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Vulvar malignant melanoma is the second most common subtype of vulvar cancer, accounting for 5–10% of all vulvar cancers. The prognosis is still very poor, although some advances have been achieved in the last years. One of the most significant changes in its management has been the development of less invasive surgical techniques that diminish the risk of postoperative morbidity and long-lasting sequelae. In this article, we review the surgical management of the pathology, based on the comment of 3 cases with vulvar melanoma treated at our institution.

Fertility preservation in breast cancer patients. Aims. - Study in breast cancer patients whether fertility preservation (FP) can affect the onset of the oncological treatment and the pathological response in those patients who underwent neoadjuvant chemotherapy (NAC). Methods. - Patients with breast cancer who underwent fertility preservation and NAC are matched 1:2.45 to non-FP controls by age and date al diagnosis and are studied: -Timing between the diagnosis of breast cancer and the onset of oncological treatment was performed. The following variables were chosen: 1.- Confirmation (pathologic result), 2.- FP visit, 3.- Onset FP, 4.- Final FP, 5. - Onset oncological treatment. The periods analyzed (median in days) were: 1.- Period of FP visit (AP result-FP visit), 2.- Period of FP (FP beginning -FP ending), 3.- Period of onset of oncological treatment (FP ending-onset of oncological treatment), 4.- Overall period (AP result-onset of oncological treatment). -Studying the pathological complete response (Miller Payne scale) among patients with FP compare to non-FP control group was also performed.Results. - 20 patients with FP and NAC are studied between 2010-2019 and were compared to 49 non-FP patients. The median age at diagnosis was 36 years (28-39). The oncological characteristics of the patients are shown in Table 1.The time analysis in FP group was: 1.- Period of FP visit was 4 days (1-26), 2.- the period of FP (start of the stimulation treatment until the recovery of the oocytes) 12 days (7-20), 3.- the Period of onset of oncological treatment 7 days (1-27). The overall period took 26 days (18-51) compared to 17.5 days (1-60) in non-FP group (NS). Pathological complete response (Miller Payne 5): The pathological complete response was 80% (16/20) in FP group versus 40.8% (20/49) in non-FP group. Analyzed by tumor subtype in FP group, a MP5 was achieved in 72.7% luminal tumor (8/11), 75% positive-HER2 (3/4), 100% triple negative (5/5) versus 19% luminal tumor (4/21), 41.6% (5/12) positive-HER2 and 68.7% triple negative (11/16) in non-FP group. Conclusion. - FP does not delay the onset of oncological treatment and our data do not suggest an adverse impact of FP on pathological complete response to NAC. Table 1. Oncological patient’s characteristicsPatient’s characteristicsCases (%) (range)FP groupNon-FP groupN (patients)20 (100)49 (100)Median age (years)36 (28-39)38 (29-41)Tumor stage-T1c3 (15)6 (12.2)-T216 (80)37 (75.6)-T31 (5)6 (12.2)Lymph node involvement-Positive8 (40)21 (42.8)-Negative12 (60)28 (57.2)Tumor Histology:-IDC15 (83.3)46 (93.8)-ILC3 (16.7)3 (6.2)-NA2Hormone Receptors-Positive14 (70)30 (61.3)-Negative6 (30)19 (38.7)HER2-Positive4 (20)12 (24.5)-Negative16 (80)37 (75.5)Tumor subtype-Luminal11 (55)21 (42.8)-HER2+4 (20)12 (24.5)-Triple negative5 (25)16 (32.7) Citation Format: Sonia Baulies, Maxim Izquierdo, Marta Devesa, Ignacio Rodriguez, Francesc Tresserra, Rafael Fàbregas. Fertility preservation in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-72.

Background & Aims Besides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored. Methods STARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs). Results Patients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, β-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation. Conclusions The study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation. Lay summary Effective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation., We acknowledge support from grants PID2019-111669RB-100, SAF2017-85877R and SAF2015-73579-JIN from Plan Nacional de I+D funded by the Agencia Estatal de Investigación (AEI), the Fondo Europeo de Desarrollo Regional (FEDER) and CIBEREHD; the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA / NIH; as well as support from AGAUR of the Generalitat de Catalunya SGR-2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network, the ‘ER stress-mitochondrial cholesterol axis in obesity-associated insulin resistance and comorbidities’-Ayudas FUNDACION BBVA and the Red Nacional 2018-102799-T de Enfermedades Metabólicas y Cáncer, and Project 201916/31 "Contribution of mitochondrial oxysterol and bile acid metabolism to liver carcinogenesis" 2019 by Fundació Marato TV3. We also acknowledge the support from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI16/00598, co-funded by European Regional Development Fund / European Social Fund, ‘Investing in your future’) and Centro Internacional sobre el Envejecimiento (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from R01 CA2344128 and U01 AA022614 grants to M.K.

Intestinal stem cells (ISCs) are highly proliferative cells that fuel the continuous renewal of the intestinal epithelium. Understanding their regulatory mechanisms during tissue homeostasis is key to delineating their roles in development and regeneration, as well as diseases such as bowel cancer and inflammatory bowel disease. Previous studies of ISCs focused mainly on the position of these cells along the intestinal crypt and their capacity for multipotency. However, evidence increasingly suggests that ISCs also exist in distinct cellular states, which can be an acquired rather than a hardwired intrinsic property. In this Review, we summarise the recent findings into how ISC identity can be defined by proliferation state, signalling crosstalk, epigenetics and metabolism, and propose an update on the hallmarks of ISCs. We further discuss how these properties contribute to intestinal development and the dynamics of injury-induced regeneration.

