PARP inhibitors (PARPi) have revolutionized the management of high-grade epithelial ovarian cancer (HGOC) treatment. However, a significant number of patients relapse or progress under PARPi, leading ...to the introduction of a new line of systemic therapy such as chemotherapy. In patients with a limited number of metastatic sites at progression, −referred to as an oligometastatic progression- a potential indication for local therapy followed by re-introduction or continuation of PARPi treatment rather than initiating a new line of chemotherapy could be proposed. However, the impact of such strategies on progression free survival (PFS) in these patients remains unknown.
This international multicenter retrospective study evaluated the efficacy of PARPi continuation or re-introduction in patients with HGOC after local treatment for oligometastatic progression. The main objective was to assess PFS under PARPi after local therapy (PFS post-LT). Secondary objectives included safety and overall survival (OS).
74 patients were identified in 20 centers between April 2020 and November 2021. 65% of patients were BRCA mutated and 92% had received ≥2 lines of prior systemic chemotherapy before the initial introduction of PARPi. Main progression sites were lymph nodes (42%), peritoneum (27%), liver (16%), other visceral (16%) and abdominal wall (4%). Local therapies included radiotherapy (45%), surgery (43%), both (7%), percutaneous thermal ablation (4%) or chemoembolization (1%). Median PFS post-LT was 11.5 months 95% CI 7.4; 17.2. After a median follow up of 14.8 months, 6 patients (8.1%) discontinued PARPi due to toxicity. The 1-year overall survival rate was 90.7% 95% CI 79.1; 96.0.
With close to one year without progression or introduction of a new line of systemic therapy, this study reports the feasibility and potential benefit of this original strategy in patients with oligometastatic progression under PARPi.
•Oligoprogression on PARP inhibitors is a potential indication for local therapy followed by reintroduction or continuation of PARP inhibitors.•This is a multicenter international retrospective cohort-type study.•The sites of progression were mainly lymph nodes and the local treatment mainly radiotherapy.•After a median follow-up of 14.8 months, median progression-free survival after local treatment was 11.5 months.•Patients with a single target lesion seem to benefit the most from this strategy.
Abstract
Background
The aim of this prospective multicenter study was to compare a flexible 19 G needle with nitinol shaft (19 G Flex) with a standard 22 G needle for transduodenal endoscopic ...ultrasound (EUS)-guided sampling of pancreatic head tumors.
Methods
Patients with pancreatic head tumors requiring tissue diagnosis were randomized into two arms: puncture with either a 19 G Flex needle or a 22 G needle. The primary end point was diagnostic accuracy for malignancy. The secondary end points were ergonomic scores, sample cytohistological quality, and complications. A 6-month follow-up was performed.
Results
125 patients were randomized and 122 were analyzed: 59 patients in the 19 G Flex arm and 63 patients in the 22 G arm. The final diagnosis was malignancy in 111 patients and benign condition in 11. In intention-to-treat analysis, the diagnostic accuracy for malignancy of the 19 G Flex and 22 G needles was 69.5 % (95 % confidence interval CI 56.1 % – 80.8 %) vs. 87.3 % (95 %CI 76.5 % – 94.4 %), respectively (
P
= 0.02). In per-protocol analysis excluding eight technical failures in the 19 G Flex group, the diagnostic accuracy of the 19 G Flex and 22 G needles was not statistically different: 80.4 % (95 %CI 66.9 % – 90.2 %) vs. 87.3 % (95 %CI 76.5 % – 94.4 %;
P
= 0.12). Technical success was higher in the 22 G arm than in the 19 G Flex arm: 100 % (95 %CI 94.3 % – 100 %) vs. 86.4 % (95 %CI 75.0 % – 94.0 %), respectively (
P
= 0.003). Transduodenal EUS-guided sampling was more difficult with the 19 G Flex (odds ratio 0.68, 95 %CI 0.47 – 0.97).
Conclusion
The 19 G Flex needle was inferior to a standard 22 G needle in diagnosing pancreatic head cancer and more difficult to use in the transduodenal approach.
DNA mutational analysis of pancreatic cystic fluid (CF) is a useful adjunct to the evaluation of pancreatic cysts. KRAS/GNAS or RAF/PTPRD/CTNNB1/RNF43 mutations are highly specific to precancerous or ...advanced neoplasia. Several studies recently demonstrated the ability of next-generation sequencing (NGS) analysis to detect DNA mutations in pancreatic CF, but few studies have performed a systematic comparative analysis between pancreatic CF and neoplastic surgical tissue (NT). The value of CF-NGS analysis indicators for determining surgical resection necessitates evaluation.
