Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

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.

Distant lymph node metastases in gastroesophageal junction adenocarcinoma: impact of endoscopic ultrasound-guided fine-needle aspiration.

OBJECTIVE: Endoscopic ultrasound (EUS) is established as the most accurate technique for pre-operative locoregional staging of gastroesophageal junction (GEJ) adenocarcinoma, the purpose of the present study was to evaluate the distant lymph nodes (LNs) EUS-fine-needle aspiration (FNA) impact in therapeutic decision for patients with GEJ adenocarcinoma. MATERIALS AND METHODS: Retrospective study was made, with cross-sectional, non-probabilistic analysis from prospectively collected database for all GEJ adenocarcinoma staging patients referred between January 2009 and August 2012 in Paoli-Calmette Institute in Marseille-France. RESULTS: A total of 154 patients with GEJ adenocarcinoma were managed in our institution, of whom 113 (73.3%) had non-distant metastatic disease at computed tomography (CT) scan and underwent EUS for initial tumor staging prior to a treatment decision. On A total of 113 patients undergoing EUS, 8 (7%) patients underwent endoscopic resection and 6 (5.3%) underwent direct surgical resection. Of the remaining 99 patients (87.6%), 24 (21.2%) distant LN EUS-FNA were made. Seventeen LN had EUS malignant features, including 9 (52.9%) that were confirmed as malignant and underwent palliative treatment with chemotherapy. Ninety (79.6%) patients were treated with pre-operative neoadjuvant therapy and were revaluated after. 4 (4.4%) had metastatic disease at CT scan (underwent palliative treatment) and 65 (72.2%) underwent EUS restaging to treatment decision revaluation. Of these, twelve (18.4%) distant LN EUS-FNA were performed. Seven had LN EUS malignancy features, including 4 (57.1%) that were confirmed as malignant and underwent palliative treatment. The remaining 61 patients underwent surgery. As stated above, 21 patients (23.3%) did not undergo EUS restaging, including 10 (47.6%) that did not go to surgery because patient's age, poor general status and comorbidities, 6 (28.5%) had a loss of follow-up, 1 (4.7%) underwent to surgery due to chemotherapy collateral effects, 3 (14.2%) were still on pre-operative chemotherapy and 1 (4.7%) died for sepsis after mediastinal EUS-FNA, this was the only complication event evidenced. EUS-FNA changed clinical management in 54.2% of patients who met the criteria inclusion (distant LN with malignancies EUS features), which corresponds to 11.5% of patients with GEJ adenocarcinoma. CONCLUSION: EUS-FNA was able to provide a different tumor staging and these differences were associated with treatment received. EUS-FNA had a significant impact on treatment decision.

Radiofrequency ablation associated to mucosal resection in the oesophagus: experience in a single centre.

UNLABELLED: Endoscopic resection (EMR) and radiofrequency ablation (RFA) form part of the treatment of Barrett's oesophagus (BO), dysplasia, superficial adenocarcinoma (OAC) associated with BO. PATIENTS AND METHODS: Between June 2008 and April 2011, 34 patients underwent treatment with RFA (HALO system(®)), in a tertiary centre. For the study, patients were divided into two groups. Group 1 (16 patients of average 60 years old; 14 men, two women) received EMR and RFA. Group 2 (18 patients averaging 59 years age; 14 men, four women) received RFA without EMR in the year preceding the RFA. RESULTS: In group 1, high grade dysplasia (HGD) was eradicated in 12 cases (92%), low grade dysplasia (LGD) in three cases (100%). Complete response occurred in nine cases (56%), partial response in 100% of cases. Mean follow-up was 15 months. In group 2, HGD was eradicated in one patient (100%), LGD in three patients (64%). A complete response was achieved in eight patients, partial response in four cases (77%). Mean follow-up was 10 months. The complication rate for groups 1 and 2 was of 18% and 10% respectively. No complication prevented completion of treatment or continued monitoring. Recurrence was evaluated to 5% in both groups. CONCLUSION: RFA associated with EMR is feasible, offering probably better results and a very important advantage: a more complete histology before follow-up. Our results show effective treatment of BO and associated dysplasia with a low rate of complication. Nevertheless, when new techniques of BO ablation are used, the need to obtain histology before treatment should not be forgotten.

Neoadjuvant chemoradiation and pancreaticoduodenectomy for initially locally advanced head pancreatic adenocarcinoma.