Background & Aims Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. Methods Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah−/−/Rag2−/−/Il2rg−/−/NOD (FRGN) mice to create mice with humanized livers. Results Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. Conclusions In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2., We acknowledge the support from grants SAF2014–57674R, SAF-2015–69944R, and SAF2017–85877R from Plan Nacional de I+D, Spain, and by the CIBEREHD; the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health (NIH); the NIH R01DK06715 and the USC Research Center for Liver Diseases P30DK485522 Instrumentation (NK), as well as support from AGAUR of the Generalitat de Catalunya SGR-2017–1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network, and the Fundación BBVA.

e12538 Background: The ovary stimulation and the follicular response is related with estradiol level. Study in breast cancer patients after IVF if ovarian response or number of IVF cycles affects the prognostic factors. Methods: Patients with breast cancer who underwent IVF are studied the prognostic factors (Ki67, HER2, estrogen receptor (ER), progesterone receptor (PR), oncogene p53, histologic grade) in relation to the ovary response and number of IVF cycles. Results: 73 patients with breast cancer after IVF are studied. They performed 135 cycles of IVF, 36 (49’3%) with 1 IVF and 37 (50’7%) with more than one IVF. Hyper response was present in at least one IVF in 24 (32.9%) patients and there was no hyper response in any IVF in 49 (67.1%) patients. The prognostic factors were: Ki 67> 20 in 31'91% (15/47) Ki 67

e12613 Background: Study in breast cancer patients to assess whether fertility preservation (FP) can affect the onset of the oncological treatment and the pathological response in those patients who underwent neoadjuvant chemotherapy (NAC). Methods: Patients with breast cancer who underwent fertility preservation and NAC are matched 1:2.45 to non-FP controls by age and date al diagnosis and are studied: -Timing between the diagnosis of breast cancer and the onset of oncological treatment was performed. The following variables were chosen: 1.- Confirmation (pathologic result), 2.- FP visit, 3.- Onset FP, 4.- Final FP, 5. – Onset oncological treatment. The periods analyzed (median in days) were: 1.- Period of FP visit (AP result-FP visit), 2.- Period of FP (FP beginning –FP ending), 3.- Period of onset of oncological treatment (FP ending-onset of oncological treatment), 4.- Overall period (AP result-onset of oncological treatment). -Studying the pathological complete response (Miller Payne scale) among patients with FP compare to non-FP control group was also performed. Results: 20 patients with FP and NAC are studied between 2010-2019 and were compared to 49 non-FP patients. The median age at diagnosis was 36 years (28-39). The oncological characteristics of the patients are shown in Table 1. The time analysis in FP group was: 1.- Period of FP visit was 4 days (1-26), 2.- the period of FP (start of the stimulation treatment until the recovery of the oocytes) 12 days (7-20), 3.- the Period of onset of oncological treatment 7 days (1-27). The overall period took 26 days (18-51) compared to 17.5 days (1-60) in non-FP group (NS). Pathological complete response (Miller Payne 5): The pathological complete response was 80% (16/20) in FP group versus 40.8% (20/49) in non-FP group. Analyzed by tumor subtype in FP group, a MP5 was achieved in 72.7% luminal tumor (8/11), 75% positive-HER2 (3/4), 100% triple negative (5/5) versus 19% luminal tumor (4/21), 41.6% (5/12) positive-HER2 and 68.7% triple negative (11/16) in non-FP group. Conclusions: FP does not delay the onset of oncological treatment and our data do not suggest an adverse impact of FP on pathological complete response to NAC. [Table: see text]

Oxidative stress is a major factor involved in the pathogenesis of renal ischemia/reperfusion (I/R). Exogenous zinc (Zn) was suggested as a potent antioxidant; however, the mechanism by which it strengthens the organ resistance against the effects of reactive oxygen species (ROS) is not yet investigated. The present study aims to determine whether acute zinc chloride (ZnCl2) administration could attenuate endoplasmic reticulum (ER) stress, autophagy, and inflammation after renal I/R. Rats were subjected to either sham operation (Sham group, n = 6), or 1 hr of bilateral ischemia followed by 2 hr of reperfusion (I/R groups, n = 6), or they received ZnCl2 orally 24 hr and 30 min before ischemia (ZnCl2 group, n = 6). Rats were subjected to 1 hr of bilateral renal ischemia followed by 2 hr of reperfusion (I/R group, n = 6). Our results showed that ZnCl2 enhances renal function and reduces cytolysis (p, The Tunisian Ministry of Higher Education and Scientific Research, Tunisia, Grant number: UR12ES11; Plan Nacional de I +D, Spain, Grant numbers: SAF-2014-57674- R, SAF-2015-69944-R; The Generalitat de Catalunya, Spain, Grant number: 2014- SGR785; NIAAA/NIH, Grant number: P50AA011999

