Surgical outcomes of gallbladder cancer:the OMEGA retrospective, multicentre, international cohort study

Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84–1.29], p = 0.711 and HR 1.18 [0.95–1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79–1.17], p = 0.67 and HR 1.48 [1.16–1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02–1.74], p = 0.037) and OS (HR 1.26 [1.03–1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3–3.52], p &lt; 0.0010), resection of additional organs (OR 2.22 [1.62–3.02], p &lt; 0.0010) and major hepatectomy (OR 3.81 [2.55–5.73], p &lt; 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02–1.37], p = 0.031) but not OS (HR 1.05 [0.91–1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding:Cambridge Hepatopancreatobiliary Department Research Fund.</p

Surgical outcomes of gallbladder cancer:the OMEGA retrospective, multicentre, international cohort study

Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84–1.29], p = 0.711 and HR 1.18 [0.95–1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79–1.17], p = 0.67 and HR 1.48 [1.16–1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02–1.74], p = 0.037) and OS (HR 1.26 [1.03–1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3–3.52], p &lt; 0.0010), resection of additional organs (OR 2.22 [1.62–3.02], p &lt; 0.0010) and major hepatectomy (OR 3.81 [2.55–5.73], p &lt; 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02–1.37], p = 0.031) but not OS (HR 1.05 [0.91–1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding:Cambridge Hepatopancreatobiliary Department Research Fund.</p

Role of renal urothelium proliferation in the onset of calcium oxalate stones

International audienceBackgroundMost mice kidney stone models induce nephrocalcinosis rather than urolithiasis.Materials and methodsC57B6 mice under vitamin D and water containing 4% hydroxyl-L-proline, ammonium chloride (0.28M) and calcium (0.25%) were follow up until day 42. A group receiving Fibroblast Growth Factor 7 (FGF7 i.p. once a week), a urothelial cell mitogen was compared to control group. Localization and identification of crystal deposits were performed with polarizing microscopy, infrared imager and Scanning Electron Microscopy. Urothelial and tubular phenotypes were studied by immunohistochemistry, immunofluorescence and RT PCR.ResultsCalcium oxalate monhydrate (COM) deposits in fornices were detected in all kidneys as soon as day 14 with very few crystals in tubules. On day 21, crystal number was increased in FGF7 compared to control group. Though osteopontin (OPN) was unregulated and detected in urothelial cells, de novo expression of CD44 (osteopontin receptor) receptor was induced only in proliferating urothelial cells either induced by FGF7 or by long standing urine crystal exposure altogether with a loss of apical uroplakines III expression. ConclusionOur model seems interesting to study in KO mice, in order to investigate the critical events leading to urolithiasis. Our data show that urothelial cells proliferation promotes renal crystal retention especially within fornices, probably through different processes involving specific and non-specific crystal adhesion, and thus appears per se as a relevant risk factor for stone formation

Role of vasa recta and chemical diversity in Randall’s plaque pathogenesis

International audienceBackgroundAlexander Randall identified calcium phosphate plaques in renal papillae as the origin of kidney stones. However, little is known about the early steps of Randall’s plaque formation, preceding the onset of urolithiasis. Our objectives were to characterize the composition and the initial formation site of incipient Randall’s plaque.Material and MethodsFifty-four healthy papillae from kidneys removed for cancer have been analyzed by immunohistochemistry and Von Kossa staining, Field Emission-Scanning Electron Microscopy with Energy Dispersive X-ray analysis, µ-Fourier Transform Infrared Spectroscopy, Cryo-Transmission Electron Microscopy coupled to Selected-Area Electron Diffraction and Electron Energy Loss Spectroscopy. ResultsIncipient Randall’s plaque has been observed in 72.7% of kidneys. Carbonated apatite was the main component of microcalcifications altogether with amorphous calcium phosphate and whitlockite. Incipient plaques stood in the deepest part of the papillae, around the loop of Henle tip but also vasa recta (respectively 62.4 % and 37.2 % of microcalcifications). Microcalcifications were often made of several nanocrystals inside organic material looking like microvesicles. ConclusionIncipient Randall’s plaque is frequent and appears at the tip of renal papillae, around the hairpin structure of the loop of Henle and vasa recta as well. Nanoscale analyses suggest a local nucleation process promoting nanocrystal growth in a supersaturated milieu

Heterogeneity of management practices surrounding operable gallbladder cancer – results of the OMEGA-S international HPB surgical survey

Background: Gallbladder cancer (GBC) is an aggressive, uncommon malignancy, with variation in operative approaches adopted across centres and few large-scale studies to guide practice. We aimed to identify the extent of heterogeneity in GBC internationally to better inform the need for future multicentre studies. Methods: A 34-question online survey was disseminated to members of the European-African Hepatopancreatobiliary Association (EAHPBA), American Hepatopancreatobiliary Association (AHPBA) and Asia–Pacific Hepatopancreatobiliary Association (A-PHPBA) regarding practices around diagnostic workup, operative approach, utilization of neoadjuvant and adjuvant therapies and surveillance strategies. Results: Two hundred and three surgeons responded from 51 countries. High liver resection volume units (>50 resections/year) organised HPB multidisciplinary team discussion of GBCs more commonly than those with low volumes (p < 0.0001). Management practices exhibited areas of heterogeneity, particularly around operative extent. Contrary to consensus guidelines, anatomical liver resections were favoured over non-anatomical resections for T3 tumours and above, lymphadenectomy extent was lower than recommended, and a minority of respondents still routinely excised the common bile duct or port sites. Conclusion: Our findings suggest some similarities in the management of GBC internationally, but also specific areas of practice which differed from published guidelines. Transcontinental collaborative studies on GBC are necessary to establish evidence-based practice to minimise variation and optimise outcomes

Heterogeneity of management practices surrounding operable gallbladder cancer – results of the OMEGA-S international HPB surgical survey

Background: Gallbladder cancer (GBC) is an aggressive, uncommon malignancy, with variation in operative approaches adopted across centres and few large-scale studies to guide practice. We aimed to identify the extent of heterogeneity in GBC internationally to better inform the need for future multicentre studies. Methods: A 34-question online survey was disseminated to members of the European-African Hepatopancreatobiliary Association (EAHPBA), American Hepatopancreatobiliary Association (AHPBA) and Asia–Pacific Hepatopancreatobiliary Association (A-PHPBA) regarding practices around diagnostic workup, operative approach, utilization of neoadjuvant and adjuvant therapies and surveillance strategies. Results: Two hundred and three surgeons responded from 51 countries. High liver resection volume units (>50 resections/year) organised HPB multidisciplinary team discussion of GBCs more commonly than those with low volumes (p < 0.0001). Management practices exhibited areas of heterogeneity, particularly around operative extent. Contrary to consensus guidelines, anatomical liver resections were favoured over non-anatomical resections for T3 tumours and above, lymphadenectomy extent was lower than recommended, and a minority of respondents still routinely excised the common bile duct or port sites. Conclusion: Our findings suggest some similarities in the management of GBC internationally, but also specific areas of practice which differed from published guidelines. Transcontinental collaborative studies on GBC are necessary to establish evidence-based practice to minimise variation and optimise outcomes. © 2022 International Hepato-Pancreato-Biliary Association Inc