I read with a great interest a recently published clinical study of Takala et al 1 on metaplastic carcinoma of the breast. The authors explored 78 patients with the diagnosis of metaplastic carcinoma in the period 2002‐2016. In line with previous studies, the authors confirmed predominantly triple‐negative phenotype of metaplastic carcinomas (85%) exhibiting a poor therapeutic response with an ag‐ gressive clinical course and poor outcome. Two things are worthy of further discussion: First, 12% of the pa‐ tients were estrogen receptor (ER)‐positive, eight of which received adjuvant endocrine therapy. I would appreciate more information from the authors regarding the percentage of ER positivity in these metaplastic carcinomas and a potential response to endocrine treat‐ ment. It is well known that most metaplastic carcinomas are ER‐neg‐ ative and if ER‐positive, the percentage of positive cancer cells is usually low (range, 1%‐10%). This fact may substantially affect the response to endocrine therapy, as the patients with lower ER posi‐ tivity in their breast cancers are less responsive to anti‐ER treatment modalities. Another important issue is a targeted therapy of metaplastic carcinomas that has recently come into focus. Multiple molecular studies have revealed potentially targetable biomarkers in met‐ aplastic carcinomas of the breast. These include PI3K (PIK3CA, PTEN, PIK3R1), MAPK (NF1, KRAS, NRAS), RB1, and Wnt path‐ ways.2‐9 Of these, PI3K pathway alterations are of particular im‐ portance in metaplastic carcinoma given that several studies have shown their relevance in predicting the response to mTOR/PIK3CA inhibitors.6,10‐13 In addition, programmed death‐ligand 1 (PD‐L1) expression in cancer and/or inflammatory cells, as a predictor of response to immune checkpoint inhibitors, has also been described in a substantial proportion of metaplastic carcinomas.3,14‐16 A pecu‐ liar case report of Adams et al revealed an impressive therapeutic response of the PD‐L1‐positive metaplastic carcinoma to the com‐ bined treatment with pembrolizumab (anti‐PD‐1 drug) and nab‐ paclitaxel therapy.16 Of note, the Food and Drug Administration (FDA) has recently approved atezolizumab, an anti‐PD‐L1 drug, for the treatment of PD‐L1‐positive triple‐negative breast cancers.17,18 Given the period of your cohort, I was wondering if any of the pa‐ tients were profiled for the aforementioned targetable biomarkers and treated accordingly? Semir Vranic MD, PhD

Breast cancer is the second most common cause of cancer-related deaths among women worldwide. It is a heterogeneous disease with four major molecular subtypes. One of the subtypes, human epidermal growth factor receptor 2 (HER2)-enriched (HER2-positive) is characterized by the absence of estrogen and progesterone receptors and overexpression of HER2 receptor, and accounts for 15–20% of all breast cancers. Despite the anti-HER2 and cytotoxic chemotherapy, HER2 subtype is an aggressive disease with significant mortality. Recent advances in molecular biology techniques, including gene expression profiling, proteomics, and microRNA analysis, have been extensively used to explore the underlying mechanisms behind human breast carcinogenesis and metastasis including HER2-positive breast cancer, paving the way for developing new targeted therapies. This review focuses on recent advances on gene expression and miRNA status in HER2-positive breast cancer.

