Role of the Mosaic Cisternal Maturation Machinery in Glycan Synthesis and Oncogenesis.

Tumorigenesis is associated with the deregulation of multiple processes, among which the glycosylation of lipids and proteins is one of the most extensively affected. However, in most cases, it remains unclear whether aberrant glycosylation is a cause, a link in the pathogenetic chain, or a mere consequence of tumorigenesis. In other cases, instead, studies have shown that aberrant glycans can promote oncogenesis. To comprehend how aberrant glycans are generated it is necessary to clarify the underlying mechanisms of glycan synthesis at the Golgi apparatus, which are still poorly understood. Important factors that determine the glycosylation potential of the Golgi apparatus are the levels and intra-Golgi localization of the glycosylation enzymes. These factors are regulated by the process of cisternal maturation which transports the cargoes through the Golgi apparatus while retaining the glycosylation enzymes in the organelle. This mechanism has till now been considered a single, house-keeping and constitutive function. Instead, we here propose that it is a mosaic of pathways, each controlling specific set of functionally related glycosylation enzymes. This changes the conception of cisternal maturation from a constitutive to a highly regulated function. In this new light, we discuss potential new groups oncogenes among the cisternal maturation machinery that can contribute to aberrant glycosylation observed in cancer cells. Further, we also discuss the prospects of novel anticancer treatments targeting the intra-Golgi trafficking process, particularly the cisternal maturation mechanism, to control/inhibit the production of pro-tumorigenic glycans.

Oxigenoterapia de alto flujo: Experiencia en pediatría en un hospital general / High-flow oxygen therapy: Experience in pediatrics at a general hospital

Introducción: La Oxigenoterapia de Alto Flujo (OAF) es una técnica de soporte respiratorio no invasiva, que ofrece un flujo de aire y oxígeno, caliente y humidificado, por encima del flujo pico inspiratorio del paciente, a través de una cánula nasal. En este artículo se presenta la experiencia con OAF en una sala de pediatría de mediana y baja complejidad para el tratamiento de bronquiolitis/ infección respiratoria aguda baja (IRAB). Materiales y métodos: Se diseñó un protocolo para la implementación de OAF. Criterios de inclusión: Pacientes cursando bronquiolitis/ IRAB con: Score de Tal modificado ≥6, Sat O2 < 92% y/o mala mecánica ventilatoria, a pesar de recibir más de 2 lt/ min de O2 por cánula nasal ó FiO2 >40%. Criterios de exclusión, pCO2 ≥55 mmHg; pH: < 7,20; Apneas ≥20 segundos; Glasgow ≤10; Peso >15 kg. Inestabilidad hemodinámica; Alteraciones craneofaciales. Resultados: En el periodo 2017- 2018 se internaron 441 pacientes con infección respiratoria aguda baja. Se administró OAF a 54 pacientes (12%). La mediana de edad mediana 7,4 meses (r: 27 días-36 meses). Los pacientes ingresados no presentaban comorbilidades asociadas. El 22,2% (12/54) fueron trasladados a UTIP (2,7% del total de los internados). El 64.8% de los pacientes que permanecieron en sala de internación, mostró mejoría en FC y FR a las 4 hs. Por el contrario, en el 75% de los pacientes que requirieron UTIP no se evidenció mejoría en estos parámetros. Conclusiones: La OAF es una alternativa terapéutica que podría disminuir el ingreso a UTIP en pacientes con dificultad respiratoria moderada. En nuestra experiencia resultó fácil de implementar, sin efectos adversos graves (AU)

Introduction: High-flow oxygen (HFO) therapy is a non-invasive oxygen support technique that provides hot and humidified air and oxygen flow above the peak inspiratory flow of the patient through a nasal cannula. In this study we present our experience with HFO on a intermediate and low complexity ward for the treatment of bronchiolitis/acute lower respiratory tract infection (LRTI). Material and methods: A protocol for the implementation of HFO was designed. Inclusion criteria: Patients with bronchiolitis/ALRI with: Modified Tal score ≥6, Sat O2 < 92%, and/or poor ventilatory mechanism, in spite of receiving more than 2 L/ min O2 by nasal cannula or FiO2 >40%. Exclusion criteria: pCO2 ≥55 mmHg; pH: < 7.20; Apnea ≥20 seconds; Glasgow score ≤10; Peso >15 kg. Hemodynamic instability; Craniofacial abnormalities. Results: During 2017- 2018, 441 patients were admitted with LRTI. HFO was administered to 54 patients (12%). Median age was 7.4 months (r: 27 days-36 months). The patients that were included in the study did not have associated morbidities. Overall, 22.2% (12/54) were transferred to the PICU (2.7% of all hospitalized patients). Of the patients who remained on the ward, 64.8% improved FC and FR after 4 hours. On the other hand, in 75% of the patients that required PICU admission these parameters did not improve. Conclusions: HFO is a therapeutic option to decrease PICU admission of patients with moderate respiratory difficulties. The protocol was easy to implement and was not associated with severe adverse effects (AU)

