Male breast cancer: a report of 127 cases at a Moroccan institution

Background: Male breast cancer (MBC) is a rare disease representing less than 1% of all malignancies in men and only 1% of all incident breast cancers. Our study details clinico-pathological features, treatments and prognostic factors in a large Moroccan cohort. Findings: One hundred and twenty-seven patients were collected from 1985 to 2007 at the National Institute of Oncology in Rabat, Morocco. Median age was 62 years and median time for consultation 28 months. The main clinical complaint was a mass beneath the areola in 93, 5% of the cases. Most patients have an advanced disease. Ninety-one percent of tumors were ductal carcinomas. Management consisted especially of radical mastectomy; followed by adjuvant radiotherapy and hormonal therapy with or without chemotherapy. The median of follow-up was 30 months. The evolution has been characterized by local recurrence; in twenty two cases (17% of all patients). Metastasis occurred in 41 cases (32% of all patients). The site of metastasis was the bone in twenty cases; lung in twelve cases; liver in seven case; liver and skin in one case and pleura and skin in one case. Conclusion: Male breast cancer has many similarities to breast cancer in women, but there are distinct features that should be appreciated. Future research for better understanding of this disease at national or international level are needed to improve the management and prognosis of male patients

WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids

Self-organization of discrete fates in human gastruloids is mediated by a hierarchy of signaling pathways. How these pathways are integrated in time, and whether cells maintain a memory of their signaling history remains obscure. Here, we dissect the temporal integration of two key pathways, WNT and ACTIVIN, which along with BMP control gastrulation. CRISPR/Cas9-engineered live reporters of SMAD1, 2 and 4 demonstrate that in contrast to the stable signaling by SMAD1, signaling and transcriptional response by SMAD2 is transient, and while necessary for pluripotency, it is insufficient for differentiation. Pre-exposure to WNT, however, endows cells with the competence to respond to graded levels of ACTIVIN, which induces differentiation without changing SMAD2 dynamics. This cellular memory of WNT signaling is necessary for ACTIVIN morphogen activity. A re-evaluation of the evidence gathered over decades in model systems, re-enforces our conclusions and points to an evolutionarily conserved mechanism

Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG repeats in the huntingtin gene (HTT). Although HD has been shown to have a developmental component, how early during human embryogenesis the HTT-CAG expansion can cause embryonic defects remains unknown. Here, we demonstrate a specific and highly reproducible CAG length-dependent phenotypic signature in a synthetic model for human gastrulation derived from human embryonic stem cells (hESCs). Specifically, we observed a reduction in the extension of the ectodermal compartment that is associated with enhanced activin signaling. Surprisingly, rather than a cell-autonomous effect, tracking the dynamics of TGFβ signaling demonstrated that HTT-CAG expansion perturbs the spatial restriction of activin response. This is due to defects in the apicobasal polarization in the context of the polarized epithelium of the 2D gastruloid, leading to ectopic subcellular localization of TGFβ receptors. This work refines the earliest developmental window for the prodromal phase of HD to the first 2 weeks of human development, as modeled by our 2D gastruloids

An in vitro model of early anteroposterior organization during human development.

The body plan of the mammalian embryo is shaped through the process of gastrulation, an early developmental event that transforms an isotropic group of cells into an ensemble of tissues that is ordered with reference to three orthogonal axes1. Although model organisms have provided much insight into this process, we know very little about gastrulation in humans, owing to the difficulty of obtaining embryos at such early stages of development and the ethical and technical restrictions that limit the feasibility of observing gastrulation ex vivo2. Here we show that human embryonic stem cells can be used to generate gastruloids-three-dimensional multicellular aggregates that differentiate to form derivatives of the three germ layers organized spatiotemporally, without additional extra-embryonic tissues. Human gastruloids undergo elongation along an anteroposterior axis, and we use spatial transcriptomics to show that they exhibit patterned gene expression. This includes a signature of somitogenesis that suggests that 72-h human gastruloids show some features of Carnegie-stage-9 embryos3. Our study represents an experimentally tractable model system to reveal and examine human-specific regulatory processes that occur during axial organization in early development

Postoperative chemoradiation in patients with localized gastric adenocarcinoma: Single center experience

