Total hip arthroplasty in patients with colostomy: impact on inpatient complications, hospital costs, and length of stay.

INTRODUCTION: The presence of permanent end-colostomy is traditionally thought of as a risk factor for complications following orthopedic joint replacement; however, literature supporting this association is scarce. This study aims to discern how length of stay, cost of stay, and inpatient complications following total hip arthroplasty (THA) are impacted by presence of colostomy. METHODS: Data from the National Inpatient Sample was analyzed by International Classification of Diseases, 10th Revision, Clinical Modification regarding THA in patients with and without end-colostomy. Unmatched and matched analyses comparing length of stay, cost of stay, and post-operative adverse outcomes between the two groups were conducted. In the unmatched analysis, 445 THA patients with colostomy were compared to 367,449 THA patients without colostomy. The colostomy patients were then matched for age, sex, race, diabetes, obesity, and the matched groups consisted of 445 patients with and 425 patients without colostomy, respectively. RESULTS: Compared to the THA without colostomy group, the colostomy group was significantly older, had longer hospital stays, and greater cost of stay. When matched for age and comorbidities, length of hospital stay (p < 0.001) and cost of stay (p = 0.002) remained significantly higher. The colostomy group was at significantly increased risk for periprosthetic fracture, dislocation, and infection compared to all THA patients. When matched for age and common comorbidities, the colostomy group had significantly higher risk in only periprosthetic dislocation [p = 0.003, OR 11.8 (1.6-4.6, 95% CI)] and periprosthetic infection [p < 0.05, OR 2.7 (0.97-7.7 95% CI)]. CONCLUSION: Patients with colostomy are at risk of longer hospital courses and greater incurred costs following THA compared to patients without colostomy. They are additionally at significantly increased risk of periprosthetic dislocation and periprosthetic infection, warranting treatment as high-risk patients. STUDY DESIGN: Retrospective cohort study.

Cruciate-Retaining Total Knee Arthroplasty: Current Concepts Review.

Posterior cruciate-retaining (CR) total knee arthroplasty for osteoarthritis of the knee is a popular implant choice. At present, there is no consensus on whether sacrifice or retention of the posterior cruciate ligament (PCL) offers superior outcomes. This review explores the current literature available on CR total knee arthroplasty (TKA). PubMed was searched by keyword to find relevant articles for inclusion. Additional sources came from article references and joint registry reports. CR design knees have distinct kinematic gait patterns from posterior-stabilizing (PS) knees and exhibit paradoxical anterior femoral movement with less femoral rollback. While CR implants offer less flexion than PS designs, the difference is not clinically detectable as clinical scores are similar in the short and long term. CR implants have better long-term survival compared to PS knees, likely due to lower risk of aseptic loosening. CR total knee arthroplasties also have shorter operating times and lower risk of peri-prosthetic fractures. Because the CR implant is unconstrained, there may be an increased risk of instability compared to PS designs, but the literature is mixed. Overall, the current literature supports the continued use of CR TKAs due to their lower risk of complications, durability, and demonstrated equivalence in function to posterior-substituting models.

Femoral neck stress fracture return to activity and the effect of metabolic dysfunction on recovery: A systematic review.

Background: Femoral neck stress fractures are rare fractures traditionally found in athletes and military personnel. There is limited literature on return to activity. Objectives: To report return to activity rates and times, and long-term outcomes for femoral neck stress fractures reported in the literature. To examine the effects of bone metabolic dysfunction and surgical management on return to activity following FNSF. Research design & methods: A systematic literature review of case reports and case series on adults with femoral neck stress fracture that were diagnosed by gross fracture line on X-ray or gold-standard diagnosis with MRI was conducted. Initial search was limited to articles published from January 1997 to Jan 2023 listed in Medline, Embase, and Scopus. Additional articles were manually added via search of retained paper sources. Patient demographics, fracture type, return to activity time, and surgical vs non-surgical treatment modality were collected. In addition, long-term outcomes and metabolic effects, if reported, were abstracted. Results: A total of 40 case reports or case series were retained. 123 stress fractures of the femoral neck from 103 patients were compiled. Of the 103 patients, data on return to activity at least one year following treatment was available for 53 patients. 71% (37/53) of those with long-term follow-up information returned to full pre-injury activity. 24% (13/53) at long-term follow-up had functional recovery but did not return to pre-injury activity due to residual pain. 4% (3/53) had disabling pain. Metabolic workup information was available for 36 patients. Conclusion: Long-term follow-up and return to activity information following FNSF treatment are not commonly reported. Based on the available data, outcomes appear benign with most returning to full activity. There is a clear need for standardization of follow-up periods and hip function measure after FNSF treatment. Additionally, a sizable proportion of FNSF occurred in a new population of low-activity individuals with abnormal bone metabolism, which warrants further exploration.

Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers.

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation.

Aliphatic amines are viable pro-drug moieties in phosphonoamidate drugs.

Phosphate and phosphonates containing a single PN bond are frequently used pro-drug motifs to improve cell permeability of these otherwise anionic moieties. Upon entry into the cell, the PN bond is cleaved by phosphoramidases to release the active agent. Here, we apply a novel mono-amidation strategy to our laboratory's phosphonate-containing glycolysis inhibitor and show that a diverse panel of phosphonoamidates may be rapidly generated for in vitro screening. We show that, in contrast to the canonical l-alanine or benzylamine moieties which have previously been reported as efficacious pro-drug moieties, small and long-chain aliphatic amines demonstrate greater drug release efficacy for our phosphonate inhibitor. These results expand the scope of possible amine pro-drugs that can be used as second pro-drug leave groups for phosphate or phosphonate-containing drugs.

Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase: Proof of Concept Study.

Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.

Why Great Mitotic Inhibitors Make Poor Cancer Drugs.

Chemotherapy is central to oncology, perceived to operate only on prolific cancerous tissue. Yet, many non-neoplastic tissues are more prolific compared with typical tumors. Chemotherapies achieve sufficient therapeutic windows to exert antineoplastic activity because they are prodrugs that are bioactivated in cancer-specific environments. The advent of precision medicine has obscured this concept, favoring the development of high-potency kinase inhibitors. Inhibitors of essential mitotic kinases exemplify this paradigm shift, but intolerable on-target toxicities in more prolific normal tissues have led to repeated failures in the clinic. Proliferation rates alone cannot be used to achieve cancer specificity. Here, we discuss integrating the cancer specificity of prodrugs from classical chemotherapeutics and the potency of mitotic kinase inhibitors to generate a class of high-precision cancer therapeutics.

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model.

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.

Novel MDM2 inhibitor SAR405838 (MI-773) induces p53-mediated apoptosis in neuroblastoma.

Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common childhood extracranial malignant tumor. In NB, somatic mutations of the tumor suppressor, p53, are exceedingly rare. Unlike in adult tumors, the majority of p53 downstream functions are still intact in NB cells with wild-type p53. Thus, restoring p53 function by blocking its interaction with p53 suppressors such as MDM2 is a viable therapeutic strategy for NB treatment. Herein, we show that MDM2 inhibitor SAR405838 is a potent therapeutic drug for NB. SAR405838 caused significantly decreased cell viability of p53 wild-type NB cells and induced p53-mediated apoptosis, as well as augmenting the cytotoxic effects of doxorubicin (Dox). In an in vivo orthotopic NB mouse model, SAR405838 induced apoptosis in NB tumor cells. In summary, our data strongly suggest that MDM2-specific inhibitors like SAR405838 may serve not only as a stand-alone therapy, but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact MDM2-p53 axis.

Pulmonary thromboendarterectomy in a patient with giant cell arteritis.

This report describes the case of a young woman presenting with signs and symptoms of chronic thromboembolic pulmonary hypertension who underwent pulmonary thromboendarterectomy (PTE) with concomitant coronary artery bypass. She died in the intensive care unit 1 day postoperatively. At autopsy the patient was found to have giant cell arteritis of the pulmonary arteries and ascending aorta. It is important to differentiate this disease from chronic thromboembolic pulmonary hypertension because its management and that of systemic vasculitis differs considerably.