To confirm whether CF genomic profiles are a reliable malignancy predictor by comparing NGS mutational analyses of CF and NT.
Patients requiring surgery for high-risk pancreatic cysts were included in a multicenter prospective pilot study. DNA from CF (collected by endoscopic ultrasound-guided fine needle aspiration (known as EUS-FNA)) and NT (collected by surgery) were analyzed by NGS. The primary objective was to compare the mutation profiles of paired DNA samples. The secondary objective was to correlate the presence of specific mutations (KRAS/GNAS, RAF/ PTPRD/CTNNB1/RNF43/POLD1/TP53) with a final cancer diagnosis. Sensitivity and specificity were also evaluated.
Between December 2016 and October 2017, 20 patients were included in this pilot study. Surgery was delayed for 3 patients. Concordant CF-NT genotypes were found in 15/17 paired DNA, with a higher proportion of mutated alleles in CF than in NT. NGS was possible for all pancreatic CF collected by EUS-FNA. In 2 cases, the presence of a KRAS/GNAS mutation was discordant between CF and NT. No mutations were found in 3 patients with NT or pancreatic cysts with high-grade dysplasia. The sensitivity and specificity of KRAS/GNAS mutations in CF to predict an appropriate indication for surgical resection were 0.78 and 0.62, respectively. The sensitivity and specificity of RAF/PTPRD/CTNNB1 /RNF43/POLD1/TP53 mutations in CF were 0.55 and 1.0, respectively.
Mutational analyses of CF and NT were highly concordant, confirming the value of NGS analysis of CF in the preoperative malignancy assessment. However, these results need to be confirmed on a larger scale.
Background. Antireflux mucosectomy, a new endoscopic treatment for gastroesophageal reflux disease, consists of endoscopic mucosal resection at the esophagogastric junction. This study aim was to ...evaluate the medium-term efficacy of the antireflux mucosectomy technique for patients with severe gastroesophageal reflux disease symptoms (proton pump inhibitor treatment-dependent or proton pump inhibitor treatment-resistant gastroesophageal reflux disease). Methods. Between January 2017 and June 2018, 13 patients with severe gastroesophageal reflux disease without hiatal hernia, with positive pH reflux, were included in this monocentric prospective pilot study. The primary outcome was clinical success, defined by improvement evaluated by the Gastroesophageal Reflux Disease Health Related Quality of Life Questionnaire at 24 months. Secondary outcomes were technical success, decreased use of proton pump inhibitors, patient satisfaction, and adverse events. Results. Thirteen patients females=8 (62%), mean age 59 (range, 54-68), were included. The antireflux mucosectomy procedure had technical success in all patients. At 24 months, for 11 patients, gastroesophageal reflux disease symptoms were significantly improved, and mean gastroesophageal reflux disease score decreased from 33 (range, 26-42) to 3 (range, 0-7) (p=0.001). Ninety-one percent (n=10) of patients had a lower proton pump inhibitor intake at 24 months. One patient had 3 endoscopic balloon dilatations for EGJ stenosis, two patients had melena ten days after procedure, and seven patients had thoracic or abdominal pain. Patient’s satisfaction at 24 months was 81%. Conclusions. In patients with severe gastroesophageal reflux disease, despite occurrence of several short-term adverse events, antireflux mucosectomy seemed effective in improving gastroesophageal reflux disease symptoms at 24 months. This trial is registered with ClinicalTrials: NCT03357809.
Apoptosis is the most common pathway of neutrophil death under both physiological and inflammatory conditions. In this study, we describe an apoptotic pathway in human neutrophils that is triggered ...via the surface molecule CD24. In normal neutrophils, CD24 ligation induces death through depolarization of the mitochondrial membrane in a manner dependent on caspase-3 and caspase-9 and reactive oxygen species. Proinflammatory cytokines such as TNF-α, IFN-γ, and GM-CSF upregulated the expression of CD24 in vitro, favoring the emergence of a new CD16(high)/CD24(high) subset of cultured neutrophils. We observed that CD24 expression (at both mRNA and protein levels) was significantly downregulated in neutrophils from sepsis patients but not from patients with systemic inflammatory response syndrome. This downregulation was reproduced by incubation of neutrophils from healthy controls with corticosteroids or with plasma collected from sepsis patients, but not with IL-10 or TGF-β. Decreased CD24 expression observed on sepsis neutrophils was associated with lack of functionality of the molecule, because cross-ligation of CD24 failed to trigger apoptosis in neutrophils from sepsis patients. Our results suggest a novel aspect of CD24-mediated immunoregulation and represent, to our knowledge, the first report showing the role of CD24 in the delayed/defective cell death in sepsis.
