Upfront Laparoscopic Management of Common Bile Duct Stones: What Are the Risk Factors of Failure?

BACKGROUND: Treatment of common bile duct stones (CBDS) includes laparoscopic cholecystectomy (LC) with either laparoscopic common bile duct exploration (LCBDE) or perioperative endoscopic retrograde cholangiopancreatography (ERCP). The main objective of this study was to identify predictive factors for the failure of upfront and exclusive surgical treatment by LCBDE. METHODS: This is a single-center, retrospective study on patients with CBDS and operated for LC between 2007 and 2019. The use of intra- or postoperative endoscopy for CBD clearance within 6 months after surgery was considered as failure of LCBDE. Predictors for the failure of LCBDE were investigated and outcomes were compared. RESULTS: Among 222 operated patients, LCBDE was successfully performed in 173 patients (78%) and 49 (22%) required ERCP with sphincterotomy (intraoperative (n=29) or postoperative (n=20)). Independent risk factors for surgical failure were male sex (OR: 2.525 (1.111-5.738); p=0.027), anesthesia induction time ≥ 4 p.m. (OR: 4.858 (1.731-13.631); p=0.003), pediculitis (OR: 4.147 (1.177-14.606); p=0.027), and thin CDB < 4mm (OR: 11.951 (3.562-40.097), p< 0.0001). Age, ASA score, cystic anatomy, presence of cholecystitis, and the surgeon's experience were not identified as predictors for surgical failure. A general anesthesia number >1 (6% vs. 33%; p < 0.0001), length of initial stay (6 [1-42] vs. 8 [2-27], p=0.012), total length of hospitalization (6 [1-45] vs. 9 [2-27]; p=0.010), and the rate of emergency readmissions (3.5% vs. 12.2%; p=0.027) were significantly higher in the LCBDE failure group. CONCLUSIONS: Upfront LCBDE for CBDS was associated with improved outcomes compared to intra-/postoperative ERCP recourse. Male sex, pediculitis, thin CBD, and surgery later than 4 p.m were associated with LCBDE failure and the need for endoscopic treatment. REGISTRATION NUMBER AND AGENCY: The present retrospective study was approved by our local ethics committee and was declared on ClinicalTrials.gov (ID: NCT04467710).

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage.

Double-strand breaks (DSBs) are harmful lesions and a major cause of genome instability. Studies have suggested a link between the nuclear envelope and the DNA damage response. Here, we show that lamin B1, a major component of the nuclear envelope, interacts directly with 53BP1 protein, which plays a pivotal role in the DSB repair. This interaction is dissociated after DNA damage. Lamin B1 overexpression impedes 53BP1 recruitment to DNA damage sites and leads to a persistence of DNA damage, a defect in nonhomologous end joining and an increased sensitivity to DSBs. The identification of interactions domains between lamin B1 and 53BP1 allows us to demonstrate that the defect of 53BP1 recruitment and the DSB persistence upon lamin B1 overexpression are due to sequestration of 53BP1 by lamin B1. This study highlights lamin B1 as a factor controlling the recruitment of 53BP1 to DNA damage sites upon injury.

Outcomes of elective left colectomy in renal-transplanted patients: a single-center case-control study (LECoRT study).

