MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.

The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.

Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer.

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.

Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma.

Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies.

Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia.

Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML) the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, increased lethality and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase Polrmt and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic, and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.

A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia.

Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin ß7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgß7 signaling axis as a key regulatory control point for bcCML growth and dissemination.

An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia.

Aggressive myeloid leukemias such as blast crisis chronic myeloid leukemia and acute myeloid leukemia remain highly lethal. Here we report a genome-wide in vivo CRISPR screen to identify new dependencies in this disease. Among these, RNA-binding proteins (RBPs) in general, and the double-stranded RBP Staufen2 (Stau2) in particular, emerged as critical regulators of myeloid leukemia. In a newly developed knockout mouse, loss of Stau2 led to a profound decrease in leukemia growth and improved survival in mouse models of the disease. Further, Stau2 was required for growth of primary human blast crisis chronic myeloid leukemia and acute myeloid leukemia. Finally, integrated analysis of CRISPR, eCLIP and RNA-sequencing identified Stau2 as a regulator of chromatin-binding factors, driving global alterations in histone methylation. Collectively, these data show that in vivo CRISPR screening is an effective tool for defining new regulators of myeloid leukemia progression and identify the double-stranded RBP Stau2 as a critical dependency of myeloid malignancies.

HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway.

HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) is a conserved long non-coding RNA (lncRNA) involved in myeloid and neural differentiation that is deregulated in acute myeloid leukemia and other cancers. Previous studies focused on the nuclear unspliced HOTAIRM1 transcript, however cytoplasmic splice variants exist whose roles have remained unknown. Here, we report novel functions of HOTAIRM1 in the kidney. HOTAIRM1 transcripts are induced during renal lineage differentiation of embryonic stem cells and required for expression of specific renal differentiation genes. We show that the major HOTAIRM1 transcript in differentiated cells is the spliced cytoplasmic HM1-3 isoform and that HM1-3 is downregulated in >90% of clear cell renal cell carcinomas (ccRCCs). Knockdown of HM1-3 in renal cells deregulates hypoxia-responsive and angiogenic genes, including ANGPTL4. Furthermore, HOTAIRM1 transcripts are downregulated by hypoxia-mimetic stress and knockdown of the cytoplasmic HM1-3 isoform in normoxic cells post-transcriptionally induces Hypoxia-Inducible Factor 1α (HIF1α) protein, a key activator of ANGPTL4. Our results demonstrate the pervasive downregulation of the specific HOTAIRM1 cytoplasmic isoform HM1-3 in ccRCC and suggest possible roles of HOTAIRM1 in kidney differentiation and suppression of HIF1-dependent angiogenic pathways.

A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma.

Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.

Global isoform-specific transcript alterations and deregulated networks in clear cell renal cell carcinoma.

Extensive genome-wide analyses of deregulated gene expression have now been performed for many types of cancer. However, most studies have focused on deregulation at the gene-level, which may overlook the alterations of specific transcripts for a given gene. Clear cell renal cell carcinoma (ccRCC) is one of the best-characterized and most pervasive renal cancers, and ccRCCs are well-documented to have aberrant RNA processing. In the present study, we examine the extent of aberrant isoform-specific RNA expression by reporting a comprehensive transcript-level analysis, using the new kallisto-sleuth-RATs pipeline, investigating coding and non-coding differential transcript expression in ccRCC. We analyzed 50 ccRCC tumors and their matched normal samples from The Cancer Genome Altas datasets. We identified 7,339 differentially expressed transcripts and 94 genes exhibiting differential transcript isoform usage in ccRCC. Additionally, transcript-level coexpression network analyses identified vasculature development and the tricarboxylic acid cycle as the most significantly deregulated networks correlating with ccRCC progression. These analyses uncovered several uncharacterized transcripts, including lncRNAs FGD5-AS1 and AL035661.1, as potential regulators of the tricarboxylic acid cycle associated with ccRCC progression. As ccRCC still presents treatment challenges, our results provide a new resource of potential therapeutics targets and highlight the importance of exploring alternative methodologies in transcriptome-wide studies.

Promoting and Providing HPV Vaccination in Hawaii: Barriers Faced by Health Providers.