Axillary web syndrome assessment using a self-assessment questionnaire: a prospective cohort study.

BACKGROUND: Surgical procedure for breast cancer is not without its side effects and one such side effect is axillary web syndrome (AWS), characterized by palpable fibrotic-like cords in the operated arm. As physical evaluation is the only gold standard method used, our study aims to assess the incidence and early detection of AWS with a self-assessment questionnaire. METHODS: From July 2013 to July 2014, 370 breast cancer patients were enrolled. AWS incidence was 51.1%, with 94.1% onset in the first 4 weeks after surgery; 43.5% of the patients did not recover in the first 8 weeks. Univariate analysis showed that BMI (P < 0.001), age (P < 0.001), educational level (P = 0.01), and exercise frequency in the eighth week of follow-up (P < 0.001) were significantly associated with the AWS detection, and multivariate analyses confirmed that younger patients (age < 50) have significantly higher AWS detection (OR = 2.38 (95%CI 1.53, 3.71) and that BMI is associated with AWS, with normal weight patients (BMI ≤ 25) having a significantly greater AWS detection with an odds ratio of 2.11 (95%CI 1.33, 3.36). CONCLUSION: Our findings indicated that the incidence of AWS is high in breast cancer patients, particularly in the first month after surgery. Not all patients achieved recovery during our 8 week follow-up, suggesting that evaluation and treatment should be longer. Double AWS detection was found for patients who were younger (age < 50) and with normal weight.

Physical function of the upper limb after breast cancer surgery. Results from the SOUND (Sentinel node vs. Observation after axillary Ultra-souND) trial.

BACKGROUND: The SOUND (Sentinel node vs. Observation after axillary Ultra-souND) trial is an ongoing prospective randomized study comparing sentinel node biopsy vs. no axillary surgical staging in patients with small breast cancer and negative pre-operative ultra-sound of the axilla. PATIENTS AND METHODS: The first 180 recruited patients were administered the QuickDASH (Disability Arm and Shoulder) questionnaire at different time points (before surgery, 1 week, 6 months and 1 year after surgery) to evaluate the physical function of the ipsilateral upper limb, The QuickDASH score ranges from 0 (no disability) to 100 (complete disability). RESULTS: 176 patients were available for analysis (94 in SNB arm and 82 in observation arm). The two groups were comparable with respect to age, tumor characteristics and treatments. Pre-surgery score values were 3.0% and 2.7% in the SNB arm and observation arm, respectively (P = 0.730). One week after surgery, the score increased to 24.0% in the SNB arm and 10.6% in the observation arm (P < 0.001). After 6 and 12 months, the score decreased in both arms to values similar to baseline values. The overall trend in time of the score was significantly different between the two arms (P < 0.001), even after the exclusion of five patients who received AD in the SNB arm (P < 0.001). CONCLUSIONS: Patients who underwent SNB had a significantly higher rate of disability in the early post-operative period compared to patients who did not. The avoidance of SNB might translate into a considerable reduction of physical and emotional distress.

Sentinel node biopsy after neoadjuvant treatment in breast cancer: Five-year follow-up of patients with clinically node-negative or node-positive disease before treatment.

