PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice.

BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. METHODS: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.

IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .

Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial.

BACKGROUND: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. METHODS: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. RESULTS: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. CONCLUSION: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017.

Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour.

PURPOSE: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor α kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a ≥fourth-line therapy. Here, we report the phase I study results of intrapatient dose escalation (IPDE) in patients with GIST treated across second, third and later lines of therapy. METHODS: Patients with advanced GIST who experienced disease progression (PD) at ripretinib 150 mg QD could dose escalate to 150 mg twice daily (BID). Progression-free survival (PFS) 1 was calculated from the date of the first dose of ripretinib 150 mg QD to PD (as per Response Evaluation Criteria in Solid Tumours 1.1); PFS2 was from the date of IPDE (150 mg BID) to PD or death. Treatment-emergent adverse events (TEAEs) were summarised by dosing periods and compared descriptively. RESULTS: Of 142 patients with GIST receiving ripretinib 150 mg QD, 67 underwent IPDE. IPDE provided benefit across all lines of therapy; the median PFS2 was 5.6, 3.3 and 4.6 months for patients on second-, third- and ≥fourth-line therapy, respectively. A partial metabolic response after IPDE was demonstrated in 13 of 37 patients with available positron emission tomography scans. TEAEs reported at both doses were similar. CONCLUSION: Ripretinib IPDE after PD provided continued clinical benefit in advanced GIST across second, third and later lines of therapy with a similar safety profile to that observed with the QD regimen.

Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study.

BACKGROUND: Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. MATERIALS AND METHODS: Tumor imaging was performed every 28-day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. PERIOD: Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. RESULTS: Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7-6.4) and median PFS2 was 3.7 months (95% CI, 3.1-5.3). Median overall survival was 18.4 months (95% CI, 14.5-not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3-4 treatment-emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. CONCLUSION: Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth-line GISTs. IMPLICATIONS FOR PRACTICE: Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.

Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. FINDINGS: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months (0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). INTERPRETATION: Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. FUNDING: Deciphera Pharmaceuticals.

A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study.

Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status. ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy versus SoC in patients with PD-L1(-) tumors (Sub-study B). Eligible patients are those with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal growth factor receptor tyrosine kinase activating mutations or anaplastic lymphoma kinase rearrangements, who have received at least 2 prior systemic regimens, including 1 platinum-based chemotherapy regimen. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include the proportion of patients alive at 12 months, objective response rate, duration of response, progression-free survival at 6 and 12 months, safety and tolerability, pharmacokinetics, immunogenicity, and quality of life. The exploratory endpoints will assess potential biomarkers of treatment response. Recruitment started in January 2015 and is ongoing.

A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation.

OBJECTIVES: Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C). METHODS: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 µ g oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration ' s (FDA ' s) primary end point for IBS-C (responder: improvement of ≥ 30 % in average daily worst abdominal pain score and increase by ≥ 1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50 % of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9 / 12 weeks. Adverse events (AEs) were monitored. RESULTS: The trial evaluated 800 patients (mean age = 43.5 years, female = 90.5 % , white = 76.9 % ). The FDA end point was met by 136 / 405 linaclotide-treated patients (33.6 % ), compared with 83 / 395 placebo-treated patients (21.0 % ) ( P < 0.0001) (number needed to treat: 8.0, 95 % confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6 / 12 treatment period weeks, a reduction of ≥ 30 % in abdominal pain (50.1 vs. 37.5 % , P = 0.0003) and an increase of ≥ 1 CSBM from baseline (48.6 vs. 29.6 % , P < 0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points ( P < 0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points ( P < 0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7 % of linaclotide and 0.3 % of placebo patients. CONCLUSIONS: Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.

Elongation of simulated whipstitch post anterior cruciate ligament reconstruction tibial fixation after cyclic loading.

