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Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.)

Background: The benefits of systematic re-excision (RE) after initial unplanned excision (UE) of soft tissue sarcoma (STS) are unknown., Objective: The aim of this study was to evaluate the impact of delayed RE versus systematic RE after UE on overall survival (OS), metastatic relapse-free survival (MRFS), local relapse-free survival (LRFS), and rate of amputation., Methods: Patients who underwent complete UE, without metastasis or residual disease, for primary extremity or superficial STS between 2007 and 2013 were analyzed. The amputation rate, LRFS, MRFS, and OS were assessed in cases of systematic RE in sarcoma referral centers (Group A), systematic RE outside of community centers (Group B), or without RE (Group C)., Results: Groups A, B, and C included 300 (48.2%), 71 (11.4%), and 251 (40.4%) patients, respectively. Median follow-up was 61 months and 5-year OS was 88.4%, 87.3%, and 88% in Groups A, B, and C, respectively (p = 0.22), while 5-year MFRS was 85.4%, 86.2%, and 84.9%, respectively (p = 0.938); RE (p = 0.55) did not influence MRFS. The 5-year LRFS was 83%, 73.5%, and 63.8% in Groups A, B and C, respectively (p = 0.00001). Of the 123 local recurrences observed, 0/28, 1/15, and 5/80 patients in Groups A, B, and C, respectively, required amputation (p = 0.41). Factors influencing LRFS were adjuvant radiotherapy [hazard ratio (HR) 0.21; p = 0.0001], initial R0 resection (HR 0.24, p = 0.0001), and Group A (HR 0.44; p = 0.01)., Conclusion: Systematic RE in sarcoma centers offers best local control but does not impact OS. Delayed RE at the time of local relapse, if any, could be an option.

Background: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry., Patients and Methods: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497)., Results: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]., Conclusion: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Guidelines recommend that retroperitoneal sarcoma (RPS) be managed in a reference sarcoma center (RSC), but the benefit remains to be demonstrated. This study investigated the impact of initial surgery performed within the NetSarc network on overall survival (OS)., Methods: NetSarc is a network of 26 RSCs with specialized multidisciplinary tumor boards (MDTs) that is funded by the French NCI. Since 2010, presentation to an MDT and second pathological review are mandatory for sarcoma patients, and data have been collected in a nationwide database. We extracted data for all patients who received surgery in or outside the network and who presented at a NetSarc center (NSC) for primary nonmetastatic RPS between 2010 and 2017., Results: A total of 2945 patients were included: 1078 (36.6%) underwent the first surgery in an NSC, and 1867 (63.4%) in an out-of-network center. The median number of operations at an NSC during the study period was 23 (range: 3-209), and the corresponding median was 1 (range: 1-2) at out-of-network centers. The diagnostic procedures followed significantly more clinical practice guidelines within NetSarc, where there were significantly more first R0 resections [452 (41.9%) vs. 230 (12.3%)]. The OS was significantly superior for patients treated within NetSarc, with a 2-year OS of 87% vs. 70% (p < 0.001). In the multivariate analysis, surgery within an NSC was an independent predictor of OS, with a twofold lower odds ratio of death., Conclusions: In this national study, surgery for primary RPS within an NSC was associated with a better OS.