BACKGROUND: The most accepted treatment for locally advanced pancreatic adenocarcinoma (LAPA) is chemoradiotherapy (CRT). We sought to determine the benefit of pancreaticoduodenectomy (PD) in patients with LAPA initially treated by neoadjuvant CRT. METHODS: From January 1996 to December 2006, 64 patients with LAPA (borderline, n=49; unresectable, n=15) received 5-fluorouracil-cisplatin-based CRT. Of the 64 patients, 47 had progressive disease at restaging. Laparotomy was performed for 17 patients, and PD was performed in 9 patients (resected group). Fifty-five patients had CRT followed by gemcitabine-based chemotherapy (unresected group). RESULTS: The median survival and overall 5 years survival duration of all 64 patients were 14 months and 12%, respectively. The mean delay between diagnosis and surgical resection was 5.5 months. Mortality and morbidity from PD were 0% and 33%, respectively. The median survival of the resected group vs. the unresected group was 24 months vs. 13 months. Three specimens presented a major pathological response at histological examination. No involved margins were found and positive lymph nodes were found in one patient. Resected patients developed distant metastases. CONCLUSIONS: PD after CRT was safe and resected patients had interesting survival rates. However, resected patients developed metastatic disease and new neoadjuvant regimens are needed to improve the survival of these patients.

Strategies for the treatment of synchronous liver metastasis.

AIM: Observe the outcomes after complete simultaneous or delayed resection of synchronous liver metastasis (SLM) from colorectal cancer (CRC). METHODS: From 1994 to 2005, 119 patients were diagnosed with CRC and SLM; 57 patients had simultaneous resection (group I) and 62 patients had staged resection (group II). Perioperative chemotherapy was considered completed if all expected cycle were administrated. RESULTS: Overall survival rates of group I-group II at 1, 3 and 5 years were respectively 91%-93% (p=0,3), 59%-57% (p=0,09) and 32%-25% (p=0,06). The median survival time of group I-group II were respectively 46 months-40 months (p=0,07). There was no statistical difference on survival regarding location of metastasis (p=0,09) or primary tumor location (p=0,2). Patients with simultaneous or staged resection receiving optimal treatment (R0 liver surgery and complete chemotherapy) were respectively 89% and 67% (p=0,04). Twenty three patients developed isolated liver recurrence with higher frequency in staged patients (26% vs 9% p=0,03) without impairment of survival. CONCLUSIONS: Because of postoperative morbidity and prolonged tiring treatment, many patients having staged resection were under treated. However we did not observe statistical difference on survival but we supported that simultaneous resection has to be prefer to achieve an optimal treatment. Lung and bone metastasis are the new challenge for oncologists.

[Pelvic posterior exenteration with immediate colo-rectal anastomosis: is it justified and feasible in advanced stage ovarian carcinoma?]. / Une exentération pelvienne postérieure avec anastomose est-elle faisable et justifiée dans le traitement des cancers de l'ovaire à un stade évolué?

PURPOSE: The aim of this study is to show that the removal of the rectum is not an obstacle to implement an optimal surgery in advanced epithelial cancer of the ovary. MATERIAL AND METHODS: Retrospective study on a population of 44 women with advanced epithelial cancer of the ovary. The surgery was realized between January 95 and July 03, and all surgeries required a posterior exenteration. This treatment was completed by chemotherapy for 36 of them. RESULTS: The median survival of this population is 36.6 months. 6/44 patients (13.6%) had post-operative complications. The completion of chemotherapy started after an average of 5.2 weeks after surgery. All the assessable patients (43/44) have an anal satisfactory continence. CONCLUSION: The posterior exenteration, when it's necessary, for advanced epithelial cancer of the ovary must not be an obstacle to obtain an optimal surgery. Anal continence is respected and there are no more complications. This surgical act is safe for the management of this pathology without delaying the others therapeutics and allowing a satisfactory quality of life.

Long term morbidity of neoadjuvant chemoradiation for pancreatic head adenocarcinoma.

PURPOSE: To report the long term risks of neoadjuvant chemoradiation (NCRT) after duodenopancreatectomy (DP) for adenocarcinoma of the head of pancreas. METHODS: Between January 1996 and December 2002, 26 patients with biopsy-proven adenocarcinoma of the head of pancreas were treated by this combination of therapies. RESULTS: Two patients had delayed NCRT-related small bowel infarction: one died from superior mesenteric artery stenosis 36 months after DP without recurrence at laparotomy; there was one limited infarction 16 months after DP. CONCLUSIONS: Long term vascular morbidity after NCRT is significant.

