A prognostic regulatory pathway in stage I epithelial ovarian cancer: new hints for the poor prognosis assessment.

BACKGROUND: Clinical and pathological parameters of patients with epithelial ovarian cancer (EOC) do not thoroughly predict patients' outcome. Despite the good outcome of stage I EOC compared with that of stages III and IV, the risk assessment and treatments are almost the same. However, only 20% of stage I EOC cases relapse and die, meaning that only a proportion of patients need intensive treatment and closer follow-up. Thus, the identification of cell mechanisms that could improve outcome prediction and rationalize therapeutic options is an urgent need in the clinical practice. PATIENTS AND METHODS: We have gathered together 203 patients with stage I EOC diagnosis, from whom snap-frozen tumor biopsies were available at the time of primary surgery before any treatment. Patients, with a median follow-up of 7 years, were stratified into a training set and a validation set. RESULTS AND CONCLUSIONS: Integrated analysis of miRNA and gene expression profiles allowed to identify a prognostic cell pathway, composed of 16 miRNAs and 10 genes, wiring the cell cycle, 'Activins/Inhibins' and 'Hedgehog' signaling pathways. Once validated by an independent technique, all the elements of the circuit resulted associated with overall survival (OS) and progression-free survival (PFS), in both univariate and multivariate models. For each patient, the circuit expressions have been translated into an activation state index (integrated signature classifier, ISC), used to stratify patients into classes of risk. This prediction reaches the 89.7% of sensitivity and 96.6% of specificity for the detection of PFS events. The prognostic value was then confirmed in the external independent validation set in which the PFS events are predicted with 75% sensitivity and 94.7% specificity. Moreover, the ISC shows higher classification performance than conventional clinical classifiers. Thus, the identified circuit enhances the understanding of the molecular mechanisms lagging behind stage I EOC and the ISC improves our capabilities to assess, at the time of diagnosis, the patient risk of relapse.

Functional Interaction Between the ESCRT-I Component TSG101 and the HSV-1 Tegument Ubiquitin Specific Protease.

Similar to phosphorylation, transient conjugation of ubiquitin to target proteins (ubiquitination) mediated by the concerted action of ubiquitin ligases and de-ubiquitinating enzymes (DUBs) can affect substrate function. As obligate intracellular parasites, viruses rely on different cellular pathways for their own replication and the well conserved ubiquitin conjugating/de-conjugating system is not an exception. Viruses not only usurp the host proteins involved in the ubiquitination/de-ubiquitination process, but they also encode their own ubiquitin ligases and DUBs. Here we report that an N-terminal variant of the herpes simplex virus (HSV) type-1 large tegument protein VP1/2 (VP1/2(1-767)), encompassing an active DUB domain (herpesvirus tegument ubiquitin specific protease, htUSP), and TSG101, a component of the endosomal sorting complex required for transport (ESCRT)-I, functionally interact. In particular, VP1/2(1-767) modulates TSG101 ubiquitination and influences its intracellular distribution. Given the role played by the ESCRT machinery in crucial steps of both cellular pathways and viral life cycle, the identification of TSG101 as a cellular target for the HSV-1 specific de-ubiquitinating enzyme contributes to the clarification of the still under debate function of viral encoded DUBs highly conserved throughout the Herpesviridae family.

Clear cell endometrial cancer: a CTF multicentre Italian study.

UNLABELLED: Endometrial clear cell carcinoma (CCC) is a rare entity and only accounts for 1-6% of all endometrial cancers. CCC is considered an aggressive subtype of endometrial cancer with worse prognosis compared with type I cancer and more frequent relapses at distant and extrapelvic sites. These characteristics require specific treatment modalities, but rarity of the disease does not allow to identify evidence based indications for therapies. Objective of the present study is to analyse a series of cases treated in a multicentre Italian setting. MATERIALS AND METHODS: Sixty-five endometrial CCC were treated in the period 1990-2010 in the participating institutions. Slides of the pathological specimens were reviewed by a single pathologist of each institution and debatable cases were collegially reviewed. Clinical records were collected by a common database. Demographic, surgical pathological, and follow-up data were registered. Results: All patients received primary surgery. Stage of disease according FIGO 2009 was as follow: l a: 16.9%, lb: 35.4%, 2: 9.2%, 3a: 9.2%, 3b: 3.1%, 3c: 16.9%, 4a: 3.1%, and 4b: 6.1%. Adjuvant post-operative treatment was adopted in 53.8% of cases. A relapse was detected in 29.2% of cases with a majority of extrapelvic sites (68.4%). Five-year survival rate was significantly related to stage of disease with an excellent prognosis for Stage Ia e lb disease with a complete staging. In these cases adjuvant treatment does not show significant improvement of survival. Relapsed cases show a response rate to treatment in 26% of cases (predominantly chemotherapy). CONCLUSION: CCC requires extensive surgical staging. Stage I disease completely staged does not require adjuvant therapy. More advanced stages require adjuvant chemotherapy.

