Correction: Alkhaleefah et al. Connected-SegNets: A Deep Learning Model for Breast Tumor Segmentation from X-ray Images. Cancers 2022, 14, 4030.

In the original publication [...].

Challenges and Considerations in Identifying the Origin of Peritoneal Carcinomatosis: A Case Report.

Invasive lobular cancer (ILC) of the breast is the second most common type of invasive breast cancer. Clinical determination of the growth pattern of ILC of the breast is difficult. Furthermore, the ILC of the breast has a unique metastatic pattern that involves gastrointestinal and peritoneal sites. Our patient was initially misdiagnosed with left ovarian cancer based on the findings of positron emission tomography and computed tomography. Herein, we report a case of ILC of the breast presenting as peritoneal carcinomatosis. The ESMO Clinical Practice Guidelines for cancers of unknown primary sites were used in the diagnosis of the carcinoma of unknown primary origin. Image-guided biopsy and immunohistochemical staining are also useful in the diagnosis of these cancer types.

Prognostic Comparison between Oncotype DX® and a 23-Gene Classifier, RecurIndex®, on the Taiwan Breast Cancer Population.

The applicability of the Oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA) recurrence score (RS) in Asian populations is unclear. A 23-gene classifier, RecurIndex® (Amwise Diagnostics, Pte. Ltd., Singapore), has been developed based on the gene expression profiles of early-stage breast cancer patients of ethnic Han Chinese population in Taiwan. This study aimed to compare the performance of the Oncotype DX® RS with the RecurIndex® recurrence index (RI) for predicting relapse-free survival. Therefore, we calculated both the RI and RS for 110 early stage breast cancer patients, with the cut-off value for high-risk recurrence set at 26 and 29 for the RS and the RI, respectively. With relapse-free interval (RFI) as the primary endpoint, the concordance between RS and RI was 78.2% (Kappa value = 0.297). For a median follow-up interval of 27 months, there was a statistically significant difference in RFI between the high- and low-risk groups defined by the RI (p = 0.04) but not between risk groups defined by the RS (p = 0.66). In conclusion, whereas there was high concordance between the RecurIndex® RI and the Oncotype DX RS, the current data showed that the RI had a better discrimination for recurrence risk than the RS. Subsequent studies with larger sample sizes will be needed to confirm the superiority of the RI over the RS in the Asian population.

Connected-SegNets: A Deep Learning Model for Breast Tumor Segmentation from X-ray Images.

Inspired by Connected-UNets, this study proposes a deep learning model, called Connected-SegNets, for breast tumor segmentation from X-ray images. In the proposed model, two SegNet architectures are connected with skip connections between their layers. Moreover, the cross-entropy loss function of the original SegNet has been replaced by the intersection over union (IoU) loss function in order to make the proposed model more robust against noise during the training process. As part of data preprocessing, a histogram equalization technique, called contrast limit adapt histogram equalization (CLAHE), is applied to all datasets to enhance the compressed regions and smooth the distribution of the pixels. Additionally, two image augmentation methods, namely rotation and flipping, are used to increase the amount of training data and to prevent overfitting. The proposed model has been evaluated on two publicly available datasets, specifically INbreast and the curated breast imaging subset of digital database for screening mammography (CBIS-DDSM). The proposed model has also been evaluated using a private dataset obtained from Cheng Hsin General Hospital in Taiwan. The experimental results show that the proposed Connected-SegNets model outperforms the state-of-the-art methods in terms of Dice score and IoU score. The proposed Connected-SegNets produces a maximum Dice score of 96.34% on the INbreast dataset, 92.86% on the CBIS-DDSM dataset, and 92.25% on the private dataset. Furthermore, the experimental results show that the proposed model achieves the highest IoU score of 91.21%, 87.34%, and 83.71% on INbreast, CBIS-DDSM, and the private dataset, respectively.

Prevalence of mutations in BRCA and homologous recombination repair genes and real-world standard of care of Asian patients with HER2-negative metastatic breast cancer starting first-line systemic cytotoxic chemotherapy: subgroup analysis of the global BREAKOUT study.