Aim Barrett’s esophagus (BE) is a predisposing factor of esophageal adenocarcinoma/gastroesophageal junction adenocarcinoma (ECA/GEJ Aca). BE patients are stratified and subsequently monitored according to the risk of malignant progression by the combination of endoscopy and biopsy. This study is to evaluate the maspin expression patterns as early diagnostic markers of malignancy in BE patients. Materials and methods Immunohistochemistry (IHC) staining was performed on 62 archival core biopsies from 35 patients, including BE without dysplasia (intestinal metaplasia, IM), BE with low grade dysplasia, BE with high grade dysplasia, carcinoma in situ, and well to poorly differentiated ECA/GEJ Aca (PD-ECA/GEJ Aca). The intensity and the subcellular distribution of immunoreactivity were evaluated microscopically. Statistical analysis was performed using the χ2 and Fisher exact tests. Results The level of epithelial-specific tumor suppressor maspin protein inversely correlated with the progression from IM to PD-ECA/GEJ Aca. Lesions of each pathological grade could be divided into subtypes that exhibited distinct maspin subcellular distribution patterns, including nuclear only (Nuc), combined nuclear and cytoplasmic (Nuc+Cyt), cytoplasmic only (Cyt) and overall negligible (Neg). The Cyt subtype, which was minor in both IM and dysplasia (approximately 10%), was predominant in ECA/GEJ Aca as early as well-differentiated lesions (more than 50%: p = 0.0092). In comparison, nuclear staining of the tumor suppressor TP53 was heterogeneous in dysplasia, and did not correlate with the differentiation grades of ECA/GEJ Aca. Conclusion The Cyt subtype of maspin expression pattern in core biopsies of BE patients may serve as a molecular marker for early diagnosis of ECA/GEJ Aca.

Dear Editor, We highly appreciate Dr Altundag's feedback regarding our recently published manuscript in The Breast Journal.1 We are also thankful to the editor in chief (Dr S. Masood) for giving us the opportunity to address Dr Altundag's comments. Neo‐adjuvant chemotherapy has been widely used for breast cancer treatment due to the effective pathologic responses seen with newer therapeutic agents.2 Recently, it has also been introduced for the treatment of early breast cancer.3 Despite this, there is ongoing debate and controversies related to the use of neo‐adjuvant chemotherapy in breast cancer (critically appraised in a recent review by Vaidya et al2). We find Dr Altundag's point regarding our neo‐adjuvant cohort quite valid. In our study, ~43% of patients with invasive apocrine carcinoma (IAC) presented at the advanced stage (III or IV) with only 19% of the patients having the tumor size ≤2 cm at presentation. This is mainly due to the lack of organized screening program at the national level. In this regard, our small IAC cohort treated in neo‐adjuvant setting is somehow biased but it essentially reflected the previous and current overall breast cancer presentation in Bosnia and Herzegovina. Consequently, the response rates to neo‐adjuvant therapy in our study may be different from the previously published data. Noteworthy, IAC is a rare breast cancer subtype (~1%‐2% of all breast cancers)4,5 and future larger and multi‐institutional studies are required to validate the effectiveness of (neo)adjuvant chemotherapy in patients with IAC.

Micro‐Abstract Neuroendocrine breast cancer lacks specific therapy, but similar common neuroendocrine carcinomas may offer guidance for therapy development. This study, for the first time, identified several biomarkers for targeted therapy approaches in patients with breast neuroendocrine carcinoma. Introduction: Neuroendocrine carcinoma (NEC) of the breast is a rare, special type of breast cancer, reportedly constituting 2% to 5% of all breast cancers. Although breast NEC does not have a specific targeted therapy, several new targeted therapies based on specific biomarkers were recently investigated in the NEC of lung and in other types of breast carcinoma, which may provide guidance to their feasibility in breast NEC. Materials and Methods: Twenty breast NECs were profiled for biomarkers of therapy including antibody‐drug conjugates (DLL3, TROP‐2, and FOLR1), histone deacetylase (H3K36Me3) inhibitors, tropomyosin receptor kinases (NTRK1/2/3 gene fusions) targeted inhibitors, alkylating agents (MGMT), and immune checkpoint inhibitors (PD‐L1, TMB, and MSI) using immunohistochemistry and DNA/RNA next‐generation sequencing assays. Results: Predictive expression of TROP‐2, FOLR1, and H3K36Me3 were detected in different subsets of tumors and may pave the way for development of novel targeted therapies in some patients with breast NECs. There was no evidence of DLL3 expression, NTRK gene fusions, or MGMT hypermethylation. No biomarkers predictive of immune checkpoint inhibitor efficacy (programmed death‐ligand 1 expression, tumor mutational burden, microsatellite instability) were identified. FGFR and CCND1 gene amplifications were detected in isolated cases. Conclusions: This study identified several potential targets for novel therapies in breast NEC, including farletuzumab and mirvetuximab soravtansine (FOLR1), sacituzumab govitecan (TROP‐2), and HDAC inhibitors (H3K36Me3). In some cases, CCND1 gene amplification may indicate the usefulness of investigational therapies. The reported results should serve as an early indication of potential clinical relevance in selected patients with breast NEC.

