Patients Undergoing Hip Arthroscopy with Concomitant Periacetabular Osteotomy Demonstrate Clinically Meaningful Improvement at 2 years using the PROMIS and iHOT-12.

PURPOSE: To report the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) values using the Patient-Reported Outcome Measurement Information System (PROMIS) and International Hip Outcome Tool 12 (iHOT-12) in patients undergoing hip arthroscopy (HA) with concomitant periacetabular osteotomy (PAO), HA+PAO for acetabular dysplasia and intra-articular pathology with minimum 2-year follow up. METHODS: Data from patients who underwent HA+PAO was prospectively collected and retrospectively analyzed. Inclusion criteria consisted of patients who had a diagnosis of hip dysplasia or hip instability and had minimum 2-year PROMs follow up. Data was collected electronically preoperatively and postoperatively at 6 months, 1year, and 2 years. Outcome measures analyzed were the iHOT -12 and PROMIS computer adaptive tests (CAT): Physical Function (PF), Pain Interference (PI), and Global Physical Health (GPH). MCID and SCB were calculated for these measures. RESULTS: 106 patients were included in the study with an average age of 23.5 ± 6.6, an average body mass index (BMI) of 24.3, and the majority being female (94%). The values for MCID were calculated to be 40.9, 40.7, 60.2, and 43.5 and the percentage achieving MCID at 2 years was 82.6%, 82.9%, 79.6%, and 80.1% for the iHOT-12, PROMIS-PF, PROMIS-PI, and PROMIS-GPH respectively. The 1 year and 2-year SCB scores for ≥ 80% satisfaction and percent achieving were as follows respectively: iHOT-12 (71.8 (60.3%), 61.9 (65.1%)); PROMIS-PF (47.1 (64.2%), 47.2 (71.7%)); PROMIS-PI (50.6 (48.1%), 52.3 (49.1%)); PROMIS-GPH (49.3 (54.7%), 49.3 (55.7%)). The 1 year and 2 year SCB scores for 100% satisfaction and percent achieving were as follows respectively: iHOT-12 (80.2 (44.3%), 81.3 (47.2%)); PROMIS-PF (50.7 (46.2%), 50.3 (56.6%)); PROMIS-PI (52.4 (34.9%), 52.4 (49.1%)); PROMIS-GPH (52.5 (36.8%), 49.3 (55.7%)). CONCLUSION: This study reports values for MCID and SCB for PROMIS and iHOT-12 at 2-year follow up in patients undergoing HA+PAO for hip dysplasia or instability. The percentage of patients achieving MCID ranged from 79.6%-82.9% at 2-year follow-up. In addition, the percentage of patients achieving SCB at 2-year follow up for ≥ 80% satisfaction ranged from 49.1%-71.2% and the percentage for 100% satisfaction ranged from 49.1%-56.6.

Bacterial surface lipoproteins mediate epithelial microinvasion by Streptococcus pneumoniae.

Streptococcus pneumoniae, a common colonizer of the upper respiratory tract, invades nasopharyngeal epithelial cells without causing disease in healthy participants of controlled human infection studies. We hypothesized that surface expression of pneumococcal lipoproteins, recognized by the innate immune receptor TLR2, mediates epithelial microinvasion. Mutation of lgt in serotype 4 (TIGR4) and serotype 6B (BHN418) pneumococcal strains abolishes the ability of the mutants to activate TLR2 signaling. Loss of lgt also led to the concomitant decrease in interferon signaling triggered by the bacterium. However, only BHN418 lgt::cm but not TIGR4 lgt::cm was significantly attenuated in epithelial adherence and microinvasion compared to their respective wild-type strains. To test the hypothesis that differential lipoprotein repertoires in TIGR4 and BHN418 lead to the intraspecies variation in epithelial microinvasion, we employed a motif-based genome analysis and identified an additional 525 a.a. lipoprotein (pneumococcal accessory lipoprotein A; palA) encoded by BHN418 that is absent in TIGR4. The gene encoding palA sits within a putative genetic island present in ~10% of global pneumococcal isolates. While palA was enriched in the carriage and otitis media pneumococcal strains, neither mutation nor overexpression of the gene encoding this lipoprotein significantly changed microinvasion patterns. In conclusion, mutation of lgt attenuates epithelial inflammatory responses during pneumococcal-epithelial interactions, with intraspecies variation in the effect on microinvasion. Differential lipoprotein repertoires encoded by the different strains do not explain these differences in microinvasion. Rather, we postulate that post-translational modifications of lipoproteins may account for the differences in microinvasion.IMPORTANCEStreptococcus pneumoniae (pneumococcus) is an important mucosal pathogen, estimated to cause over 500,000 deaths annually. Nasopharyngeal colonization is considered a necessary prerequisite for disease, yet many people are transiently and asymptomatically colonized by pneumococci without becoming unwell. It is therefore important to better understand how the colonization process is controlled at the epithelial surface. Controlled human infection studies revealed the presence of pneumococci within the epithelium of healthy volunteers (microinvasion). In this study, we focused on the regulation of epithelial microinvasion by pneumococcal lipoproteins. We found that pneumococcal lipoproteins induce epithelial inflammation but that differing lipoprotein repertoires do not significantly impact the magnitude of microinvasion. Targeting mucosal innate immunity and epithelial microinvasion alongside the induction of an adaptive immune response may be effective in preventing pneumococcal colonization and disease.

Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma.

B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.

Claw Toe Deformity After Revision Hip Arthroscopy with Concomitant Periacetabular Osteotomy: A Case Report.

CASE: A 22-year-old woman underwent revision right hip arthroscopy (HA) with concomitant periacetabular osteotomy (PAO). The total procedure time was 5.5 hours. After completion of the 3 hour HA portion, the traction boots were loosened. Eleven weeks postoperatively, she developed a left claw toe deformity. After failed conservative management, she underwent lengthening of the left flexor hallucis longus and flexor digitorum longus tendons. CONCLUSION: This is a case of a claw toe deformity after revision right HA with concomitant PAO. The possibility of this complication should be considered in cases with prolonged intraoperative times because of the use of traction boots.

Outcomes of distal biceps tendon repair using a dual incision, cortical button technique: a single surgeon study.

BACKGROUND: The purpose of this study was to evaluate patient-reported outcomes, function, complication rates, and radiographs in a series of patients with distal biceps tendon repair using the dual incision cortical button technique by a single surgeon. By having a single surgeon perform the surgery, the technique is standardized to all patients. Twenty-two patients consented to participate in the study. The average time from surgery to review was 2.2 years. Patient satisfaction was assessed using the DASH, Oxford, and Mayo Elbow Performance Scores. METHODS: Range of movement was assessed and compared to the unaffected limb using a goniometer. Isometric flexion and supination strength was tested using a standardized dynamometer-both measurements taken by a single physiotherapist. Radiographs were discussed at the time of the review by 2 orthopedic surgeons to check for heterotopic ossification. RESULTS: The mean DASH score was 6.3 postsurgery at the time of follow-up. There was no significant difference in active range of movement between the repaired and nonrepaired arm in flexion, extension, supination, or pronation. Four radiographs showed evidence of heterotopic ossification (HTO)-none showed synostosis. For patients with HTO, there was evidence that supination was inhibited compared to those patients who did not have HTO. CONCLUSION: Our study found that at an average of 2 years of follow-up these patients had good outcomes clinically with no major complications. HTO was present in only 4 patients, and there was a significant difference in supination compared to those who did not have HTO. These patients had an average DASH of 14 compared to a score of 4.5 in those who did not have an HTO. The study showed that the dual incision cortical button repair remains a procedure with excellent patient outcomes at the risk of HTO.

Combined CCNE1 high-level amplification and overexpression is associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma.

CCNE1 amplification is a recurrent alteration associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma (HGSC). We aimed to investigate whether immunohistochemistry (IHC) can be used to identify CCNE1 amplification status and to validate whether CCNE1 high-level amplification and overexpression are prognostic in HGSC. A testing set of 528 HGSC samples stained with two optimised IHC assays (clones EP126 and HE12) was subjected to digital image analysis and visual scoring. DNA and RNA chromogenic in situ hybridisation for CCNE1 were performed. IHC cut-off was determined by receiver operating characteristics (ROC). Survival analyses (endpoint ovarian cancer specific survival) were performed and validated in an independent validation set of 764 HGSC. Finally, combined amplification/expression status was evaluated in cases with complete data (n = 1114). CCNE1 high-level amplification was present in 11.2% of patients in the testing set and 10.2% in the combined cohort. The optimal cut-off for IHC to predict CCNE1 high-level amplification was 60% positive tumour cells with at least 5% strong staining cells (sensitivity 81.6%, specificity 77.4%). CCNE1 high-level amplification and overexpression were associated with survival in the testing and validation set. Combined CCNE1 high-level amplification and overexpression was present in 8.3% of patients, mutually exclusive to germline BRCA1/2 mutation and significantly associated with a higher risk of death in multivariate analysis adjusted for age, stage and cohort (hazard ratio = 1.78, 95 CI% 1.38-2.26, p < 0.0001). CCNE1 high-level amplification combined with overexpression identifies patients with a sufficiently poor prognosis that treatment alternatives are urgently needed. Given that this combination is mutually exclusive to BRCA1/2 germline mutations, a predictive marker for PARP inhibition, CCNE1 high-level amplification combined with overexpression may serve as a negative predictive test for sensitivity to PARP inhibitors.