[Major hepatectomy for metastasis of colorectal cancer improves survival in the elderly]. / Hépatectomie majeure pour métastases de cancers colorectaux chez le sujet âgé.

OBJECTIVE: Assessing impact of major liver resection (LR) for hepatic metastasis of colorectal cancer (HMCC) on post operative courses and long term survival in the elderly. PATIENTS AND METHOD: Thirty-three consecutive patients aged over 70 years-old were treated in our institution for up to 3 resectable metachronous HMCC. Fifteen patients had major LR (9 right hepatectomy, 3 extended right hepatectomy, 3 left hepatectomy) without pre or postoperative chemotherapy (group 1) and 18 patients were exclusively treated by chemotherapy (group 2) because of high ASA score (ASA 3) or patients refusal. RESULTS: No patients died of another cause that colorectal cancer disease during observation time. All patients of group 2 died during observation time. Post operative mortality and morbidity of group 1 were respectively 0% and 33%. Survival at 1 and 2 years of group 1-2 were respectively 73-50% (P=0,04) and 47-15% (P=0,05). Median survival of group 1 and 2 were respectively 22 and 12 months (P=0,03). CONCLUSIONS: Major LR for HMCC could be proposed regardless the age. High ASA score, multiple (more than 4) metastasis location, evolutive disease could justify an exclusive medical approach.

Gastric duplication in an adult mimicking mucinous cystadenoma of the pancreas.

Gastric duplication cyst (GDC) in an adult can have several clinical presentations. A review of the literature showed previously reported cases of GDC presenting as pancreatic pseudocyst or with greatly raised concentrations of carbohydrate antigen 19-9 (CA 19-9). It is often difficult to discriminate GDC from pancreatic cystic tumour, in particular pancreatic mucinous cystadenoma, in which concentrations of carcinoembryonic antigen and CA 19-9 are classically raised. This report describes an adult case of GDC mimicking a mucinous cystadenoma of the pancreas. This is the first report of a simultaneous increase in carcinoembryonic antigen and CA 19-9 in GDC in the absence of malignancy. Although few cases of carcinoma arising from a GDC having been reported, the production of oncofetal antigens raises the problem of a precancerous condition in long standing intestinal duplications. In this situation surgical resection must be performed.

A reappraisal of preoperative chemoradiation for localized pancreatic head ductal adenocarcinoma in a 5-year single-institution experience.

Resection of localized pancreatic head ductal adenocarcinoma (LPHDA) has a limited impact on survival. Mechanisms of improvement provided by preoperative chemoradiation therapy (CRT) remain under debate. This study analyzes the outcome of patients treated for LPHDA to delineate the benefits of CRT. Among 87 patients with LPHDA, 17 had a pancreaticoduodenectomy alone (group I). Thirty-nine with initially resectable cancers received CRT with 5-fluorouracil-based chemotherapy (group II). Thirty-one with initially unresectable cancers were similarly treated by CRT (group III). Patients in groups II and III were restaged after completion of CRT. In patients with resectable disease, resection was planned. Patients in groups I and II were statistically comparable in terms of age, sex, and pretherapeutic stage. Median survival and 2-year overall survival in group I were 13.7 months and 31%, respectively. In group II, 23 patients (59%) had a pancreaticoduodenectomy (group IIa) and 16 patients (41%) did not have resection (group IIb). Median survival and 2-year overall survival were as follows: group IIa, 26.6 months and 51%; and group IIb, 6.1 months and 0%, respectively. In group IIa, pathologic examination revealed eight major responses (35%) including two sterilized specimens, and none of the patients had locoregional recurrence. In group III, none of the patients had resection, and median survival was 8 months with one 2-year survivor. Patient selection appears to play a major role with regard to results achieved with preoperative CRT followed by pancreaticoduodenectomy. However, a high histologic response rate and excellent local control can also be achieved.

Long-term results of preoperative radiotherapy for 113 cases of UT3 and UT4 rectal cancer: a need for long-term follow-up.