Objective: We present a 17-year-old boy with an incidentally diagnosed left adrenal ganglioneuroma during the diagnostic workup of alopecia areata. Clinical Presentation and Intervention: Laboratory investigations revealed vitamin D deficiency. Laparoscopic adrenalectomy was performed and ganglioneuroma was confirmed histologically. At follow-up, the vitamin D supplements improved the vitamin D levels followed by a gradual regression of alopecia areata. However, it recurred 18 months later despite the normal levels of serum vitamin D and no tumor recurrence. Conclusion: Further studies should reveal the relationship between alopecia areata and ganglioneuroma as well as the role of vitamin D in alopecia areata.

Breast cancer is the most frequent cause of cancer-related deaths among women worldwide. It is classified into four major molecular subtypes. Triple-negative breast cancers (TNBCs), a subgroup of breast cancer, are defined by the absence of estrogen and progesterone receptors and the lack of HER-2 expression; this subgroup accounts for ~15% of all breast cancers and exhibits the most aggressive metastatic behavior. Currently, very limited targeted therapies exist for the treatment of patients with TNBCs. On the other hand, it is important to highlight that knowledge of the molecular biology of breast cancer has recently changed the decision-making process regarding the course of cancer therapies. Thus, a number of new techniques, such as gene profiling and sequencing, proteomics, and microRNA analysis have been used to explore human breast carcinogenesis and metastasis including TNBC, which consequently could lead to new therapies. Nevertheless, based on evidence thus far, genomics profiles (gene and miRNA) can differ from one geographic location to another as well as in different ethnic groups. This review provides a comprehensive and updated information on the genomics profile alterations associated with TNBC pathogenesis associated with different ethnic backgrounds.

The aim of this study is to explore the outcome of Teucrium polium (TP) medicinal plant consumption on the early stage of fetal development. We used the chicken embryo at 3 days of incubation as a model to evaluate the effect of TP plant extract during embryogenesis. In addition, quantitative polymerase chain reaction (qPCR) was applied to explore the expression of six genes related to cell proliferation, apoptosis, sur-vival, angiogenesis, and migration. Our data revealed that TP exposure inhibits angiogenesis of the chicken embryo and its chorioallantoic membrane. In addition, we found that TP extract significantly harms the normal development of the embryos since around 95% of TP-exposed embryos died after 1-3 days of treatment. Macroscopic examination did not show any anomalies in these embryos. However, qPCR analysis of activation transcription factor-3, B-cell lymphoma-2, caspase 8, inhibin subunit beta A, vascular endothelial growth factor-C, and Cadherin-6 type-2 genes revealed that these genes are considerably deregulated in heart and brain tissues from TP-exposed embryos in comparison with their matched tissues from unexposed ones. Our study implies that TP plant can have very toxic effects on the early stage of the embryo. Therefore, it is important to alert expectant women to avoid the use of this medicinal plant during pregnancy.