Despite the availability of HPV prophylactic vaccines, uptake has been suboptimal in the US. In the state of Hawaii, HPV vaccine coverage has decreased among females and remains low among males aged 13-17. The reasons for low uptake are unknown and may indicate the existence of critical barriers to HPV vaccination. The purpose of this investigation was to identify policy, system and environmental barriers and promoters of pediatric HPV vaccination in Hawaii. An online 86-item survey addressing knowledge, attitudes, beliefs, practices, and barriers to HPV vaccination was distributed to practicing physicians in Hawaii specializing in Pediatrics, Family Medicine, and Obstetrics-Gynecology. Survey responses were received from a total of 120 physicians. Private practice physicians reported more concerns with vaccine ordering and stocking costs (p < 0.0001), reimbursement levels (p < 0.0001), and insurance coverage (p < 0.0001) compared to physicians in large group practices. Eighty-three percent of providers cited lack of parent knowledge and understanding of HPV infection as a barrier. Over half of physicians (58 %) reported that completion of the 3-dose schedule was a barrier. Most physicians did not use tracking or reminder systems to ensure dose completion. A majority (58 %) of providers cited the lack of school-based vaccination requirements as a barrier. Uptake of HPV vaccination in Hawaii may be impeded by physician perception of parent knowledge and attitudes. Cost-related system barriers are particular barriers among those in private practice. Completion of the 3-dose schedule also remains a challenge.

Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats.

Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.

Conductive interpenetrating networks of polypyrrole and polycaprolactone encourage electrophysiological development of cardiac cells.

Conductive and electroactive polymers have the potential to enhance engineered cardiac tissue function. In this study, an interpenetrating network of the electrically-conductive polymer polypyrrole (PPy) was grown within a matrix of flexible polycaprolactone (PCL) and evaluated as a platform for directing the formation of functional cardiac cell sheets. PCL films were either treated with sodium hydroxide to render them more hydrophilic and enhance cell adhesion or rendered electroactive with PPy grown via chemical polymerization yielding PPy-PCL that had a resistivity of 1.0 ± 0.4 kΩ cm, which is similar to native cardiac tissue. Both PCL and PPy-PCL films supported cardiomyocyte attachment; increasing the duration of PCL pre-treatment with NaOH resulted in higher numbers of adherent cardiomyocytes per unit area, generating cell densities which were more similar to those on PPy-PCL films (1568 ± 126 cells mm(-2), 2880 ± 439 cells mm(-2), 3623 ± 456 cells mm(-2) for PCL with 0, 24, 48 h of NaOH pretreatment, respectively; 2434 ± 166 cells mm(-2) for PPy-PCL). When cardiomyocytes were cultured on the electrically-conductive PPy-PCL, more cells were observed to have peripheral localization of the gap junction protein connexin-43 (Cx43) as compared to cells on NaOH-treated PCL (60.3 ± 4.3% vs. 46.6 ± 5.7%). Cx43 gene expression remained unchanged between materials. Importantly, the velocity of calcium wave propagation was faster and calcium transient duration was shorter for cardiomyocyte monolayers on PPy-PCL (1612 ± 143 µm/s, 910 ± 63 ms) relative to cells on PCL (1129 ± 247 µm/s, 1130 ± 20 ms). In summary, PPy-PCL has demonstrated suitability as an electrically-conductive substrate for culture of cardiomyocytes, yielding enhanced functional properties; results encourage further development of conductive substrates for use in differentiation of stem cell-derived cardiomyocytes and cardiac tissue engineering applications. STATEMENT OF SIGNIFICANCE: Current conductive materials for use in cardiac regeneration are limited by cytotoxicity or cost in implementation. In this manuscript, we demonstrate for the first time the application of a biocompatible, conductive polypyrrole-polycaprolactone film as a platform for culturing cardiomyocytes for cardiac regeneration. This study shows that the novel conductive film is capable of enhancing cell-cell communication through the formation of connexin-43, leading to higher velocities for calcium wave propagation and reduced calcium transient durations among cultured cardiomyocyte monolayers. Furthermore, it was demonstrated that chemical modification of polycaprolactone through alkaline-mediated hydrolysis increased overall cardiomyocyte adhesion. The results of this study provide insight into how cardiomyocytes interact with conductive substrates and will inform future research efforts to enhance the functional properties of cardiomyocytes, which is critical for their use in pharmaceutical testing and cell therapy.

The interplay of long non-coding RNAs and MYC in cancer.

