Calpain-mediated Mechanoptosis in Breast Adenocarcinoma.

Calpains belong to a family of important calcium-dependent cysteine proteases. They are involved in intracellular processes including cytoskeleton disorganization and substrate proteolysis. They also enhance apoptosis and cell to cell adhesion. Calpains demonstrate also a mechanosensory function in neoplastic and malignant cells due to their implication in mechanoptosis. This is a specific type of apoptotic death induced by strong external mechanical stimuli. Anti-cytoskeleton rigidity inhibition strategies based on calpain induction lead to increased apoptosis of tumor transformed cells. Elevated intracellular calcium concentration mediated by specific receptors and channels activates calpains. In the current molecular review, we explored the role of calpains in calcium-dependent signa transduction pathways in breast adenocarcinoma in conjunction with novel agents that activate their important anti-tumor functions.

Metaplastic Carcinoma of the Breast: Case Series of a Single Institute and Review of the Literature.

Metaplastic carcinoma of the breast (MpBC) is a very rare and aggressive type of breast cancer. Data focusing on MpBC are limited. The aim of this study was to describe the clinicopathological features of MpBC and evaluate the prognosis of patients with MpBC. Eligible articles about MpBC were identified by searching CASES SERIES gov and the MEDLINE bibliographic database for the period of 1 January 2010 to 1 June 2021 with the keywords metaplastic breast cancer, mammary gland cancer, neoplasm, tumor, and metaplastic carcinoma. In this study, we also report 46 cases of MpBC stemming from our hospital. Survival rates, clinical behavior, and pathological characteristics were analyzed. Data from 205 patients were included for analysis. The mean age at diagnosis was 55 (14.7) years. The TNM stage at diagnosis was mostly stage II (58.5%) and most tumors were triple negative. The median overall survival was 66 (12-118) months, and the median disease-free survival was 56.8 (11-102) months. Multivariate Cox regression analysis revealed that surgical treatment was associated with decreased risk of death (hazard ratio 0.11, 95% confidence interval 0.02-0.54, p = 0.01) while advanced TNM stage was associated with increased risk of death (hazard ratio 1.5, 95% confidence interval 1.04-2.28, p = 0.03). Our results revealed that surgical treatment and TNM stage were the only independent risk factors related to patients' overall survival.

DNA Mismatch Repair System Imbalances in Breast Adenocarcinoma.

DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved system in bacteria, prokaryotic, and eukaryotic cells, and provides the highest protection to DNA by repairing micro-structural alterations. DNA MMR proteins are involved in the detection and repair of intra-nucleotide base-to-base errors inside the complementary DNA strand recognizing the recently synthesized strand from the parental template. During DNA replication, a spectrum of errors including base insertion, deletion, and miss-incorporation negatively affect the molecule's structure and its functional stability. A broad spectrum of genomic alterations such as promoter hyper methylation, mutation, and loss of heterozygosity (LOH) in MMR genes including predominantly hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 lead to their loss of base-to-base error repairing procedure. Microsatellite instability (MSI) refers to the DNA MMR gene alterations that are observed in a variety of malignancies of different histological origins. In the current review, we present the role of DNA MMR deficiency in breast adenocarcinoma, a leading cancer-based cause of death in females worldwide.

Epigenetic Mechanisms in Breast Adenocarcinoma: Novel DNA Methylation Patterns.

Breast adenocarcinoma is a leading cause of death in females worldwide. A broad spectrum of genetic and epigenetic alterations has been already identified and reported in millions of examined cancerous substrates, evidence of a high-level genomic heterogeneity that characterizes these malignancies. Concerning epigenetic changes and imbalances that critically affect progression and prognosis in the corresponding patients, DNA methylation, histone modifications (acetylation), micro-RNAs (miRs) alterations and chromatin re-organization represent the main mechanisms. Referring to DNA methylation, promoter hyper-hypo methylation in critical tumour suppressor and oncogenes is implicated in normal epithelia transformation to their neoplastic and finally malignant cyto-phenotypes. The current review is focused on the different methylation patterns and mechanisms detected in breast adenocarcinoma and their impact on the corresponding groups of patient response to specific chemotherapeutic regimens and life span prognosis.

Adjuvant Treatment of Elderly Breast Cancer Patients: Offer the Best Chances of Cure.