BACKGROUND: The multinational BREAKOUT study (NCT03078036) sought to determine the prevalence of germline BRCA1/2 (gBRCA1/2) and somatic BRCA1/2 (sBRCA1/2) mutations and mutations in other homologous recombination repair (HRR) genes in women with HER2-negative metastatic breast cancer (MBC) starting first-line chemotherapy. METHODS: Genetic testing for gBRCA, sBRCA, and HRR gene mutations was performed in patients who started first-line chemotherapy for MBC in the last 90 days (341 patients across 14 countries) who were not selected based on risk factors for gBRCA mutations. We report data from the Asian cohort, which included patients in Japan (7 sites), South Korea (10 sites), and Taiwan (8 sites). RESULTS: Of 116 patients screened, 104 patients were enrolled in the Asian cohort. The median age was 53.0 (range 25-87) years. gBRCA1/2, gBRCA1, and gBRCA2 mutations were detected in 10.6% (11/104), 5.8% (6/104), and 4.8% (5/104) of patients, respectively; none had mutations in both gBRCA1 and gBRCA2. gBRCA1/2 mutations were detected in 10.0% (6/60) and 11.6% (5/43) of patients with hormone receptor-positive and triple-negative MBC, respectively. HRR gene mutations were tested in 48 patients without gBRCA mutations, and 5 (10.4%) had at least one HRR mutation in sBRCA, ATM, PALB2, and CHEK2. CONCLUSION: We report for the first time the prevalence of gBRCA and HRR mutations in an Asian cohort of patients with HER2-negative MBC. Our results suggest that BRCA mutation testing is valuable to determine appropriate treatment options for patients with hormone receptor-positive or triple-negative MBC. STUDY REGISTRATION: NCT03078036.

MicroRNA-21 Plays Multiple Oncometabolic Roles in Colitis-Associated Carcinoma and Colorectal Cancer via the PI3K/AKT, STAT3, and PDCD4/TNF-α Signaling Pathways in Zebrafish.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Patients with inflammatory bowel disease (IBD) have a high risk of developing CRC. Inflammatory cytokines are regulated by complex gene networks and regulatory RNAs, especially microRNAs. MicroRNA-21 (miR-21) is amongst the most frequently upregulated microRNAs in inflammatory responses and cancer development. miR-21 has become a target for genetic and pharmacological regulation in various diseases. However, the association between inflammation and tumorigenesis in the gut is largely unknown. Hence, in this study, we generated a zebrafish model (ImiR-21) with inducible overexpression of miR-21 in the intestine. The results demonstrate that miR-21 can induce CRC or colitis-associated cancer (CAC) in ImiR-21 through the PI3K/AKT, PDCD4/TNF-α, and IL-6/STAT3 signaling network. miR-21 activated the PI3K/AKT and NF-κB signaling pathways, leading to initial inflammation; thereafter, miR-21 and TNF-α repressed PDCD4 and its tumor suppression activity. Eventually, active STAT3 stimulated a strong inflammatory response and activated the invasion/metastasis process of tumor cells. Hence, our findings indicate that miR-21 is critical for the development of CRC/CAC via the PI3K/AKT, STAT3, and PDCD4/TNF-α signaling networks.

Colo-pancreaticoduodenectomy for locally advanced colon carcinoma-feasibility in patients presenting with acute abdomen.