Whipstitch-post (WSP) tibial fixation is one of the most widely used and clinically successful methods of soft tissue graft fixation for anterior cruciate ligament reconstruction (ACLR). However, some consider the method prone to laxity. We hypothesized that WSP would have low elongation rates after experimental cyclic loading. Eight cadaveric human semitendinosus and gracilis (ST/Gr) tendons had whipstitches woven into their overlapped ends. The grafts were looped around a metal bar, pneumatically clamped, and cyclically loaded. The adjusted mean experimental graft elongation for the WSP was 1.13 mm with a maximum elongation of 1.64 mm and a standard deviation of 0.32. These values are equivalent to the lowest published cyclic loading tibial fixation elongation data. Whipstitch-post tibial ACLR fixation is biomechanically sound with among the lowest rates of elongation after laboratory cyclic loading.

A meta-analysis of the incidence of anterior cruciate ligament tears as a function of gender, sport, and a knee injury-reduction regimen.

PURPOSE: The literature has shown that anterior cruciate ligament (ACL) tear rates vary by gender, by sport, and in response to injury-reduction training programs. However, there is no consensus as to the magnitudes of these tear rates or their variations as a function of these variables. For example, the female-male ACL tear ratio has been reported to be as high as 9:1. Our purpose was to apply meta-analysis to the entire applicable literature to generate accurate estimates of the true incidences of ACL tear as a function of gender, sport, and injury-reduction training. METHODS: A PubMed literature search was done to identify all studies dealing with ACL tear incidence. Bibliographic cross-referencing was done to identify additional articles. Meta-analytic principles were applied to generate ACL incidences as a function of gender, sport, and prior injury-reduction training. RESULTS: Female-male ACL tear incidences ratios were as follows: basketball, 3.5; soccer, 2.67; lacrosse, 1.18; and Alpine skiing, 1.0. The collegiate soccer tear rate was 0.32 for female subjects and 0.12 for male subjects. For basketball, the rates were 0.29 and 0.08, respectively. The rate for recreational Alpine skiers was 0.63, and that for experts was 0.03, with no gender variance. The two volleyball studies had no ACL tears. Training reduced the ACL tear incidence in soccer by 0.24 but did not reduce it at all in basketball. CONCLUSIONS: Female subjects had a roughly 3 times greater incidence of ACL tears in soccer and basketball versus male subjects. Injury-reduction programs were effective for soccer but not basketball. Recreational Alpine skiers had the highest incidences of ACL tear, whereas expert Alpine skiers had the lowest incidences. Volleyball may in fact be a low-risk sport rather than a high-risk sport. Alpine skiers and lacrosse players had no gender difference for ACL tear rate. Year-round female athletes who play soccer and basketball have an ACL tear rate of approximately 5%. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Magnetic resonance imaging measurement of the contralateral normal meniscus is a more accurate method of determining meniscal allograft size than radiographic measurement of the recipient tibial plateau.

PURPOSE: The purpose of this study was to develop and validate magnetic resonance imaging (MRI) scanning of the contralateral meniscus as a more accurate method of determining the needed size of a meniscal allograft than the traditional method of inferring meniscal size from radiographic measurement of the ipsilateral tibial plateau. METHODS: Tissue bank meniscal size records from the left and right knees of 500 meniscal donors were analyzed for symmetry. The menisci of 10 cadaveric knees were then sized indirectly via the radiographic tibial plateau method and directly via MRI and actual physical measurement. The MRI and radiographic methods were then compared. Statistical analysis was carried out to determine error rates for each imaging method by comparison to the physical meniscal measurements. RESULTS: Of the 500 pairs of menisci, 97% were found to be within 3 mm of each other in both the anterior-posterior and medial-lateral dimensions. In the cadaveric study MRI measurement predicted actual meniscal size significantly better than the radiographic tibial plateau method. CONCLUSIONS: Human knee menisci are bilaterally symmetric in size. Direct MRI measurement of the contralateral intact meniscus better predicts actual meniscal size than estimation of size indirectly from measurement of the tibial plateau on which it is located. We, therefore, propose contralateral MRI meniscal measurement as a new gold standard to size menisci before transplantation. LEVEL OF EVIDENCE: Level II, diagnostic study of consecutive patients with a universally applied gold standard.

A meta-analysis of stability of autografts compared to allografts after anterior cruciate ligament reconstruction.

