Identification of CD5/SOX11 double-negative pleomorphic mantle cell lymphoma.

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(-) cyclin D1(+) SOX11(-), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement.

Integration of the cancer cell secretome and transcriptome reveals potential noninvasive diagnostic markers for bladder cancer.

PURPOSE: Bladder cancer (BLCA) is a major cancer of the genitourinary system. Although cystoscopy is the standard protocol for diagnosing BLCA clinically, this procedure is invasive and expensive. Several urine-based markers for BLCA have been identified and investigated, but none has shown sufficient sensitivity and specificity. These observations underscore the importance of discovering novel BLCA biomarkers and developing a noninvasive method for detection of BLCA. Exploring the cancer secretome is a good starting point for the development of noninvasive biomarkers for cancer diagnosis. EXPERIMENTAL DESIGN: In this study, we established a comprehensive secretome dataset of five representative BLCA cell lines, BFTC905, TSGH8301, 5637, MGH-U1, and MGH-U4, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Expression of BLCA-specific secreted proteins at the transcription level was evaluated using the Oncomine cancer microarray database. RESULTS: The expressions of four candidates-COMT, EWSR1, FUSIP1, and TNPO2-were further validated in clinical human specimens. Immunohistochemical analyses confirmed that transportin-2 was highly expressed in tumor cells relative to adjacent noncancerous cells in clinical tissue specimens from BLCA patients, and was significantly elevated in BLCA urine compared with that in urine samples from aged-matched hernia patients (controls). CONCLUSIONS: Collectively, our findings suggest TNPO2 as a potential noninvasive tumor-stage or grade discriminator for BLCA management.

Factors Associated with Axillary Lymph Node Status in Clinically Node-Negative Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy.

Adequate axillary lymph node (ALN) staging is critical for patients with invasive breast cancer. However, neoadjuvant chemotherapy (NAC) was associated with a lower risk of ALN metastasis compared with those who underwent primary surgery among clinically node-negative (cN0) patients. This study aimed to investigate the factors associated with ALN status among patients with cN0 breast cancer undergoing NAC. A total of 222 consecutive patients with cN0 breast cancer undergoing NAC between January 2012 and December 2021 were reviewed. Univariate and multivariate analyses were performed to compare factors associated with positive ALN status. Seventeen patients (7.7%) had ALNs metastases. Here, 90 patients (40.5%) achieved pathologic complete response in the breast (breast-pCR), and all had negative ALN status. Lymphovascular invasion (odds ratio: 29.366, p < 0.0001) was an independent risk predictor of ALN metastasis in all study populations. Among patients without breast-pCR, mastectomies were performed more frequently in patients with ALN metastasis (52.9%) than in those without metastasis (20.9%) (p = 0.013). Our findings support the omission of axillary surgery in patients who achieve breast-pCR. Prospective studies are needed to confirm the feasibility of a future two-stage surgical plan for breast-conserving surgery in patients who are likely to achieve breast-pCR during clinical evaluation.

Deep Learning-Based Nuclear Morphometry Reveals an Independent Prognostic Factor in Mantle Cell Lymphoma.

Blastoid/pleomorphic morphology is associated with short survival in mantle cell lymphoma (MCL), but its prognostic value is overridden by Ki-67 in multivariate analysis. Herein, a nuclear segmentation model was developed using deep learning, and nuclei of tumor cells in 103 MCL cases were automatically delineated. Eight nuclear morphometric attributes were extracted from each nucleus. The mean, variance, skewness, and kurtosis of each attribute were calculated for each case, resulting in 32 morphometric parameters. Compared with those in classic MCL, 17 morphometric parameters were significantly different in blastoid/pleomorphic MCL. Using univariate analysis, 16 morphometric parameters (including 14 significantly different between classic and blastoid/pleomorphic MCL) emerged as significant prognostic factors. Using multivariate analysis, Biologic MCL International Prognostic Index (bMIPI) risk group (P = 0.025), low skewness of nuclear irregularity (P = 0.020), and high mean of nuclear irregularity (P = 0.047) emerged as independent adverse prognostic factors. Additionally, a morphometric score calculated from the skewness and mean of nuclear irregularity (P = 0.0038) was an independent prognostic factor in addition to bMIPI risk group (P = 0.025), and a summed morphometric bMIPI score was useful for risk stratification of patients with MCL (P = 0.000001). These results demonstrate, for the first time, that a nuclear morphometric score is an independent prognostic factor in MCL. It is more robust than blastoid/pleomorphic morphology and can be objectively measured.

