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Immunotherapy has changed the course of cancer treatment. The initial steps were made through tumor-specific antibodies that guided the setup of an antitumor immune response. A new and successful generation of antibodies are designed to target immune checkpoint molecules aimed to reinvigorate the antitumor immune response. The cellular counterpart is the adoptive cell therapy, where specific immune cells are expanded or engineered to target cancer cells. In all cases, the key for achieving positive clinical resolutions rests upon the access of immune cells to the tumor. In this review, we focus on how the tumor microenvironment architecture, including stromal cells, immunosuppressive cells and extracellular matrix, protects tumor cells from an immune attack leading to immunotherapy resistance, and on the available strategies to tackle immune evasion., Competing Interests: RS is a consultant for and a research grant from INmune Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bruni, Mercogliano, Mauro, Cordo Russo and Schillaci.)

Breast cancer is the most common cancer in women and the leading cause of death. HER2 overexpression is found in approximately 20% of breast cancers and is associated with a poor prognosis and a shorter overall survival. Tratuzumab, a monoclonal antibody directed against the HER2 receptor, is the standard of care treatment. However, a third of the patients do not respond to therapy. Given the high rate of resistance, other HER2-targeted strategies have been developed, including monoclonal antibodies such as pertuzumab and margetuximab, trastuzumab-based antibody drug conjugates such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), and tyrosine kinase inhibitors like lapatinib and tucatinib, among others. Moreover, T-DXd has proven to be of use in the HER2-low subtype, which suggests that other HER2-targeted therapies could be successful in this recently defined new breast cancer subclassification. When patients progress to multiple strategies, there are several HER2-targeted therapies available; however, treatment options are limited, and the potential combination with other drugs, immune checkpoint inhibitors, CAR-T cells, CAR-NK, CAR-M, and vaccines is an interesting and appealing field that is still in development. In this review, we will discuss the highlights and pitfalls of the different HER2-targeted therapies and potential combinations to overcome metastatic disease and resistance to therapy.

Background: The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion., Methods: We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes., Results: In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors., Conclusions: These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance., Competing Interests: Competing interests: RS is a consultant for and a research grant from INmune Bio. All other authors declare they have no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction and Importance: Liposarcoma (LPS) represents the most common type of retroperitoneal sarcoma (RPS) and can be classified into four subtypes. Preoperative diagnosis of retroperitoneal liposarcoma (RLPS) is a challenge because of its late and nonspecific clinical presentation. Imaging may be helpful for determining the correct diagnosis. Surgery represents a potentially curative treatment of RLPS., Case Presentation: A 55-year-old Caucasian female presented to the Emergency Department with a two-day history of abdominal pain, abdominal distension, inability to pass gas or stool, nausea, vomiting and lipothymia. Abdominal examination revealed abdominal distention, abdominal pain without obvious muscle guarding and a giant non-tender mass. Laboratory tests reported neutrophilic leukocytosis and anemia. Abdominal contrast-enhanced computed tomography (CECT) showed a heterogeneous and hypodense giant retroperitoneal mass compressing and displacing the surrounding organs and vessels. The patient underwent excision of a giant retroperitoneal mass. The postoperative course of the patient was uneventful., Clinical Discussion: RLPS is a malignant neoplasm that can slowly grow to enormous size with possible involvement of adjacent organs and vessels; it may recur locally and has a minimal capacity to metastasize. Preoperative diagnosis and staging of RLPS are important to establish appropriate management and prognosis. Surgery represents the gold standard for non-metastatic RLPS treatment., Conclusion: RLPS is a rare malignant neoplasm generally difficult to detect early due to its late and nonspecific clinical presentation. CECT represents the most commonly used modality for diagnosis, staging and preoperative evaluation. Surgery represents the appropriate treatment of non-metastatic RLPS., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The aim of this study was to compare the short-term outcomes of laparoscopic right hemicolectomy between intracorporeal (IA) and extracorporeal (EA) anastomosis techniques., Methods: A retrospective chart review of 77 consecutive patients who underwent laparoscopic right hemicolectomy from January 2016 to June 2018 was performed. The intracorporeal group included 36 patients and the extracorporeal group 41 patients., Results: Patient demographics and disease-related characteristics were similar. Mean operative time was 152±38.3 minutes in IA vs. 148±34.8 minutes in EA (P=0.664). IA was not associated with less overall postoperative complications and decreased rate of surgical site infections. There was no statistically significant difference in the incidence of postoperative leak, length of stay, mortality in both groups. There was no perioperative difference in median number of lymph node harvested. There was statistically significant difference in the length of larger incision (50 [50-70] mm in IA vs. 80 [70-100] mm in EA; P<0.001), length of the specimen (323±52.7 mm in IA vs. 295±64.7 mm in EA; P<0.05), free tumor margin (113.6±47.4 in IA vs. 75.6±37.4 mm in EA; P<0.001). There was a statistically significant difference in IA in the less postoperative use of analgesics (P<0.032) and return of bowel function (P<0.021)., Conclusions: IA seems feasible and safe; it does not significantly affect the length of surgery, and it guarantees maintenance of radical oncological standards. Furthermore, IA significantly improves cosmesis and patient comfort postoperatively, reducing the rates of emesis, which leads to higher rates of early regular diet tolerance. Therefore, laparoscopic right hemicolectomy with intracorporeal anastomosis is associated with improved short-term outcomes.

Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC., (© 2022. The Author(s).)

Diagnosis of pancreatic cancer is challenging in the initial phases because its progression is rapid. The pancreatic tail and body roughly accounts for 20-30% of all cancerous cases. The standard treatment for symptomatic benign, malignant, and premalignant diseases of the pancreatic tail and body is distal pancreatectomy. This technique has been modified over the years to fit certain indications, with the goal of enhancing post-operative results as well as reducing patient trauma. In cases of a premalignant and symptomatic benign condition, the spleen must be preserved either using Kimura's splenic vessel preservation technique or Warshaw's splenic vessel resection technique. A better long-term prognosis is ensured by regional lymph node dissection and radical R0 resection. Radical antegrade modular pancreatosplenectomy was proposed to tackle the shortcomings of traditional surgery for pancreatic tail and body cancer. In this review, study techniques and results of laparoscopic distal pancreatectomy for malignant and benign pancreatic ailments were described with the intention of providing knowledge on various suitable techniques reported for pancreatic cancer treatment. Furthermore, this study will serve as a ready reckoner for surgeons and could serve to boost their confidence levels during surgery by avoiding confusion on the selection of suitable for the pancreatic diseases diagnosed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Termedia.)

Introduction and Importance: Meckel's diverticulum (MD) is a vestigial remnant of the omphalomesenteric duct, representing the most common congenital malformation of the gastrointestinal tract. Diagnosis of MD is a challenge because of its rarity and frequent asymptomaticity. Radiological exams generally aren't useful for its diagnosis. Intestinal obstruction represents the most common complication of MD in adults. Surgery is the appropriate treatment of complicated MD., Case Presentation: A 70-year-old Caucasian male was admitted to the Emergency Department with a two-day history of abdominal pain associated with inability to pass gas or stool, nausea and vomiting. Physical examination revealed abdominal distention and abdominal pain without Blumberg's sign. Abdominal contrast-enhanced computed tomography (CECT) showed small bowel obstruction caused by suspected MD. Laboratory tests reported high serum levels of glycemia, LDH, C-reactive protein and leukocytosis. After diagnosis of intestinal obstruction, the patient underwent exploratory laparotomy: a segmental resection of ischemic distal ileum bearing a necrotic MD was performed. The postoperative course of patient was uneventful., Clinical Discussion: MD is found in 2%-4% of the population in large autopsy and surgical series. MD is mostly asymptomatic and incidentally discovered if not complicated; a debate exist about management of asymptomatic MD. Surgery represents the definitive treatment of complicated MD., Conclusion: MD is a true diverticulum rarely discovered in adults. Diagnosis of MD is difficult even with the help of radiological exams. Although surgical resection represents the correct treatment of symptomatic MD, nowadays there is no consensus on the optimal treatment of asymptomatic and incidentally discovered MD., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Human papilloma virus infection (HPV) is the most common sexually transmitted disease. Little is known about male infection. Nonavalent vaccine against types 6/11/16/18/31/33/45/52/58 was approved and neutral gender immunization programs have been proposed. This study evaluates the potential impact of nonavalent vaccine compared to quadrivalent in male living in Sicily (Italy). 58.7% of samples were HPV positive and forty-four types of HPV were identified. A significant higher estimated coverage of nonavalent vaccine than quadrivalent was observed (64.3% vs. 45.8%), with absolute and relative additional impact of 20.1% and 47.2%, respectively. Low impact of the vaccine were calculated as the empirical probability of HPV genotypes 6/11/16/18/31/33/45/52/58 alone or in combination; the high impact as empirical probability of HPV6/11/16/18/31/33/45/52/58 genotypes alone or in association with other genotypes. The potential impact of the nonavalent vaccine vs quadrivalent was significant for low and high impact (29.7% > 18:8%; 34:6% > 26.6%, respectively). Particularly, in men with lesions and risky sexual contact was significant only for low impact (35.5% > 29.7%; 31.4% > 19.7%, respectively). In partners with positive females was significant for low impact (26.3% > 15.1%) and high impact (33.7% > 23.2%). Nonavalent vaccine offers broader protection in men with HPV positive partners, who would have a potential role in the transmission of the infection.