Background: Breast cancer remains the most common cancer in women and a leading cause of death. Elderly people have a higher incidence of breast cancer since it increases with age. Furthermore, the extended life expectancy and advances in imaging techniques have led to an increased number of cases. Guidelines concerning the management of this specific age group are rare, mainly due to underrepresentation of seniors in clinical trials. Moreover, increased frailty, comorbidities, and a poor performance status make it complex to determine the best therapeutic approach. Summary: In this review, we attempt to summarize the current literature and aim to provide specific approaches and recommendations for prompt diagnosis, treatment, and management of breast cancer in the elderly. Key Messages: The establishment of applicable protocols is imperative and efforts are being made in this direction. A careful geriatric assessment and adequate consultation should be the standard of care and patient's preferences should always be considered.

Depressive Symptoms and Burnout Among Medical Students: a Prospective Study.

BACKGROUND: Depressive symptoms and burnout are common among medical students. However, few studies have investigated their trajectory over the course of medical school. OBJECTIVE: Evaluate year-by-year changes in depressive and burnout symptoms over the course of medical school training. DESIGN: Prospective study. PARTICIPANTS: Medical students who matriculated at a private medical school in Maryland from 2010 to 2016 (n=758). MAIN MEASURES: Clinically significant depressive symptoms were defined as a score of ≥10 on the 9-item Patient Health Questionnaire (PHQ-9), and burnout was measured using the Maslach Burnout Inventory (MBI). High emotional exhaustion, high depersonalization, and low personal accomplishment were defined as scores of ≥ 27, ≥10, and ≤33 on the respective MBI subscales. KEY RESULTS: At matriculation, the prevalences of significant depressive symptoms, high emotional exhaustion, high depersonalization, and low personal accomplishment were 4.3%, 9.4%, 8.6%, and 37.7%, respectively. After adjustment for age, sex, race/ethnicity, marital status, and cohort, compared with year 1, the odds of significant depressive symptoms was significantly higher at the beginning of the 2nd, 3rd, and 4th years of study (ORs=2.63, 2.85, and 3.77, respectively; all ps<0.001). Compared with the 1st year, the odds of high emotional exhaustion also increased during the 2nd, 3rd, and 4th years of study, (ORs=3.46, 4.79, 8.20, respectively; all ps<0.001), as did the odds of high depersonalization (ORs=3.55, 6.14, 12.53, respectively; all ps<0.001). The odds of low personal accomplishment did not significantly differ across years of study. CONCLUSIONS: The results of this study suggest that symptoms of depression and burnout may increase during medical school. Because of the high prevalence of depressive symptoms and burnout in medical students, interventions earlier in the medical career pathway that aim to prevent, detect, and treat these symptoms may be of benefit to the physician community.

Germline mutations in a clinic-based series of pregnancy associated breast cancer patients.

BACKGROUND: Pregnancy-associated breast cancer (PABC) defined as breast cancer diagnosed during gestation, lactation or within 1 year after delivery, represents a truly challenging situation with significantly increasing incidence rate. The genomic background of PABC has only recently been addressed while the underlying mechanisms of the disease still remain unknown. This analysis aims to further elucidate the frequency of PABC cases attributable to genetic predisposition and identify specific cancer susceptibility genes characterizing PABC. METHODS: A comprehensive 94-cancer gene panel was implemented in a cohort of 20 PABC patients treated in our clinic and descriptive correlation was performed among the results and the patients' clinicopathological data. RESULTS: In the present study, 35% of PABC patients tested carried pathogenic mutations in two known cancer predisposition genes (BRCA1 and CHEK2). In total, 30% of the patients carried BRCA1 pathogenic variants. An additional 5% carried pathogenic variants in the CHEK2 gene. Variants of unknown/uncertain significance (VUS) in breast cancer susceptibility genes BRCA2, CHEK2 and BRIP1 were also identified in three different PABC patients (15%). Not all patients carrying germline mutations reported known family history of cancer. CONCLUSIONS: Genetic testing should be considered as an option for PABC patients since the disease is highly associated with genetic susceptibility among other predisposing factors. Germline mutation identification may further modify PABC management approach and improve the prognostic outcome.

Whole Breast Invasive Lobular Carcinoma Not Detected Radiographically.

Breast cancer is the most commonly occurring cancer in women, with invasive lobular carcinoma being the second most common histologic form. A 78-year-old female patient presented complaining of an enlarged palpable lymph node in the left axilla. Breast ultrasound, digital mammography, and contrast-enhanced spectral mammography (CESM) revealed no abnormal findings. Core needle biopsy of the lymph node revealed infiltrative, diffuse neoplastic growth suggestive of adenocarcinoma, indicating that the primary site should be sought in the breast. The patient underwent mastectomy and the histopathology was suggestive of invasive lobular carcinoma throughout the whole extent of the breast parenchyma. Breast cancer should be definitely included in the differential diagnosis of enlarged axillary lymph nodes, even if there is no other clinical or radiographic presentation of breast disease.