Aim: Zinc has proved its efficacy in many models of ischemia reperfusion (I/R) injury. In this study, we used zinc acexamate (ZAC) as an exogenous source of zinc against renal I/R injury and we investigated whether its protective effects are mediated by the decrease of oxidative stress, inflammation, and mitochondria inducedapoptosis. Methods: Rats were orally pretreated with vehicle or ZAC (10 or 100 mg/kg) 24 h and 30 min prior to 1 h of bilateral renal warm ischemia and 2 h of reperfusion. Results: Our data showed that 10 mg/kg of ZAC, but not 100 mg/kg, improved renal architecture and function. Also, the low dose of ZAC up-regulated antioxidant enzymes activities and glutathione level and decreased lipids and proteins oxidation. Interestingly, the use of ZAC resulted in a significant reduce of pro-inflammatory cytokines (IL-1ß, IL-6 and MCP-1), enhanced mitochondria integrity and decreased expression of the pro-apoptotic protein caspase-9. Conclusion: We conclude that renal I/R induced oxidative stress, inflammation and apoptosis and that the use of ZAC at 10 mg/kg, but not 100 mg/kg, protects rat kidneys from I/R injury by down-regulating these processes., This work was supported by grants from: The Tunisian Ministry of Higher Education and Scientific Research (UR12ES11); SAF-2014- 57674-R, SAF-2015-69944-R from Plan Nacional de I + D, Spain and CIBEREHD; the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH; and AGAUR of the Generalitat de Catalunya2014-SGR785.

Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol) accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM) permeabilization. Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC), by depleting mitochondrial GSH (mGSH) due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC) and SLC25A11 (2-oxoglutarate carrier, OGC) have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA depleted mGSH levels and sensitized HCC cells to hypoxia-induced ROS generation and cell death as well as impaired cell growth in three-dimensional multicellular HCC spheroids, effects that were reversible upon mGSH replenishment by GSH ethyl ester, a membrane permeable GSH precursor. We also show that OGC regulates mitochondrial respiration and glycolysis. Moreover, OGC silencing promoted hypoxia-induced cardiolipin peroxidation, which reversed the inhibition of cholesterol on the permeabilization of MOM-like liposomes induced by Bax or Bak. Genetic OGC knockdown reduced the ability of tumor-initiating stem-like cells to induce liver cancer. These findings underscore the selective overexpression of OGC as an adaptive mechanism of HCC to provide adequate mGSH levels in the face of mt-cholesterol loading and suggest that OGC may be a novel therapeutic target for HCC treatment., Graphical abstract fx1, Highlights • OGC overexpression in HCC ensures unrestricted mGSH levels despite cholesterol loading. • OGC protects HCC cells against hypoxia-induced ROS generation, cardiolipin peroxidation and cell death. • OGC promotes mitochondrial oxygen consumption and glycolysis. • OGC silencing decreases in vivo liver tumorigenesis.

To identify the characteristics of uterine sarcomas and assess the impact of morcellation on prognosis.Case-control study. (Canadian Task Force classification II-2).Hospital Quiron-Dexeus, an academic hospital.Patients with uterine sarcoma histologically diagnosed and treated in our center between 1987 and 2013.All descriptive data, including type of surgery and clinical and pathological data, were reviewed. Survival analysis was performed comparing patients with hysterectomy/myomectomy without any type of morcellation and patients with morcellation during surgery.A total of 37 sarcomas were diagnosed during the study period. The most common symptom was metrorrhagia (50%). The indication for surgery was related to myoma growth in 40% of cases and to metrorrhagia in 37.1% of cases. Open surgery was performed in 23 patients (62.2%), and laparoscopy was performed in 9 (24.3%). Myomectomy was performed in 14 patients (37.8%), and 23 patients (62.1%) underwent hysterectomy as initial surgery. Morcellation for tumor extraction was done in 8 cases (21.6%). Survival analysis by surgical approach showed increased disease-free survival (DFS) in the laparotomy group compared with the laparoscopy group (median, 70.3 months vs 10.4 months; p = .018). Median DFS according to type of surgery was 6.3 months in morcellation cases, 11.9 months in vaginal fragmentation cases, and 149.9 months in nonmorcellated cases (p.002). The median time to progression was shorter in morcellated cases (laparocopic and vaginal) compared with nonmorcellated cases (11.9 vs 14.9 months; p.001). No statistically significant differences in prognosis were related to myomectomy versus hysterectomy; however, there were significants difference between morcellation and nonmorcellation cases.Taking into account the negative impact of morcellation in sarcomas, the use of this technique should be reconsidered in cases of myoma with atypical clinical presentation or symptomatology. Patients must be informed about the possibility of a nonidentified sarcoma and the possible impact on prognosis resulting from its morcellation.