Long non-coding RNAs (lncRNAs) are a class of RNA molecules that are changing how researchers view eukaryotic gene regulation. Once considered to be non-functional products of low-level aberrant transcription from non-coding regions of the genome, lncRNAs are now viewed as important epigenetic regulators and several lncRNAs have now been demonstrated to be critical players in the development and/or maintenance of cancer. Similarly, the emerging variety of interactions between lncRNAs and MYC, a well-known oncogenic transcription factor linked to most types of cancer, have caught the attention of many biomedical researchers. Investigations exploring the dynamic interactions between lncRNAs and MYC, referred to as the lncRNA-MYC network, have proven to be especially complex. Genome-wide studies have shown that MYC transcriptionally regulates many lncRNA genes. Conversely, recent reports identified lncRNAs that regulate MYC expression both at the transcriptional and post-transcriptional levels. These findings are of particular interest because they suggest roles of lncRNAs as regulators of MYC oncogenic functions and the possibility that targeting lncRNAs could represent a novel avenue to cancer treatment. Here, we briefly review the current understanding of how lncRNAs regulate chromatin structure and gene transcription, and then focus on the new developments in the emerging field exploring the lncRNA-MYC network in cancer.

Evaluating the potential for a Helicobacter pylori drinking water guideline.

Helicobacter pylori is a microaerophilic, gram-negative bacterium that is linked to adverse health effects including ulcers and gastrointestinal cancers. The goal of this analysis is to develop the necessary inputs for a quantitative microbial risk assessment (QMRA) needed to develop a potential guideline for drinking water at the point of ingestion (e.g., a maximum contaminant level, or MCL) that would be protective of human health to an acceptable level of risk while considering sources of uncertainty. Using infection and gastric cancer as two discrete endpoints, and calculating dose-response relationships from experimental data on humans and monkeys, we perform both a forward and reverse risk assessment to determine the risk from current reported surface water concentrations of H. pylori and an acceptable concentration of H. pylori at the point of ingestion. This approach represents a synthesis of available information on human exposure to H. pylori via drinking water. A lifetime risk of cancer model suggests that a MCL be set at <1 organism/L given a 5-log removal treatment because we cannot exclude the possibility that current levels of H. pylori in environmental source waters pose a potential public health risk. Research gaps include pathogen occurrence in source and finished water, treatment removal rates, and determination of H. pylori risks from other water sources such as groundwater and recreational water.

Total hip replacement after failed femoral head and neck excision in two dogs and two cats.

OBJECTIVE: To document outcome in 2 dogs and 2 cats after conversion of femoral head and neck excision (FHNE) to total hip replacement (THR). STUDY DESIGN: Case series. ANIMALS: Dogs (n = 2) and 2 cats. METHODS: For 1 dog and 2 cats, THR was performed using cemented acetabular and femoral components. Noncemented acetabular and cemented femoral components were used in 1 dog. RESULTS: All animals presented with severe hip pain and chronic lameness after unsuccessful FHNE. Potential causes of suboptimal outcome after FHNE were incomplete resection of the femoral neck (n = 3) and fibrous adhesions involving the sciatic nerve (n = 2). Post-FHNE remodeling of the proximal femur and acetabulum necessitated unconventional modifications of surgical technique. In all 4 cases, final clinical outcome and radiographic reassessment were satisfactory. Aseptic loosening of the acetabular bone-cement interface necessitating surgical revision was the only complication noted in 1 cat. CONCLUSIONS: Despite severe preoperative pain and chronic functional impairment in all cases, conversion of FHNE to THR produced marked clinical improvement including return to unrestricted exercise within 12 weeks of surgery.

The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of type 2 diabetes mellitus.

Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.

String-of-pearls locking plate and cerclage wire stabilization of periprosthetic femoral fractures after total hip replacement in six dogs.

OBJECTIVE: To report use of, and outcome after, string-of-pearls (SOP™) plate and multiple cerclage wire fixation for treatment of periprosthetic femoral fractures (PFF) associated with total hip replacement (THR) in dogs. STUDY DESIGN: Case series. ANIMALS: Dogs (n=6) with PFF after THR. METHODS: Clinical records (2005-2010) and radiographic evaluations of dogs that had PFF associated with THR, treated with a SOP™ plate and cerclage wires were retrospectively reviewed. Clinical and radiographic postoperative assessments were performed 4, 12, and 24 weeks postoperatively. Telephone follow-up was performed >12 months postoperatively. RESULTS: Three fractures occurred intraoperatively and 3 occurred postoperatively. One SOP™ failed at 2 weeks necessitating revision using 2 parallel SOP™ implants. One dog was euthanatized because of quadriceps muscle tie-down at 6 weeks. Other dogs were free of lameness with full range of motion of the stifle and hip joints at final clinical examination, and positive outcomes were maintained at >12 month telephone questionnaire. There was no evidence of implant failure and positive evidence of fracture healing at final radiographic follow-up. CONCLUSIONS: Stabilization resulted in bone healing in 5 dogs; failure in 1 dog may be attributable to technical error. Optimal technical guidelines for use of the SOP™ in this circumstance are unknown, particularly where fracture configuration varies.