Introduction: Soft tissue sarcomas (STS) are rare malignant tumors that require management by an expert center. Monitoring modalities are not consensual. The objective of our study is to report systematic radiological monitoring data obtained by local MRI and by thoracic-abdominal-pelvic computed tomography (TAP CT)., Material and Methods: 113 consecutive patients managed at "Centre Georges François Leclerc, Dijon", between 2008 and 2016, for an initially localized STS were included. Patient follow-up consisted of a local MRI and a TAP CT. Follow-up exams schedule was initially every 4 months during 2 years, followed by every 6 months during 3 years and finally every year during 5 years., Results: Median follow-up time was 37.2 months [min = 2.4 - max = 111.6]. After 5 years of surveillance, local recurrence (LR) rate was 8.8% and diagnosed by imaging in 60% of cases. No deep LR was clinically found. Median LR diagnosis time was 23.9 months [min = 2.0 - max = 52.4]. 50% of patients locally treated for their LR were alive without recurrence. Metastatic recurrence (MR) rate was 31%. 42.8% had extra-pulmonary involvement and 17.1% had exclusive extrathoracic metastases. The median time to diagnosis of MR was 17.4 months [min = 2.7- max = 77.2]. High-grade tumors relapsed more (20.4%) and earlier (all before the 5th year) than low grade., Conclusion: Local MRI seems particularly suitable for monitoring deep tumors. In addition, the systematic monitoring by TAP CT highlighted a limited number of cases of exclusive extrathoracic metastases. The schedule of local and remote monitoring should primarily be adjusted to tumor grade., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: An important challenge of the longitudinal analysis of health-related quality of life (HRQOL) is the potential occurrence of a Response Shift (RS) effect. While the impact of RS effect on the longitudinal analysis of HRQOL has already been studied, few studies have been conducted on its impact on the determination of the Minimal Important Difference (MID). This study aims to investigate the impact of the RS effect on the determination of the MID over time for each scale of both EORTC QLQ-C30 and QLQ-BR23 questionnaires in breast cancer patients., Methods: Patients with breast cancer completed the EORTC QLQ-C30 and the EORTC QLQ-BR23 questionnaires at baseline (time of diagnosis; T0), three months (T1) and six months after surgery (T2). Four hospitals and care centers participated in this study: cancer centers of Dijon and Nancy, the university hospitals of Reims and Strasbourg At T1 and T2, patients were asked to evaluate their HRQOL change during the last 3 months using the Jaeschke transition question. They were also asked to assess retrospectively their HRQOL level of three months ago. The occurrence of the RS effect was explored using the then-test method and its impact on the determination of the MID by using the Anchor-based method., Results: Between February 2006 and February 2008, 381 patients were included of mean age 58 years old (SD = 11). For patients who reported a deterioration of their HRQOL level at each follow-up, an increase of RS effect has been detected between T1 and T2 in 13/15 dimensions of QLQ-C30 questionnaire, and 4/7 dimensions of QLQ-BR23 questionnaire. In contrast, a decrease of the RS effect was observed in 8/15 dimensions of QLQ-C30 questionnaire and in 5/7 dimensions of QLQ-BR23 questionnaire in case of improvement. At T2, the MID became ≥ 5 points when taking into account the RS effect in 10/15 dimensions of QLQ-C30 questionnaire and in 5/7 dimensions of QLQ-BR23 questionnaire., Conclusions: This study highlights that the RS effect increases over time in case of deterioration and decreases in case of improvement. Moreover, taking the RS into account produces a reliable and significant MID.

Background: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy., Methods: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher., Results: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease., Conclusions: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy. (Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31.).

Background and Aims: We assess the respective relationship of high depressive symptoms and antidepressant use (ATD) with baroreflex sensitivity (BRS) in subjects from the community who enrolled the Paris Prospective Study III., Methods: Recruitment took place in a large health preventive centre in Paris (France), between May 2008 and June 2012. BRS was investigated by spectral analysis of the spontaneous carotid distension rate and RR intervals using non-invasive high-resolution ultrasound carotid-echotracking. A total score ≥7 on a 13-item standardized questionnaire defined the presence of high depressive symptoms. Information on ATD use was obtained on a face-to-face interview with a medical doctor who checked the most recent medical prescriptions and/or medical package., Results: There were 9213 participants aged 50-75 years (38.6% of women), including 5.6% with high-depressive symptoms and 5.2% on ATD. High depressive symptoms were not associated with low BRS (below the median) even in unadjusted logistic regression analysis (OR = 1.09; 95%CI: 0.91-1.30). Instead, ATD use was related to low BRS in multivariate logistic regression analysis (OR = 1.27; 95% CI: 1.04-1.54). This association remains after adjusting for and matching on propensity score of receiving ATD. A specific association with serotonin and norepinephrine reuptake inhibitors was observed (OR = 1.94; 95% CI: 1.16-3.22)., Conclusions: ATD use and serotonin and norepinephrine reuptake inhibitors in particular, but not high depressive symptoms, is associated with low BRS. If confirmed, these results may bring novel insights into the mechanisms linking depressive symptoms and/or ATD use with cardiovascular disease onset., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Tumor-infiltrating T and B lymphocytes could have the potential to affect cancer prognosis. The objective of this study was to investigate the prognostic significance of tumor infiltration by CD8 and CD4 T cells, and B lymphocytes in patients with localized gastric cancer. In a retrospective cohort of 82 patients with localized gastric cancer and treated by surgery we quantitatively assessed by immunohistochemistry on surgical specimen, immune infiltrates of IL-17 + , CD8 + , Foxp3 + , Tbet + T cells and CD20 + B cells both in the tumor core and at the invasive margin via immunohistochemical analyses of surgical specimens. We observed that CD8 + and IL17 + T-cell densities were not significantly associated with gastric cancer prognosis. In contrast, high infiltration of Tbet + T cells, high numbers of CD20 + B-cell follicles, and low infiltration of Foxp3 + T cells, were associated with better relapse-free survival. Interestingly, treatment with neoadjuvant chemotherapy or histological tumor type (diffuse versus intestinal) did not influence type and density of immune infiltrates or their prognostic value. Immunohistochemical analysis of the gastric cancer stromal microenvironment revealed organized T and B cell aggregates, with strong structural analogies to normal secondary lymphoid organs and which could be considered as tertiary lymphoid structures. Using transcriptomic data from an independent cohort of 365 localized gastric cancer, we confirmed that a coordinated Th1, and B cell stromal gene signature is associated with better outcome. Altogether, these data suggest that tumor infiltration by B and Th1 T cells could affect gastric cancer prognosis and may be used to better define the outcome of patients with localized gastric cancer.