Highlights • Breast sarcoma is a rare but aggressive entity. • Core biopsy will be the procedure of choice for the diagnosis. • Lymph node metastases are uncommon and surgery represents the only potentially curative therapy. • Tumor size and, specially, an adequate resection margin are the most important prognostic factors and determinant of long-term survival. • There is no consensus in the use of adjuvant therapy, it will depend mainly on the risk of tumor recurrence., Introduction Breast sarcomas are rare with an annual incidence of 4.6 cases/1,000,000 women. They can appear as primary forms or secondary to radiation therapy or chronic lymphedema. Presentation of case A 41 year old woman attended our hospital after having noticed an increase in the size of her fibroadenoma. The examination revealed a 7 cm retroareolar nodule. Breast sonography described a hypoechoic bilobulated lesion and MRI showed a large size polinodular image, suggesting a Phyllodes tumor. A core needle biopsy was performed with a histological result of low-grade fusiform cells sarcoma on Phyllodes tumor so we proceeded to surgical treatment with a mastectomy. After two years and a half she noticed a tough nodule over the mastectomy scar, which was resected with a histological result of fusiform cells sarcoma. Considering the diagnosis of recurrence of the disease, surgery was undertaken. Discussion Breast sarcoma is a rare but aggressive entity. Core biopsy is the procedure of choice for the diagnosis. Lymphatic spread is uncommon so nodal status in breast sarcoma is less informative. Staging study differs from other breast tumors and chest computed tomography is helpful since lungs are the predominant metastatic sites. The use of radiotherapy or chemotherapy is controversial and will depend on the risk of tumor recurrence. Conclusion Surgery represents the only potentially curative therapy for breast sarcoma. Tumor size and adequate resection margin are the most important prognostic factors. Approximately 80% of recurrences appear in the first two years.

The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the proregenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAPintoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration., Work in the authors' laboratory is supported by CIBERehd and Grants from Instituto de Salud Carlos III (ISCIII) co-financed by 'Fondo Europeo de Desarrollo Regional' (FEDER) 'Una manera de hacer Europa', numbers: FIS PI13/00359, PI13/00385 and PI16/01126. Grants SAF2015-66515-R, SAF201569944-R, SAF 2016-75972 R from Ministerio de Economía y Competitividad, and the center grant P50AA011999 funded by NIAAA. 'Ramón y Cajal-I3' contract to MUL, Mineco-FPI Fellowship to MB-V. Marie Curie EU contract to MGF-B. Fundación M Torres; Fundación Eugenio Rodríguez Pascual; Fundación Mario Losantos; Fundación Familia Puig-Infante and Fundación Bancaria La CaixaHepacare Project.

Mitochondria are considered cholesterol-poor organelles, and obtain their cholesterol load by the action of specialized proteins involved in its delivery from extramitochondrial sources and trafficking within mitochondrial membranes. Although mitochondrial cholesterol fulfills vital physiological functions, such as the synthesis of bile acids in the liver or the formation of steroid hormones in specialized tissues, recent evidence indicates that the accumulation of cholesterol in mitochondria may be a key event in prevalent human diseases, in particular in the development of steatohepatitis (SH) and its progression to hepatocellular carcinoma (HCC). Mitochondrial cholesterol accumulation promotes the transition from simple steatosis to SH due to the sensitization to oxidative stress and cell death. However, mitochondrial cholesterol loading in HCC determines apoptosis resistance and insensitivity to chemotherapy. These opposing functions of mitochondrial cholesterol in SH and HCC define its paradoxical role in cell death as a pro- and anti-apoptotic factor. Further understanding of this conundrum may be useful to modulate the progression from SH to HCC by targeting mitochondrial cholesterol trafficking., The work was supported by CIBEREHD, Fundacio la Marato TV3, SGR2014-785, and Grants SAF2014-57674-R (MINECO/FEDER) and SAF2015-69944-R (MINECO/FEDER) from the Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER), and the center grant P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, NIAAA/NIH).

We report our experience in neoadjuvant breast cancer chemotherapy in a single centre between 2000 and 2011. We looked for predictive factors for response to neoadjuvant chemotherapy in the present study. A total of 110 consecutive breast cancer patients were treated with neoadjuvant chemotherapy in our centre. Pathological response was achieved in 24 HR+/HER2- (38.7%), 25 HER2+ (67.6%) and five triple-negative (45.5%) (p = 0.02) patients. No statistically significant differences were found in pathological tumour response according to T stage. The multivariate analysis revealed tumour subtype was the only associated factor for pathological response, with HER2 + tumours the best responders, OR 3.9 (1.5-9.9): 5-year DFS was 40% HER2+/no response; 78% HER2+/response; 65% HR+/HER2-/no response; 82% HR+/HER2-/response; 25% triple-negative/no response and 100% triple-negative/response. HR and HER2 status were the only prognostic factors for pathological response. pCR was correlated with survival in all tumour subtypes.