Background : 5-Flourouracil (FU)-based chemotherapy (CT) and concurrent 45 Gy radiotherapy (RT) is one of the standard postoperative approaches currently used in gastric carcinoma. The high toxicity rates of this treatment leads to interruption of treatment in the majority of patients. In our study, we investigated the rates of toxicity and treatment discontinuation observed during postoperative FU-based chemoradiotherapy (CRT); retrospectively evaluated the effect of CRT and the other prognostic factors on local and distant control and survival. Patients and Methods: A total of 160 patients consisting of 97 total and 63 subtotal gastrectomy receiving postoperative CRT, have been studied retrospectively. Results : Patients who had to discontinue the treatment for a median of 6 (range, 3-13) days experienced toxicity during treatment at a rate of 43%. During the 21 (range, 4-68) months of follow-up local recurrences were observed in 8 (5%) patients and distant recurrences were observed in 41 (25.6%) patients. While the 1-3 year overall survival (OS) rates were 75% and 42%, 13-year disease-free survival (DFS) rates were 63% and 42%, respectively. In the univariate analysis for OS and DFS demonstrated statistical significance for below those 60 years of age, D1-D2 dissection type, negative surgical margin, early treatment beginning, the absence of invasion, and early stage disease. D1D2 dissection type, early treatment begining, age below 60 years and early stage disease significantly improve OS and DFS in multivarite analysis. Conclusions: Survival is worse in patients older than 60 years, had late treatment begining, advanced stage and D0 dissection

Postoperative chemoradiation in patients with localized gastric adenocarcinoma: Single center experience

Background : 5-Flourouracil (FU)-based chemotherapy (CT) and concurrent 45 Gy radiotherapy (RT) is one of the standard postoperative approaches currently used in gastric carcinoma. The high toxicity rates of this treatment leads to interruption of treatment in the majority of patients. In our study, we investigated the rates of toxicity and treatment discontinuation observed during postoperative FU-based chemoradiotherapy (CRT); retrospectively evaluated the effect of CRT and the other prognostic factors on local and distant control and survival. Patients and Methods: A total of 160 patients consisting of 97 total and 63 subtotal gastrectomy receiving postoperative CRT, have been studied retrospectively. Results : Patients who had to discontinue the treatment for a median of 6 (range, 3-13) days experienced toxicity during treatment at a rate of 43%. During the 21 (range, 4-68) months of follow-up local recurrences were observed in 8 (5%) patients and distant recurrences were observed in 41 (25.6%) patients. While the 1-3 year overall survival (OS) rates were 75% and 42%, 13-year disease-free survival (DFS) rates were 63% and 42%, respectively. In the univariate analysis for OS and DFS demonstrated statistical significance for below those 60 years of age, D1-D2 dissection type, negative surgical margin, early treatment beginning, the absence of invasion, and early stage disease. D1D2 dissection type, early treatment begining, age below 60 years and early stage disease significantly improve OS and DFS in multivarite analysis. Conclusions: Survival is worse in patients older than 60 years, had late treatment begining, advanced stage and D0 dissection

Low risk stage I endometrial carcinoma: Prognostic factors and outcomes

Objectives: The aim of the study is to evaluate clinical features of patients with low-risk stage I endometrium cancer, who received adjuvant therapy or followed with observation only and to analyse the effects of known prognostic factors in this group of patients. Materials and Methods: A total of 246 patients (median age: 53, range: 31-77) with low-risk stage I endometrial cancer, who were just followed postoperatively (156 patients) or received adjuvant radiotherapy (90 patients) between 1996 and 2007 were reviewed retrospectively. Results: Local recurrence was detected in four patients, distant metastasis occurred in seven patients, and two patients had both local recurrence and distant metastasis. The 83.3% of recurrences were on the vaginal stump. Five- and ten-year local control (LC) and overall survival (OS) rates are 97.6%, 97.6% and 96.4%, 93.5% in the observation and adjuvant therapy groups, respectively, whereas distant control rates are 96.7% and 96.3%. In multivariate analysis, only age and lymphovascular invasion (LVI) were found to affect OS and disease-free survival (DFS). Conclusions: LC and OS rates are high in the low-risk group of patients; however, current adjuvant therapies did not improve the outcomes. Age over 60 years and the presence of LVI have negative effects on outcomes in this group of patients