Training in esophageal peroral endoscopic myotomy (POEM) on an ex vivo porcine model: learning curve study and training strategy.

BACKGROUND: Peroral endoscopic myotomy (POEM) is a very effective treatment for achalasia. However, training remains non-standardized. We evaluated a training curriculum, including ex vivo cases, followed by patients' cases under expert supervision. The objective was to establish a learning curve of POEM. MATERIALS AND METHODS: Four operators having completed advanced endoscopy fellowship were involved. They had already observed > 30 cases performed by experts. They performed 30 POEMs standardized (tunnel and myotomy lengths) procedures on ex vivo porcine model. Procedural times, number/volume of injections, mucosal and serous perforations, and myotomy length were collected. The learning curve was assessed using dissection speed (DS) and a dedicated performance score (PS), including learning rate (LR) and learning plateau (LP). RESULTS: The operators completed all cases within 4 months (median of 3.5 cases/week). The mean procedural time was 43.3 min ± 14.4. Mean myotomy length was 70.0 mm ± 15.6 mm. Dissection speed averaged 1.78 mm/min ± 0.78. Using DS and PS as parameter, the LR was reached after 12.2 cases (DS = 2.0 mm/min) and 10.4 cases, respectively. When comparing the LP and the plateau phase, the DS was slower (1.3 ± 0.5 mm/min versus 2.1 ± 0.54 mm/min, p < 0.005) and perforations were decreased: 0.35 ± 0.82 in LP vs. 0.16 ± 0.44 in PP. Following this training, all operators performed 10 supervised cases and are competent in POEM. CONCLUSION: The association of observed cases and supervised ex vivo model training is effective for starting POEM on patients. The learning curve is 12 cases to reach a plateau.

Assessment of the Smartpill, a Wireless Sensor, as a Measurement Tool for Intra-Abdominal Pressure (IAP).

Background: The SmartPill, a multisensor ingestible capsule, is marketed for intestinal motility disorders. It includes a pressure sensor, which could be used to study intra-abdominal pressure (IAP) variations. However, the validation data are lacking for this use. Material and Methods: An experimental study was conducted on anesthetized pigs with stepwise variations of IAP (from 0 to 15 mmHg by 3 mmHg steps) generated by laparoscopic insufflation. A SmartPill, inserted by endoscopy, provided intragastric pressure data. These data were compensated to take into account the intrabdominal temperature. They were compared to the pressure recorded by intragastric (IG) and intraperitoneal (IP) wired sensors by statistical Spearman and Bland-Altmann analysis. Results: More than 4500 pressure values for each sensor were generated on two animals. The IG pressure values obtained with the SmartPill were correlated with the IG pressure values obtained with the wired sensor (respectively, Spearman ρ coefficients 0.90 ± 0.08 and 0.72 ± 0.25; bias of -28 ± -0.3 mmHg and -29.2 ± 0.5 mmHg for pigs 1 and 2). The intragastric SmartPill values were also correlated with the IAP measured intra-peritoneally (respectively, Spearman ρ coefficients 0.49 ± 0.18 and 0.57 ± 0.30; bias of -29 ± 1 mmHg and -31 ± 0.7 mmHg for pigs 1 and 2). Conclusions: The SmartPill is a wireless and painless sensor that appears to correctly monitor IAP variations.

Correction: Efficiency of an endoscopic resection strategy in the management of submucosal tumors less than 20 mm in size and located in the upper gastrointestina.

[This corrects the article DOI: 10.1055/a-1783-8675.].

Efficiency of an endoscopic resection strategy for management of submucosal tumors < 20 mm in the upper gastrointestinal tract.

Background and study aims The histologic diagnosis of submucosal tumors (SMTs) < 20 mm is challenging. Monitoring is the main option offered, but compliance is debatable. Endoscopic resection (ER) of malignant SMTs or those with an uncertain diagnosis is an alternative that has already been reported about and proposed in our center. The aims of this study were to confirm the safety of this resection strategy and to perform long-term follow-up of malignant SMTs after resection. Patients and methods All patients who underwent ER for SMTs < 2 cm in a single center between 2007 and 2019 were included retrospectively. Patients were classified into two groups according to the need for postresection follow-up: benign SMTs (B-SMTs) and follow-up SMTs (FU-SMTs). Results One hundred and one patients were included. The mean tumor size was 16.7 mm. In total, 92 of 101 SMTs had an uncertain diagnosis. Macroscopic resection was completed for 95 SMTs (93.1 %), with en bloc resection in 94 (92.1%). The morbidity rate was 3 %, with no mortality. A total of 84 of 101 SMTs (84 %) were B-SMTs and did not need monitoring, and 17 SMTs (19.7 %) were FU-SMTs (8 gastrointestinal stromal tumors, 6 neuroendocrine tumors, and 3 others). No relapse was reported in the FU-SMT group, with a median follow-up duration of 33 months [4-127] (61 months [17-127] for the gastrointestinal stroma tumor group). Conclusions The study results suggest ER is a potentially reliable and effective strategy for upper gastrointestinal tract SMTs < 20 mm. Although the strategy needs further validation in advanced care units, it could eliminate the need for long-term monitoring, therefore targeting such follow-up efforts to patients with FU-SMTs.