PURPOSE: Renal-transplanted patients are reported to have a high anastomotic leakage (AL) rate after colorectal surgery. We aimed to define AL-related morbidity and mortality rates after elective left colectomy in renal-transplanted patients. METHODS: Data were prospectively collected between 2010 and 2015 from patients who underwent elective left colectomy with supra-peritoneal anastomosis in a single French referral hospital. We compared AL rate, and morbidity and mortality rates between renal-transplanted patients and controls. RESULTS: We identified 120 patients who underwent elective left colectomy during the study period. We retrospectively divided this cohort into 20 (17%) kidney-transplanted recipients (KTR-group) and the remaining 100 patients comprised the control group (C-group). There were no significant differences in sex, age, ASA score, body mass index, history of abdominal surgery and benign/malignant disease ratio between the KTR-group and the C-group. The AL rate was approximately four times higher in the KTR-group versus the C-group (25% vs 7%, p = 0.028). Intra-abdominal septic complications (p = 0.0005) and reoperation rates (p = 0.025) were also higher in the KTR-group. The laparoscopic approach was performed less in the KTR-group (35% versus 93%, p < 0.0001). CONCLUSION: Renal transplantation was identified as a risk factor of AL following elective left colectomy, as well as increased intra-abdominal septic morbidity and higher reoperation rate. Further multicentric studies are required to identify potential independent risk factors of AL after colorectal surgery in these frail populations. TRIAL REGISTRATION: The present study was declared on ClinicalTrials.gov (ID: NCT04495023).

A role for BLM in double-strand break repair pathway choice: prevention of CtIP/Mre11-mediated alternative nonhomologous end-joining.

The choice of the appropriate double-strand break (DSB) repair pathway is essential for the maintenance of genomic stability. Here, we show that the Bloom syndrome gene product, BLM, counteracts CtIP/MRE11-dependent long-range deletions (>200 bp) generated by alternative end-joining (A-EJ). BLM represses A-EJ in an epistatic manner with 53BP1 and RIF1 and is required for ionizing-radiation-induced 53BP1 focus assembly. Conversely, in the absence of 53BP1 or RIF1, BLM promotes formation of A-EJ long deletions, consistent with a role for BLM in DSB end resection. These data highlight a dual role for BLM that influences the DSB repair pathway choice: (1) protection against CtIP/MRE11 long-range deletions associated with A-EJ and (2) promotion of DNA resection. These antagonist roles can be regulated, according to cell-cycle stage, by interacting partners such as 53BP1 and TopIII, to avoid unscheduled resection that might jeopardize genome integrity.

Oxydative stress alters nuclear shape through lamins dysregulation: a route to senescence.

Progeroid phenotypes are mainly encountered in 2 types of syndromes: in laminopathies, which are characterized by nuclear shape abnormalities due to lamin A alteration, and in DNA damage response defect syndromes. Because lamin A dysregulation leads to DNA damages, it has been proposed that senescence occurs in both types of syndromes through the accumulation of damages. We recently showed that elevated oxidative stress is responsible for lamin B1 accumulation, nuclear shape alteration and senescence in the DDR syndrome, ataxia telangiectasia (A-T). Interestingly, overexpression of lamin B1 in wild type cells is sufficient to induce senescence without the induction of DNA damages. Here, we will discuss the importance of controlling the lamins level in order for maintenance nuclear architecture and we will comment the relationships of lamins with other senescence mechanisms. Finally, we will describe emerging data reporting redox control by lamins, leading us to propose a general mechanism by which reactive oxygen species can induce senescence through lamin dysregulation and NSA.

Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation.

We report crosstalk between three senescence-inducing conditions, DNA damage response (DDR) defects, oxidative stress (OS) and nuclear shape alterations. The recessive autosomal genetic disorder Ataxia telangiectasia (A-T) is associated with DDR defects, endogenous OS and premature ageing. Here, we find frequent nuclear shape alterations in A-T cells, as well as accumulation of the key nuclear architecture component lamin B1. Lamin B1 overexpression is sufficient to induce nuclear shape alterations and senescence in wild-type cells, and normalizing lamin B1 levels in A-T cells reciprocally reduces both nuclear shape alterations and senescence. We further show that OS increases lamin B1 levels through p38 Mitogen Activated Protein kinase activation. Lamin B1 accumulation and nuclear shape alterations also occur during stress-induced senescence and oncogene-induced senescence (OIS), two canonical senescence situations. These data reveal lamin B1 as a general molecular mediator that controls OS-induced senescence, independent of established Ataxia Telangiectasia Mutated (ATM) roles in OIS.