Large cyst of the vaginal wall in pregnancy.

Large vaginal cysts during pregnancy are rare and can mislead Obstetricians to a false diagnosis, that of "Protruding membranes". Aspiration of the cyst can be easily performed, resulting in the collapsing of the cyst and an uneventful vaginal delivery can be conducted.

Evaluation of MET T1010I and MET rs40239 single-nucleotide polymorphisms in triple-negative breast cancer: a case-control study.

Aim: The purpose of this study is to evaluate the role of MET T1010I and MET rs40239 as potential risk factor and/or prognostic markers in patients with triple-negative breast cancer (TNBC). Methods: 114 samples of DNA from paraffin-embedded breast normal tissues of patients with TNBC and 124 samples of healthy controls were collected and analyzed for MET T1010I and MET rs40239 polymorphisms. Results: MET T1010I CT genotype was associated with increased risk of TNBC in both univariate and multivariate analysis. The status of rs40239 was not associated with a higher risk for TNBC at either the univariate or the multivariate analysis. None of the examined polymorphisms was associated with overall survival at the univariate or multivariate Cox regression analysis (adjusted HR=1.35, 95% CI: 0.31-5.97 for MET T1010I CT/TT vs CC; adjusted HR=1.78, 95% CI: 0.73-4.35 for rs40239 AG/GG vs AA). Conclusion: Our case-control study suggests that MET T1010I seems to be a risk factor for TNBC in the Caucasian Greek population, in contrast with MET rs40239, where no correlation was found.

Breast cancer treatment in women over the age of 80: A tailored approach.

Breast cancer treatment in women over the age of 80 remains a complex issue due to pre-existing comorbidities, therapy-related toxicities, and the lack of evidence-based data in this population, leading to both overtreatment and under treatment. The average life expectancy of an 80-year-old woman is 9.7 years and chronologic age alone should not be a factor in withholding therapy. Women over age 80 should be treated on an individual basis, taking into account their overall health and life expectancy, their risk of dying from breast cancer versus other causes, and the benefits versus toxicities of therapies for their tumor. Invaluable online tools are readily available to easily assess life expectancy (ePrognosis), as well as the absolute survival benefits for every tumor type and stage in individual patients (PREDICT, Ajuvant!). This information should be presented to the patient so that they are able to make an informed decision based on their goals, wishes and quality of life. Vulnerable patients should not be bullied or scared into taking unwanted or unnecessary treatments.

Health and wellness among incoming resident physicians: A multi-domain survey.

INTRODUCTION: Burnout and depression are well-described in medical students and physicians and can lead to adverse personal and patient outcomes; however, their time course and risk factors remain understudied. Here, we measured multiple domains of mental and physical health and wellness and assessed gender differences among incoming physician trainees beginning residency at an academic medical center. METHODS: Using a cross-sectional study design, all incoming trainees (i.e. housestaff) at Johns Hopkins Hospital received a questionnaire assessing depression, burnout, sleep, exercise, and alcohol consumption, among other domains. Standardized instruments were utilized for questionnaire development. Tests of significance were two-tailed. RESULTS: 196 of 229 incoming housestaff (86%) completed the survey, and 49% were female. A history of depression was reported in 8%, and 5.4% met criteria for at least moderate depression by Patient Health Questionnaire (PHQ-9). Females were more likely to report a history of depression than males (13% vs. 3%, p=0.02) but had similar PHQ-9 scores. Four percent of participants reported feeling they were in the wrong profession. Goal and mean sleep were 7 and 6.7 hours/night, respectively. Forty-seven percent reported exercising once/week or not at all. While mean reported weekly alcohol consumption was three drinks, participants reported consuming ≥5 drinks in one sitting on average 1.6 times in the prior 6 months, and 4% used alcohol to sleep. CONCLUSIONS: Incoming housestaff reported generally favorable mental and physical health at the beginning of residency training. However, exercise rates were low, and ill-suited alcohol consumption was noted, though infrequent. The few areas of possible improvement were largely similar between males and females. Wellness interventions might capitalize on the relatively high morale and health at the completion of medical school by helping to promote healthy habits, including regular exercise and avoidance of excess alcohol consumption, throughout future training and practice.

Evaluation of pre-mir-34a rs72631823 single nucleotide polymorphism in triple negative breast cancer: A case-control study.