Is there a role for postoperative treatment in patients with stage Ib2-IIb cervical cancer treated with neo-adjuvant chemotherapy and radical surgery? An Italian multicenter retrospective study.

PURPOSE: Neoadjuvant chemotherapy [NACT] followed by radical hysterectomy is an alternative therapeutic option to concurrent chemotherapy-radiotherapy for locally advanced cervical cancer. However there are very few data about the effectiveness of any post-operative treatment in this clinical setting. The purpose of this study was to correlate the patterns of recurrence and the clinical outcomes of cervical cancer patients who received NACT, with postoperative adjuvant treatment. PATIENTS AND METHODS: This retrospective multicenter study included 333 patients with FIGO stage Ib2-IIb cervical cancer who underwent platinum-based NACT followed by radical surgery. Pathological responses were retrospectively assessed as complete; optimal partial; and suboptimal response. Overall optimal response rate was the sum of complete and optimal partial response rates. RESULTS: On the whole series, recurrence-free survival was significantly longer in patients who achieved an overall optimal response than in those who did not (p<0.0001), and in patients who received adjuvant chemotherapy compared to those who did not (p=0.0001). On multivariate analysis, consolidation therapy (p=0.0012) was the only independent prognostic variable for recurrence-free survival; whereas FIGO stage (p=0.0169) and consolidation therapy (p=0.0016) were independent prognostic variables for overall survival. CONCLUSION: Optimal responders after chemo-surgical treatment for FIGO stage Ib2-IIb cervical cancer do not need any further treatment. Additional cycles of chemotherapy could be of benefit for patients with suboptimal response and intra-cervical residual disease. Both adjuvant chemotherapy and adjuvant radiation treatments do not seem to improve the clinical outcome of patients with extra-cervical residual disease compared to no further treatment.

Adjuvant treatment and analysis of failures in patients with high-risk FIGO Stage Ib-II endometrial cancer: an Italian multicenter retrospective study (CTF study).

OBJECTIVES: The purpose of this retrospective study was to assess the clinical outcome of patients with high-risk, early-stage endometrioid endometrial cancer (stage Ib or II with myometrial invasion >50%, grade 2-3). METHODS: We assessed 192 patients who underwent hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy, had histologically negative pelvic nodes, and had negative CT findings for aortic node involvement. RESULTS: Tumor relapsed in 36 patients after a median time of 21.2 months. The recurrence was vaginal in 7 (19.4%), distant in 16 (44.4%), aortic in 8 (22.2%), and involved multiple sites in 5 (13.9%). There was a trend to a lower vaginal recurrence rate in the 143 patients who received adjuvant radiotherapy (+chemotherapy) compared with the 46 who did not (2.1% versus 8.7%). Distant or aortic recurrences were lower in the 37 patients who received adjuvant chemotherapy (+radiotherapy) than in the 152 who did not (2.7% versus 18.4%, p=0.02). Of the 29 patients who received sequential adjuvant chemotherapy and radiotherapy, none developed local recurrence and only one had distant recurrence. There was a trend for a better 5-year progression-free survival and overall survival for the patients who received chemotherapy (+radiotherapy) compared with those who did not (86.0% versus 71.3%, and 92.3% versus 75.6%, respectively). CONCLUSIONS: Our data appear to suggest that adjuvant chemotherapy reduces the risk of distant or aortic recurrences and that sequential adjuvant chemotherapy and radiotherapy achieve an excellent local and distant control of disease in these clinical settings.