PURPOSE: It is controversial whether sentinel node biopsy (SNB) without axillary dissection (AD) should be performed in cN1/2 breast cancer patients who become cN0 after neoadjuvant treatment, since the false negative rate (FNR) may be unacceptably high. We assessed outcomes to address this issue. METHODS: We retrospectively assessed 396 cT1-4, cN0/1/2 patients, who became or remained cN0 after neoadjuvant treatment and underwent SNB with at least one sentinel node (SN) found, and AD not performed if the SN was negative. RESULTS: After a median follow-up of 61 months (interquartile range 38-82), five-year overall survival was 90.7% (95% CI, 87.7-93.7) in the whole cohort, 93.3% (95% CI, 90.0-96.6) in those initially cN0, and 86.3% (95% CI, 80.6-92.1) in those initially cN1/2 (P = 0.12). Axillary failure occurred in only 1 (0.7%) initially cN1/2 patient who became cN0. In initially cN0 patients, and also initially cN1/2 patients who responded well to neoadjuvant treatment (ypT0/ypTx), SN-negativity was a significant predictor of good outcome, consistent with the known prognostic significance of axillary status, and suggesting that SN status accurately reflected axillary status. By contrast, in initially cN1/2 patients found to be ypT1/2/3, SN status (and whether or not AD was performed) had no influence on survival. CONCLUSIONS: These findings suggest that SNB is acceptable in cN1/2 patients who become cN0 after neoadjuvant therapy.

NET amyloidogenic backbone in human activated neutrophils.

Activated human neutrophils produce a fibrillar DNA network [neutrophil extracellular traps (NETs)] for entrapping and killing bacteria, fungi, protozoa and viruses. Our results suggest that the neutrophil extracellular traps show a resistant amyloidogenic backbone utilized for addressing reputed proteins and DNA against the non-self. The formation of amyloid fibrils in neutrophils is regulated by the imbalance of reactive oxygen species (ROS) in the cytoplasm. The intensity and source of the ROS signal is determinant for promoting stress-associated responses such as amyloidogenesis and closely related events: autophagy, exosome release, activation of the adrenocorticotrophin hormone/α-melanocyte-stimulating hormone (ACTH/α-MSH) loop and synthesis of specific cytokines. These interconnected responses in human activated neutrophils, that have been evaluated from a morphofunctional and quantitative viewpoint, represent primitive, but potent, innate defence mechanisms. In invertebrates, circulating phagocytic immune cells, when activated, show responses similar to those described previously for activated human neutrophils. Invertebrate cells within endoplasmic reticulum cisternae produce a fibrillar material which is then assembled into an amyloidogenic scaffold utilized to convey melanin close to the invader. These findings, in consideration to the critical role played by NET in the development of several pathologies, could explain the structural resistance of these scaffolds and could provide the basis for developing new diagnostic and therapeutic approaches in immunomediated diseases in which the innate branch of the immune system has a pivotal role.

Risk of subsequent in situ and invasive breast cancer in human epidermal growth factor receptor 2-positive ductal carcinoma in situ.

BACKGROUND: To assess the prognostic role of human epidermal growth factor receptor 2 (HER2) overexpression in patients with ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: We identified patients with HER2-positive DCIS among a population of 1667 cases, prospectively diagnosed and surgically treated at the European Institute of Oncology from 1996 to 2008. Rates of subsequent DCIS or invasive cancer in HER2-positive disease were estimated. We evaluated Cumulative Incidence of In Situ Breast Cancer Recurrence (isBCR), INvasive Breast Cancer Recurrence (IBCR) and any Breast Cancer Recurrence (BCR). isBCR, IBCR and BCR were defined as the time from surgery to breast cancer recurrence as first event (in situ, invasive or both, respectively) or last visit in case of no events. RESULTS: We identified 560 (33.5%) patients with HER2-positive DCIS. The median follow-up was 7.6 years (interquartile range 5.9-9.5). We observed 422 events out of 1667 patients, with 141 in situ recurrences, 201 invasive recurrences and 80 other events (64 second primaries and 16 deaths). The 10-year isBCR proportions were 11.8% [95% confidence interval (CI) 9.0% to 15.4%] in the HER2-positive group and 8.8% (95% CI 6.9% to 11.0%) in the HER2-negative group (Gray test, P = 0.010). At multivariable analysis, the adjusted risk of isBCR was higher in the HER2-positive group than in the HER2-negative group [hazard ratio (HR) HER2 positive versus negative: 1.59 (95% CI 1.06-2.39)]. We observed significant differences both in BCR and isBCR for patients treated by quadrantectomy without radiotherapy versus patients treated with radiotherapy [adjusted HR HER2 positive versus negative: 1.53 (95% CI 1.07-2.18) and adjusted HR HER2 positive versus negative: 2.18 (95% CI 2.18-3.69), respectively]. CONCLUSION: HER2 overexpression predicts an increased risk of isBCR. Radiotherapy reduces local failure rates in HER2-positive DCIS.

Second Axillary Sentinel Lymph Node Biopsy for Breast Tumor Recurrence: Experience of the European Institute of Oncology.