AIM: The purpose of this study is to evaluate the role of pre-miR34a rs72631823 as potential risk factor and/or prognostic marker in patients with triple negative breast cancer. METHODS: 114 samples of DNA from paraffin embedded breast normal tissues of patients with triple negative breast cancer and 124 samples of healthy controls were collected and analyzed for pre-miR34a rs72631823 polymorphism. RESULTS: Pre-miR34a rs72631823 A allele was associated with increased TNBC risk both in univariate and multivariate analysis. The number of pre-miR34a rs72631823 AA subjects was very small and the association did not reach significance (p = 0.176, Fisher's exact test). The examined polymorphism was not associated with overall survival at the univariate or multivariate Cox regression analysis (adjusted HR = 1.60, 95%CI: 0.64-3.96 for miR34 rs72631823 GA/AA vs. GG). CONCLUSION: Our case-control study suggests that pre-miR34a rs72631823 A allele is associated with increased triple negative breast cancer risk.

Breast lymphoma in a patient with B-cell Non Hodgkin Lymphoma: A case report study.

INTRODUCTION: Breast involvement in Non Hodgkin Lymphoma is a rare entity as it accounts for 2.2% of all extranodal lymphomas. PRESENTATION OF CASE: A 59-year-old woman was referred to our Breast Unit because of two nodules of the right breast newly discovered during her annual mammography. Moreover, during the physical examination, a red-brown itchy lump of the scalp was discovered. The punch biopsies of the scalp lesion and ultrasound-guided core biopsies of both nodules of the right breast, revealed the presence of diffuse large B-cell Non Hodgkin Lymphoma in all tissue specimen sites. DISCUSSION: Breast lymphomas represent an uncommon form of localized extranodal lymphomas that can be classified as Primary (PBL) or Secondary (SBL) breast lymphomas. CONCLUSION: The value of preoperative diagnosis should be underlined as the patient avoids unnecessary surgical intervention and has earlier initiation of chemotherapy.

Pyoderma Gangrenosum of the breast: A case report study.

INTRODUCTION: Pyoderma gangrenosum (PG) of the breast is a rare and rapidly spreading disease, which usually co-exists with severe underlying systemic conditions. PG often presents secondary to breast surgery with skin lesions and signs of infection, even though it is a non-infectious, necrotizing dermatological entity. PRESENTATION OF CASE: We present a case of de novo unilateral breast PG in 37-year-old woman, with a clear medical history whatsoever. The patient was treated with corticosteroids and, in a two-month follow up, presents with nearly no signs of PG. DISCUSSION: PG of the breast presents with atypical clinical signs and is characterized by an exclusion-based diagnosis. It often mimics inflammation but is resistant to antibiotics. CONCLUSION: The optimal treatment for PG is systemic use of corticosteroids and surgical debridement of the necrotic tissue, while the timely onset of the therapeutic approach is of outmost importance.

A prepubertal giant juvenile fibroadenoma in a 12-year-old girl: Case report and brief literature review.

INTRODUCTION: Giant juvenile fibroadenomas represent only the 0.5% of all fibroadenomas, constituting a rare condition in adolescence. In prepuberty, the presence of this condition is extremely rare. PRESENTATION OF CASE: We describe a rare case of a 12- year-old Caucasian girl who presented to our Hospital complaining of a palpable mass with rapid enlargement in her right breast that she had first noticed 3 months ago. Her menarche hadn't occurred yet. DISCUSSION: Physical examination showed a giant mass of 15 × 13 cm in the right breast. The patient was further evaluated via ultrasonography showing a sole large lesion of 13 × 12 cm in the right breast. A surgical procedure under general anesthesia was performed. Histopathological findings after the surgical excision were suggestive of giant juvenile fibroadenoma. The patient has a normal breast development over a period of 9 month follow up. CONCLUSION: Giant juvenile fibroadenomas should be included in differential diagnosis of a breast mass in prepubertal girls despite the fact that they are very rare in prepuberty, tend to appear later during adolescence and their prevalence is lower in Caucasians. The remarkable size and the rapid growth of the lesion should not be ruled out in the diagnostic process of an adolescent breast.

Cancer in pregnancy: disentangling treatment modalities.

Pregnancy-associated cancer constitutes an uncommon and difficult to manage clinical situation. It is defined as the cancer diagnosed from the first day of childbearing to 1 year post partum. Coexistence of cancer with pregnancy adds complexity to treatment recommendations, as both the mother and the fetus may be affected. The optimal therapeutic management of pregnant women with cancer diagnosis should take into account, apart from medical factors, a host of other parameters (ethical, psychological, religious, legal, etc). Unfortunately, this situation becomes more complex as more women delay childbearing, and consequently the incidence of cancer during pregnancy is constantly increasing. This manuscript summarises the general principles in managing pregnant patients with cancer and gives detailed instructions in the management of pregnant patients with breast cancer, ovarian cancer, melanoma, lymphoma, lung cancer, soft-tissue sarcoma and cervical cancer. Of note, management of pregnant women with cancer diagnosis should be performed in specialised centres with experience and all cases should be discussed in multidisciplinary meetings composed of multiple specialists (medical oncologists, obstetricians, surgeons, radiologists and paediatricians).