Allografts have recently become increasingly popular for anterior cruciate ligament reconstruction (ACLR) in the United States even though many studies have shown high allograft failure rates (Gorschewsky et al. in Am J Sports Med 33:1202, 2005; Pritchard et al. in Am J Sports Med 23:593, 2005; Roberts et al. in Am J Sports Med 19:35, 2006) and no meta-analysis or systematic review of allograft clinical stability rates in comparison to autog rafts has previously been performed. We hypothesized that allografts would demonstrate overall lower objective stability rates compared to autografts. To test this hypothesis we performed a meta-analysis of autograft and allograft stability data. A pubmed literature search of all allograft series in humans published in English was performed. Articles were then bibliographically cross-referenced to identify additional studies. Series inclusion criteria were arthrometric follow-up data using at least 30 lb or maximum manual force, stratified presentation of stability data and minimum two-year follow-up. Twenty allograft series were thus selected and compared to a previously published data set of all BPTB and Hamstring (HS) autograft ACLR series using the same study inclusion criteria and analytic and statistical methodology. IKDC standards of 0-2 mm (normal) and >5 mm (abnormal) side-to-side differences were adopted to compare studies. Normal stability for all autografts was 72 versus 59% for all allografts (P < 0.01). Abnormal stability was 5% for all autografts versus 14% for all allografts (P < 0.01). Bone-patellar-tendon-bone (BPTB) autograft normal stability was 66% versus 57% for BPTB allografts (P < 0.01). Abnormal BPTB autograft stability was 6 versus 16% for BPTB allograft. Hamstring autograft normal or abnormal stability rates were 77% and 4% and were compared to soft tissue allografts as a group which were 64% and 12% (P < 0.01). This is the first meta-analysis comparing autograft to allograft stability in ACLR. Allografts had significantly lower normal stability rates than autografts. The allograft abnormal stability rate, which usually represents graft failure, was significantly higher than that of autografts: nearly three times greater. It would therefore appear that autografts are the graft of choice for routine ACLR with allografts better reserved for multiple ligament-injured knees where extra tissue may be required.

A meta-analysis of stability after anterior cruciate ligament reconstruction as a function of hamstring versus patellar tendon graft and fixation type.

PURPOSE: Four-strand hamstring graft (4HS) is stronger than 10-mm bone-patellar tendon-bone graft (BPTB) and has equal tunnel pullout strength, but is believed by some to produce lower rates of stability after anterior cruciate ligament reconstruction (ACLR). Our purpose was to test the hypothesis that 4HS ACLR with modern fixation would produce equal or greater stability than BPTB ACLR. TYPE OF STUDY: Meta-analysis. METHODS: A computer search was used to find all published reports of ACLR series using HS and/or BPTB. Inclusion criteria were minimum 24-month follow-up, stratified presentation of arthrometric stability data, and at least 30-lb arthrometric testing force. Twenty-four 4HS, 8 2-strand hamstring (2HS), and 32 BPTB series met these criteria and were subdivided into groups according to fixation type. We used the International Knee Documentation Committee classification of a side-to-side instrumented Lachman test difference of < or = 2 mm as normal stability, and > 5 mm difference as abnormal stability. Series with at least 80% normal and at most 3% abnormal stability were designated as high-stability. Meta-analytic methods were used to determine group level differences. RESULTS: Total 4HS had a higher normal stability rate than total BPTB: 77% versus 66%, P < .001; and lower abnormal stability: 4.4% versus 5.9%, P = .029. The 4HS ACLR using the EndoButton (Smith & Nephew Endoscopy, Andover, MA) and second-generation tibial fixation (EB2-4HS) had higher normal stability (80%) and lower abnormal stability (1.7%) than all other subgroups, including BPTB with 2 interference screws (70% normal, 5.0% abnormal) P < .001; 84% of the series in the EB2-4HS group were high-stability series. No more than 33% of the series from any other group were high-stability. CONCLUSIONS: The recent literature would suggest that 4HS ACLR produces higher stability rates than BPTB, that 4HS stability rates are fixation dependent, that aperture fixation offers no stability advantage, and that EndoButton with second-generation tibial fixation produces consistently high stability rates. LEVEL OF EVIDENCE: Level IV.