Survival and toxicity of radical radiotherapy (with or without brachytherapy) for FIGO stage I and II cervical cancer: a mono-institutional analysis.

PURPOSE OF INVESTIGATION: To add to the existing outcome data regarding radical radiotherapy (RT) for FIGO Stage I and II cervical cancer in a mono-institutional series and to evaluate the cost-benefit ratio of the addition of brachytherapy (BRA) to external-beam radiotherapy (EBRT). MATERIALS AND METHODS: The authors report on 240 patients (pts) with FIGO Stage I and II cervical cancer, consecutively treated with radical RT from 1990 through 2009 at the Istituto del Radio "O. Alberti" (EBRT alone, 32, EBRT and BRA, 189, BRA alone, 19). BRA was delivered with low dose rate (LDR, 133.64%) until 2003 and then with high dose rate (HDR, 75.36%). RT was associated with concomitant chemotherapy (CHT), mainly weekly cisplatin 40 mg/m2, in 87 pts, mostly after 2000. The Chi-square test was used to compare the different variables, the Log-Rank test to compare the actuarial survival values, and the Cox-model for the multivariate analysis. RESULTS: Five-year actuarial overall survival (OS) equalled 65%, disease specific survival (DSS) 77%. Regardless of disease stage, better DSS was evident in pts treated with EBRT and BRA compared with those treated with EBRT alone (82% and 58% respectively, p = 0.005); pts treated with concomitant CHT (dose intensity > or = 50%) and higher RT doses (RT cumulative EQD2 > or = 75 Gy) obtained better DSS. Complete response (CR) rate approached 88.4% (206/233 evaluable pts) and more than half of the subsequent failures (21/36) were in distant sites. Older patients and those given BRA had better OS and DSS, while BRA dose rate did not result related with these outcomes. Chronic G3/G4 toxicity involved more frequently the intestinal/rectal tract than other organs at risk. Rectal and vaginal serious chronic sequelae developed mainly in pts treated with EBRT and BRA and suggest the need for more advanced treatment techniques. CONCLUSIONS: the present mono-institutional analysis confirms the efficacy of radical RT for the treatment of cervical cancer and provides support to the role of BRA to obtain better outcomes. An effort to reduce long-term toxicity of the treatment is needed.

Pathological response on surgical samples is an independent prognostic variable for patients with Stage Ib2-IIb cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy: an Italian multicenter retrospective study (CTF Study).

OBJECTIVES: The purpose of this retrospective multicenter study was to correlate patterns of recurrences and clinical outcome of cervical cancer patients who underwent neoadjuvant chemotherapy [NACT] to surgery. METHODS: This study was conducted on 333 patients with FIGO stage Ib2-IIb cervical cancer who underwent NACT to surgery with pelvic lymphadenectomy. The median follow-up was 66.5 months (range, 8-212 months). Overall optimal response rate was the sum of complete and optimal partial response rates. RESULTS: An overall optimal response was obtained in 64 patients (19.2%). As for the 220 sub-optimal responders (66.1%), 127 patients had negative nodes and negative parametria and/or surgical margins, 75 patients had positive nodes with positive or negative parametria and/or surgical margins, and 18 patients had positive parametria and/or surgical margins with negative nodes. At the time of the present analysis, 79 (23.7%) of the 333 patients had a recurrence after a median time of 14.9 months (range, 4.5-123 months). Recurrent disease was pelvic in 50 (63.3%), extra-pelvic in 22 (27.9%), and both in 7 (8.8%). On multivariate analysis, pathological response to NACT was an independent prognostic variable for recurrence-free and overall survival. Patients who did not achieve an overall optimal response had a 2.757-fold higher risk of recurrence and a 5.413-fold higher risk of death than those who obtained an overall optimal response. CONCLUSIONS: Results appear to suggest that the chemo-surgical approach is an effective therapeutic option for patients with stage Ib2-IIb cervical cancer and that pathological response to NACT is the strongest prognostic factor for the outcome.

Analysis of failures and clinical outcome of advanced epithelial ovarian cancer in patients with microscopic residual disease at second-look reassessment following primary cytoreductive surgery and first-line platinum-based chemotherapy.