Background: This prospective multicenter study aimed to study the impact of the recalibration component of response-shift (RS) on time to deterioration (TTD) in health related quality of life (QoL) scores in breast cancer (BC) patients and the influence of baseline QoL expectations on TTD., Methods: The EORTC-QLQ-C30 and BR-23 questionnaires were used to assess the QoL in a prospective multicenter study at inclusion (T0), at the end of the first hospitalization (T1) and, three (T2) and 6 months after the first hospitalization (T3). Recalibration was investigated by the then-test method. QoL expectancy was assessed at diagnosis. Deterioration was defined as a 5-point decrease in QoL scores, considered a minimal clinically important difference (MCID). TTD was estimated using the Kaplan-Meier method. Cox regression analyses were used to identify factors influencing TTD., Results: From February 2006 to February 2008, 381 women were included. Recalibration of breast cancer patients' internal standards in the assessment of their QoL had an impact on TTD. Median TTD were significantly shorter when recalibration was not taken into account than when recalibration was taken into account for global health, role-functioning, social-functioning, body-image and side effects of systemic therapy. Cox multivariate analyses showed that for body image, when recalibration was taken into account, radiotherapy was associated with a shorter TTD (HR: 0.60[0.38-0.94], whereas, no significant impact of surgery type on TTD was observed. For global health, cognitive and social functioning dimensions, patients expecting a deterioration in their QoL at baseline had a significantly shorter TTD., Conclusions: Our results showed that RS and baseline QoL expectations were associated with time to deterioration in breast cancer patients.

Background: The occurrence of response shift (RS) in longitudinal health-related quality of life (HRQoL) studies, reflecting patient adaptation to disease, has already been demonstrated. Several methods have been developed to detect the three different types of response shift (RS), i.e. recalibration RS, 2) reprioritization RS, and 3) reconceptualization RS. We investigated two complementary methods that characterize the occurrence of RS: factor analysis, comprising Principal Component Analysis (PCA) and Multiple Correspondence Analysis (MCA), and a method of Item Response Theory (IRT)., Methods: Breast cancer patients (n = 381) completed the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires at baseline, immediately following surgery, and three and six months after surgery, according to the "then-test/post-test" design. Recalibration was explored using MCA and a model of IRT, called the Linear Logistic Model with Relaxed Assumptions (LLRA) using the then-test method. Principal Component Analysis (PCA) was used to explore reconceptualization and reprioritization., Results: MCA highlighted the main profiles of recalibration: patients with high HRQoL level report a slightly worse HRQoL level retrospectively and vice versa. The LLRA model indicated a downward or upward recalibration for each dimension. At six months, the recalibration effect was statistically significant for 11/22 dimensions of the QLQ-C30 and BR23 according to the LLRA model (p ≤ 0.001). Regarding the QLQ-C30, PCA indicated a reprioritization of symptom scales and reconceptualization via an increased correlation between functional scales., Conclusions: Our findings demonstrate the usefulness of these analyses in characterizing the occurrence of RS. MCA and IRT model had convergent results with then-test method to characterize recalibration component of RS. PCA is an indirect method in investigating the reprioritization and reconceptualization components of RS.