Total hip replacement with dorsal acetabular rim augmentation using the SOP(TM) implant and polymethylmethacrylate cement in seven dogs with dorsal acetabular rim deficiency.

OBJECTIVE: To describe a surgical technique for reinforced augmentation of the dorsal acetabular rim (DAR) using a string-of-pearls (SOP™) locking plate and polymethylmethacrylate (PMMA) bone cement, and to report clinical outcome in 7 dogs. STUDY DESIGN: Case series. ANIMALS: Dogs (n=7). METHODS: Medical records (November 2009-April 2010) of 7 dogs with large DAR deficits, that had total hip replacement (THR) with reinforced augmentation of the DAR using a SOP™ plate and PMMA were evaluated retrospectively. Reinforced augmentation of the DAR involved anchorage of a precontoured 2.0 or 2.7 mm SOP™ plate dorsal to the acetabulum followed by application of PMMA cement to cover the reamed acetabulum and plate. Cemented acetabular components were used. Implant associated complications were recorded and ≥6-month follow-up obtained. RESULTS: In all dogs, lameness improved at medium-term reassessment (median, 8 months; range, 6-11 months). Complications included transient sciatic neurapraxia in 2 dogs, which resolved by 3 months. CONCLUSIONS: Reinforced augmentation of the DAR using a SOP™ plate and PMMA cement may facilitate placement of acetabular THR component implantation in dogs with severe DAR insufficiency.

Outcome after repair of a sarcoma-related pathologic fracture in dogs: a Veterinary Society of Surgical Oncology Retrospective Study.

OBJECTIVE: To report outcome in dogs after internal fixation of a sarcoma-related pathologic fracture of the appendicular skeleton. STUDY DESIGN: Multi-institutional case series. ANIMALS: Dogs (n=16). METHODS: Medical records of participating VSSO members were reviewed for dogs with pathologic fracture associated with a confirmed bone sarcoma of the appendicular skeleton repaired by external or internal fixation. Dogs were included if they had a histological diagnosis of osteosarcoma or sarcoma and excluded if they had radiation before fracture. Data collected were analyzed for signalment, fracture location, staging performed, method of fracture fixation, histopathology, adjunctive treatment and outcome. RESULTS: Signalment and fracture location of 16 dogs that met the inclusion criteria was similar to dogs with appendicular OSA without fracture. One of 14 dogs had pulmonary metastasis and 3 of 5 dogs had bone metastasis. Bone plate or interlocking nail were used for repair in 12 dogs. Limb use immediately after surgery in 13 dogs was good (4), weight-bearing but lame (7) and non-weight bearing (2). Adjunctive therapy was administered in 5 dogs (chemotherapy, 3; radiation, 4; pamidronate, 3). Survival time ranged from 18 to 897 days; median survival was 166 days. CONCLUSIONS: Repair of pathologic fracture can result in palliation and prolonged survival.

Feline ilial fractures: assessment of screw loosening and pelvic canal narrowing after lateral plating.

OBJECTIVE: To report the incidence of (1) screw loosening and (2) severity of pelvic canal narrowing in cats after repair of ilial fractures by a lateral bone plate. STUDY DESIGN: Case series. ANIMALS: Cats (n=21) with ilial fractures. METHODS: Medical records (June 1994 to February 2004) and radiographs were reviewed. Retrieved data were: signalment, fracture description, screw purchase, screw loosening, complications, and clinical outcome. Sacral index (SI) was used to objectively assess degree of pelvic canal narrowing. Long-term follow-up was by owner telephone interview or postal questionnaire. RESULTS: Screw loosening occurred in 13 cats (62%), with a mean loss of total screw purchase of 13% (range, 0-46%). Pelvic canal narrowing (mean decrease, 25%; range, 5-60%) occurred in all cats. Six cats (28%) had severe pelvic canal narrowing (mean, 52%); 5 of these had signs of recurrent constipation within 12 months postoperatively. Mean loss of total screw purchase in cats with severe pelvic narrowing was 28% compared with 9% for all other cats with narrowing. CONCLUSIONS: Lateral plating of ilial fractures in cats is associated with a high incidence of screw loosening. CLINICAL RELEVANCE: Pelvic canal narrowing >45% is associated with a high risk of recurrent constipation.