The clinical relevance of humoral immune responses to Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 and expression of Globo H in metastatic breast cancer.

An international randomized phase II trial of Globo H (GH) vaccine, adagloxad simolenin/OBI-821 in 349 patients with metastatic breast cancer showed longer progression-free survival (PFS) in vaccinated patients who developed anti-Globo H (anti-GH) IgG than those who did not and the placebo group. The impacts of anti-GH IgM and GH expression on peak anti-GH IgG and clinical outcome were further evaluated. The titers of anti-GH IgG and IgM were determined by ELISA. GH expression in tumor was examined by immunohistochemical staining. Immunophenotyping was conducted by flow cytometry. Adagloxad simolenin elicited anti-GH IgM which peaked at titers ≥1:80 between weeks 5 and 13. The mean anti-GH IgG titer peaked at week 41 and decreased thereafter on the completion of vaccination. One log increase in peak IgM was associated with 10.6% decrease in the HR of disease progression (HR: 0.894, 95% CI: 0.833 to 0.960, p=0.0019). Patients with anti-GH IgM ≥1:320 within first 4 weeks after vaccination had significantly higher maximum anti-GH IgM (p<0.0001) and IgG titers (p<0.0001) than those with <1:320. Moreover, the median PFS appears to be longer for patients with anti-GH IgM ≥1:320 within first 4 weeks than those with anti-GH IgM titer <1:320 (11.1 vs 7.3 months, p=0.164), but not statistically significant. Among patients with H score ≥80 for GH expression by immunohistochemistry, the vaccination group (n=42) seemed to have better PFS than the placebo group (n=23) (HR=0.59; 95% CI: 0.32 to 1.10, p=0.10), but the difference did not reach statistical significance. In addition, peak levels of anti-GH IgM were higher in patients who had lower percentage of activated regulatory T cells (Treg cells; CD4+CD45RA-Foxp3high) at baseline than those who had higher activated Treg cells (p=0.042). This study demonstrates that adagloxad simolenin induced both IgG and IgM antibodies against GH. Anti-GH IgM ≥1:320 within first 4 weeks or low activated Treg cells at baseline may help to select patients who are likely to produce a higher level of GH-specific IgM and IgG in the future.

MicroRNAs as Predictors of Future Uterine Malignancy in Endometrial Hyperplasia without Atypia.

The histological criteria for classifying endometrial hyperplasia (EH) are based on architectural crowding and nuclear atypia; however, diagnostic agreement among pathologists is poor. We investigated molecular biomarkers of endometrial cancer (EC) risk in women with simple hyperplasia or complex hyperplasia without atypia (SH/CH-nonA). Forty-nine patients with EC preceded by SH/CH-nonA were identified, of which 23 were excluded (15 with complex atypical hyperplasia (CAH), six not consenting, one with a diagnosis <6 months prior, and one lost to follow-up). The EH tissues of these patients were compared with those of patients with SH/CH-nonA that did not progress to EC (control) through microRNA (miRNA) array analysis, and the results were verified in an expanded cohort through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). MiRNA arrays analyses revealed 20 miRNAs that differed significantly (p < 0.05, fold change >4) between the control (n = 12) and case (n = 6) patients. Multiplex RT-qPCR for the 20 miRNAs in the expanded cohort (94 control and 25 case patients) led to the validation of miR-30a-3p (p = 0.0009), miR-141 (p < 0.0001), miR-200a (p < 0.0001), and miR-200b (p < 0.0001) as relevant biomarkers, among which miR-141, miR-200a, and miR-200b regulate the expression of phosphatase and tensin homolog (PTEN). For the prediction of EC, the area under the curve for miR-30a-3p, miR-141, miR-200a, and miR-200b was 0.623, 0.754, 0.783, and 0.704, respectively. The percentage of complete PTEN loss was significantly higher in the case group than in the control group (24% vs. 0%, p < 0.001, Fisher's exact test). A combination of complete PTEN loss and miR-200a provided optimal prediction performance (sensitivity = 0.760; specificity = 1.000; positive predictive value = 1.000; negative predictive value = 0.937; accuracy = 0.947). MiR-30a-3p, miR-141, miR-200a, miR-200b, and complete PTEN loss may be useful tissue biomarkers for predicting EC risk among patients with SH/CH-nonA.

Prenatal Diagnosis of Placental Mesenchymal Dysplasia with 46, X, Isochromosome Xq/45, X Mosaicism.