Background: The aim of this study was to assess long-term quality of life (QoL) over a period of 6 years in women with breast cancer (BC) who underwent sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND), or SLNB followed by ALND., Methods: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ)-C30 and the EORTC-QLQ-BR-23 questionnaires were used to assess QoL before surgery, just after surgery, 6, 12 and 72 months later. The longitudinal effect of surgical modalities on QoL was assessed with a mixed model analysis of variance for repeated measurements., Results: Five hundred and eighteen BC patients were initially included. The median follow-up was 6 years. During the follow-up, 61 patients died. None of the patients of the SLNB group developed lymphedema during follow-up and the relapse rate was similar in the different groups (P=0.62). Before surgery, global health status (P=0.52) and arm symptoms (BRAS) (P=0.99) QoL scores were similar whatever the surgical procedure. The BRAS score (P=0.0001) was better in the SLNB group 72 months after surgery. Moreover, during follow-up, patients treated with SLNB had lower arm symptoms scores than ALND patients and there was no difference for arm symptoms between patients treated with ALND and those treated with SLNB followed by complementary ALND., Conclusion: Long-term follow-up showed that SLNB was associated with less morbidity than ALND.

Purpose: To characterize response shift effects in patients with breast cancer (BC)., Methods: The QLQ-C30, BR23, and EurQOL-EQ-5D were assessed at baseline and at the end of the first hospitalization. We used the then-test approach to characterize changes in internal standards by calculating the mean difference between the then-test (retrospective measure) and pre-test baseline QoL assessments. The Ideal Scale Approach was also used to assess changes in standards by comparing health and QoL expectancies between baseline and the end of the first hospitalization. Successive Comparison Approach was used to assess changes in values through the longitudinal assessment of the relative importance of EuroQOL dimensions., Results: The results of this study showed that recalibration RS effects occurred early after the first hospitalization for 6/15 dimensions of QLQ-C30 (emotional, cognitive, fatigue, insomnia, appetite loss, diarrhea) and 2/8 of BR-23 (future perspective, systemic therapy side effects). Moreover, health and QoL expectancies changed between the baseline and the end of the first hospitalization, and changes in values were seen for the self-care and usual activities dimensions of the EuroQOL-EQ-5D., Conclusions: The occurrence of RS early after the first hospitalization suggests that it needs to be taken into account to interpret QoL changes in BC.

Purpose: This prospective multicenter study explored different definitions of time to deterioration (TTD) in quality of life (QoL) scores, according to different cutoffs of the minimal clinically important difference (MCID) as a modality for longitudinal QoL assessment in breast cancer patients., Methods: QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and BR-23 before surgery, after surgery, and 6 and 12 months later. The global health score, arm symptoms score (BRAS), and breast symptoms score were analyzed. For a given baseline score, QoL was considered to have deteriorated if this score decreased by ≥5 points at any time point after baseline. Analyses were repeated using an MCID of 10 points and taking the score after surgery as the reference score (to explore the occurrence of response shift). TTD was calculated using the Kaplan-Meier method and Cox regression was used to identify independent factors associated with TTD., Results: Two hundred thirty-five patients underwent axillary lymph node dissection (ALND), 222 underwent sentinel lymph node biopsy (SLNB), and 61 underwent SLNB plus ALND. Patients who underwent SLNB had a significantly longer TTD for the BRAS dimension than those who underwent ALND. Cox multivariate analyses showed that treatment using SLNB and age >59 years were independently associated with longer TTD for the BRAS, whereas surgery elsewhere than at the Centre Georges François Leclerc was associated with a shorter TTD., Conclusion: Exploration of different definitions of TTD in QoL provides meaningful longitudinal QoL results for clinicians.