AIM: To assess the pattern of failure and survival of advanced ovarian cancer patients with microscopic residual disease at second-look following cytoreductive surgery and platinum-based chemotherapy. MATERIALS AND METHODS: Nine-five women were retrospectively analyzed. Residual disease after initial surgery was > one cm in 58 (61.1%) patients, first-line chemotherapy was paclitaxel/platinum-based in 70 (73.7%) patients, second-look findings showed no macroscopic residuum but positive random peritoneal biopsies and/or positive washing ("true" microscopic residual disease) in 79 (83.2%) patients, and a macroscopic residuum which was completely resected (converted complete response) in 16(16.8%) patients. RESULTS: Eight-one (85.2%) patients developed recurrent disease after a median time of 14 months (range four to 51). The abdomen (29.6%) and the pelvis (28.4%) were the most common sites of failure. Two- and five-year survival after second-look were 78.1% and 31.0%, respectively. The clinical and pathological features with prognostic relevance at presentation (age, histotype, and tumor grade), as well as type of first-line chemotherapy and treatment after second-look were not related to the clinical outcome. There was a trend for a better survival in patients with optimal primary cytoreduction compared with those with suboptimal primary cytoreduction (five-year survival = 42.7% vs 23.4%). There was no significant difference in survival between the converted complete responders and the patients with "true" microscopic residual disease. CONCLUSIONS: These data confirm the unsatisfactory clinical outcome of patients with microscopic residual disease after first-line chemotherapy and the limited benefit of second-look reassessment.

A case series of fetal lymphatic malformations and a review of the literature.

Lymphatic malformations are rare benign developmental anomalies of the lymphatic system that can be diagnosed by prenatal ultrasound. Depending on their anatomical site and size, the lesions can cause a variety of aesthetic and functional deficits. Several treatment options are available, the most suitable is still under debate. The experience gained at our Centre and the review of the literature can be useful to improve prenatal counseling, that is challenging due to the heterogeneity of clinical presentation and treatment.

Spatially resolved diagnostics for optimization of large ion beam sources.

Giant negative ion sources for neutral beam injectors deliver huge negative ion currents, thanks to their multi-beamlet configuration. As the single-beamlet optics defines the transmission losses along the beamline, the extraction of a similar current for all beamlets is extremely desirable, in order to facilitate the beam source operation (i.e., around perveance match). This Review investigates the correlation between the vertical profile of beam intensity and the vertical profiles of plasma properties at the extraction region of the source, focusing on the influence of increasing cesium injection. Only by the combined use of all available source diagnostics, described in this Review, can beam features on the scale of the non-uniformities be investigated with a sufficient space resolution. At RF power of 50 kW/driver, with intermediate bias currents and a filter field of 2.4 mT, it is found that the central part of the four vertical beam segments exhibits comparable plasma density and beamlet currents; at the edges of the central segments, both the beam and electron density appear to decrease (probably maintaining fixed electron-to-ion ratio); at the bottom of the source, an increase of cesium injection can compensate for the vertical drifts that cause a much higher presence of electrons and a lower amount of negative ions.

Cancer in pregnancy: maternal and fetal implications on decision-making.

BACKGROUND: Cancer complicates one out of 1,000 pregnancies. No standardized therapeutic interventions have been reported for these patients. METHODS: Fifteen patients with cancer during pregnancy were diagnosed between 6.5 and 36 weeks of gestational age between January 1991 and December 2007. RESULTS: Among the 15 cases one patient with early diagnosis (11 weeks) asked for interruption of pregnancy, two patients rejected chemotherapy in order to avoid fetal effects, seven patients underwent surgery during the first or second trimester, and two patients agreed to start the treatment only after delivery. Standard platinum-based chemotherapy (cisDDP) was postponed in six patients to the second trimester (administered after surgery in 2 cases). Chemotherapy was started between 18.3 and 29.6 weeks (median 22.3 weeks). One patient had pPROM (22.3 weeks) after chemotherapy with cisDDP. Ten patients were delivered by elective cesarean section and three by vaginal delivery. Mean gestational age at delivery was 33.5 weeks (range 32.1-40.0); mean weight at birth was 2,550 g (range 1,250-3,450). None of the newborns showed congenital malformations, and all had normal Apgar scores. Anemia occurred in two newborns. At a median follow-up of 56 months (range 2-198 months) all children were well and healthy. Eleven out of 15 mothers are alive and well, and one is alive with disease. An advanced neoplasm was diagnosed in three patients who died. CONCLUSION: When platinum-based chemotherapy is administered during the 2nd-3rd trimester, adverse effects in newborns are comparable to those in the general population. Deliberate treatment delay to achieve fetal viability or to improve fetal outcome may be reasonable for patients with early-stage cancer.

[Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases]. / Histoire naturelle des leucodystrophies avec mutation EIF2B: étude rétrospective multicentrique de 24 cas adultes.

INTRODUCTION: The childhood ataxia with central nervous system hypomyelination-vanishing white matter syndrome (CACH-VWM) was first characterized in children (2-5 years) on clinical and MRI criteria: cerebellospastic signs associated with episodes of rapid deterioration following stress and extensive cavitatingleucoencephalopathy. Causative mutations were found in the five genes encoding the subunits of the eukaryotic initiation factor 2B (eIF2B), involved in protein synthesis and its regulation under cellular stresses. A broad clinical spectrum has been subsequently described from congenital to adult-onset forms leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders. METHODS: The inclusion criteria were based on the presence of EIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis was also included. Clinical and MRI findings were retrospectively recorded in all patients. This multicentric study included 24 patients from 22 families. RESULTS: A sex-ratio imbalance was noted (male/female=5/19). The mean age of onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20), psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years, range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients. Magnetic resonance imaging findings consisted of cerebral atrophy (92%), extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found at a homozygous state in 58% of the 24 eIF2B-mutated patients. CONCLUSION: eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by screening for the recurrent p.Arg113His-eIF2Be mutation.

Possible role of palliative surgery for bowel obstruction in advanced ovarian cancer patients.

OBJECTIVES: Bowel obstruction is a relatively common event (30-40%) in advanced or recurrent ovarian cancer patients. No definitive data are available on the optimal management of this serious complication and treatment is generally limited to adoption of palliative measures. These modalities include both surgical and medical procedures. The aim of this study was to define selection criteria for subjects who would benefit from palliative surgery. STUDY DESIGN: Out of 270 epithelial ovarian cancer patients treated in the period 1984-2005, 75 (28%) developed bowel obstruction related to progression/recurrence of the disease. Palliative treatment - both medical and surgical - was applied on an individual basis. A new score developed by these authors was retrospectivelly applied to this group of patients with the aim of defining a subgroup that could benefit from surgical treatment. RESULTS: Fifty cases (66.7%) were medically treated whereas 25 patients (33.3%) underwent surgery. Mean and median survival rates were 34 and 28 weeks in the surgical group versus 12 and four weeks in the medical group. Distribution according to score showed 53 cases (71%) in the low score group (< 14) and 22 (29%) in the high score group (> 14). A significantly better survival was observed in the low-score group (p < 0.0001) and in the surgically treated patients (p < 0.001). According to the risk score variables patients treated surgically for obstruction with low scores had a longer survival (p < 0.005) compared to medical treatment but this difference was not found in the high-risk group (p < 0.05). CONCLUSIONS: The prognosis of patients with bowel obstruction in relation to advanced ovarian cancer is best determined by comprehensive assessment of all prognostic parameters to define a subgroup of patients in a low-risk group that may benefit from surgical treatment.

Analysis of current-voltage characteristics for Langmuir probes immersed in an ion beam.

Movable electrical probes were used to diagnose the beam flux profile and potential of ion beams since the early 1960s. Experimental measurements of beam plasmas can provide essential data related to the space charge neutralization, but the current-voltage characteristics obtained from such electrical probes are dominated by beam ion impact and ion-induced secondary emission. In this work, we present an analysis of the Langmuir characteristics obtained in a negative ion beam. We identify and discuss separately the contributions to the collected current given by secondary plasma ions and electrons, stripped electrons, beam ions, and ion-induced secondary electron emission. We present the beam plasma parameters obtained at different beam energies in NIO1.