PURPOSE: Eighty percent of local recurrence after resection of rectal adenocarcinoma classically occurs within two years of surgery. Pretherapeutic staging is frequently limited to clinical examination, although the accuracy of endoanal ultrasonography has been demonstrated. The aim of this study was to report the long-term results of preoperative radiation therapy and resection of pretherapeutic endoanal ultrasonography-staged T3 and T4 rectal adenocarcinoma. METHODS: This retrospective review analyzed a series of 113 patients who underwent radiation therapy followed by surgery. All patients underwent an endoanal ultrasonography. Median follow-up was 75 months. RESULTS: Fifty-seven percent of patients were pT3 or T4. Thirty-six percent had involvement of lymph nodes. Five-year rates of survival, local recurrence-free survival, and disease-free survival were 79, 73, and 68 percent, respectively. Ten-year rates were 65, 63, and 62 percent, respectively. Median time to detection of local recurrence was 39 months. Eight of ten local recurrences occurred after two years of follow-up. Eight of ten patients with local recurrence had pretherapeutic endoanal ultrasonography-staged N+ tumors. CONCLUSION: These results appear to justify a follow-up program for patients with pretherapeutic endoanal ultrasonography-staged N+ tumor. However, a minimum of seven years of follow-up is needed to obtain an accurate assessment of results.

An endogenous adrenoceptor ligand potentiates excitatory synaptic transmission in cultured hippocampal neurons.

Noradrenergic inputs modulate hippocampal function via distinct receptors. In hippocampal neuronal cultures, mRNA expression of adrenoceptor subtypes is maintained from 1 day in vitro (DIV) to 22 DIV. Noradrenaline dose-dependently stimulates phosphoinositide (PI) breakdown in both immature and mature cultures through the activation of alpha1 receptors. At 22 DIV, basal PI breakdown depends on excitatory synaptic activity since it is decreased by tetrodotoxin or glutamate receptor antagonists. At 22 DIV, a similar decrease of basal PI breakdown is also observed with alpha1, alpha2 or beta adrenoceptor antagonists. These effects are not additive with that produced by tetrodotoxin. Adrenergic antagonists also strongly reduce spontaneous excitatory post-synaptic currents (sEPSC) as evidenced by whole cell recording. Therefore, in hippocampal cultures, excitatory transmission is modulated by a tonic activation of adrenoceptors probably produced by an endogenous ligand. Indeed, (i) the depletion of catecholamine pools by reserpine also decreases both basal PI metabolism and sEPSC; (ii) hippocampal neurons possess both tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase mRNAs, encoding enzymes required for catecholamine synthesis; and (iii) some hippocampal neurons show TH-immunoreactivity. TH-positive cells are also detected in E18 hippocampal sections. Thus, cultured hippocampal neurons synthesize and release an adrenergic-like ligand, which tonically potentiates excitatory synaptic transmission in mature cultures.

A bizarre giant leiomyoma.

We report the clinical and imaging features of a huge deep leiomyoma of the rectus abdominis treated surgically in an 84-year-old man. Hypotheses are put forward to elucidate the etiology of this enigmatic localization, apparently the first described in the literature.

Potentiation of glutamatergic agonist-induced inositol phosphate formation by basic fibroblast growth factor is related to developmental features in hippocampal cultures: neuronal survival and glial cell proliferation.

We investigated the modulation by growth factors of phospholipase C (PLC)-linked glutamate receptors during in vitro development of hippocampal cultures. In defined medium, glial cells represent between 3 and 14% of total cell number. When we added basic fibroblast growth factor (bFGF) 2 h after plating, we found: (i) a neuroprotection from naturally occurring death for up to 5 days; (ii) a proliferation of glial cells from day 3; and (iii) a potentiation of quisqualate (QA)-induced inositol phosphate (IP) formation from 1 to 10 days in vitro (DIV) and 1S, 3R-amino-cyclopentane-1,3-dicarboxylate (ACPD) response from 3 to 10 DIV. The antimitotic cytosine-beta,D-arabinofuranoside (AraC) blocked glial cell proliferation induced by bFGF, but not neuroprotection. Under these conditions, the early potentiation of the QA response (1-3 DIV) was not changed, while the ACPD and late QA response potentiations were prevented (5-10 DIV). Epidermal growth factor was not neuroprotective but it induced both glial cell proliferation and late QA or ACPD potentiation. Surprisingly, the early bFGF-potentiated QA-induced IP response was blocked by 6, 7-dinitro-quinoxaline-2,3-dione (DNQX), suggesting the participation of ionotropic (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate (KA) receptors. The delayed bFGF-potentiated ACPD-induced IP response is inhibited by (S)-alpha-methyl-4-carboxyphenylglycine (MCPG), indicating possible activation of glial metabotropic receptors. These results suggest that, in hippocampal cultures, bFGF modulates AMPA and metabotropic glutamate receptors linked to the IP cascade, possibly in relation to the regulation of neuronal survival and glial cell proliferation, respectively.

