that LPCAT4 is involved in the deregulation of PC(16:0/16:1) in CRC. In an immunohistochemical analysis, LPCAT4 was shown to be overexpressed in CRC. These data indicate the potential usefulness of PC(16:0/16:1) for the clinical diagnosis of CRC and implicate LPCAT4 in the elevated expression of PC(16:0/16:1) in CRC.

Human breast cancer tissues contain abundant phosphatidylcholine(36∶1) with high stearoyl-CoA desaturase-1 expression.

Breast cancer is the leading cause of cancer and mortality in women worldwide. Recent studies have argued that there is a close relationship between lipid synthesis and cancer progression because some enzymes related to lipid synthesis are overexpressed in breast cancer tissues. However, lipid distribution in breast cancer tissues has not been investigated. We aimed to visualize phosphatidylcholines (PCs) and lysoPCs (LPCs) in human breast cancer tissues by performing matrix assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), which is a novel technique that enables the visualization of molecules comprehensively. Twenty-nine breast tissue samples were obtained during surgery and subjected to MALDI-IMS analysis. We evaluated the heterogeneity of the distribution of PCs and LPCs on the tissues. Three species [PC(32∶1), PC(34∶1), and PC(36∶1)] of PCs with 1 mono-unsaturated fatty acid chain and 1 saturated fatty acid chain (MUFA-PCs) and one [PC(34∶0)] of PCs with 2 saturated fatty acid chains (SFA-PC) were relatively localized in cancerous areas rather than the rest of the sections (named reference area). In addition, the LPCs did not show any biased distribution. The relative amounts of PC(36∶1) compared to PC(36∶0) and that of PC(36∶1) to LPC(18∶0) were significantly higher in the cancerous areas. The protein expression of stearoyl-CoA desaturase-1 (SCD1), which is a synthetic enzyme of MUFA, showed accumulation in the cancerous areas as observed by the results of immunohistochemical staining. The ratios were further analyzed considering the differences in expressions of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and Ki67. The ratios of the signal intensity of PC(34:1) to that of PC(34:0) was higher in the lesions with positive ER expression [corrected]. The contribution of SCD1 and other enzymes to the formation of the observed phospholipid composition is discussed.

Hepatitis B virus reactivation in adjuvant chemotherapy for breast cancer.

Immunosuppressive therapy, such as chemotherapy or the use of corticosteroids, may stimulate reactivation of hepatitis B virus (HBV). Most of these episodes occur in patients whose hepatitis B surface antigens are positive (HBsAg+). We report a case of HBV reactivation in a patient with negative HBsAg during chemotherapy for breast cancer, in spite of avoiding corticosteroids. A 68-year-old woman received adjuvant chemotherapy for breast cancer. Her serological examinations showed that HBsAg, HBeAg, and HBV-DNA were all negative. Her chemotherapy consisted of CAF (cyclophosphamide 500 mg/m(2), doxorubicin 50 mg/m(2), fluorouracil 500 mg/m(2)) without administration of corticosteroids. She received six cycles of CAF. At day 27 after her sixth CAF, she was admitted to the hospital with acute hepatitis B virus (HBV) reactivation. She received glycyrrhizinic acid by intravenous injection (80 mg/day), ursodeoxycholic acid (300 mg/day), and entecavir (0.5 mg/day). Then she received interferon by intravenous injection (3 million units/day), prednisolon by intravenous injection (45 mg/day), and plasma exchange therapy. However, she died of liver failure. This is a rare case in which HBV reactivation occurred in an HBsAg negative patient during chemotherapy without using corticosteroids. This episode suggests that HBV reactivation may occur during chemotherapy in any patient with a history of HBV infection. Therefore, we recommend checking HBsAg, HBsAb, and HBcAb before starting chemotherapy. Moreover, with positive HBsAb or/and HBcAb patients, HBV-DNA should be checked before starting chemotherapy and monitored during chemotherapy by a sensitive PCR method.

Clinicopathological significance of invasive micropapillary carcinoma component in invasive breast carcinoma.

Invasive micropapillary carcinoma (IMP) of the breast is a rare variant of invasive breast carcinoma and most cases of IMP are associated with nodal metastasis and lymphatic invasion. Lesions composed of an IMP component alone are rare and almost always coexist with other pathological components. However, few reports have documented IMP along with its proportion and the coexistent pathological type. We analyzed the total 486 breast cancer lesions operated in our hospital in 1998. We classified the lesions into five groups by the proportion of the IMP component in each lesion. Then we evaluated the incidence of nodal metastasis and lymphatic invasion in each group. The incidence of the invasive carcinoma containing any IMP components was 8.4%. The incidence of nodal metastasis and lymphatic invasion in lesions with an IMP component were significantly higher than that in those with no IMP. No correlation was seen between the incidence of nodal metastasis and the coexistent pathological type, shape of tumor clusters, nuclear grade and the expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 and gross cystic disease fluid protein-15 in IMP components. The presence of IMP components was a significant predictive factor for nodal metastasis, even if it is detected in only a small proportion of the tumor.

High-grade breast cancers include both highly sensitive and highly resistant subsets to cytotoxic chemotherapy.

PURPOSE: We reported that breast cancers achieving pathological complete response (pCR) or progressive disease (PD) to neoadjuvant chemotherapy (NAC), which are considered exact opposites on the chemosensitivity spectrum, have certain clinicopathological features in common. To determine the highly sensitive and highly resistant subsets to cytotoxic chemotherapy, we evaluated predictive factors for pCR and PD to NAC, and assessed the similarities in these factors. METHODS: Subjects comprised 300 women with 304 stage II or III breast cancers treated with chemotherapy that was anthracycline-based, taxane, or both, followed by surgery between 2007 and 2008. We retrospectively evaluated pre-NAC clinicopathological features including chemotherapy regimen, clinical T stage, nuclear grade (NG), hormone receptor (HR) status, and human epidermal growth factor receptor-2 (HER2) status in pCR and PD, using univariate chi(2) testing and multivariate logistic regression analyses. RESULTS: Of 304 tumors, 30 (10%) achieved pCR and 22 (7%) showed PD to NAC. Multivariate analysis demonstrated that anthracycline plus taxane chemotherapy (P = 0.006), NG3 (P = 0.006), HR-negativity (P = 0.013), and HER2-positivity (P = 0.010) were significant predictors of pCR, and T3-4 (P = 0.002) and NG3 (P = 0.010) were significant predictors of PD. CONCLUSIONS: High-grade breast cancers include both highly sensitive and highly resistant subsets to cytotoxic chemotherapy. Three factors can help discriminate between these subsets. HR-negative and HER2-positive can be predictive of high chemosensitivity. Advanced primary tumor stage can be predictive of high chemoresistance.