AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer.

PURPOSE: To assess the safety and efficacy of AN0025 in combination with preoperative radiotherapy and chemotherapy in either short course (SCRT) or long course radiotherapy (LCRT) settings for those with locally advanced rectal cancer. PATIENTS AND METHODS: Twenty-eight subjects with locally advanced rectal cancer participated in this multicenter, open-label, Phase Ib trial. Enrolled subjects received either 250 mg or 500 mg of AN0025 once daily for 10 weeks with either LCRT or SCRT with chemotherapy (7 subjects/group). Participants were assessed for safety/efficacy starting from the first dose of study drug administration and were followed for 2 years. RESULTS: No treatment-emergent adverse or serious adverse events meeting dose-limiting criteria were observed, with only 3 subjects discontinuing AN0025 treatment due to adverse events. Twenty-five of 28 subjects completed 10 weeks of AN0025 and adjuvant therapy and were evaluated for efficacy. Overall, 36.0% of subjects (9/25 subjects) achieved a pathological complete response or a complete clinical response, including 26.7% of subjects (4/15 subjects who underwent surgery) who achieved a pathological complete response. A total of 65.4% of subjects had magnetic resonance imaging-confirmed down-staging ≤ stage 3 following completion of treatment. With a median follow-up of 30 months. The 12-month disease-free survival and overall survival were 77.5% (95% confidence interval [CI]: 56.6, 89.2) and 96.3% (95% CI: 76.5, 99.5), respectively. CONCLUSIONS: Treatment with AN0025 administered for 10 weeks along with preoperative SCRT or LCRT did not appear to worsen the toxicity in subjects with locally advanced rectal cancer, was well-tolerated and showed promise in inducing both a pathological and complete clinical response. These findings suggest its activity deserves further investigation in larger clinical trials.

Short versus long cephalomedullary nailing of intertrochanteric fractures: a meta-analysis of 3208 patients.

OBJECTIVES: The purpose of the study was to compare treatment outcomes after short or long cephalomedullary nailing for intertrochanteric femur fractures. DATA SOURCES: A systematic review of perioperative outcomes after short or long cephalomedullary nailing for intertrochanteric femur fractures was performed. The following databases were used: using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-2019), and MEDLINE (1980-2019). The queries were performed in June 2019. STUDY SELECTION: The following search term query was used: "Intramedullary Nail AND Intertrochanteric Fracture OR "Long OR Short Nail AND intertrochanteric Fracture." Studies were excluded if they were "single-arm" studies (i.e., reporting on either long or short CMN but not both), or did not report at least one of the outcomes being meta-analyzed. Furthermore, cadaveric studies, animal studies, basic science articles, editorial articles, surveys and studies were excluded. DATA EXTRACTION: Two investigators independently reviewed abstracts from all identified articles. Full-text articles were obtained for review if necessary, to allow further assessment of inclusion and exclusion criteria. Additionally, all references from the included studies were reviewed and reconciled to verify that no relevant articles were missing from the systematic review. DATA SYNTHESIS: Short nails were associated with statistically significantly less estimated blood loss and operative time compared to long nails. There were no significant differences in transfusion rates, implant failures or overall re-operation rates between implant lengths. Similarly, there was no significant difference in peri-implant fracture between implant lengths. CONCLUSIONS: Overall, the available clinical evidence supports the use of short cephalomedullary nails for the majority of intertrochanteric femur fractures. STUDY DESIGN/LEVEL OF EVIDENCE: Meta-analysis; Level III, therapeutic.

Incidence and Management of Articular Impaction in Geriatric Olecranon Fractures.

INTRODUCTION: Olecranon fractures are common in the elderly. Articular impaction is encountered occasionally, but the incidence and outcomes after treatment of this injury pattern have not been well characterized. METHODS: We evaluated a cohort of geriatric olecranon fractures to determine the incidence of articular impaction and describe a technique for open reduction and internal fixation. RESULTS: Of the 63 patients in our series, 31 had associated intraarticular impaction (49.2%). Patients with articular impaction did not have significantly different rates of postoperative complications (11/31, 35.5% versus 10/31, 32.3%; P = 1.00) or revision surgery (10/31, 32.3% versus 8/31, 25.8%; P = 0.780) compared with those without articular impaction. CONCLUSION: Articular impaction is a common feature of geriatric olecranon fractures. Surgeons must maintain a high index of suspicion and have a surgical plan in place for managing this component of the injury.