Placental mesenchymal dysplasia is an uncommon vascular anomaly of the placenta with characteristics of placentomegaly and multicystic appearance and with or without association with fetal chromosomal anomaly. We present a unique placental mesenchymal dysplasia patient with amniotic fluid karyotyping as 46, X, iso(X) (q10). Detailed molecular testing of the amniotic fluid, fetal cord blood, non-dysplastic placenta and dysplastic placenta was conducted after termination of pregnancy, from which we proved biparental/androgenetic (46, X, i(X) (q10)/45, X) mosaicism in different gestational tissues. A high portion of androgenetic cells in dysplastic placenta (74.2%) and near 100% of biparental cells in the fetus's blood and amniotic fluid were revealed. Delicate mosaic analyses were performed, and possible pathogenesis and embryogenesis of this case were drawn up.

Nodular mass-A case of auricular schwannoma.

Schwannomas are benign tumors derived from the sheath of Schwann cells. Though it is common to see schwannomas in the head and neck region, auricular schwannomas are rare and only few cases have been reported. There are no distinguishing clinical findings or images; therefore, the histopathological diagnosis is mandatory. We describe a case of auricular schwannoma with clinical pictures and discuss the differential diagnoses according to histopathologic findings.

Contrast-Enhanced Mammographic Features of In Situ and Invasive Ductal Carcinoma Manifesting Microcalcifications Only: Help to Predict Underestimation?

BACKGROUND: The contrast-enhanced mammographic features of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) manifesting microcalcifications only on mammograms were evaluated to determine whether they could predict IDC underestimation. METHODS: We reviewed patients who underwent mammography-guided biopsy on suspicious breast microcalcifications only and received contrast-enhanced spectral mammography (CESM) within 2 weeks before the biopsy. Those patients who were proven to have cancers (DCIS or IDC) by biopsy and subsequently had surgical treatment in our hospital were included for analysis. The presence or absence, size, morphology and texture of enhancement on contrast-enhanced spectral mammography were reviewed by consensus of two radiologists. RESULTS: A total of 49 patients were included for analysis. Forty patients (81.6%) showed enhancement, including 18 (45%) DCIS and 22 (55%) IDC patients. All nine unenhanced cancers were pure DCIS. Pure DCIS showed 72.22% nonmass enhancement and 83.33% pure ground glass enhancement. IDC showed more mass (72.2% vs. 27.8%) and solid enhancements (83.33% vs. 16.67%). The cancer and texture of enhancement were significantly different between pure DCIS and IDC, with moderate diagnostic performance for the former (p-value < 0.01, AUC = 0.66, sensitivity = 93%, specificity = 39%) and the latter (p-value < 0.01, AUC = 0.74, sensitivity = 65%, specificity = 83%). Otherwise, pure DCIS showed a significant difference in enhanced texture compared with upgraded IDC and IDC (p = 0.0226 and 0.0018, respectively). CONCLUSIONS: Nonmass and pure ground glass enhancements were closely related to pure DCIS, and cases showing mass and unpurified solid enhancements should be suspected as IDC. Unenhanced DCIS with microcalcifications only has a low DCIS upgrade rate. The CESM-enhanced features could feasibly predict IDC underestimation.

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models.

Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.

Discrepancy of Breast and Axillary Pathologic Complete Response and Outcomes in Different Subtypes of Node-positive Breast Cancer after Neoadjuvant Chemotherapy.

Few studies have analyzed the discrepancy between breast pathologic complete response (B-pCR) and axillary node pCR (N-pCR) rates and their impact on survival outcomes in different intrinsic subtypes of early breast cancer after neoadjuvant chemotherapy (NAC). We retrospectively reviewed B-pCR, N-pCR, and total (breast and axillary node) pCR (T-pCR) after NAC to assess the discrepancy and outcomes between 2005 and 2017. A total of 968 patients diagnosed with cT1-4c, N1-2, and M0 breast cancer were enrolled in the study. The median age was 49 years and the median follow-up time was 45 months. Of these patients, 213 achieved T-pCR, 31 achieved B-pCR with axillary node pathologic non-complete response (N-non pCR), 245 achieved N-pCR with breast pathologic non-complete response (B-non pCR), and 479 achieved total (breast and axillary node) pathologic non-complete response (T-non pCR) after NAC. The highest B-pCR and N-pCR rates were found in the hormone receptor-negative, human epidermal growth factor receptor 2-positive HR(-)HER2(+) subtype, while the lowest B-pCR rate was found in the HR(+)HER2(-) subtype. The N-pCR rate was correlated to the B-pCR rate (P<0.001), but was higher than the B-pCR rate in all subtypes. The 5-year overall survival (OS) rates for patients with T-pCR, B-pCR, and N-pCR were 91.2%, 91.7%, and 91.9%, respectively. For non-pCR, non-pCR, and non-pCR, the 5-year OS rates were 73.6%, 78.9%, and 74.7%, respectively (P<0.0001). B-non pCR patients had a lower risk of recurrence than T-non pCR or N-non-pCR patients, although there were no differences in OS among them. In conclusion, the N-pCR rate was higher than the B-pCR rate after NAC in all intrinsic subtypes, and N-non pCR or T-non pCR patients had the worst outcomes.