PURPOSE: This retrospective study aimed to determine the feasibility, accuracy, and recurrence rates of lymphoscintigraphy and the new sentinel lymph node biopsy (SLNB) for patients with ipsilateral breast tumor recurrences who were treated previously with conservative surgery and had negative SLNB results. METHODS: The study was conducted at the European Institute of Oncology in Milan and included 212 patients with the diagnosis of operable local breast cancer recurrence. They had been treated previously with conservative surgery and showed negative SLNB results. They subsequently underwent additional breast surgery and a second SLNB between May 2001 and December 2011. RESULTS: Preoperative lymphoscintigraphy demonstrated at least one new axillary sentinel lymph node (SLN) in 207 patients (97.7 %), whereas no drainage was observed in five patients (2.3 %). One or more SLNs were surgically removed from 196 of the 207 patients. Isolation of SLNs from the remaining 11 patients could not be accomplished. The success rate for the SLNB was 92.5 %. Extra-axillary drainage pathways were visualized in 17 patients (8 %). The annual axillary recurrence rate after a median follow-up period of 48 months was 0.8 %, and the cumulative incidence of axillary recurrence at 5 years was 3.9 %. CONCLUSIONS: A second SLNB should be considered for patients with operable local breast tumor recurrence who underwent conservative surgery and had negative SLNB results. The procedure is technically feasible and accurate for selected patients.

Changes in PgR and Ki-67 in residual tumour and outcome of breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Limited data are available on the prognostic value of changes in the biological features of residual tumours following neoadjuvant therapies in breast cancer patients. PATIENTS AND METHODS: We collected information through the institutional clinical database on all consecutive breast cancer patients treated with neoadjuvant chemotherapy at the European Institute of Oncology (IEO), Milan, Italy, between 1999 and 2011. We selected patients who did not achieve pathological complete response at final surgery. All patients had a pathological evaluation, including ER, PgR, HER2 protein and Ki-67 expression carried out at the IEO both at diagnostic core biopsy and at final surgery. RESULTS: We identified a total of 904 patients. The 5% of patients who were ER positive at diagnostic biopsy had ER-negative residual tumour at final surgery. For PgR expression, 67% of the patients, whose tumours had a PgR >20% at diagnostic biopsy had a PgR <20% at final surgery. The Ki-67 expression changed from >20% to <20% in 40% of the patients. At the multivariate analysis, the decrease of PgR-immunoreactive cells correlated with improved outcome in terms of disease-free survival (DFS) [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.54-1.00, P 0.046]. In addition, the decrease of Ki-67 expression to <20% of the cells at final surgery was found to be associated with better outcome both in terms of DFS (HR 0.52; 95% CI 0.40-0.68 P < 0.0001) and overall survival (HR 0.45; 95% CI 0.32-0.64, P < 0.0001). CONCLUSION: The decrease of PgR and Ki-67 expression after preoperative chemotherapy has a prognostic role in breast cancer patients with residual disease.

Long-term follow-up of 5262 breast cancer patients with negative sentinel node and no axillary dissection confirms low rate of axillary disease.

AIM: It is established that axillary dissection (AD) can be safely avoided in breast cancer patients with a negative sentinel node (SN). In the present study we assessed whether the rate of axillary disease was sufficiently low on long term follow-up to consolidate the policy of AD avoidance. METHODS: We retrospectively analysed data on 5262 consecutive primary breast cancer patients with clinically negative axilla and negative SN, treated from 1996 to 2006, who did not receive AD. We used univariate and multivariate analyses to assess the influence of patient and tumour characteristics on first events and survival. The primary endpoint was the development of axillary disease as first event. RESULTS: After a median follow-up of 7.0 years (interquartile range 5.4-8.9 years) survival for the series was high (91.3%; 95% CI 90.3-92.3 at 10 years) and only 91 (1.7%) patients developed axillary disease as first event. Axillary disease was significantly more frequent in patients with the following characteristics: <35 years at diagnosis, tumour >1 cm, multifocality/multicentricity, G3, ductal histotype, Ki67 ≥ 30%, peritumoral vascular invasion, luminal B-like subtype, HER2 positivity, mastectomy, and not receiving radiotherapy. CONCLUSION: Long-term follow-up of our large series confirms that axillary metastasis is infrequent when AD is omitted in SN-negative breast cancer patients, and has low impact on overall survival.

Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator.

Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in ΔF508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells.

Progesterone receptor loss identifies Luminal B breast cancer subgroups at higher risk of relapse.

BACKGROUND: The immunohistochemical (IHC) evaluation of estrogen receptor (ER), progesterone receptor (PgR), Ki-67 and HER2 is considered a surrogate means for identifying the molecular subtypes of breast cancer with different prognosis. PATIENTS AND METHODS: We explored patterns of recurrence in 4837 women with breast cancer defined as Luminal B (ER-positive and/or PgR-positive, HER2 positive and/or Ki-67≥14%) by IHC classification. We evaluated four subgroups within the Luminal B subtype according to HER2 expression and PgR status. RESULTS: Patients within the ER+/PgR+/HER2- subgroup presented a 5-year breast cancer-related survival (BCS) of 97% (95% confidence interval (CI), 96-97) and overall survival (OS) of 95% [95% CI, 95-96], the best survivals of the Luminal B subgroups. In the multivariate analysis, the ER+/PgR-/HER2- subgroup was associated with a reduced BCS (HR 1.71; 95%CI, 1.25-2.35) and OS (HR 1.47; 95%CI, 1.10-1.96) when compared with the ER+/PgR+/HER2- subgroup. Also patients within the ER+/PgR-/HER2+ subgroup had a reduced BCS (HR 1.93; 95%CI, 1.32-2.83) and OS (HR 1.62; 95%CI, 1.14-2.30) when compared with ER+/PgR+/HER2- subgroup. On the other hand, no statistically significant differences were found with regard to BCS and OS among patients with ER+/PgR+/HER2+ and patients with ER+/PgR+/HER2- disease. CONCLUSIONS: PgR loss identifies Luminal B breast cancer subgroups at higher risk of relapse and death, both with HER-2-positive and HER-2-negative disease.

Prognostic value of Ki-67 labeling index in patients with node-negative, triple-negative breast cancer.

The aim of this analysis was to investigate the usefulness of Ki-67 labeling index (LI) for the identification of different prognostic subgroups in primary node-negative, triple negative breast cancer (TNBC) patients. From January 1997 to December 2005, 1,053 patients operated for TNBC were identified through the institutional clinical database. The study was performed in accordance with REMARK criteria. The relationship between Ki-67LI and the risk of breast-related deaths was evaluated with a multivariable Cox regression model. Cubic splines were used to model Ki-67LI as a continuous variable. We selected 496 consecutive patients with node-negative TNBC. Median age was 52 years, median Ki-67LI 48% (range 4-95), and median follow up 6 years (range 0.5-13). Total deaths and deaths from BC were 52 (10.5%) and 38 (7.7%), respectively. Ki-67LI increased with decreasing age (P<0.01), increasing tumor size (P<0.01), and grade (P<0.01). When analyzing Ki-67LI as a continuous variable, the risk of death from BC increased steeply with increasing Ki-67LI up to about 35% and remained flat for higher values (adjusted effect of Ki-67 P=0.049; adjusted nonlinear effect P=0.021). Accordingly, when dividing patients into lower (≤35%) and higher (>35%) Ki-67LI subgroups, the 5-year cumulative incidence of breast-related deaths were 2.3 and 9.0%, respectively, with an adjusted HR(>35 vs ≤35) of 2.3 (95% CI 1.0-5.8, P=0.046). Within the group of patients with node-negative TNBC, Ki-67LI was associated with different prognoses subgroups. Ki-67LI might be useful in the design of trials of risk-adapted adjuvant therapies.

Why do women accept to undergo a nipple sparing mastectomy or to reconstruct the nipple areola complex when nipple sparing mastectomy is not possible?

In a retrospective study, we investigated the reasons why women accepted to undergo a nipple sparing mastectomy (NSM) and why women who could not keep their nipple areola complex (NAC) decided to reconstruct it. We intended to investigate whether keeping the NAC plays a psychological role, to state possible advantages of NSM. Between 2004 and 2006, 310 women with NAC sparing and 143 patients with successive NAC reconstruction were mailed a single open-ended question at follow-up 12 months after final breast reconstruction surgery or final NAC reconstruction with tattoo. The purpose was to explore personal motivations that drove women to accept NSM or to perform a NAC tattoo reconstruction. Responses were classified into 11 categories by five reviewers. We performed an analysis of the relative frequency of emerging issues. Socio-demographic and clinical data were collected. Among the patients who responded to the open-ended question, 190 patients preserved their NAC, and 100 patients received postponed NAC reconstruction. Women in the NSM group were significantly younger (P = 0.02), more highly educated (P < 0.0001), and more frequently lived in Northern Italy (P = 0.03). The reasons for accepting NSM were more frequently related to body image satisfaction and integrity of the body (P = 0.002), reduction of psychological distress (P = 0.003), and surgeon's influence (P < 0.0001). Esthetic reasons were highly associated to the control group. These results help us to better understand the psychological impact of NAC sparing versus NAC reconstruction. NSM was accepted because it was perceived as a technique that preserved the integrity of the body, reduced the feeling of mutilation, improved the breast cosmetic results, and reduced psychological distress regarding the loss of the breast.