Background/aims: Experimental studies in vitro suggest that somatostatin and some of its analogues used in clinical practice, such as octreotide, may have potent antiangiogenic properties. However, the clinical transposition of these data is difficult., Methods: To address this issue, we designed a comparative study of the effects of somatostatin and octreotide on the interactions between neoplastic endocrine cells and endothelial cells in several in vitro and in vivo experimental models, including primary cultures of human umbilical vein endothelial cells (HUVEC), indirect cocultures between HUVEC and the somatostatin-producing endocrine cell line STC-1, and an animal model of intrahepatic dissemination of STC-1 cells., Results: 10(-8)M octreotide markedly inhibited both basal and VEGF-stimulated HUVEC proliferation, had no effect on endothelial cell migration, but inhibited endothelial tubule formation. HUVEC cocultured with the somatostatin- and VEGF-producing STC-1 cells presented a markedly decreased proliferation, a slightly increased motility and an increased capacity of tubule formation; in this system, the inhibition of endothelial cell proliferation was abolished by neutralizing anti-somatostatin but was restored in the presence of anti-VEGF antibodies. This suggests that somatostatin is able to antagonize the effects of VEGF on endothelial cell proliferation but not on endothelial cell sprouting. Finally, no significant effect of octreotide on tumor growth and intratumoral microvascular density was detected in an experimental model of intrahepatic dissemination of STC-1 cells., Conclusion: The in vitro antiangiogenic effects of somatostatin and its analogues are likely to be efficiently counterbalanced in the tumor microenvironment by the concomitant release of proangiogenic factors like VEGF., (Copyright © 2011 S. Karger AG, Basel.)

Background: The aim of this population-based study was to assess independent prognostic factors in ovarian cancer using relative survival (RS) and to investigate changes in RS rates from 1982 to 2005., Methods: Data on 748 patients with ovarian cancer were provided by the Côte d'Or gynaecologic cancer registry. The RS was estimated using a generalized linear model with a Poisson error structure. Relative survival and its 95% confidence interval (CI) were described at the following specific time points 1, 3 and 5 years. The effect of prognostic factors on survival was assessed with multivariate analyses of RS., Results: The median follow-up was 12 years. The RS rates at 1, 3 and 5 years were 81%, 55% and 44%, respectively. As compared with the period 1982-1989, an improvement in survival was found for the period 1998-2005: HR = 0.52[0.40-0.67]. Women who lived in urban areas had better RS: HR = 0.82[0.67-0.99]. Patients with epithelial types of ovarian cancer other than mucinous or endometrioid cancer had worse RS than those with serous histology. Age ≥ 70 years was associated with lower survival., Conclusions: Period of diagnosis, stage at diagnosis, histology, place of residence and age were independent prognostic factors for survival in ovarian cancer. An improvement in the survival rate was observed after 1998 but a significant improvement was limited to advanced stage cancers.

Background: We sought to assess morbidity and mortality in primary retroperitoneal soft tissue sarcomas (RSTS) treated by a frontline aggressive surgical approach., Methods: A total of 249 consecutive patients with primary RSTS were treated by a frontline aggressive surgical approach at two major European institutions. Multivariable models were used for exploring the relationship between postsurgical morbidity and the number of organs resected, with adjustment for clinical variables. The impact of morbidity on local and distant recurrence-free survival was explored by multivariable models, adjusting for the main known prognostic factors., Results: Median follow-up was 37 months (interquartile [IQ] range, 16-61 months). Median tumor size was 17 cm (IQ range, 11-26 cm). The median number of organs resected en bloc with the tumor was 2 (IQ range, 1-3). Complete macroscopic resection was achieved in 232 cases (93%). At 5 years, overall survival was 65.4% (95% confidence interval [95% CI], 56.8-72.7); local and distant recurrence crude cumulative incidences were 22.3% (95% CI, 16.5-30.2) and 24.2% (95% CI, 18.4-31.9), respectively. Postsurgical morbidity requiring at least one invasive therapeutic procedure was observed in 45 patients (18%; 95% CI, 14-23). Surgical reintervention was necessary in 30 patients (12%; 95% CI, 8-17). Eight patients died of postoperative complications (3%; 95% CI, 1-6). No statistically significant association between postsurgical morbidity and any clinical variable was detected. For number of resected organs, we documented an increased risk of morbidity for more than three organs (P = 0.007). Postsurgical morbidity did not affect oncologic outcome., Conclusions: Frontline aggressive surgical approach to primary RSTS is safe when carried out at high-volume centers. It could be systematically considered in primary RSTS.

Purpose: The main aim of this study was to show the interest of pelvic posterior exenteration to obtain complete resection of the tumor in case of invasion of the rectum by contiguity in advanced-stage ovarian cancer. The secondary aim was to determine the morbidity of this surgery., Methods: It is a multicentric, retrospective study of a series of 41 patients, who underwent posterior pelvectomy for advanced-stage ovarian cancer, over a period of 18 years, from July 1989 to July 2007., Results: The surgery resulted in macroscopically complete resection in 19 patients (46.34%), a residual tumor <2 cm in 19 patients (46.34%) and >2 cm in 3 patients (7.32%). In 34 patients (34/41), digestive continuity with satisfactory anal sphincter function was restored immediately or in the short term. The mean delay to the start of complementary treatment was 36 days. Median overall survival was 33 months., Conclusion: The main aim of surgery for ovarian peritoneal carcinomatosis is to obtain a complete resection. In the case of direct invasion of the rectum by contiguity, when there is no cleavage plane between the uterus and the rectum, pelvic posterior exenteration is an effective method to achieve this objective. Morbidity is relatively high, but acceptable given the poor prognosis of this disease, the improved survival after surgery, and improvements in post-operative quality of life and functions.