RhoA and RhoC differentially modulate estrogen receptor α recruitment, transcriptional activities, and expression in breast cancer cells (MCF-7).

PURPOSE: RhoA and RhoC are closely related, small GTPases that are clearly involved in breast cancer tumorigenesis. Nonetheless, their specific roles in the control of estrogen receptor alpha (ERα) activities have not been elucidated. METHODS: We used siRNA sequences to specifically down-regulate RhoA and RhoC expression in ERα-positive breast adenocarcinoma MCF-7 cells. We then analyzed the consequences of down-regulation on ERα expression, ERα recruitment to the promoters of four target genes, and the mRNA levels of those genes. RESULTS: We demonstrated that RhoA and RhoC clearly and similarly modulated ERα recruitment to the vitellogenin estrogen responsive element (ERE) present in a luciferase reporter gene and to the promoters of progesterone receptor (PR), cathepsin D, and pS2 genes. Besides, RhoA up-regulated the ERE-luciferase reporter gene activity and PR mRNA expression and tended to down-regulate cathepsin D and pS2 mRNA expression. Conversely, RhoC inhibition had no significant effect at the mRNA level. Furthermore, RhoA inhibition, and to a lesser extent RhoC inhibition, increased ERα expression. No alteration in ERα mRNA levels was observed, suggesting potential post-translational control. CONCLUSIONS: Taken together, our results strongly suggest that RhoA and RhoC play different, but clear, roles in ERα signaling. These GTPases are definitely involved, along with RhoB, in ERα recruitment and, to some extent, ERα cofactor balance. We hypothesize a differential role of RhoA in breast cancer tumors that depend on hormone status.

RhoB modifies estrogen responses in breast cancer cells by influencing expression of the estrogen receptor.

INTRODUCTION: RhoB has been reported to exert positive and negative effects on cancer pathophysiology but an understanding of its role in breast cancer remains incomplete. Analysis of data from the Oncomine database showed a positive correlation between RhoB expression and positivity for both estrogen receptor alpha (ERα) and progesterone receptor (PR). METHODS: This finding was validated by our analysis of a tissue microarray constructed from a cohort of 113 patients and then investigated in human cell models. RESULTS: We found that RhoB expression in tissue was strongly correlated with ERα and PR expression and inversely correlated with tumor grade, tumor size and count of mitosis. In human breast cancer cell lines, RhoB attenuation was associated with reduced expression of both ERα and PR, whereas elevation of RhoB was found to be associated with ERα overexpression. Mechanistic investigations suggested that RhoB modulates ERα expression, controlling both its protein and mRNA levels, and that RhoB modulates PR expression by accentuating the recruitment of ERα and other major co-regulators to the promoter of PR gene. A major consequence of RhoB modulation was that RhoB differentially regulated the proliferation of breast cancer cell lines. Interestingly, we documented crosstalk between RhoB and ERα, with estrogen treatment leading to RhoB activation. CONCLUSION: Taken together, our findings offer evidence that in human breast cancer RhoB acts as a positive function to promote expression of ERα and PR in a manner correlated with cell proliferation.

Tipifarnib plus tamoxifen in tamoxifen-resistant metastatic breast cancer: a negative phase II and screening of potential therapeutic markers by proteomic analysis.

PURPOSE: Tipifarnib, a farnesyltransferase inhibitor, has antitumor activity in heavily pretreated metastatic breast cancer patients. Preclinical data suggest that FTIs could restore tamoxifen responsiveness in tamoxifen-resistant disease. Thus, combining FTIs and tamoxifen may be a promising clinical approach after relapse or progression on tamoxifen. EXPERIMENTAL DESIGN: Postmenopausal patients with measurable estrogen receptor- and/or progesterone receptor-expressing metastatic breast cancers were enrolled. Only patients with disease progression on tamoxifen were eligible, but there was no limitation regarding prior chemotherapy or hormone therapy regimens. Patients were immediately treated with 300 mg (n = 12) or 200 mg (n = 10) tipifarnib twice daily for 21 of 28-day cycles plus tamoxifen once daily. Serum was collected at baseline and after 8 weeks of treatment to enable proteomic comparison and identify possible predictive response markers. RESULTS: Twenty patients were enrolled and evaluated for efficacy: one patient had an objective response (liver metastasis) and nine had stable disease after 6 months for a clinical benefit rate of 50%; median duration of benefit was 10.3 (range, 7.4-20.2) months. The proteomic analysis by SELDI-TOF and LTQ-FT-Orbitrap identified a known peptide of fibrinogen alpha, the intensity of which was significantly increased in patients with progression compared with patients who benefited from the combined treatment after 8 weeks. CONCLUSIONS: Because the primary end point of efficacy (three objective responses) was not achieved, the study is negative. Nevertheless, the identified peptide could be of interest in discriminating, at 8 weeks of treatment, responders from nonresponders.