Neuroendocrine breast cancer (NEBC) is a group of rare tumors, which could benefit from therapy targeting the somatostatin receptors (SSTRs). In particular, SSTR2A and SSTR5 are potential targets given their consistent expression in gastrointestinal and pancreatic primary and metastatic neuroendocrine cancers. Currently, there are no studies describing the expression of SSTRs in NEBC. The purpose of our study was to characterize the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of NEBC. Thirty-one primary NEBC cases were analyzed, and SSTR2A and SSTR5 immunohistochemistry performed and scored using the modified immunoreactive score proposed by Remmele and Stanger. All patients were females with a mean age of 66.6 years (SD = 14). 77% of cases were histological grade 2. SSTR2A showed a weak positivity in 11 cases (35.5%), moderate positivity in 6 cases (19.4%) and strong positivity in 5 cases (16.1%). Nine cases were negative for SSTR2A (29%). SSTR5 showed a weak positivity in 16 cases (51.6%), moderate positivity in 6 cases (19.4%), while no cases showed strong positivity. Nine cases were negative for SSTR5 (29%). Five cases were negative for both SSTR2A and SSTR5. A weak to moderate SSTR2A and SSTR5 expression was observed in 50-70% of the cases. A subset of NEBCs with strong SSR2A expression may benefit from SSTRs targeted therapy. These results need further validation in a larger series including metastatic NEBC, to provide potential therapeutic targets for patients with advanced disease.

Gastric necrosis with perforation is a rare and potentially life-threatening condition in childhood beyond the neonatal period. We report a case of gastric necrosis and perforation of a portion of the great curvature due to a massive gastric dilatation caused by pathological aerophagia in a 13-years-old, mentally impaired adolescent girl. Despite the successful surgical treatment, the patient's condition rapidly deteriorated post-operatively and she died due to the multisystem organ failure and multiple infections. In addition, we surveyed the literature on this rare condition and assessed the preventive actions to reduce this life-treating condition.

Rationale: Hydrocele of the canal of Nuck is a rare developmental disorder and represents of a homolog of hydrocele of spermatic cord in males. Hydrocele of the canal of Nuck is a very rare cause of inguinal swelling in female infants and children. It results from the failure of obliteration of the distal portion of evaginated parietal peritoneum within the inguinal canal, which forms a sac containing fluid. Patient concerns: We describe a case of hydrocele of the canal of Nuck in an 11-month-old girl with a past medical history of duodenal atresia and Arnold-Chiari malformation. Diagnosis: Physical examination and ultrasound revealed a soft, cystic, noncompressible, and non-fluctuant labial mass measuring approximately 5 cm. Interventions: The patient underwent surgical exploration through a right skin crease incision. The cystic lesion was histologically confirmed to be a non-communicated hydrocele of canal of Nuck. Outcomes: The child is doing well at 1-year follow-up with no swelling or recurrence on the operated side. Lessons: Hydrocele of the canal of Nuck is a rare developmental disorder but should be considered in a differential diagnosis in young girls with an inguino-labial swelling.

Pleomorphic ductal carcinoma (PDC) is a very rare subtype of invasive ductal carcinoma of no‐special type (NST), characterized by the presence of highly atypical/bizarre (>6‐fold variation in nuclear size) and multinucleated (giant) neoplastic cells comprising >50% of the tumor cell population (Figure 1A). PDC is typically triple‐negative breast cancer (TNBC), associated with an aggressive clinical course and a poor outcome.2–4 So far, no single study explored novel predictive biomarkers for the precision medicine purposes in the patients with PDC. Formalin‐fixed paraffin‐embedded tissue samples of the six PDC patients (four primary and two metastatic cases) were sequenced for 592‐genes using NextSeq platform (Illumina, La Jolla, CA, USA). Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations; high TML was considered when it was ≥17 mutations/Mb. Microsatellite instability (MSI) status was explored by the direct analysis of known MSI loci in the target regions of the sequenced genes. Cases were considered microsatellite instable (MSI‐H) if they exhibited ≥46 altered microsatellite loci (the threshold was established by comparing to the PCR‐based MSI FA result from ~2100 cases). Copy number variations (CNVs) were determined by comparing the depth of sequencing of genomic loci with a diploid control. Calculated gains ≥6 copies were considered amplified. ArcherDx FusionPlex Assay was used to detect gene fusions (52 gene targets). Immunohistochemistry was used to detect expression of PD‐L1 (SP142 antibody, Ventana) in tumor cells (TC) and immune cells (IC). PD‐L1 positivity in TC was defined as 2+ intensity in ≥5% of tumor cells. PD‐L1 status