Prediction of Myometrial Invasion in Stage I Endometrial Cancer by MRI: The Influence of Surgical Diagnostic Procedure.

Young women with endometrial cancer (EC) can choose fertility-sparing treatment for stage 1A disease without myometrial invasion (MI). The surgical diagnostic procedure (SDP) may affect the accuracy of magnetic resonance imaging (MRI) to assess MI. Here, we evaluated different SDP and compared the MI on MRI results with further pathologic results after hysterectomy. We retrospectively collected data on 263 patients with clinical stage IA EC diagnosed between January 2013 and December 2015. Patients were classified into four groups based on SDP, including diagnostic hysteroscopic biopsy (DHB, group 1), operative hysteroscopic partial resection (OHPR, group 2), operative hysteroscopic complete resection (OHCR, group 3), and cervical dilatation and fractional curettage (D&C, group 4). The sensitivity, specificity, diagnostic accuracy, positive predictive value, and negative predictive value of MRI to assess MI were 73.1%, 46.7%, 63.9%, 71.8%, and 48.3%, respectively. Three hysteroscopic procedures (groups 1 to 3) had a trend with a higher odds ratio of discrepancy between MRI and histopathology (p = 0.068), especially in group 2 (odds ratio 2.268, p = 0.032). Here, we found MRI accuracy of MI was better in patients with EC diagnosed with D&C. Three diagnostic procedures using hysteroscopy might interfere with the diagnostic power of MI on MRI.

Development of a Multi-Institutional Prediction Model for Three-Year Survival Status in Patients with Uterine Leiomyosarcoma (AGOG11-022/QCGC1302 Study).

BACKGROUND: The existing staging systems of uterine leiomyosarcoma (uLMS) cannot classify the patients into four non-overlapping prognostic groups. This study aimed to develop a prediction model to predict the three-year survival status of uLMS. METHODS: In total, 201 patients with uLMS who had been treated between June 1993 and January 2014, were analyzed. Potential prognostic indicators were identified by univariate models followed by multivariate analyses. Prediction models were constructed by binomial regression with 3-year survival status as a binary outcome, and the final model was validated by internal cross-validation. RESULTS: Nine potential parameters, including age, log tumor diameter, log mitotic count, cervical involvement, parametrial involvement, lymph node metastasis, distant metastasis, tumor circumscription and lymphovascular space invasion were identified. 110 patients had complete data to build the prediction models. Age, log tumor diameter, log mitotic count, distant metastasis, and circumscription were significantly correlated with the 3-year survival status. The final model with the lowest Akaike's Information Criterion (117.56) was chosen and the cross validation estimated prediction accuracy was 0.745. CONCLUSION: We developed a prediction model for uLMS based on five readily available clinicopathologic parameters. This might provide a personalized prediction of the 3-year survival status and guide the use of adjuvant therapy, a cancer surveillance program, and future studies.

Identification of nodal micrometastasis in colorectal cancer using deep learning on annotation-free whole-slide images.