How are peri-implant fractures below short versus long cephalomedullary nails different?

BACKGROUND: Cephalomedullary nails are a commonly used implant for the treatment of many pertrochanteric femur fractures and are available in short and long configurations. There is no consensus on ideal nail length. Relative advantages can be ascribed to short and long intramedullary nails, yet both implant styles share the potentially devastating complication of peri-implant fracture. Determining the clinical sequelae after fractures below nails of different lengths would provide valuable information for surgeons choosing between short or long nails. Thus, the purpose of the study was to compare injury patterns and treatment outcomes following peri-implant fractures below short or long cephalomedullary nails. METHODS: This was a multicenter retrospective cohort study that identified 33 patients referred for treatment of peri-implant fractures below short and long cephalomedullary nails (n = 19 short, n = 14 long). We compared fracture pattern, treatment strategy, complications, and outcomes between these two groups. RESULTS: Short nails were associated with more diaphyseal fractures (odds ratio [OR] 13.75, CI 2.2-57.9, p 0.002), which were treated more commonly with revision intramedullary nailing (OR, infinity; p 0.01), while long nails were associated with distal metaphyseal fractures (OR 13.75, CI 2.2-57.9, p 0.002), which were treated with plate and screw fixation (p 0.002). After peri-implant fracture, there were no differences in blood loss, operative time, weight bearing status, or complication rates based on the length of the initial nail. In patients treated with revision nailing, there was greater estimated blood loss (EBL, median 300 cc, interquartile range [IQR] 250-1200 vs median 200 cc, IQR 100-300, p 0.03), blood product utilization and complication rates (OR 11.1, CI 1.1-135.7, p 0.03), but a trend toward unrestricted post-operative weight-bearing compared to patients treated with plate and screw constructs. CONCLUSION: Understanding fracture patterns and patient outcomes after fractures below nails of different lengths will help surgeons make more informed implant choices when treating intertrochanteric hip fractures. Revision to a long nail for the treatment of fractures at the tip of a short nail may be associated with increased patient morbidity.

Metaphyseal callus formation in pilon fractures is associated with loss of alignment: Is stiffer better?

OBJECTIVE: To assess the relationship between metaphyseal callus formation and preservation of distal tibial alignment in pilon fractures treated with internal plate fixation. DESIGN: Retrospective Review SETTING: Academic Level I Trauma Center PATIENTS: Forty-two patients with AO/OTA type C2 or C3 pilon fractures treated with plate fixation. INTERVENTION: Internal fixation with anterolateral plating, medial plating, or both. Modified Radiographic Union Score in Tibial fracture (mRUST) scores were determined from six-month radiographs. MAIN OUTCOME MEASUREMENTS: Change in lateral and anterior distal tibial angles (LDTA and ADTA) at six months post-operatively. RESULTS: High callus formation (mRUST ≥ 11 at six months) was associated with a greater loss of coronal reduction as measured by LDTA compared to low callus formation (mRUST < 11): 3.8 vs 2.1° (p = .019), with no difference in ADTA change between groups. In a multivariable logistic regression controlling for age, smoking, obesity, and open fracture, higher mRUST scores were a predictor of coronal reduction loss of five or more degrees (OR 1.71, p=.039). Dual column plating did not independently predict maintenance of alignment. CONCLUSIONS: Recent literature has popularized dual column fixation for pilon fractures, but it remains unknown whether increased metaphyseal stiffness enhances or impairs healing. In this series, decreased metaphyseal callus formation was associated with maintained coronal alignment, suggesting that a stiffer mechanical environment may be preferable to prevent short term reduction loss in these complex injuries. LEVEL OF EVIDENCE: III.

How do pilon fractures heal? An analysis of dual plating and bridging callus formation.