IntroductionEndometriosis is defined as the emergence and growth of endome-trial tissue (glands and stroma) outside of the uterus. It affects 8–15%ofthepopulationandismostfrequentlyfoundintheovary.Extrapelvicimplantationmayoccurinanyorganortissue,butisrareintheabdom-inal wall. When it does occur there, a history of surgery, whetherlaparotomy or laparoscopy, is usually present.Malignancy of this type of endometriosis in an abdominal wall scarmay occur from just a few months until up to 18 years after surgery(Hensen et al., 2006). The case we discuss below deals with themalignant transformation of cesarean scar endometriosis with nodalmetastasis at preperitoneal level. This is interesting because no otherknown cases have ever been reported.Case presentationWehereinpresentthecaseofa49 year-oldpatientwithahistoryofappendectomy, two births, a cesarean section, and removal of theendometriotic mass in the cesarean scar, 15 years before.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and refers to a spectrum of disorders ranging from steatosis to steatohepatitis, a disease stage characterized by inflammation, fibrosis, cell death and insulin resistance (IR). Due to its association with obesity and IR the impact of NAFLD is growing worldwide. Consistent with the role of mitochondria in fatty acid (FA) metabolism, impaired mitochondrial function is thought to contribute to NAFLD and IR. Indeed, mitochondrial dysfunction and impaired mitochondrial respiratory chain have been described in patients with non-alcoholic steatohepatitis and skeletal muscle of obese patients. However, recent data have provided evidence that pharmacological and genetic models of mitochondrial impairment with reduced electron transport stimulate insulin sensitivity and protect against diet-induced obesity, hepatosteatosis and IR. These beneficial metabolic effects of impaired mitochondrial oxidative phosphorylation may be related not only to the reduction of reactive oxygen species production that regulate insulin signaling but also to decreased mitochondrial FA overload that generate specific metabolites derived from incomplete FA oxidation (FAO) in the TCA cycle. In line with the Randle cycle, reduced mitochondrial FAO rates may alleviate the repression on glucose metabolism in obesity. In addition, the redox paradox in insulin signaling and the delicate mitochondrial antioxidant balance in steatohepatitis add another level of complexity to the role of mitochondria in NAFLD and IR. Thus, better understanding the role of mitochondria in FA metabolism and glucose homeostasis may provide novel strategies for the treatment of NAFLD and IR. © 2013 Informa UK, Ltd.

PMCID: PMC3779525.-- et al., [Background & Aims]: The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD. [Methods]: We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase-/- mice fed alcohol. [Results]: Alcohol feeding increased SREBP-1c, DGAT-2, and FAS mRNA in ASMase+/+ but not in ASMase-/- mice. Compared to ASMase+/+ mice, ASMase-/- mice exhibited decreased expression of ER stress markers induced by alcohol, but the level of tunicamycin-mediated upregulation of ER stress markers and steatosis was similar in both types of mice. The increase in homocysteine levels induced by alcohol feeding was comparable in both ASMase+/+ and ASMase-/- mice. Exogenous ASMase, but not neutral SMase, induced ER stress by perturbing ER Ca2+ homeostasis. Moreover, alcohol-induced mChol loading and StARD1 overexpression were blunted in ASMase-/- mice. Tunicamycin upregulated StARD1 expression and this outcome was abrogated by tauroursodeoxycholic acid. Alcohol-induced liver injury and sensitization to LPS and concanavalin-A were prevented in ASMase-/- mice. These effects were reproduced in alcohol-fed TNFR1/R2-/- mice. Moreover, ASMase does not impair hepatic regeneration following partial hepatectomy. Of relevance, liver samples from patients with alcoholic hepatitis exhibited increased expression of ASMase, StARD1, and ER stress markers. [Conclusions]: Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved., The work was supported by CIBEREHD, Fundació la Marató de TV3, la Mutua Madrileña, and grants PI10/02114, PI09/0056 and PI09/1164 (Instituto de Salud Carlos III), SAF2008-02199, SAF2009-11417, SAF2010-15760, SAF2011-23031, SAF2012-34831, and BFU2010-18826 (Plan Nacional de I+D), Spain; and P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, NIAAA/NIH).

Nonalcoholic steatohepatitis is one of the leading causes of liver disease. Dietary factors determine the clinical presentation of steatohepatitis and can influence the progression of related diseases. Cholesterol has emerged as a critical player in the disease and hence consumption of cholesterol-enriched diets can lead to a progressive form of the disease. The aim was to investigate the impact of liver cholesterol overload on the progression of the obstructive cholestasis in mice subjected to bile duct ligation surgery. Mice were fed with a high cholesterol diet for two days and then were subjected to surgery procedure; histological, biochemical, and molecular analyses were conducted to address the effect of cholesterol in liver damage. Mice under the diet were more susceptible to damage. Results show that cholesterol fed mice exhibited increased apoptosis and oxidative stress as well as reduction in cell proliferation. Mortality following surgery was higher in HC fed mice. Liver cholesterol impairs the repair of liver during obstructive cholestasis and aggravates the disease with early fatal consequences; these effects were strongly associated with oxidative stress., This work was supported by grants of the CONACYT 252942, 236558, and 166042, CONACYT Fronteras de la Ciencia 1320, Asociación Mexicana de Hepatología, and SEP-PRODEP-913026-1461211, Universidad Autónoma Metropolitana Iztapalapa, by grants SAF-2011-23031 and SAF-2012-34831 from Plan Nacional de I+D, Spain, Fundació la Marató de TV3, La Mutua Madrileña, PI11/0325 (META) Grant from the Instituto Salud Carlos III, by the support of CIBEREHD, and by the Center Grant P50-AA-11999 from Research Center for Liver and Pancreatic Diseases funded by NIAAA/NIH.