Detection of nodal micrometastasis (tumor size: 0.2-2.0 mm) is challenging for pathologists due to the small size of metastatic foci. Since lymph nodes with micrometastasis are counted as positive nodes, detecting micrometastasis is crucial for accurate pathologic staging of colorectal cancer. Previously, deep learning algorithms developed with manually annotated images performed well in identifying micrometastasis of breast cancer in sentinel lymph nodes. However, the process of manual annotation is labor intensive and time consuming. Multiple instance learning was later used to identify metastatic breast cancer without manual annotation, but its performance appears worse in detecting micrometastasis. Here, we developed a deep learning model using whole-slide images of regional lymph nodes of colorectal cancer with only a slide-level label (either a positive or negative slide). The training, validation, and testing sets included 1963, 219, and 1000 slides, respectively. A supercomputer TAIWANIA 2 was used to train a deep learning model to identify metastasis. At slide level, our algorithm performed well in identifying both macrometastasis (tumor size > 2.0 mm) and micrometastasis with an area under the receiver operating characteristics curve (AUC) of 0.9993 and 0.9956, respectively. Since most of our slides had more than one lymph node, we then tested the performance of our algorithm on 538 single-lymph node images randomly cropped from the testing set. At single-lymph node level, our algorithm maintained good performance in identifying macrometastasis and micrometastasis with an AUC of 0.9944 and 0.9476, respectively. Visualization using class activation mapping confirmed that our model identified nodal metastasis based on areas of tumor cells. Our results demonstrate for the first time that micrometastasis could be detected by deep learning on whole-slide images without manual annotation.

Adenoid Cystic Carcinoma of the Breast.

BACKGROUND: Contrast-enhanced spectral mammogram (CESM) is a modern technique providing additional information to detect or diagnose breast cancers. INTRODUCTION: We present a rare ACC of the breast on CESM. METHODS: A 49-year-old woman with surgicopathological proved ACC was reported with tumor features on CESM, sonography and contrast-enhanced magnetic resonance imaging (CE-MRI). RESULTS: Sonography revealed a 1.4 cm × 1.2 cm × 1 cm circumscribe round mass in the upper outer quadrant of the left breast that was diagnosed with fibroadenoma. The mammogram did not show any discernible mass, however, the recombined subtracted images displayed a circumscribe mass with thin rim enhancement and enhanced internal patches that were resembling CE-MRI. Finally, the mass was proved to ACC. CONCLUSION: CESM facilitates the detection of isodense cancer and provides the enhanced features for differential diagnosis. Resembling CE-MRI, CESM displayed rim enhancement and internal enhanced patches as diagnostic clues for this case of ACC.

Neutrophil elastase inhibitor (MPH-966) improves intestinal mucosal damage and gut microbiota in a mouse model of 5-fluorouracil-induced intestinal mucositis.

BACKGROUND: 5-Fluorouracil (5-FU)-based chemotherapy is first-line chemotherapy for colorectal cancer. However, 5-FU-induced intestinal mucositis (FUIIM) is a common adverse effect that severely impairs drug tolerance and results in poor patient health. METHODS: Male C57BL/6 mice were given 5-FU (50 mg/kg/day, i.p.) and treated with MPH-966 (5 and 7.5 mg/kg/day, p.o.) for five days. The body weight loss and the amount of food intake, and histopathological findings were recorded and analyzed. In addition, the neutrophil infiltration, levels of neutrophil serine proteases and pro-inflammatory cytokines, and tight junction proteins expression in intestinal tissues were determined. The ecology of gut microbiota was performed through next-generation sequencing technologies. RESULTS: Neutrophil elastase (NE) overexpression is a key feature in FUIIM. This study showed that treatment with the specific NE inhibitor MPH-966 (7.5 mg/kg/day, p.o.) significantly reversed 5-FU-induced loss in body weight and food intake; reversed villous atrophy; significantly suppressed myeloperoxidase, NE, and proteinase 3 activity; and reduced pro-inflammatory cytokine expression in an FUIIM mouse model. In addition, MPH-966 prevented 5-FU-induced intestinal barrier dysfunction, as indicated by the modulated expression of the tight junction proteins zonula occludin-1 and occludin. MPH-966 also reversed 5-FU-induced changes in gut microbiota diversity and abundances, specifically the Firmicutes-to-Bacteroidetes ratio; Muribaculaceae, Ruminococcaceae, and Eggerthellaceae abundances at the family level; and Candidatus Arthromitus abundance at the genus level. CONCLUSION: These data indicate that NE inhibitor is a key treatment candidate to alleviate FUIIM by regulating abnormal inflammatory responses, intestinal barrier dysfunction, and gut microbiota imbalance.

The association between immune-related adverse events and survival outcomes in Asian patients with advanced melanoma receiving anti-PD-1 antibodies.

BACKGROUND: The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. METHODS: We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, the patients who experienced grade 1-2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27-0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24-1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21-0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17-0.69, p = 0.003) than patients without any of these irAEs. CONCLUSIONS: Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1-2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Ductal Carcinoma In Situ Underestimation of Microcalcifications Only by Stereotactic Vacuum-Assisted Breast Biopsy: A New Predictor of Specimens without Microcalcifications.