Pseudomamma of the inguinal region in a female patient: A case report.

INTRODUCTION: Supernumerary breasts are relative common benign congenital anomalies. General population occurrence rates vary up to 6% according to ethnicity and gender. Higher incidence is recorded in Asian individuals, especially Japanese. Embryonic breast development of the mammary ridge (milk line) is explained and supernumerary breast tissue resulting from involution failure of any portion of the embryonic mammary folds is described. PRESENTATION OF CASE: We report a case of supernumerary breast (pseudomamma) in a female occupying her right inguinal region that was treated in the breast unit of our hospital. Differential diagnosis, imaging methods, operative approach, surgical treatment and histological verification are specified. DISCUSSION: Classification system for supernumerary breast tissue is presented, high risk population is identified and congenital malformations linked to it are outlined. Evaluation of diagnostic workup and limitations are stated. Cancerous degeneration and justification for surgical removal of the accessory gland is discussed. CONCLUSION: Differential diagnosis of lesions along the milk line should always be inclusive of developmental abnormalities such as any type of supernumerary breast, often overlooked due to small size, although carrying a malignant potential equal to normally positioned breasts. Surgical correction is a sensible approach, often encouraged by the patients. Additional evaluation is recommended due to the frequent accompanying urinary tract and cardiac anomalies.

The impact of genetics profile (gene polymorphisms) in obese non-PCOS women entering an IVF/ICSI program.

Data concerning the effects of increased body mass index (BMI) on ovarian and pregnancy outcome are rich, but the results are rather controversial. Regarding pharmacogenetics, gene polymorphisms of hormonal receptor genes, such as Estrogen Receptor alpha (ESR1), Estrogen Receptor beta (ESR2) and FSH receptor (FSHR) genes, are associated with ovarian stimulation and pregnancy outcome and may constitute a useful tool for ART experts for the prediction of this outcome. The aim of this study is to track differences in the distribution of gene polymorphisms among obese non-PCOS and non-obese patients concerning three distinct genes which are involved in the ovarian stimulation mechanism: PvuII polymorphism of ESR1 gene, RsaI polymorphism of ESR2 gene and Ser680Asn variation of FSHR gene, using restriction fragment length polymorphism analysis and real-time polymerase chain reaction. A total of 151 normally ovulating female patients underwent IVF or ICSI. Interestingly, the pregnancy rate in the BMI≥30 kg/m² group was higher in a statistically significant way (40.9% versus 17.8%, p=0.023). The obese patients of this study were in need of increased total FSH dose in order to achieve a satisfactory oocyte number (p<0.001) and needed more days of stimulation (p=0.002), but also presented lower basal FSH levels (p=0.032), which may explain, to an extend, the better pregnancy outcome. Concerning the polymorphisms of ESR1, ESR2 and FSHR genes, we did not observe differences in the genotype distribution when we compared the obese non-PCOS population with the non-obese population. Thus, obesity does not constitute an additional indication to perform a genetic analysis before entering an IVF/ICSI program.

Breast tuberculosis: Diagnosis, management and treatment.

INTRODUCTION: Mammary (breast) tuberculosis is a rare manifestation of extra-pulmonary localization of the disease which accounts for less than 0.1% of breast conditions in developed countries, but reaches 3-4% in regions where the disease presents with high incidence (India, Africa). It appears mostly in women of reproductive age, multiparous, lactating. It has been scarcely reported to infect male patients, mainly before puberty, as well as women of older age. The most common presentation is that of a tumor in the middle or upper-outer quadrant of the breast, with multifocal involvement being rarely documented. The differential diagnosis includes breast cancer and abscess formation. PRESENTATION OF CASE: We report a case of breast tuberculosis that was treated in the Breast Unit of our hospital. Differential diagnosis, imaging methods, operative diagnostic approach and surgical treatment, histological verification of the disease and further therapeutic management are described. DISCUSSION: High risk population is identified, primary and secondary disease is described and clinical presentations are analyzed. Evaluation of diagnostic workup and limitations are reported. CONCLUSION: In accordance with the present worldwide revival of the disease, mainly because of massive numbers of migrating population, this subject is reviewed, reminding us of a rather uncommon clinical entity.