The standard of care (SOC) for the treatment of HCV genotype 2 (HCV‐2) was pegylated interferon alpha plus ribavirin (PEG‐IFN/RBV) at weight‐based doses for a response‐guided duration. The launches ...of sofosbuvir and daclatasvir in 2014 have resulted in new, better tolerated and shorter treatment. The combination of sofosbuvir and RBV for 12 weeks appears to be the new SOC in both European and American guidelines. The cost and therefore the access to this treatment remains a problem in many countries because of major economic constraints. For the few more difficult‐to‐treat patients, a combination of direct acting antivirals may be suitable and is being studied in ongoing trials. Because of rapidly changing treatment recommendations, the decision to treat HCV‐2 patients with currently approved drugs or to wait until a better option is available in the future, must be made according to the stage of fibrosis.
Background and Aim
Endoscopic access to the common bile duct (CBD) remains difficult in 10% of cases, requiring alternative techniques .CBD access was difficult after either five unsuccessful ...attempts, five unintentional insertions into the pancreatic duct or >10‐min‐long unsuccessful attempts. This retrospective study with historical controls aimed to evaluate the benefit of the double guidewire (DGW) technique after failure of standard CBD cannulation.
Methods
From January 2012 to December 2014, all patients requiring therapeutic endoscopic retrograde cholangiopancreatography (ERCP) with difficult access to CBD were included in a Studied group. This group was compared to a historical ERCP control group from January 2009 to December 2011. In the Studied group, a sequential strategy including DGW technique was done when the guidewire was unintentionally passed into the pancreatic duct. In the control group, only pre‐cut technique was used.
Results
Among the 538 patients with naive papilla eligible for ERCP, 73 had difficult CBD access. Successful CBD access rate was higher in the Studied group: 91% (50/55) versus 67% (12/18) P = 0.0215. Complication rates were similar in both groups: 28% versus 20%, P = 0.5207. LOS was shorter in the Studied group (9.2 ± 8.5 vs 14.4 ± 7.4 days, P = 0.0028). Post‐ERCP cholangitis were lower in the Studied group: 2% (1/55) versus 22% (4/18), P = 0.0118.
Conclusion
After standard cannulation failure, DGW technique increased successful CBD access rate and decreased LOS without increasing complications.
Placenta accreta spectrum is a life-threatening condition that has increased dramatically in recent decades along with cesarean rates worldwide. Cesarean hysterectomy is widely practiced in women ...with placenta accreta spectrum; however, the maternal outcomes after cesarean hysterectomy have not been thoroughly compared with the maternal outcomes after alternative approaches, such as conservative management.
This study aimed to compare the severe maternal outcomes between women with placenta accreta spectrum treated with cesarean hysterectomy and those treated with conservative management (leaving the placenta in situ).
From a source population of 520,114 deliveries in 176 hospitals (PACCRETA study), we designed an observational cohort of women with placenta accreta spectrum who had either a cesarean hysterectomy or a conservative management (the placenta left in situ) during cesarean delivery. Clinicians prospectively identified women meeting the inclusion criteria and included them at delivery. Data collection started only after the women had received information and agreed to participate in the study in the immediate postpartum period. The primary outcome was the transfusion of >4 units of packed red blood cells within 6 months after delivery. Secondary outcomes were other maternal complications within 6 months. We used propensity score weighting to account for potential indication bias.
Here, 86 women had conservative management and 62 women had cesarean hysterectomy for placenta accreta spectrum during cesarean delivery. The primary outcome occurred in 14 of 86 women in the conservative management group (16.3%) and 36 of 61 (59.0%) in the cesarean hysterectomy group (risk ratio in propensity score weighted model, 0.29; 95% confidence interval, 0.19–0.45). The rates of hysterectomy, total estimated blood loss exceeding 3000 mL, any blood product transfusion, adjacent organ injury, and nonpostpartum hemorrhage-related severe maternal morbidity were lower with conservative management than with cesarean hysterectomy (all adjusted, P≤.02); but, the rates of arterial embolization, endometritis, and readmission within 6 months of discharge were higher with conservative management than with cesarean hysterectomy.
Among women with placenta accreta spectrum who underwent cesarean delivery, conservative management was associated with a lower risk of transfusion of >4 units of packed red blood cells within 6 months than cesarean hysterectomy.
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