The mammographic appearance of ductal carcinoma in situ (DCIS) is mostly observed as microcalcifications. Although stereotactic vacuum-assisted breast biopsy (VABB) is a reliable alternative to surgical biopsy for suspicious microcalcifications, underestimation of VABB-proven DCIS is inevitable in clinical practice. We therefore retrospectively analyzed the variables in the prediction of DCIS underestimation manifesting as microcalcifications only proved by stereotactic VABB. In 1147 consecutive VABB on microcalcification-only lesions from 2010 to 2016, patients diagnosed with DCIS were selected to evaluate the underestimation rate. The analyzed variables included clinical characteristics, mammographic features, VABB procedure, and biomarkers. Univariate and multivariate analyses were used, and a p value < 0.05 was considered statistically significant. Of the 131 VABB-proven DCIS, 108 cases were diagnosed with DCIS and 23 were upgraded to invasive ductal carcinoma (IDC) after subsequent surgery. The small extent of microcalcification, grouped microcalcifications distribution, nearly complete microcalcification removal, and non-calcified specimens without DCIS were low for DCIS underestimation. Among them, the results of non-calcified specimens with or without DICS were the only statistically significant variables by multivariate logistic regression. These results indicate that the histology of non-calcified specimens was highly predictive of DCIS underestimation. Specimens without DCIS had a low upgrade rate to IDC.

2-O-Methylmagnolol, a Magnolol Derivative, Suppresses Hepatocellular Carcinoma Progression via Inhibiting Class I Histone Deacetylase Expression.

Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, headache, diarrhea, and stroke. Magnolol is a phenolic compound extracted from M. officinalis, with proven antibacterial, antioxidant, anti-inflammatory, and anticancer activities. In this study, we modified magnolol to synthesize a methoxylated derivative, 2-O-methylmagnolol (MM1), and investigated the use of MM1, and magnolol in the treatment of liver cancer. We found that both magnolol and MM1 exhibited inhibitory effects on the growth, migration, and invasion of hepatocellular carcinoma (HCC) cell lines and halted the cell cycle at the G1 phase. MM1 also demonstrated a substantially better tumor-suppressive effect than magnolol. Further analysis suggested that by inhibiting class I histone deacetylase expression in HCC cell lines, magnolol and MM1 induced p21 expression and p53 activation, thereby causing cell cycle arrest and inhibiting HCC cell growth, migration, and invasion. Subsequently, we verified the significant tumor-suppressive effects of magnolol and MM1 in an animal model. Collectively, these findings demonstrate the anti-HCC activities of magnolol and MM1 and their potential for clinical use.

Synergistic effects of pazopanib and hyperthermia against uterine leiomyosarcoma growth mediated by downregulation of histone acetyltransferase 1.

Pazopanib-a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects-has shown promise in the treatment of soft-tissue sarcomas. Hyperthermia has been also applied as an adjunctive treatment to chemotherapy for these malignancies. Here, we show that pazopanib and hyperthermia act synergistically in inhibiting uterine leiomyosarcoma (LMS) cell growth. Compared with either treatment alone, the combination of pazopanib and hyperthermia exerted the highest antitumor activity in a xenograft model. Mechanistically, we found that combined treatment with pazopanib and hyperthermia inhibited histone acetyltransferase 1 (HAT1) expression in LMS cells. The Clock element on the HAT1 promoter was critical for pazopanib- and hyperthermia-induced HAT1 downregulation. Inhibition of HAT1-either by pazopanib and hyperthermia or through HAT1 silencing-was mediated by suppression of Clock. Accordingly, Clock protein reconstitution rescued both HAT1 levels and HAT1-mediated histone acetylation. Immunohistochemistry revealed a higher expression of HAT1 in uterine LMS than in leiomyomas (p = 0.007), with high HAT1 expression levels being associated with poor clinical outcomes (p = 0.007). We conclude that pazopanib and hyperthermia exert synergistic effects against LMS growth by inhibiting HAT1. Further preclinical studies on HAT1 as a potential drug target in uterine LMS are warranted, especially in combination with hyperthermia. KEY MESSAGES: Pazopanib and hyperthermia inhibit the growth of leiomyosarcoma. Their combined use inhibits HAT1 expression in leiomyosarcoma cells. The promoter Clock element is required for HAT1 downregulation. HAT1 expression is higher in leiomyosarcoma than in leiomyomas. An increased HAT1 expression is associated with poor clinical outcomes.