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) cells, and B and T lymphocytes. Within the tumor microenvironment, however, TNFα is one of the main mediators of cancer-related inflammation. It is involved in the recruitment and differentiation of immune suppressor cells, leading to evasion of tumor immune surveillance. These characteristics turn TNFα into an attractive target to overcome therapy resistance and tackle cancer. This review focuses on the diverse molecular mechanisms that place TNFα as a source of resistance to immunotherapy such as monoclonal antibodies against cancer cells or immune checkpoints and adoptive cell therapy. We also expose the benefits of TNFα blocking strategies in combination with immunotherapy to improve the antitumor effect and prevent or treat adverse immune-related effects.

The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors.

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments.

Breast cancer is the most frequently diagnosed cancer and the principal cause of mortality by malignancy in women and represents a main problem for public health worldwide. Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine whose expression is increased in a variety of cancers. In particular, in breast cancer it correlates with augmented tumor cell proliferation, higher malignancy grade, increased occurrence of metastasis and general poor prognosis for the patient. These characteristics highlight TNFα as an attractive therapeutic target, and consequently, the study of soluble and transmembrane TNFα effects and its receptors in breast cancer is an area of active research. In this review we summarize the recent findings on TNFα participation in luminal, HER2-positive and triple negative breast cancer progression and metastasis. Also, we describe TNFα role in immune response against tumors and in chemotherapy, hormone therapy, HER2-targeted therapy and anti-immune checkpoint therapy resistance in breast cancer. Furthermore, we discuss the use of TNFα blocking strategies as potential therapies and their clinical relevance for breast cancer. These TNFα blocking agents have long been used in the clinical setting to treat inflammatory and autoimmune diseases. TNFα blockade can be achieved by monoclonal antibodies (such as infliximab, adalimumab, etc.), fusion proteins (etanercept) and dominant negative proteins (INB03). Here we address the different effects of each compound and also analyze the use of potential biomarkers in the selection of patients who would benefit from a combination of TNFα blocking agents with HER2-targeted treatments to prevent or overcome therapy resistance in breast cancer., (Copyright © 2020 Mercogliano, Bruni, Elizalde and Schillaci.)

Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triple-negative breast cancer and melanoma growth associated with activation of CD4 + T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3-blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objective: Endometrial cancer (EC) is the second most common gynecological cancer worldwide. Myometrial invasion (MI) is a key event in EC dissemination. This study aimed to evaluate FXYD5/dysadherin (FXYD5/Dys) expression in EC tissue and uterine aspirate (UA) biopsies and to assess molecular/functional changes associated with its expression in cellular models. Methods: FXYD5/Dys messenger RNA (mRNA) levels were determined in EC tissue and UA biopsies. FXYD5/Dys expression was evaluated in EC RNAseq data from The Cancer Genome Atlas (TCGA) and GENEVESTIGATOR tools. FXYD5/Dys impact on E-cadherin expression and cell behavior was assessed in EC Hec1a cells treated with transforming growth factor (TGF)-β1, stably transfected with ETV5, and transiently transfected with FXYD5/Dys small interfering RNA (siRNA) or pcDNA3-FXYD5/Dys plasmid. Results: FXYD5/Dys was associated with EC aggressiveness, finding high mRNA levels in tumors depicting MI > 50%, Grade 3, and intermediate/high risk of recurrence. FXYD5/Dys was highly expressed at the tumor invasive front compared to the superficial area. Most results were recapitulated in UA biopsies. FXYD5/Dys modulation in Hec1a cells altered cell migration/adhesion and E-cadherin expression. TGF-β1 treatment of Hec1a cells induced FXYD5/Dys expression. TCGA-UCEC RNAseq analysis revealed a positive correlation between FXYD5/Dys, TGF-β1, and plasminogen activator inhibitor (PAI)-1 mRNA levels. FXYD5/Dys induced nuclear factor (NF)-κB pathway activation in Hec1a cells. FXYD5/Dys mRNA levels positively correlated with transcriptional activation of NF-κB p65-regulated genes. Survival analysis revealed patient segregation into low- and high-risk groups, the latter depicting the highest FXYD5/Dys, PAI-1, tumor necrosis factor (TNF)-α, and TGF-β1 mRNA levels and shorter survival rates. Conclusion: FXYD5/Dys is a novel biomarker of EC progression related to TGF-β1 and NF-κB pathways that collectively promote tumor dissemination and result in poor patient prognosis., (Copyright © 2019 Besso, Rosso, Lapyckyj, Moiola, Matos, Mercogliano, Schillaci, Reventos, Colas, Gil-Moreno, Wernicke, Orti and Vazquez-Levin.)