Numerical simulation of experimental tests performed on ZAO® non-evaporable-getter pump designed for neutral beam injector applications.

Vacuum systems of neutral beam injectors have very demanding requirements in terms of pumping speed, throughput, and capacity. Due to their high affinity to hydrogenic species, porous sintered Non-Evaporable Getters (NEG) are a possible candidate for deployment in giant hydrogen ion sources and neutral beam injectors for fusion. This paper presents the numerical interpretation of experimental tests on a recently developed NEG cartridge, that is part of a modular pump under development for neutral beam injectors. The cartridge is composed of six stacks of ZAO® porous sintered NEG disks and a heater. It was tested under hydrogen loads relevant for neutral beam injectors, namely, at constant pressure or constant flow, such that the hydrogen pressure was in the range of 20 mPa-40 mPa. The result of the sorption test was reproduced by a three dimensional flow simulation in molecular regime to determine the actual pumping speed, the effective sticking coefficient, and the uniformity of the gas load on the various NEG disks. The procedure developed and the results obtained provide the basic understanding for interpreting the large-scale tests on the modular pump, consisting of 34 of these cartridges.

Interpreting the dynamic equilibrium during evaporation in a cesium environment.

The cesium ovens for the prototype source of the ITER neutral beam injectors are currently tested in the CAesium Test Stand (CATS) facility, with a background pressure of 10-6 mbar. Different diagnostics are here installed: two Langmuir-Taylor detectors allow us to determine the Cs vapour evaporation rate from the oven and the Cs density at different positions in the vacuum chamber; and laser absorption spectroscopy is used to measure the density integrated over a line of sight and a quartz crystal microbalance to detect the cesium mass deposited in time over a surface. In this paper, we present a model to describe the dynamic equilibrium in the evaporation chamber of CATS with the first oven tested in order to gain information about the Cs sticking coefficient at the walls. The model hence includes sticking and energy accommodation of the Cs atoms to the walls, calculates the flux density at the surfaces, and provides the Cs atom density at any location in the volume. By this model, we simulate the Cs evaporation and the equilibrium density, comparing the modeled results with the experimental data. As a result, a sticking coefficient of 2% is obtained.

Beam energy recovery for fusion and collector design for tests on compact sources.

The next fusion project DEMO, which will be the evolution of the experimental fusion reactor [International Tokamak Experimental Reactor (ITER)], would require a high efficient energy production. As in ITER, DEMO will use fast Neutral Beam (NB) injectors to increase the plasma temperature needed for the fusion reaction. A way to recover the electric energy production efficiency in DEMO could be the beam energy recovery in the NB production, which is produced by a D- beam, neutralized by a gas cell with 60% efficiency. A compact energy recovery device with an axisymmetric cylindrical ion collector that uses only decelerating electric fields combined with the beam space charge effect has been recently proposed. It can be used for a test on the beam of the NIO1 (Negative Ion Optimization 1) source, a compact ion source (scaled down from ITER size sources) that has been developed at INFN-LNL and Consorzio RFX (Padua). The detailed collector design to be used on one of the beamlets of the NIO1 source within typical space limitation is presented and discussed here. Furthermore, a preliminary trajectory simulation for a beam with a rectangular geometry similar to the beam used in ITER to verify the beam recovery for a nonaxial symmetric geometry is also shown.

Simulation of the gas density distribution in the accelerator of the ELISE test facility.

In multiaperture electrostatic accelerators of negative ion sources, the plasma discharge is sustained by injecting gas in the plasma source, in a dynamic equilibrium with the gas flowing out through the accelerator. In this work, we present a three-dimensional numerical simulation of the gas flow inside the accelerator system of the large negative ion source ELISE at Max-Planck-Institut für Plasmaphysik Garching. ELISE has 640 apertures per electrode and lateral gaps between the electrode support structures that also contribute to the total gas conductance. Assuming molecular regime, we estimated the gas conductance, the gas density profile along the path of the ion beams from upstream of the plasma grid to downstream of the ground grid, and the transverse nonuniformities in the accelerator. The simulation included the most relevant geometrical features, while the results are compared to analytical results.