Breast cancer subtypes and outcome after local and regional relapse.

BACKGROUND: To evaluate the outcome of breast cancer patients after locoregional recurrence (LRR) according to tumor biological features evaluated at first diagnosis and at the time of recurrence. PATIENTS AND METHODS: We collected information on all consecutive breast cancer patients operated at the European Institute of Oncology between 1994 and 2005. The tumor characteristics and subsequent outcome of patients who experienced LRR were analyzed. RESULTS: Two hundred and seventy nine patients with LRR were identified, 197 and 82 patients with local and regional recurrence respectively. The overall discordance rate between primary cancer and LRR was 9% for estrogen receptor expression, 22% for progesterone receptor and 4% for human epidermal growth factor receptor 2. For patients with regional recurrence, the risk of distant metastasis was significantly higher compared with local relapse in case of late recurrence (hazard ratio [HR] = 2.76; 95% CI 1.31-5.85). Patients with triple-negative breast cancer at LRR experienced a higher risk of subsequent relapse (HR 2.87 [1.67-4.91]) and death (HR 2.00 [1.25-3.19]). CONCLUSION: LRR correlates with a high risk of subsequent events and death in particular in patients with triple-negative subtype.

Outcome of special types of luminal breast cancer.

BACKGROUND: The identification of special types of breast cancer might be of value in assessing prognosis and predicting response to therapy. METHODS: A total of 7372 consecutive patients with immunohistochemically defined luminal invasive breast cancer operated at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence by histological type. Median follow-up was 5.8 years. RESULTS: Tumors from 5707 patients were classified as invasive ductal cancer (IDC) not otherwise specified (NOS), 851 lobular, 338 mixed ductal and lobular, 250 cribriform, 143 mucinous and 83 tubular carcinomas. Compared with IDC NOS disease-free survival (DFS) was significantly longer in patients with cribriform tumors [5-year DFS 97.9% versus 87.4%; hazard ratio (HR) = 0.48; P = 0.015) and in pooled cribriform plus tubular carcinomas (5-year DFS 98.7% versus 87.4%; HR = 0.45; P = 0.005). Mucinous tumors presented similar DFS if compared with IDC (5-year DFS 93 % versus 87.4%; HR = 1.03; P = 0.91). Conversely, DFS was poorer for patients with lobular carcinoma (5-year DFS 86.8% versus 87.4%; HR = 1.27; P = 0.01). CONCLUSIONS: The diagnosis of tubular, cribriform and lobular carcinomas carry distinct prognostic implications. The identification of these special types has a significant utility in luminal breast cancer and should be considered in therapeutic algorithms.

Prognostic role of CA15.3 in 7942 patients with operable breast cancer.

To assess the prognostic value of presurgical CA15.3 in a large cohort of patients with early breast cancer. A total of 7.942 consecutive patients with breast cancer operated at the European Institute of Oncology between 1998 and 2005 and with presurgical values of CA 15.3 available were included. We explored patterns of recurrence by baseline CA 15.3 values. Mean CA15.3 was 17.0 U/ml. CA15.3 was associated with age, tumor size, nodal involvement, Ki-67 labeling index, grade, HER2 expression, molecular subtype, and perivascular invasion. CA15.3 was independently associated with distant metastases [HR > 20 U/ml vs. ≤ 20 U/ml: 1.34 (95% CI 1.15-1.56)] and death [HR > 20 U/ml vs. ≤ 20 U/ml: 1.30 (95% CI 1.11-1.53)]. When considering CA15.3 as continuous variable, we observed a constant risk of metastasis and death from the lowest values to about 15-20 U/ml, and then a significantly increasing risk with increasing values of CA15.3. Finally, CA15.3 provided significant additional information to the common prognostic factors to predict the occurrence of metastases (C-index P value 0.04). In patients with operable breast cancer, presurgical CA15.3 value is an independent prognostic factor for metastases and deaths. CA15.3 provides additional information to the common prognostic factors and should be considered in the adjuvant therapeutic algorithm.