BACKGROUND: En bloc right hemicolectomy plus pancreaticoduodenectomy (PD) is administered for locally advanced colon carcinoma that invades the duodenum and/or pancreatic head. This procedure may also be called colo-pancreaticoduodenectomy (cPD). Patients with such carcinomas may present with acute abdomen. Emergency PD often leads to high postoperative morbidity and mortality. Here, we aimed to evaluate the feasibility and outcomes of emergency cPD for patients with advanced colon carcinoma manifesting as acute abdomen. METHODS: We retrospectively reviewed 4898 patients with colorectal cancer who underwent curative colectomy during the period from 1994 to 2018. Among them, 30 had locally advanced right colon cancer and had received cPD. Among them, surgery was performed in 11 patients in emergency conditions (bowel obstruction: 6, perforation: 3, tumor bleeding: 2). Selection criteria for emergency cPD were the following: (1) age ≤ 60 years, (2) body mass index < 35 kg/m2, (3) no poorly controlled comorbidities, and (4) perforation time ≤ 6 h. Three patients did not meet the above criteria and received non-emergency cPD after a life-saving diverting ileostomy, followed by cPD performed 3 months later. We analyzed these patients in terms of their clinicopathological characteristics, the early and long-term postoperative outcomes, and compared findings between emergency cPD group (e-group, n = 11) and non-emergency cPD group (non-e-group, n = 19). After cPD, staged pancreaticojejunostomy was performed in all e-group patients, and on 15 of 19 patients in the non-e-group. RESULTS: The non-e-group was older and had a higher incidence of associated comorbidities, while other clinicopathological characteristics were similar between the two groups. None of the patients in the two groups succumbed from cPD. The postoperative complication rate was 63.6% in the e-group and 42.1% in the non-e-group (p = 0.449). The 5-year overall survival rate were 15.9% in the e-group and 52.6% in the non-e-group (p = 0.192). CONCLUSIONS: Emergency cPD is feasible in highly selected patients if performed by experienced surgeons. The early and long-term positive outcomes of emergency cPD are similar to those after non-emergency cPD in patients with acute abdominal conditions.

The duration of endocrine therapy and breast cancer patients' survival: A nationwide population-based cohort study.

As research progressed, the recommended duration of endocrine therapy for breast cancer patients has been extended from 5 to 10 years. This study aimed to investigate how the duration of endocrine medication and therapy affect survival rate in the real world. By using the National Health Insurance Research Database (NHIRD), this study examined 1002 breast cancer patients newly diagnosed between 2000 and 2005 as research subjects, and conducted follow-up until 2013. Among these subjects, 51 used aromatase inhibitors (AIs), 561 used tamoxifen, and 390 alternated between the use of tamoxifen and AIs. The mean follow-up period in this study was 9.63 years, and the mean duration of taking endocrine medication was 4.04 years. The tamoxifen group had the longest follow-up period (9.87 years), shortest endocrine therapy duration (3.29 years), and best survival rate (86.1%). Patients were divided into 3 groups based on the duration of endocrine therapy: under 2 years, 2 to 5 years, and over 5 years. It was found that patients who received medication for less than 2 years showed the lowest survival rate with statistically significant differences (P < .001). Therefore, the extension of endocrine therapy duration is critical in improving breast cancer patients' survival rate.

Novel imidazopyridine suppresses STAT3 activation by targeting SHP-1.

The unregulated activation of STAT3 has been demonstrated to occur in many cancers and enhances tumour growth, migration, and invasion. Stimulation by cytokines, growth factors, and hormones triggers this activation by phosphorylating STAT3 at tyrosine 705. Novel imidazopyridine compounds were synthesized to evaluate the inhibition of STAT3 at Y705. Among the tested compounds, 16 reduced the level of phospho-STAT3, inhibited the downstream signalling cascade and subsequently attenuated the survival of hepatocellular carcinoma (HCC) cells. Further assays showed that the reduction effects of compound 16 on tyrosine 705 of STAT3 were attributed to up-regulation of protein tyrosine phosphatase SHP-1.

Curcumin causes DNA damage and affects associated protein expression in HeLa human cervical cancer cells.

