Rucaparib in the landscape of PARP inhibition in ovarian cancer

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.     

The role of lncRNA MSC-AS1/miR-29b-3p axis-mediated CDK14 modulation in pancreatic cancer proliferation and Gemcitabine-induced apoptosis

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related death due to the failure of traditional therapies. In the present study, we attempted to construct a lncRNA-miRNA-mRNA network which may modulate PDAC cell proliferation and Gemcitabine-induced cell apoptosis starting from CDK14, a new member of the CDK family and an oncogene in many cancers. Based on TCGA data, a significant positive correlation was observed between lncRNA MSC-AS1 and CDK14. Moreover, MSC-AS1 expression was upregulated in PDAC tissues. Higher MSC-AS1 expression was correlated with poorer prognosis in patients with PDAC. MSC-AS1 knockdown in Panc-1 and BxPC-3 cells significantly inhibited the cell proliferation. Moreover, miR-29b-3p, which has been reported to act as a tumor suppressor, was predicted to bind to both MSC-AS1 and CDK14. Contrary to MSC-AS1, higher miR-29b-3p expression was correlated to better prognosis in patients with PDAC. In both PDAC cell lines, miR-29b-3p negatively regulated MSC-AS1 and CDK14. As confirmed using luciferase reporter gene and RIP assays, MSC-AS1 served as a ceRNA for miR-29b-3p to counteract miR-29b-mediated CDK14 repression. MSC-AS1 knockdown inhibited CDK14 protein levels and PDAC proliferation and enhanced gemcitabine-induced cell death and apoptosis while miR-29b-3p inhibition exerted an opposing effect; the effect of MSC-AS1 knockdown was partially attenuated by miR-29b-3p inhibition. Taken together, we demonstrated that MSC-AS1/miR-29b-3p axis modulates the cell proliferation and GEM-induced cell apoptosis in PDAC cell lines through CDK14. We provided a novel experimental basis for PDAC treatment from the perspective of lncRNA-miRNA-mRNA network.     

Factors associated with needle breakage of antegrade suture passer and effect of intratendinous remnant needle tip on clinical outcomes after arthroscopic rotator cuff repair

ObjectiveThe aim of this study was to evaluate factors associated with the needle breakage of antegrade suture passer and the effect of intratendinous remnant needle tip on clinical outcomes after rotator cuff repair.MethodsWe retrospectively reviewed 283 patients (138 men and 145 women; mean age: 59.7 ± 9.3 years) who underwent arthroscopic repair for full-thickness rotator cuff tear. We evaluated the characteristics of 16 patients in whose needle tip had been broken and embedded and remained in the rotator cuff (remnant needle group) and compared them with the remaining 267 patients (control group). Afterwards, another 64 patients were selected from control group (1:4 matching) after propensity score matching (PSM). The groups were compared anatomically with MRI or ultrasonography and functionally (serial pain VAS and ROM; ASES, Constant, UCLA and SST scores) at a minimum follow-up of 1 year.ResultsThe remnant needle group showed preoperative thicker tendon (6.72 mm vs 5.33 mm, p = 0.047), higher tendinosis (mean grade, 1.88 vs. 1.43, p = 0.029), and more frequent delaminated tears (p = 0.035) compared with control group. When we compare the clinical outcomes after PSM, the initial pain VAS of the remnant needle tip group was higher up to 3 months (pain VAS: 4.13 ± 2.07 vs 2.48 ± 1.61 (p = 0.032) at 5 weeks and 3.79 ± 2.12 vs 2.25 ± 1.76 (p = 0.044) at 3 months), however the difference disappeared after 6 months postoperatively. In final evaluation, there was no significant differences in every outcome parameters (all p > 0.05).ConclusionBreakage of the needle of the antegrade suture passer occurred more frequently in the thicker tendon, higher tendinosis, and delaminated tears. The retained broken needle tip was associated with higher pain scores during the early postoperative period, but revealed no difference in final outcomes by using PSM.Level of EvidenceLevel III, Therapeutic Study     

Umbrella handle technique for fixation of FDP avulsion fracture

We present the treatment course of a 29-year-old male patient with for a Type 3 FDP avulsion (Jersey's finger) of a fifth finger treated with umbrella handle technique. The patient had a volar base fracture of distal phalanx with dorsal subluxation of DIP joint after a fall. Following open reduction of the FDP avulsion fracture and fixation was achieved with a 0.9 mm one edge hooked Kirschner wire under fluoroscopy control. The straight edge of the wire was driven out in a central position in sterile nail matrix just distal to lunula. The wire was removed at the fifth week when the complete union of the fracture was observed. The patient achieved full flexion in DIP joint without an extension lag.     

Nationwide outcomes of newborns with rectosigmoid versus long-segment Hirschsprung disease

PurposeHirschsprung Disease (HD) is a common congenital intestinal disorder. While aganglionosis most commonly affects the rectosigmoid colon (rectosigmoid HD), outcomes for patients in which aganglionosis extends to more proximal segments (long-segment HD) remain understudied. This study sought to compare postoperative outcomes among newborns with rectosigmoid and long-segment HD.MethodsThe Nationwide Readmission Database was queried from 2016 to 2018 for newborns with HD. Newborns were stratified into those with rectosigmoid or long-segment HD. Those who received no rectal biopsy or pull-through procedure during their newborn hospitalization were excluded. A propensity score-matched analysis (PSMA) of newborns with either type of HD was constructed utilizing 17 covariates including demographics, comorbidities, and congenital-perinatal conditions.ResultsThere were 1280 newborns identified with HD (82% rectosigmoid HD, 18% long-segment HD). Patients with rectosigmoid HD had higher rates of laparoscopic resections (35% vs. 12%) and less frequently received a concomitant ostomy (14% vs. 84%), both p < 0.001. Patients with long-segment HD were more likely to have a delayed diagnosis (12% vs. 5%) and require multiple bowel operations (19% vs. 4%), both p < 0.001. They experienced higher rates of complications, including small bowel obstructions (10% vs. 1%), infections (45% vs. 20%), and Hirschsprung-associated enterocolitis (11% vs. 5%), all p < 0.001. After PSMA, newborns with long-segment HD were found to have a longer length of stay and higher hospitalization costs.ConclusionNewborns with long-segment HD experience significant delays in diagnosis, surgery, and complications compared to those with rectosigmoid HD. This information should be utilized to improve healthcare delivery for this patient population.Type of StudyRetrospective comparative study.Level of EvidenceIII.     

聚腺苷二磷酸核糖聚合酶抑制剂在肿瘤放射治疗中的应用研究进展

聚腺苷二磷酸核糖聚合酶（PARP）是一类在真核细胞中高表达的核酶，在DNA损伤修复中起关键作用。近年来，PARP抑制剂在肿瘤治疗中显示出巨大的潜力，几种小分子PARP抑制剂已被美国食品药品管理局（FDA）批准用于多种肿瘤的维持治疗。PARP抑制剂主要通过抑制PARP酶促作用和PARP捕获作用，导致DNA单链断裂的持续存在，在DNA复制的过程中，转变为双链断裂。研究证明，PARP抑制剂不仅具有显著的抗肿瘤效应，而且与放射治疗联合具有一定的协同作用。本文将阐述PARP抑制剂联合放疗的潜在理论基础，总结近年来PARP抑制剂在肿瘤放射治疗中的临床前和临床研究进展，梳理该领域目前亟待解决的问题，并对其在抗肿瘤治疗中的应用前景进行展望。