Background: Patients affected by Chronic Kidney Disease and Mineral Bone Disorder (CKD-MBD) have a high risk of cardiovascular (CV) mortality that is poorly explained by traditional risk factors. The newest medical treatments for CKD-MBD have been associated with encouraging, but still inconsistent, improvement in CV disease complications and patient survival. A better understanding of the biomarkers and mechanisms of left ventricular hypertrophy (LVH), atherosclerosis, and vascular calcification (VC) may help with diagnosis and treatment of the organ damage that occurs secondary to CKD-MBD, thus improving survival. Recent insights about fibroblast growth factor-23 (FGF23) and its co-receptor, Klotho, have led to marked advancement in interpreting data on vascular aging and CKDMBD., Conclusion: This review will discuss the current experimental and clinical evidence regarding FGF23 and Klotho, with a particular focus on their roles in LVH, atherosclerosis, and VC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Sodium prescription in patients with intradialytic hypotension remains a challenge for the attending nephrologist, as it increases dialysate conductivity in hypotension-prone patients, thereby adding to dietary sodium levels., Methods: New sodium prescription strategies are now available, including the use of a mathematical model to compute the sodium mass to be removed during dialysis as a physiological controller., Results: This review describes the sodium load of patients with end-stage renal disease on chronic hemodialysis (HD) and discusses 2 strategies to remove excess sodium in patients prone to intradialytic hypotension, namely, Profiled HD and the hemodiafiltration Aequilibrium System., Conclusion: The Profiled HD and Aequilibrium System trial both proved effective in counteracting intradialytic hypotension., (© 2017 S. Karger AG, Basel.)

Background: Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC., Methods: We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry., Results: IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1-6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma., Conclusion: In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently monitored and/or receive additional therapies.

Brucella abortus is able to persist inside the host despite the development of potent CD8 + T-cell responses. We have recently reported the ability of B. abortus to inhibit the interferon-γ-induced major histocompatibility complex (MHC)-I cell surface expression on human monocytes. This phenomenon was due to the B. abortus-mediated retention of MHC-I molecules within the Golgi apparatus and was dependent on bacterial viability. However, the implications of bacterial virulence or replicative capacity and the signaling pathways remained unknown. Here we demonstrated that the B. abortus mutant strains RB51 and virB10 - are able to inhibit MHC-I expression in the same manner as wild-type B. abortus, even though they are unable to persist inside human monocytes for a long period of time. Consistent with this, the phenomenon was triggered early in time and could be observed at 8 h postinfection. At 24 and 48 h, it was even stronger. Regarding the signaling pathway, targeting epidermal growth factor (EGF) receptor (EGFR), ErbB2 (HER2) or inhibition of tumor necrosis factor-α-converting enzyme, one of the enzymes which generates soluble EGF-like ligands, resulted in partial recovery of MHC-I surface expression. Moreover, recombinant EGF and transforming growth factor-α as well as the combination of both were also able to reproduce the B. abortus-induced MHC-I downmodulation. Finally, when infection was performed in the presence of an extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, MHC-I surface expression was significantly recovered. Overall, these results describe how B. abortus evades CD8 + T-cell responses early during infection and exploits the EGFR-ERK signaling pathway to escape from the immune system and favor chronicity.