Synthesis and biological activity of glutamic acid derivatives.

In order to develop new specific glutamate analogues at metabotropic glutamate receptors, Diels-Alder, 1-4 ionic and radical reactions were performed starting from (2S)-4-methyleneglutamic acid. Preliminary pharmacological evaluation by measuring IP accumulation using rat forebrain synaptoneurosomes has shown that (2S)-4-(2-phthalimidoethyl)glutamic acid (3a), (2S)-4-(4-phthalimidobutyl)glutamic acid (3b) and 1-[(S)-2-amino-2-carboxyethyl]-3,4-dimethylcyclohex-3-ene-1-carbox ylic acid (8) presented moderate antagonist activities.

Cadmium rapidly and irreversibly blocks presynaptic phospholipase C-linked metabotropic glutamate receptors.

Calcium ions (Cd2+) inhibit inositol phosphate (IP) formation elicited by glutamate (GLU) or K+ ions, without affecting carbachol (Carb)-induced IP response in 8-day-old rat forebrain synaptoneurosomes and synaptosomes. On the contrary, Cd2+ was almost ineffective in blocking GLU- and K(+)-responses in hippocampal neurones in culture. The mechanism of Cd2+ inhibition was thus examined in synaptoneurosomes. Extensive washing of synaptoneurosomes pretreated for 1, 5, 15, or 30 min by 100 microM Cd2+ did not modify the inhibitory effect of Cd2+ on GLU-, K(+)- and A23187-evoked IP formation or its lack of effect on Carb response. The later addition of a high affinity Cd2+ chelator (100 microM), N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) also did not reverse the inhibitory effect. TPEN, however, penetrates into synaptoneurosomes and efficiently displaces Cd2+ from the Fura-2-Cd2+ complex as shown by Fura-2 fluorescence recordings. TPEN is not easily removed from the intracellular space, as demonstrated by its ability to still block Cd(2+)-induced Fura-2 fluorescence increase after extensive washing. Pretreatment of synaptoneurosomes by this chelator did not prevent Cd2+ inhibition of GLU-induced IP formation. These data indicate that Cd2+ ions rapidly, irreversibly and extracellularly inhibit GLU-elicited IP formation in synaptoneurosomes or synaptosomes, but not in hippocampal neurones in culture. It is speculated that Cd2+ ions could allow one to distinguish the activity of presynaptic metabotropic glutamate receptors (mGLURs) linked to phosphoinositide metabolism from that of mGLURs located postsynaptically.

A modulation of glutamate-induced phosphoinositide breakdown by intracellular pH changes.

The influence of intracellular pH (pHi) changes on the formation of inositol phosphate metabolites (IPs) produced by glutamatergic stimulation was studied in 8-day-old rat brain synaptoneurosomes. For this purpose pHi was measured using 2',7'-bis-(2-carboxyl)-5,6-carboxyfluorescein (BCECF) fluorimetric assay in parallel with the basal and receptor-mediated formations of inositol monophosphate (IP1) and inositol bisphosphate (IP2). We found that glutamate (1 mM), which induces a transient acidification (delta pH = -0.05), produces an identical accumulation of IP1 and IP2. K+ (30 mM), which provokes an alkalinization of the internal medium (delta pH = +0.22), mainly leads to the formation of IP1 metabolites. Paired combinations of glutamate with 1, 5 and 10 mM NH4+ finally result in an alkalinization of the intrasynaptoneurosomal medium. These combinations produce a strong decrease of the IP2 level concomitant with an increase of the IP1 formation, compared to the levels of IP1 and IP2 evoked by glutamate alone. The total amount of IPs (IP1 + IP2) produced by these combinations is not different from that obtained with glutamate alone. Paired combinations of carbachol with NH4+ produce an identical alkalinization to that produced by NH4+ alone. These combinations produce an increased IP1 accumulation, while the IP2 formation is slightly decreased. When the internal medium is acidified by diminishing the external concentration of Na+, the ratio IP1/IP2 produced after metabotropic glutamate receptor (mGluR) activation is shifted to lower values, while it is not affected for the muscarinic stimulation. These data suggest that the mGluR-associated pathway in synaptoneurosomes is sensitive to pHi shifts, while the muscarinic receptor-associated pathway is less altered when pHi is manipulated. It may be proposed that pH-sensitive inositol phosphate dephosphorylating systems, i.e. phosphatases, are associated with mGluRs in this preparation.