Objectives: Our purpose was to assess development of sentinel lymph node biopsy (SLNB) in two Burgundy districts during the year 2005., Methods: All women undergoing breast surgery as primary care between 1 January 2005 and 1 January 2006 were eligible for inclusion. Eleven surgeons from five different breast-treatment centres took part in this prospective multicentric study. As our objective was to evaluate practices, patients were not randomized and surgeons were free to choose treatment patterns., Results: The 528 enrolled cases account for 90% of all new breast cancers in 2005 in Cote d'Or and Saône et Loire. Half of these patients (286) fulfilled requirements for SLNB. The others (242) had primary full axillary clearance (AC). Four of our five centres offer double-detection of sentinel lymph nodes as well as intraoperative pathology examination. Most tumours were invasive ductal carcinomas, with an average size of 12 mm in the SLNB group (T1C) and 22 mm in the AC group (T2). Two or three lymph nodes were removed during each SLNB procedure. Whereas most SLNB studies report around 25% positive nodes, we barely recorded 18.5% (53 of our 256 patients). Moreover, 2/3 of these node-positive patients had optimal care since additional axillary clearance was done right away., Conclusion: Sentinel lymph node biopsy has become routine practice in our Burgundy area. It is mainly dedicated to early stage breast cancer with limited metastatic risk. Our surgeons follow the most recent guidelines and indications are the same regardless of treatment centre.

Background: Intraperitoneal (i.p.) epinephrine was shown to increase the accumulation of i.p. cisplatin in tumours, and thus its antitumour effect in a model of peritoneal carcinomatosis in rats., Methods: To determine the tolerance to i.p. epinephrine with cisplatin, 18 patients with recurrent ovarian carcinoma were intraoperatively treated in this phase 1 study. After maximal cytoreductive surgery, the peritoneal cavity was filled twice for 1 h with 30 mg/l of cisplatin and increasing concentrations of epinephrine (0, 1, 2, 3 mg/l) in 3 l of saline solution at 37 degrees C., Results: No deaths occurred. Three patients were treated at each of the 0, 1 and 2 mg/l epinephrine levels without adverse events. Two of the three patients who received 3 mg/l epinephrine experienced cardiac intolerance. Six additional patients received 2 mg/l of epinephrine without toxicity. A relationship between the serum concentration of epinephrine and occurrence of cardiac toxicity was established. A 60% decrease in serum area under the curve of platinum was calculated in patients receiving i.p. epinephrine compared with i.p. cisplatin alone. Renal toxicity from cisplatin was not increased by epinephrine. No haematological or neurological toxicity was recorded. The other grade 3-4 adverse events [thromboembolism (5), peritonitis (1), abdominal bleeding (1), bowel fistula (1)] occurred as often as usually reported for this heavy surgical procedure., Conclusion: The combination of i.p. epinephrine with cisplatin as intraoperative chemotherapy after optimal cytoreductive surgery is feasible. The recommended concentration for further studies is 2 mg/l for i.p. epinephrine.