OBJECTIVES: 1) To determine the effect of single versus dual plate metaphyseal fixation for pilon fractures on callus formation and reoperation rates, 2) to determine the effect of biomechanically matched versus unmatched fixation, and 3) to determine whether patient or surgical factors were independent predictors of bridging callus formation or need for reoperation. DESIGN: Retrospective comparative study. SETTING: Single level one trauma center. PATIENTS: Fifty patients with AO/OTA type C2 or C3 pilon fractures treated with plate fixation. INTERVENTION: Internal fixation with a plate and screw construct, with comparisons made between patients with single versus dual plate fixation, and patients treated with biomechanically matched or unmatched fixation. MAIN OUTCOME MEASUREMENTS: Modified RUST (mRUST) scores at three and six months and reoperation rate. RESULTS: At six months, mean mRUST scores were significantly lower in patients treated with dual metaphyseal plates compared to a single plate (8.7 vs 10.4, p=0.046) There were 15 open fractures; eight were treated with supplemental fixation, while seven were treated with single-column fixation. Open fracture (OR 51.05, p=0.008) was a risk factor for reoperation. Screw density between 0.4 and 0.5 was a protective factor against reoperation (OR 0.03, p=0.026). Biomechanically unmatched fixation did not affect mRUST scores or reoperation rates. CONCLUSIONS: Pilon fractures treated with a single plate had more callus formation six months after surgery compared to those treated with dual plate fixation, and there was no difference in reoperation rates. Screw density between 0.4-0.5 was protective against reoperation. These data may serve as the basis of future work to determine the ideal fixation construct for the frequently comminuted metaphysis in pilon fractures. Further work is necessary to determine whether callus formation in these injuries is desirable. LEVEL OF EVIDENCE: Three.

New Technologies to Image Tumors.

The premise of this book is the importance of the tumor microenvironment (TME). Until recently, most research on and clinical attention to cancer biology, diagnosis, and prognosis were focused on the malignant (or premalignant) cellular compartment that could be readily appreciated using standard morphology-based imaging.

A Novel GUCY2C-CD3 T-Cell Engaging Bispecific Construct (PF-07062119) for the Treatment of Gastrointestinal Cancers.

PURPOSE: Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis therapy. EXPERIMENTAL DESIGN: PF-07062119 activity was evaluated in vitro in multiple tumor cell lines, and in vivo in established subcutaneous and orthotopic human colorectal cancer xenograft tumors with adoptive transfer of human T cells. Efficacy was also evaluated in mouse syngeneic tumors using human CD3ε transgenic mice. IHC and mass cytometry were performed to demonstrate drug biodistribution, recruitment of activated T cells, and to identify markers of immune evasion. Combination studies were performed with anti-PD-1/PD-L1 and anti-VEGF antibodies. Toxicity and pharmacokinetic studies were done in cynomolgus macaque. RESULTS: We demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ε bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T-cell-mediated in vitro activity and in vivo efficacy in multiple colorectal cancer human xenograft tumor models, including KRAS- and BRAF-mutant tumors, as well as in the immunocompetent mouse syngeneic tumor model. PF-07062119 activity was further enhanced when combined with anti-PD-1/PD-L1 treatment or in combination with antiangiogenic therapy. Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile. CONCLUSIONS: These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies.

Comparison of the molecular and cellular phenotypes of common mouse syngeneic models with human tumors.

BACKGROUND: The clinical success of immune checkpoint inhibitors demonstrates that reactivation of the human immune system delivers durable responses for some patients and represents an exciting approach for cancer treatment. An important class of preclinical in vivo models for immuno-oncology is immunocompetent mice bearing mouse syngeneic tumors. To facilitate translation of preclinical studies into human, we characterized the genomic, transcriptomic, and protein expression of a panel of ten commonly used mouse tumor cell lines grown in vitro culture as well as in vivo tumors. RESULTS: Our studies identified a number of genetic and cellular phenotypic differences that distinguish commonly used mouse syngeneic models in our study from human cancers. Only a fraction of the somatic single nucleotide variants (SNVs) in these common mouse cell lines directly match SNVs in human actionable cancer genes. Some models derived from epithelial tumors have a more mesenchymal phenotype with relatively low T-lymphocyte infiltration compared to the corresponding human cancers. CT26, a colon tumor model, had the highest immunogenicity and was the model most responsive to CTLA4 inhibitor treatment, by contrast to the relatively low immunogenicity and response rate to checkpoint inhibitor therapies in human colon cancers. CONCLUSIONS: The relative immunogenicity of these ten syngeneic tumors does not resemble typical human tumors derived from the same tissue of origin. By characterizing the mouse syngeneic models and comparing with their human tumor counterparts, this study contributes to a framework that may help investigators select the model most relevant to study a particular immune-oncology mechanism, and may rationalize some of the challenges associated with translating preclinical findings to clinical studies.