Background Paclitaxel is an antimitotic antitumour drug highly effective against a broad range of cancers considered refractory to conventional chemotherapy. One of the main serious side effects of paclitaxel treatment is the induction of peripheral neuropathic pain that often diminishes the patient's quality of life. In this study, we evaluated the severity of the neuropathy induced by paclitaxel and the inflammatory reaction in the dorsal horn of the spinal cord in young, adult and aged male CD1 mice. Method Hyperalgesia to noxious thermal stimulus and allodynia to non-noxious mechanical stimulus were evaluated using the plantar test and the von Frey filament model, respectively. Spinal cord microglia and astrocytes expression was assessed using Iba1 and glial fibrillary acidic protein immunofluorescence staining, respectively. Results All groups of mice showed a higher nociceptive reaction to thermal noxious (hyperalgesia) and mechanical non-noxious (allodynia) stimuli after paclitaxel treatment. However, these signs of neuropathy were enhanced in young mice followed by aged animals. Additionally, paclitaxel evoked a marked microglial and astrocytic response in the spinal cord of young and aged mice, whereas this enhanced reactivity was less important in adult mice. Indeed, the most severe glial activation observed in juvenile animals correlated well with major signs of neuropathy in this group of age. Conclusion Our results demonstrate that paclitaxel-induced neuropathy in mice is an age-dependent phenomenon whose severity devolves on glial response.

The role of lysosomes in acetaminophen (APAP) hepatotoxicity is poorly understood. Here, we investigated the impact of genetic and drug-induced lysosomal cholesterol (LC) accumulation in APAP hepatotoxicity. Acid sphingomyelinase (ASMase) mice exhibit LC accumulation and higher mortality after APAP overdose compared to ASMase littermates. ASMase hepatocytes display lower threshold for APAP-induced cell death and defective fusion of mitochondria-containing autophagosomes with lysosomes, which decreased mitochondrial quality control. LC accumulation in ASMase hepatocytes caused by U18666A reproduces the susceptibility of ASMase hepatocytes to APAP and the impairment in the formation of mitochondria-containing autolysosomes. LC extraction by 25-hydroxycholesterol increased APAP-mediated mitophagy and protected ASMase mice and hepatocytes against APAP hepatotoxicity, effects that were reversed by chloroquine to disrupt autophagy. The regulation of LC by U18666A or 25-hydroxycholesterol did not affect total cellular sphingomyelin content or its lysosomal distribution. Of relevance, amitriptyline-induced ASMase inhibition in human hepatocytes caused LC accumulation, impaired mitophagy and increased susceptibility to APAP. Similar results were observed upon glucocerebrosidase inhibition by conduritol β-epoxide, a cellular model of Gaucher disease. These findings indicate that LC accumulation determines susceptibility to APAP hepatotoxicity by modulating mitophagy, and imply that genetic or drug-mediated ASMase disruption sensitizes to APAP-induced liver injury., The work was supported by grants SAF-2011-23031, SAF-2012-34831 from Plan Nacional de I+ D, Spain, Fundació Marató de TV3, La Mutua Madrileña, PI11/0325 (META) grant from the Instituto Salud Carlos III, and by the support of CIBEREHD; the center grant P50-AA-11999 Research Center for Liver and Pancretic Diseases funded by NIAAA/NIH; R01 DK067215 and Liver Center P30DK48522 Cell Culture, Analytical/Metabolic Intstrumentation and Cell and Tissue Imaging Cores.

Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic acid (MA), a free fatty acid highly abundant in copra/palmist oils, is a predictor of nonalcoholic steatohepatitis (NASH) and stimulates ceramide synthesis. Here we investigated the synergism between MA and PA in ceramide synthesis, ER stress, lipotoxicity and NASH. Unlike PA, MA is not lipotoxic but potentiated PA-mediated lipoapoptosis, ER stress, caspase-3 activation and cytochrome c release in primary mouse hepatocytes (PMH). Moreover, MA kinetically sustained PA-induced total ceramide content by stimulating dehydroceramide desaturase and switched the ceramide profile from decreased to increased ceramide 14:0/ceramide16:0, without changing medium and long-chain ceramide species. PMH were more sensitive to equimolar ceramide14:0/ceramide16:0 exposure, which mimics the outcome of PA plus MA treatment on ceramide homeostasis, than to either ceramide alone. Treatment with myriocin to inhibit ceramide synthesis and tauroursodeoxycholic acid to prevent ER stress ameliorated PA plus MA induced apoptosis, similar to the protection afforded by the antioxidant BHA, the pan-caspase inhibitor z-VAD-Fmk and JNK inhibition. Moreover, ruthenium red protected PMH against PA and MA-induced cell death. Recapitulating in vitro findings, mice fed a diet enriched in PA plus MA exhibited lipodystrophy, hepatosplenomegaly, increased liver ceramide content and cholesterol levels, ER stress, liver damage, inflammation and fibrosis compared to mice fed diets enriched in PA or MA alone. The deleterious effects of PA plus MA-enriched diet were largely prevented by in vivo myriocin treatment. These findings indicate a causal link between ceramide synthesis and ER stress in lipotoxicity, and imply that the consumption of diets enriched in MA and PA can cause NASH associated with lipodystrophy., This work was supported by grants SAF-2011- 23031, SAF-2012-34831 from Plan Nacional de I+D, Spain, Fundació Marató de TV3, La Mutua Madrileña, PI11/0325 (META) grant from the Instituto Salud Carlos III, and by the support of CIBEREHD; the center grant P50-AA-11999 Research Center for Liver and Pancretic Diseases funded by NIAAA/NIH. Laura Martinez acknowledges support from Formación de Personal Investigador (FPI) fellowship BES-2009-027637, Boehringer Ingelheim and Journal of Cell Science Travel Fellowships.

Background: Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time. Methods: Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length. Results: The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The ‘prognostic benefit' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1–0.4) at 6 months to 2.2 (95% CI 1.3–3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1–2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4–1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group. Conclusion: From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.

The Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II has broadened the indications for cardioverter defibrillator implantation. We present a retrospective study designed to estimate the number of patients in Spain eligible for an implantable defibrillator according to the MADIT-II criteria. From January 1999 to October 2002, 758 consecutive patients were admitted to our center with the diagnosis of acute myocardial infarction. Sixty-seven had a left ventricular ejection fractionor = 30% (mean, 23[5]) and were not eligible for revascularization. Excluding patients older than 80 years and patients with marked co-morbidity, 47 patients met the MADIT-II criteria for an implantable defibrillator. After a mean follow-up of 18 months, there were 20 deaths, 6 of which were considered sudden. In conclusion, application of the MADIT-II criteria for defibrillator implantation may benefit 6% of the patients with myocardial infarction in Spain. This proportion translates as 4110 defibrillator implantations.

Raquel Fucho et al., [Background & Aims]: Acid sphingomyelinase (ASMase) is activated in non-alcoholic steatohepatitis (NASH). However, the contribution of ASMase to NASH is poorly understood and limited to hepatic steatosis and glucose metabolism. Here we examined the role of ASMase in high fat diet (HFD)-induced NASH. [Methods]: Autophagy, endoplasmic reticulum (ER) stress and lysosomal membrane permeabilization (LMP) were determined in ASMase-/- mice fed a HFD. The impact of pharmacological ASMase inhibition on NASH was analyzed in wild type mice fed a HFD. Results: ASMase deficiency determined resistance to hepatic steatosis mediated by a HFD or methionine-choline deficient diet. ASMase-/- mice were resistant to HFD-induced hepatic ER stress, but sensitive to tunicamycin-mediated ER stress, indicating selectivity in the resistance of ASMase-/- mice to ER stress and steatosis. Autophagic flux, determined in the presence of rapamycin and/or chloroquine, was lower in primary mouse hepatocytes (PMH) from ASMase-/- mice and accompanied by increased p62 levels, suggesting autophagic impairment. Moreover, autophagy suppression by chloroquine and brefeldin A caused ER stress in PMH from ASMase+/+ mice but not in ASMase-/- mice. ASMase-/- PMH exhibited increased lysosomal cholesterol loading, decreased LMP and apoptosis resistance induced by O-methyl-serine dodecylamide hydrochloride or palmitic acid, effects that were reversed by decreasing cholesterol levels by oxysterol 25-hydroxycholesterol. In vivo pharmacological ASMase inhibition by amitriptyline, a widely used tricyclic antidepressant, protected wild type mice against HFD-induced hepatic steatosis, fibrosis, and liver damage, effects indicative of early-stage NASH. [Conclusions]: These findings underscore a critical role for ASMase in diet-induced NASH and suggest the potential of amitriptyline as a treatment for patients with NASH. © 2014 European Association for the Study of the Liver, The work was supported by CIBEREHD, Fundació la Marató de TV3 and grants PI11/0325 (META) from the Instituto Salud Carlos III and grants SAF2009-11417, SAF2011-23031, and SAF2012-34831 from Plan Nacional de I+D, Spain; and the center grant P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, NIAAA/NIH).

Summary: Metastatic breast carcinoma can mimic benign cutaneous lesions. Breast surgeons should be aware of skin manifestations to be able to distinguish them and set a proper therapeutic strategy. A clinical case of cutaneous lesion after breast cancer is presented. A 41-year-old woman with a history of left breast cancer underwent a prophylactic right nipple-sparing mastectomy with immediate breast implant reconstruction. After surgery, she attended our service due to a right periareolar rash resistant to medical treatment, accompanied by cutaneous induration and fixed axillary adenopathy. A differential diagnosis of skin metastases was considered. Cutaneous metastases should be the first diagnosis of skin lesions in oncological patients due to the implications in terms of treatment and prognosis. However, differential diagnoses have to be discussed.

Background: The identification and validation of suitable predictive and prognostic factors are a challenge to improve the treatment scheme selection. Discordances in histological grade can be established between core biopsy and surgical specimens. This is important in HR-positive/HER2-negative subgroup where histological grade identifies patients at high risk and is a strong determinant for treatment scheme. Methods: A total of 350 consecutive invasive breast carcinoma biopsies were assessed and compared with surgical specimens in Institut Curie, Paris, France. Clinical, radiological and pathological data were recorded. Results: Histological grade concordance rate in the HR+/HER2− group was 75%. A grade underestimation was mainly due to mitotic index misgrading (23%). Large tumours (P

Background The global mortality caused by cardiovascular disease increases with weight. The Framingham study showed that obesity is a cardiovascular risk factor independent of other risks such as type 2 diabetes mellitus, dyslipidemia and smoking. Moreover, the main problem in the management of weight-loss is its maintenance, if it is achieved. We have designed a study to determine whether a group motivational intervention, together with current clinical practice, is more efficient than the latter alone in the treatment of overweight and obesity, for initial weight loss and essentially to achieve maintenance of the weight achieved; and, secondly, to know if this intervention is more effective for reducing cardiovascular risk factors associated with overweight and obesity. Methods This 26-month follow up multi-centre trial, will include 1200 overweight/obese patients. Random assignment of the intervention by Basic Health Areas (BHA): two geographically separate groups have been created, one of which receives group motivational intervention (group intervention), delivered by a nurse trained by an expert phsychologist, in 32 group sessions, 1 to 12 fortnightly, and 13 to 32, monthly, on top of their standard program of diet, exercise, and the other (control group), receiving the usual follow up, with regular visits every 3 months. Discussion By addressing currently unanswered questions regarding the maintenance in weight loss in obesity/overweight, upon the expected completion of participant follow-up in 2012, the IMOAP trial should document, for the first time, the benefits of a motivational intervention as a treatment tool of weight loss in a primary care setting. Trial Registration ClinicalTrials.gov Identifier: NCT01006213