Background: In a prior randomized phase II trial comparing hyperthermic isolated limb perfusion (HILP) with four different doses of tumor necrosis factor alpha (TNF-alpha), no dose effect was detected for response, but systemic toxicity was far lower with low-dose TNF-alpha. The objective of the present study was to confirm these data on a larger sample size of locally advanced or recurrent extremity soft tissue sarcomas with low-dose TNF-alpha., Methods: We assessed a prospective database comprising 100 HILP (38-40 degrees C) with melphalan (10 mg/L) and TNF-alpha (1 mg). The remnant tumor was resected 2 months later., Results: Among 52 recurrences, 18 were in a previously irradiated field. Stages according to the American Joint Committee on Cancer classification were II (19 patients), III (78 patients), and IV (3 patients). The site/size were: 30 patients/57 mm and 70 patients/86 mm for the upper and lower limbs, respectively. Tumor grades (FNCLCC) were 1 (23 patients), 2 (34 patients), and 3 (43 patients). Fifty-one patients had received systemic chemotherapy before HILP. Responses on magnetic resonance imaging were 30% complete, 49% partial, 9% no change, and 12% progression. No mortality or systemic toxicity occurred. Local toxicity (Wieberdink) attained grade 2 (16 patients), 3 (5 patients), and 4 (1 patient). Limbs were able to be saved in 87% patients. Three-year overall survival and the local recurrence rate were 89% and 18%, respectively. Age, sex, tumor size, recurrence, uni- or multifocality, grade, preoperative chemotherapy, and a previously irradiated field were not predictive of response or local toxicity., Conclusions: We confirm that 1 mg of TNF-alpha is as effective as the standard dose and results in no systemic toxicity.

Background: This prospective multicenter study assessed and compared the impact of different surgical procedures on quality of life (QoL) in breast cancer patients., Patients and Methods: The EORTC QLQ-C30 and the EORTC QLQ-BR-23 questionnaires were used to assess global health status (GHS), arm (BRAS) and breast (BRBS) symptom scales, before surgery, just after surgery and 6 and 12 months later. The Kruskal-Wallis test with the Bonferroni correction was used to compare scores. A mixed model analysis of variance for repeated measurements was then applied to assess the longitudinal effect of surgical modalities on QoL., Results: Before surgery, GHS (P = 0.7807) and BRAS (P = 0.7688) QoL scores were similar whatever the surgical procedure: sentinel node biopsy (SLNB), axillary node dissection (ALND) or SLNB + ALND. As compared with other surgical groups, GHS 75.91 [standard deviation (SD) = 17.44, P = 0.041] and BRAS 11.39 (SD = 15.36, P < 0.0001) were better in the SLNB group 12 months after surgery. Whatever the type of surgery, GHS decreased after surgery (P < 0.0001), but increased 6 months later (P = 0.0016). BRAS symptoms increased just after surgery (P = 0.0329) and until 6 months (P < 0.0001) before decreasing (P < 0.0001)., Conclusions: SLNB improved GHS and BRAS QoL in breast cancer patients. However, surgeons must be cautious, SLNB with ALND results in a poorer QoL.

Background: Trastuzumab plus chemotherapy has become the standard of care for women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Trastuzumab-based pre-operative systemic (neo-adjuvant) therapy (PST) also appears promising, warranting further investigation., Patients and Methods: Patients with HER2-positive, stage II/III non-inflammatory, operable breast cancer requiring a mastectomy (but who wished to conserve the breast) received weekly trastuzumab and 3-weekly docetaxel for six cycles before surgery. The primary end point was pathological complete response (pCR) rate, determined from surgical specimens., Results: Thirty-three patients were enrolled. The majority (79%) had T2 tumors, with 42% being N1/2. Twenty-nine patients completed six cycles of therapy and one patient withdrew prematurely due to progressive disease. A complete or partial objective clinical response was seen in 96% (73% and 23%, respectively) of patients. Surgery was performed in 30 patients, breast conserving in 23 (77%). In an intention-to-treat analysis, tumor and nodal pCR was seen in 14 (47%) patients. Treatment was generally well tolerated. Grade 3/4 neutropenia occurred in 85% of patients while febrile neutropenia was encountered in 18%. Only three patients withdrew prematurely due to toxicity. No symptomatic cardiac dysfunction was reported., Conclusions: PST with trastuzumab plus docetaxel achieved promising efficacy, with a high pCR rate and good tolerability, in women with stage II or III HER2-positive breast cancer.

Aims: Malignant transformation in extra-ovarian endometriosis is a rare but known complication. This distinct pathological entity is reviewed with a specific focus on aetiology and treatment., Methods: Studies were identified by searching the English language literature in the MEDLINE database and by an extensive review of bibliographies from articles found through that search., Findings: Up to 1% of women with endometriosis will develop endometriosis-associated neoplasm. Almost a quarter of the reported cases of malignancy in endometriosis have involved extra-ovarian tissues. In many cases, hormonal factors may play a role in its pathogenesis. Estrogen monotherapy in obese patients significantly increase the risk of malignant extra-gonadal endometrial transformation. Genetic anomalies have also been reported such as loss of heterozygosity on chromosome 5q. For patients with disease confined to the site of origin, a 82-100% 5-year survival has been noted for endometrioid cell type; disseminated intraperitoneal disease, however, has a very poor associated prognosis, with a 0-12% 5-year survival overall., Conclusions: Women with endometriosis-associated cancers most likely represent a different class of patients than traditional ovarian cancer patients and may require different therapeutic options.