Comparative Analysis of Mechanism-Associated 3-Dimensional Tibial Plateau Fracture Patterns.

BACKGROUND: The association between tibial plateau fracture morphology and injury force mechanism has not been well described. The aim of this study was to characterize 3-dimensional fracture patterns associated with hypothesized injury force mechanisms. METHODS: Tibial plateau fractures treated in a large trauma center were retrospectively reviewed. Three experienced surgeons divided fractures independently into 6 groups associated with injury force mechanisms proposed from an analysis of computed tomographic (CT) imaging: flexion varus, extension varus, hyperextension varus, flexion valgus, extension valgus, and hyperextension valgus. The fracture lines and comminution zones of each fracture were graphically superimposed onto a 3-dimensional template of the proximal part of the tibia. Fracture characteristics were then summarized on the basis of the fracture maps. The association between injury force mechanism and ligament avulsions was calculated. RESULTS: In total, 353 tibial plateau fractures were included. The flexion varus type pattern was seen in 67 fractures characterized by a primary fracture apex located posteromedially and was frequently associated with concomitant anterior cruciate ligament (ACL) avulsion (44.8%). The extension varus pattern was noted in 60 fractures with a characteristic medial fragment apex at the posteromedial crest or multiple apices symmetrically around the crest and was commonly completely articular in nature (65%). The hyperextension varus pattern was seen in 47 fractures as noted by anteromedial articular impaction, 51% with a fibular avulsion and 60% with posterior tension failure fragments. The flexion valgus pattern was observed in 51 fractures characterized by articular depression posterolaterally, often (58.9%) with severe comminution of the posterolateral cortical rim. The extension valgus patterns in 116 fractures only involved the lateral plateau, with central articular depression and/or a pure split. The hyperextension valgus pattern occurred in 12 fractures denoted by anterolateral articular depression. A moderate positive association was found between flexion varus fractures and ACL avulsions and between hyperextension varus fractures and fibular avulsions. CONCLUSIONS: Tibial plateau fractures demonstrate distinct, mechanism-associated 3-dimensional pattern characteristics. Further research is needed to validate the classification reliability among other surgeons and to determine the potential value in the diagnosis and formulation of surgical protocols.

Upregulation of PD­L1 expression by resveratrol and piceatannol in breast and colorectal cancer cells occurs via HDAC3/p300­mediated NF­κB signaling.

Programmed cell death ligand 1 (PD­L1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD­1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD­1/PD­L1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PD­L1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PD­L1 in tumor cells may help to improve the response to PD­L1 blockade therapies. In this study, we investigated whether resveratrol, a grape-derived stilbenoid with immunoregulatory activity, modulates the expression of PD­L1 in breast and colorectal cancer cells. The surface expression of PD­L1 was determined by flow cytometry in cancer cells treated with resveratrol and/or piceatannol. Each stilbenoid alone induced PD­L1 and when used in combination, elicited a synergistic upregulation of PD­L1 in some cell lines. The induction of PD­L1 by the combined use of stilbenoids was most pronounced in the Cal51 triple-negative breast cancer (TNBC) and SW620 colon cancer cells. The observed induction of PD­L1 was transcriptionally mediated by nuclear factor (NF)-κB, as shown by NF­κB reporter assays, the nuclear accumulation of the p65 subunit of NF­κB, inhibition by the IKK inhibitor, BMS­345541, and histone the modification inhibitors, resminostat, entinostat or anacardic acid. Combined treatment with resveratrol and piceatannol also decreased tumor cell survival as indicated by the upregulation of the DNA damaging marker, γH2AX, the cleavage of caspase 3, the downregulation of the survival markers, p38-MAPK/c­Myc, and G1-to-S cell cycle arrest.

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice.

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.

Two and Three-Dimensional CT Mapping of Hoffa Fractures.