Objective To evaluate the role of ultrasound in prenatal diagnosis of vasa praevia (VP) and to asses the risk of VP associated with different causal factors. Material and Methods A retrospective study of the incidence of VP in a series of 12 063 deliveries between January 2000 and March 2005. We also studied the factors that predisposed for VP and the perinatal outcome of pregnancies. Results The prevalence of VP in our centre during this period was 0.07% (9 cases). All cases were prenatally diagnosed. The mean gestational age at diagnosis was 26 weeks. Multivariate analysis revealed the following associated factors: IVF pregnancies, bilobate or succenturiate placenta, and second-trimester placenta praevia, with an odds ratio of 7.75, 22.11 and 22.86, respectively. Conclusions In our series, the prenatal diagnosis of all cases of VP achieved during the second-trimester scan allowed us to avoid any prenatal death related to this condition. Copyright © 2007 John Wiley & Sons, Ltd.

1042 Background: Neoadjuvant chemotherapy is generally used for treatment of both early stage and locally advanced breast cancer. However, robust prognostic or predictive biomarkers are needed in t...

Goals: features of Libyan breast cancer patients have not been fully investigated. The aim of this study is to evaluate the expression patterns of estrogen receptors, progesterone receptors, as well as nuclear morphometric features in these cancers, and to correlate them with clinico-pathologic features and prognosis. Methods: 62 female Libyan breast cancer patients diagnosed between 2000 and 2006 were retrospectively studied. Their clinical and pathologic data were collected and analysed. Immunohistochemical evaluation of ER and PR expression was done. Nuclear morphometry was carried out. Results: Of the 62 patients, 10 were of lobular type, 43 were invasive ductal and 9 were other carcinoma types. 47 of 62 had lymph node involvement. Positive hormonal receptor expression was more common among lymph node negative than among lymph node positive tumours. ER and PR positive patients appeared to have a better survival than ER and PR negative patients. The most significance difference in respect to survival was found between completely negative hormonal stain (J score 0) and positive staining (J score 1, 2 and 3). Larger nuclear size parameters were associated with lymph node involvement and high grade tumours (p

e22119 Background: Although it is know that pCR following neoadjuvant chemotherapy is more frequent in some subtypes of breast cancer such as Triple Negative (TN) or erb2 tumors, the predictive role of gene expression and mutation status is not well defined in this setting. Methods: We analyzed samples from 41 patients (p) prospectively treated with neoadjuvant chemotherapy (sequential AC followed by weekly TXL, or inverse sequence, plus trastuzumab for erb2 positive p). Pathologic response (PR) was classified according to Miller-Payne and RCB criteria. Radiologic evaluation was performed by ultrasonography, dynamic MR and PET-TAC after each chemotherapy sequence. We performed expression analysis of AXL, BRCA1, RAP80, BIM, EZH2, ROR1, FGFR1, PTPN12, YAP, GAS6, beta-TRCP, HIF1 alpha and ZNF217 by RT-PCR, and mutational status of p53 and PI3K genes in pretreatment biopsies. Statistical analysis was performed using Mann-Whitney U and Pearson’s chi-squared tests. Results: pCR was detected in 5 p (3TN, 2 erb2) of 25 p (9 luminal A, 5 luminal B, 6 erb2 and 5 TN) evaluated for PR at time of submitting this abstract. TN tumors had lower levels of RAP80 (p=.0013), PTPN12 (p=.003), beta TRCP (p=.001), ZNF217 (p=.014) and YAP (p=.097). Luminal B tumors had low levels of YAP and the highest levels of FGFR1 (p=.09) and ZNF217 (p=.014). Luminal A tumors had high levels of beta-TRCP (p=.003). We found no differences in BRCA1, AXL, BIM, EZH2, ROR1, GAS6 and HIF1 levels by breast cancer subtype. P with low levels of FGFR1 (p=.087), HIF1alpha (p=.07) or EZH2 (p=.005) had higher probability of pCR. No pCR was observed in p with higher levels of AXL, EZH2, RAP80, GAS6, beta TRCP, HIF alpha. Four p had p53 mutations (1 luminal B, 1 erb2 and 2 TN) and 4 p had PI3K mutations (2 luminal A, 1 erb2, 1 luminal B). There was no correlation between p53 status and PR. P with PI3K mutations did not achieve pCR vs 46% of p with wild type PI3K (p=.23). Conclusions: Gene expression profile varies by breast cancer subtype. Chemosensitivity could be higher in tumors with lower levels of FGFR1, HIF1alpha or EZH2. Further results will be presented.

The aim was to compare the clinical features and prognosis of tubular breast cancer with the rest of breast cancer grade I.