Prognosis in women with small (T1mic,T1a,T1b) node-negative operable breast cancer by immunohistochemically selected subtypes.

Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumours. We explored patterns of recurrence in 1691 women with pT1mic/T1a/T1b, pN0 and M0 breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67 < 14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67 ≥ 14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) Triple Negative. At multivariate analysis, women with the Triple Negative breast cancer subtype had an increased risk of loco-regional relapse (LRR) (Hazards Ratio (HR) 3.58; 95%CI: 1.40-9.13) and breast cancer related events (HR 2.18; 95%CI: 1.04-4.57). Overall, Luminal B subtype was not associated with a statistically significant increased risk of recurrence compared with Luminal A, while patients with Luminal B subtype tumours overexpressing HER2 had a 2 fold risk of reduced breast cancer related survival (BCS), but not an increased risk of LRR and distant metastases. Women with HER2 breast cancer subtype had a statistically significant increased risk of LRR (HR 4.53; 95%CI: 1.56-13.1), distant metastases and reduced BCS (HR 3.22; 95%CI: 1.44-7.18) and overall survival (HR 2.87; 95%CI: 1.05-7.89) when compared with the Luminal A subtype, at multivariate analysis. In conclusion, women with small size, node-negative, breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or Triple Negative disease.

Risk factors for relapse after conservative treatment in T1-T2 breast cancer with one to three positive axillary nodes: results of an observational study.

BACKGROUND: As few data are available on irradiation of the draining nodes after conservative surgery (CS), this study was designed to identify patients with T1-T2 breast cancer and one to three positive axillary nodes who needed regional radiotherapy (RT). PATIENTS AND METHODS: Five hundred seventy-five patients were treated between 1988 and 2001 with CS and RT to the breast. All but three received adjuvant chemotherapy and/or hormone therapy. Risk factors for and the relationships between local, nodal and distant relapses were analyzed. RESULTS: At a median follow-up of 7.3 years, the 10-year probability of survival free of local relapse, nodal relapse and distant metastases were 92.8%, 94.0% and 84.9%, respectively. Independent predictors of local relapse were the positive/excised node ratio, margin status and age. Predictors of nodal relapse were tumor grade, hormone receptor and margin status. Significant risk factors for distant metastases were tumor stage, grade, hormone receptor and margin status. Local and nodal relapses were related significantly with distant metastases. Only local and distant relapses were linked by temporal sequence (P=0.03). CONCLUSIONS: Overall relapse rates were low in these patients and different mechanisms appeared to underlie local, nodal or distant relapse.

Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer.

BACKGROUND: There is limited knowledge about prognosis of selected breast cancer subtypes among very young women. PATIENTS AND METHODS: We explored patterns of recurrence by age according to four immunohistochemically defined tumor subtypes: Luminal A and Luminal B (estrogen receptor positive and/or progesterone receptor positive and either human epidermal growth factor receptor 2 (HER2) positive and/or high Ki-67), HER2-positive (and) endocrine receptor absent and Triple Negative, in 2970 premenopausal patients with pT1-3, pN0-3 and M0 breast cancer. RESULTS: Patients <35 years of age (315, 11%) presented a significantly increased risk of recurrence and death [hazards ratio (HR) = 1.65, 95% confidence interval (CI) 1.30-2.10 and HR = 1.78, 95% CI 1.12-2.85, respectively] when compared with older patients (2655, 89%) with similar characteristics of disease. This was true considering patients with Luminal B [HR = 1.62, 95% CI 1.21-2.18 for disease-free survival (DFS) and HR = 2.09, 95% CI 0.96-4.53 for overall survival (OS)] and with Triple Negative (HR = 2.04, 95% CI 1.11-3.72 for DFS and HR = 2.20, 95% CI 1.10-4.41 for OS) breast cancer, observing the highest risk of recurrence in the younger patients with HER2-positive breast cancer (HR = 2.37, 95% CI 1.12-5.02) when compared with older patients. CONCLUSIONS: Very young patients with Triple Negative, Luminal B or HER2-positive breast cancer have a worse prognosis when compared with older patients with similar characteristics of disease.