BACKGROUND: Hoffa fractures, coronal-plane fractures involving the distal femoral condyles, are unstable, intra-articular fractures. The aim of this study was to define the location and frequency of fracture lines and comminution zones in Hoffa fractures using computed tomography (CT) mapping in both 2-dimensional and 3-dimensional contexts. METHODS: Seventy-five Hoffa fractures (OTA/AO types 33B3.2 and 33B3.3) were retrospectively reviewed. The directions of fracture lines were characterized in the axial and sagittal CT planes. CT images for all fractures were superimposed on one another and oriented to fit a standard template. Mapping of fracture lines and comminution zones in both the axial and sagittal planes was performed. A 3-dimensional map was created by reducing reconstructed fracture fragments to fit to a model of the distal aspect of the femur. RESULTS: This study included 1 bicondylar and 74 unicondylar (26 medial and 48 lateral) Hoffa fractures. Comminuted fractures accounted for 35.5% of all fractures and 44.9% of lateral fractures. Axial fracture mapping demonstrated that fracture lines were concentrated in the middle-third area of the lateral condyle but were less concentrated and with greater variation in the medial condyle. The mean angle of fracture lines with respect to the posterior condylar axis was 34.4° and 29.0° in the lateral and medial femoral condyles, respectively. Sagittal fracture mapping also demonstrated that fracture lines were concentrated in the middle third of the lateral condyle but were less concentrated in the medial condyle. The mean angle of fracture lines with respect to the posterior cortex of the distal femoral shaft was 23.1° and 19.3° in the lateral and medial condyles, respectively. Three-dimensional mapping demonstrated comminution zones commonly occurring in the weight-bearing zone of the lateral condylar articular surface. CONCLUSIONS: Hoffa fractures occurred more frequently in the lateral femoral condyle. In the axial plane, fractures commonly extended from anterolateral to posteromedial in the lateral condyle and from anteromedial to posterolateral in the medial femoral condyle. In the sagittal plane, fractures traversed from anteroinferior to posterosuperior. Articular comminution was more commonly seen in lateral condylar fractures and concentrated in the weight-bearing zone of the articular surface. CLINICAL RELEVANCE: Research in this area is imperative for optimal preoperative planning, such as for the selection of surgical approach and fixation constructs. Our findings lend insight into fracture morphology, which can assist with fracture classification and the design of biomechanical studies, ultimately aiding in treatment.

Reduction Techniques for Diaphyseal Femur Fractures.

Achieving and maintaining reduction in patients with a diaphyseal femur fracture may be difficult; therefore, thorough preoperative planning is required. To fully prepare for successful surgical management of diaphyseal femur fractures, surgeons must consider appropriate patient positioning and necessary tools, including surgical tables, traction devices, and instruments. Principles of acceptable reduction rely on the restoration of length, alignment, and rotation. Reduction of diaphyseal femur fractures should be attained in the least invasive manner, via percutaneous reduction techniques, if possible, to preserve fracture biology and promote successful fracture healing. Intraoperative assessment of reduction often requires imaging studies of the contralateral extremity as a reference. Intraoperative assessment for associated femoral neck fractures and postoperative clinical examination of the hip and knee are imperative to the successful management of diaphyseal femur fractures. Other reference modalities and clinical examinations are required in patients with bilateral diaphyseal femur fractures.

Ultrasound Screening for Posterior Shoulder Dislocation in Infants with Persistent Brachial Plexus Birth Palsy.

BACKGROUND: Early detection of posterior shoulder dislocation in infants with brachial plexus birth palsy (BPBP) is essential, but it may be difficult to accomplish with physical examination alone. The aim of this study was to determine the prevalence of shoulder dislocation in patients with BPBP using ultrasound and to identify which physical examination measurements correlated most with dislocation in these patients. METHODS: This study was a retrospective review of data obtained in an ultrasound screening program of infants with BPBP born from January 2011 to April 2014. Physical examination included the use of the Active Movement Scale (AMS) and measurement of passive external rotation of the shoulder. Ultrasound measurements included PHHD (percentage of the humeral head displaced posterior to the axis of the scapula) and the alpha angle (intersection of the posterior scapular margin with a line tangential to the humeral head through the glenoid). Shoulder dislocation was defined as both a PHHD of >0.5 and an alpha angle of >30°. RESULTS: Of sixty-six infants who had undergone a total of 118 ultrasound examinations (mean, 1.8; range, 1 to 5), 19 (29%) demonstrated shoulder dislocation with the shoulder positioned in internal rotation; the dislocation was first detected between 2.1 and 10.5 months of age. Infants with a dislocated shoulder demonstrated significantly less mean passive external rotation in adduction (mean, 45.8° versus 71.4°, p < 0.001) and a greater difference between internal rotation and external rotation AMS scores (mean, 5.5-point versus 3.3-point difference, p < 0.001) than those without shoulder dislocation. Passive external rotation in adduction was a better measure for discriminating between dislocation and no dislocation (area under receiver operating characteristic curve [AUC] = 0.89) than was the difference between internal and external rotation AMS scores (AUC = 0.73). A cutoff of 60° of passive external rotation in adduction (≤60° versus° >60) yielded a sensitivity of 94% and a specificity of 69%. CONCLUSIONS: Shoulder dislocation is common in infants with BPBP; 29% of the infants presenting to our tertiary care center had a dislocation during their first year of life. Ultrasound shoulder screening is appropriate for infants with BPBP. If passive external rotation in adduction is used to determine which infants should undergo ultrasound, ≤60° should be utilized as the criterion to achieve appropriate sensitivity. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.

Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs). To deliver a potent anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline-based linker, and Aur0101, an auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of cancer patients.

A Useful Preoperative Planning Technique for Transiliac-Transsacral Screws.

Stabilization of posterior pelvic ring injuries is increasingly performed using percutaneously placed iliosacral and transiliac-transsacral screws. Understanding the unique and specific anatomical variations present in each patient is paramount. Multiple methods of evaluating potential osseous fixation pathways for screw placement exist, but many require specific imaging protocols, specialized software, or modification of data. Not all surgeons and institutions have access to these options for a variety of reasons. A simple technique to preoperatively plan for safe transiliac-transsacral screws is proposed.

Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions.

PURPOSE: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival. EXPERIMENTAL DESIGN: A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for overexpressed antigens, one of which was selected to be the target of an antibody-drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification. RESULTS: We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well-annotated, low-passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor subclassification. CONCLUSIONS: These findings demonstrate the potential of PF-06647263 (anti-EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacologic evaluation of the compound, and translational studies to inform clinical development.

Carrying the burden: perspectives of African American pastors on peer support for people with cancer.

For African Americans facing advanced cancer, churches are trusted sources of support and ideal settings to improve access to supportive care. The Support Team model enhances community support for practical, emotional, and spiritual caregiving. We report on focus groups with pastors of 23 Black Churches and explore their perspective on the Support Team model for church members with cancer. Pastors describe the needs of church members facing cancer from a holistic perspective and recognize opportunities for synergistic faith-health collaboration. The results of this study indicate potential benefits of the Support Team model in Black Churches to reduce silent suffering among individuals facing cancer.

Supraphysiologic temperature enhances cytotoxic effects of bupivacaine on bovine articular chondrocytes in an in vitro study.

PURPOSE: The purpose of this study was to determine the effects of temperature or 0.25% bupivacaine treatment in combination with supraphysiologic temperatures on chondrocyte viability. METHODS: Bovine articular chondrocytes in suspension culture were treated with phosphate-buffered saline solution at 20°C, 37°C, 40°C, 42°C, 45°C, 47°C, and 50°C for 15, 30, and 60 minutes or with phosphate-buffered saline solution at 37°C, 45°C, and 50°C for 30 and 60 minutes followed by 0.25% bupivacaine at 20°C for 60 minutes. Chondrocyte viability was analyzed by flow cytometry with the LIVE/DEAD Viability/Cytotoxicity Kit (Molecular Probes, Eugene, OR). Annexin V and ethidium double staining determined whether apoptosis or necrosis occurred. RESULTS: Temperatures from 20°C to 42°C did not cause chondrocyte death. Temperatures at or above 45°C caused significant chondrocyte death, particularly at 50°C for 60 minutes, compared with 37°C at 60 minutes (P < .01). When the chondrocytes were incubated at 50°C, subsequent exposure to bupivacaine significantly increased chondrocyte death compared with the saline solution-treated control group (P < .001). There were additive cytotoxic effects when bupivacaine was combined with supraphysiologic temperatures. It was also found that bupivacaine at supraphysiologic temperatures caused necrosis of articular chondrocytes. CONCLUSIONS: Temperatures at or above 45°C caused significant chondrocyte death. Bupivacaine treatment in the presence of 45°C and 50°C temperatures significantly increased necrosis of bovine articular chondrocytes in this in vitro study. CLINICAL RELEVANCE: Immediate intra-articular injection of bupivacaine after heat-generating procedures may cause damage to the cartilage because of the additive cytotoxic effects of bupivacaine and elevated temperature.