Purpose: Pseudomyxoma peritonei is a rare disease. Recently, cytoreductive surgery with intraperitoneal hyperthermic chemotherapy has emerged as a promising treatment for this debilitating condition. The aim of this prospective study was to evaluate this treatment strategy., Method: Twenty-seven patients with pseudomyxoma peritonei who were treated by cytoreductive surgery and intraperitoneal chemohyperthermia between 1997 and 2003 were identified from a prospective database., Results: Clinical presentation included suspected appendicitis (33 percent), increased abdominal girth (30 percent), and a suspected ovarian mass (26 percent). Twenty-two patients underwent surgery elsewhere before referral. Seventeen complications occurred in 12 patients (44 percent). Six were considered major: three anastomotic leaks, two pleural effusions, and one intra-abdominal abscess. Histologic examination demonstrated Grade 1, 2, and 3 disease in 8 (30 percent), 10 (37 percent), and 9 patients (33 percent), respectively. Pathologic grade showed a significant influence on the complication rate (P = 0 0.008). The actuarial five-year survival was 100 percent for patients with Grade 1 disease, whereas actuarial one-, two-, three-, and five-year survival for Grades 2 and 3 were 100, 80, 64, and 32 percent, respectively (P = 0.008)., Conclusions: Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy is a feasible treatment for pseudomyxoma peritonei. It is associated with acceptable morbidity when performed by an experienced surgical team. Histologic grade is the major determinant of survival.

The influence of clinical and treatment factors on the risk of recurrence was analyzed from a retrospective series of 74 children and adolescents with thyroid cancer (55 girls, 19 boys; age 2-20 years). Two groups, comparable in terms of age, sex, and previous radiotherapy, were compared according to the presence (group 1) or absence (group 2) of cervical lymph nodes identified by palpation or ultrasonography. Total thyroidectomy (TT) with lymph node dissection (LND) was performed in the 19 group 1 patients, whereas in group 2 patients (n = 55) lobectomy was performed in 29, TT in 26, and LND in 7. Pathology studies showed papillary thyroid carcinoma in 95% of cases. In group 1, tumors were more frequently multifocal (89% vs. 16% in group 2), invasive with extension beyond the thyroid capsule (68% vs. 5% in group 2), and of the diffuse sclerosing variety (63% vs. 4% in group 2) (p < 0.001). With a median follow-up of 61 months, lymph node recurrence was seen in 53% of group 1 patients and in no patients in group 2. Three group 2 patients (10%) were reoperated for a local recurrence after lobectomy. Risk factors for reintervention were young age (< 15 years) (p < 0.01) and cervical lymph nodes (p < 0.001). Survivals without reintervention at 5 and 10 years were, respectively, 58% and 38% for group 1 and 94% and 90% for group 2 (p < 0.001). At the time of analysis, 68% of group 1 patients and 98% of group 2 patients were in remission. In conclusion, the presence of palpable cervical lymph nodes at diagnosis is associated with more invasive forms of malignancy and is a predictive factor of recurrence regardless of the extent of the initial surgery.

The frequency of duodenal adenomas in patients with, familial adenomatous polyposis is high. Duodenal adenoma has malignant potential, and duodenal adenocarcinoma is one of the main causes of death in patients who have had previous proctocolectomy. A conservative approach to the treatment of duodenal adenomas (nonsteroidal anti-inflammatory drugs, endoscopy, polypectomy through duodenotomy) is inefficient and unsafe. When invasive cancer occurs in duodenal adenomas, the result of surgery is poor. We have performed prophylactic pancreaticoduodenal resection (PDR) for nonmalignant severe duodenal polyposis in five patients since 1991. No operative mortality was observed. One patient developed a pancreatic fistula which was successfully managed by medical treatment. The mean follow-up was 35 months. All five patients are still alive and have a good functional outcome. Prophylactic PDR may be indicated in familial adenomatous polyposis when duodenal polyposis is severe. Stages III and IV of Spigelman's classification, periampullary adenoma, age above 40, and family history of duodenal cancer are factors that may lead to the decision to perform prophylactic PDR.