Cervical cancer is one of the most common cancers in women worldwide and it is a prominent cause of cancer mortality. Curcumin is one of the major compounds from Turmeric and has been shown to induce cytotoxic cell death in human cervical cancer cells. However, there is no study to show curcumin induced DNA damage action via the effect on the DNA damage and repair protein in cervical cancer cells in detail. In this study, we investigated whether or not curcumin induced cell death via DNA damage, chromatin condensation in human cervical cancer HeLa cells by using comet assay and DAPI staining, respectively, we found that curcumin induced cell death through the induction of DNA damage, and chromatin condensation. Western blotting and confocal laser microscopy examination were used to examine the effects of curcumin on protein expression associated with DNA damage, repair and translocation of proteins. We found that curcumin at 13 µM increased the protein levels associated with DNA damage and repair, such as O6-methylguanine-DNA methyltransferase, early-onset breast cancer 1 (BRCA1), mediator of DNA damage checkpoint 1, p-p53 and p-H2A.XSer140 in HeLa cells. Results from confocal laser systems microscopy indicated that curcumin increased the translocation of p-p53 and p-H2A.XSer140 from cytosol to nuclei in HeLa cells. In conclusion, curcumin induced cell death in HeLa cells via induction of DNA damage, and chromatin condensation in vitro.

Toxicological evaluation of Antrodia cinnamomea in BALB/c mice.

Antrodia cinnamomea is a natural component of some herbal medicines used for treatment of abdominal pain, hypertension and hepatocellular carcinoma in Taiwan and other countries. Subchronic oral toxicity studies of A. cinnamomea extracts in male and female BALB/c mice were performed to evaluate its safety. Three different concentrations of A. cinnamomea (16.67, 833.3 and 1666.67 mg/kg/day) were given orally to groups of mice (10 mice/dose) for 90 consecutive days. All animals survived to the end of the study, and there were no significant differences in body weight among the control and treatment groups. No significant differences were found in hematological and serum biochemical parameters among the control and treatment groups. No abnormalities of internal organs were observed in the treated groups.

Extract of medicinal mushroom Agaricus blazei Murill enhances the non-specific and adaptive immune activities in BALB/c mice.

Agaricus blazei Murill (AbM) is traditionally used against a wide range of conditions such as ulcerative colitis, Crohn's disease, foot-and-mouth disease and chronic hepatitis C infection. In this study, we evaluated the immunomodulatory effects of AbM. For the non-specific immune response experiments, a total of 40 female BALB/c mice were divided into control (group 1) and experimental (groups 2-4) groups of 10 animals each. Groups 2, 3 and 4 were orally-administered high (819 mg/kg), medium (273 mg/kg) and low (136.5 mg/kg) doses of AbM daily for six weeks and then six parameters related to non-specific immune response were detected. For the adaptive immune response experiments, 40 female mice were similarly divided into four groups. After six weeks of treatment, animals were immunized with the OVA immunogen. Two weeks later, splenocytes and sera were collected. Four parameters related to adaptive immune response were evaluated. We found that feeding mice with AbM extract increased the IgG level in serum, promoted phagocytosis of peritoneal macrophages and elevated the activity of Natural killer cells. We also found that the highest dose of AbM increased interleukin-2 (IL-2) levels in splenocytes and that a medium dose increased interferon-γ. The levels of interleukin-4 (IL-4) were reduced or unchanged. T-helper type 1 cytokine levels were increased. AbM increased the humoral immune response and also affected the cellular immune response. These results provide evidence that AbM can modulate innate and adaptive immunity.

Oral administration of benzyl-isothiocyanate inhibits in vivo growth of subcutaneous xenograft tumors of human malignant melanoma A375.S2 cells.

A number of experiments have demonstrated that benzyl-isothiocyanate (BITC) induces cytotoxic cell death through the induction of apoptosis in various human cancer cell lines. In the present study, we investigated the effects of BITC on the growth of A375.S2 cell xenograft tumors in nude BALB/c mice in vivo. The A375.S2 cancer cells were inoculated subcutaneously into the lower flanks of each nude mouse. After cancer cell inoculation, all animals were maintained in the animal room for seven days and all mice produced one palpable tumor. Animals were randomly divided into two groups, each mouse was individually given intraperitoneal injections of BITC (20 mg/kg) or not (control). Results from the in vivo experiments indicated that BITC did not significantly affect the body weight of nude BALB/c mice bearing xenograft A375.S2 cell tumors but did significantly decrease the tumor weight.

p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells.

Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status.