Pelvic occupation: the challenges of treating a symptomatic tarlov cyst.

Tarlov (perineural) cysts are meningeal dilations of the posterior spinal nerve root sheath located in between the peri- and endoneurium. We present a patient with a symptomatic sacral Tarlov cyst and the technical challenges faced by surgically treating the lesion by disconnection of the cyst from the subarachnoid space.

Low ATM protein expression in malignant tumor as well as cancer-associated stroma are independent prognostic factors in a retrospective study of early-stage hormone-negative breast cancer.

INTRODUCTION: The serine/threonine protein kinase ataxia telangiectasia mutated (ATM) is critical in maintaining genomic integrity. Upon DNA double-strand breaks, ATM phosphorylates key downstream proteins including p53 and BRCA1/2, thereby orchestrating complex signaling pathways involved in cell cycle arrest, DNA repair, senescence and apoptosis. Although sporadic mutation of ATM occurs rarely in breast cancer, the status of its protein expression and its clinical significance in breast cancer remain not well established. Our study was designed to investigate the influence of ATM protein in both tumor and cancer-associated stroma on clinical outcome in hormone-positive (HPBC) and hormone-negative (HNBC) early-stage breast cancer (EBC). METHODS: Tissue microarrays (TMAs), containing formalin-fixed, paraffin-embedded resected tumors from two cohorts of patients (HPBC cohort: n=130; HNBC cohort: n=168) diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, were analyzed for ATM protein expression using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA). ATM expression levels were measured within the tumor as a whole (tATM) as indicated by pan-cytokeratin expression, tumor nuclear compartment (nATM) as indicated by both DAPI and pan-cytokeratin-positive results, and cancer-associated stroma (csATM) as indicated by vimentin-positive and pan-cytokeratin-negative results. ATM expression levels within these compartments were correlated with clinical outcome. RESULTS: While tATM and nATM were significantly lower in tumors compared to normal breast epithelial tissues, csATM was significantly higher than the corresponding normal tissue compartment. In addition, the median expression level of both tATM and nATM were two- to threefold lower (P<0.001) in HNBC than in HPBC. In both HNBC and HPBC cohorts, patients with low tATM, nATM and csATM tumors had significantly poorer survival outcomes than those with a high tATM, nATM and csATM, but this effect was more pronounced in HNBC. A multivariate analysis demonstrates that these biomarkers predict survival independent of tumor size and lymph node status, but only in the HNBC cohort (P<0.001). CONCLUSIONS: Low ATM protein expression in both malignant tumor and stromal compartments likely contributes to the aggressive nature of breast cancer and is an independent prognostic factor associated with worse survival in HNBC patients.

Gait analysis in children with severe clubfeet: early results of physiotherapy versus surgical release.

Ninety children between the ages of 2 and 3 years with 127 clubfeet underwent gait analysis. Fifty-one feet had undergone posteromedial releases, 52 feet had no surgery following correction of the deformity using the French physical therapy program, and 24 feet had either tendo Achilles lengthening or posterior releases following physical therapy. Persistent internal rotation of the foot during gait was the most frequent gait disturbance and was seen in all treatment groups. Limited ankle dorsiflexion was most common in the nonoperated feet, while calcaneus deformity occurred in the posteromedial release group. Ankle motion during gait was normal in 54% of nonoperated feet compared with 39% of feet that had posteromedial releases. While gait abnormalities were common in all clubfeet, fewer deviations were documented in feet treated with physical therapy that did not require surgery. Aggressive release leads to a higher likelihood of abnormal ankle motion and internal rotation during gait.

Nonoperative clubfoot treatment using the French physical therapy method.

Ninety-eight patients (142 clubfeet) treated nonoperatively by the French physical therapy method were reviewed to determine the effectiveness of this technique. All were 3 months old or less when treatment began and were rated for initial clubfoot severity using the Dimeglio scale (moderate, severe, very severe). Follow-up averaged 35 months (range 20-62 months). Forty-two percent of the feet needed no surgery to achieve a plantigrade position, 9% needed heelcord tenotomies, 29% needed posterior releases, and 20% needed comprehensive posteromedial releases. The Dimeglio scale was prognostic for outcomes, with moderate feet having the best results and very severe feet having the worst results. The French physical therapy method significantly reduced the need for operative intervention at the authors' institution.