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Background: Glucagon-like peptide 1 (GLP-1) agonists are increasingly used in diabetics due to their cardiac and renal benefits along with their actions as antihyperglycemics. They also showed inhibitory effects in ovarian, breast, prostate, and pancreatic cancers in preclinical studies. However, to our knowledge, no studies have examined whether GLP-1 agonists have a similar effect in multiple myeloma. Using a population-based study design, we aimed to assess the association of GLP-1 agonist use in the progression of MGUS to MM in patients with diabetes mellitus (DM). Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified via ICD codes and further confirmed by a natural language processing (NLP)-based algorithm. Progression to smoldering MM (sMM) or MM was also confirmed by another NLP-based algorithm. Only patients with DM, IgG, IgA, or light chain MGUS, and black and white patients were included. We excluded patients who experienced progression within 1 year of MGUS diagnosis or within 2 years of DM diagnosis, and patients diagnosed with MGUS before DM diagnosis. We performed 1:2 matching for patients with and without GLP-1 agonist exposure based on their follow-up time. Gray’s test was performed to detect the difference between the two cumulative incidence functions (CIF) for progression stratified by GLP-1 agonist use status. The association between GLP-1 agonist use and progression was estimated by multivariable-adjusted hazard ratio (aHR) using Fine-Gray distribution hazard model with death as a competing event and time-varying GLP-1 agonist use. The covariates included age, BMI, monoclonal protein (M-spike) level (≥1.5g/dL), creatinine (>1.5 mg/dL), glycated hemoglobin (HbA1c; < 7%, 7% - 9%, and > 9%) at MGUS diagnosis, metformin and sodium-glucose co-transporter 2 inhibitor (SLGT2i) use, as well as sex, race, MGUS heavy chain subtype, light-chain MGUS, Charlson Comorbidity Index, and months from diagnoses of DM to MGUS. Results: Our NLP algorithm confirmed 19,551 patients with DM and MGUS. After applying our inclusion and exclusion criteria, we had 14,832 patients, of which 1,303 had GLP-1 agonist use. After matching, our analytic cohort included 1,303 patients with exposure, and 2,606 patients without. There is no evidence to show that CIFs were different between the exposed and unexposed groups. However, the multivariable analysis showed that GLP-1 agonist use was associated with decreased progression to MM: aHR 0.35, 95% confidence interval 0.14-0.90, p = 0.03. Conclusions: For DM patients with MGUS, GLP-1 agonist use is associated with a 65% reduction in risk of progression from MGUS to sMM/MM. Prospective studies examining whether GLP-1 agonists can be used as possible chemoprevention in MGUS patients with DM should be explored. Citation Format: Nikhil Grandhi, Lawrence Liu, Mei Wang, Theodore Thomas, Akhil Kumar, Kristin Vargo, Kristen Sanfilippo, Grahm Colditz, Su-Hsin Chang. Glucagon-like peptide 1 agonist use and the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4358.

Background: Metformin is an oral antihyperglycemic with possible antineoplastic properties based on preclinical and retrospective studies. A retrospective study of Veterans demonstrated a reduction in monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) progression in patients with diabetes mellitus (DM) treated with metformin for ≥4 years. However, it is unclear whether there are racial differences to this effect of metformin. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis and progression, including smoldering MM and MM. Only patients with DM, IgG, IgA, or light chain MGUS, and black and white patients were included in the analyses. We excluded patients who experienced progression within 6 months of MGUS diagnosis, patients who were diagnosed with MGUS before DM diagnosis, and patients who died, progressed to MM, or were lost to follow up within four years of MGUS diagnosis. We defined metformin users as those who had metformin use for ≥4 years after DM diagnosis and before MM development. Cumulative incidence functions (CIF) were stratified by metformin use status. Gray’s test was performed to detect the difference between the two functions. The association between metformin use and progression was estimated by multivariable-adjusted hazard ratio (aHR) using Fine-Gray distribution hazard model with death as a competing event. The covariates included age, BMI, monoclonal protein (M-spike) level (≥1.5g/dL), creatinine, and glycated hemoglobin (HbA1c) at MGUS diagnosis, as well as sex, race, MGUS heavy chain subtype, light-chain MGUS, and Charlson Comorbidity Index. Results: Our NLP algorithm confirmed 19,551 patients with DM and MGUS. After applying our inclusion and exclusion criteria, we had 13,068 (35% black and 65% white) patients of which, 4,268 (26.2% black and 36.2% white) were metformin users. Cumulative incidence function was stratified by metformin use status were statistically significant different (p=0.04) with a lower progression rate for metformin users (see Fig). The multivariable analysis demonstrated a statistically significant reduction in progression with metformin use in the overall cohort (aHR 0.79; 95% CI 0.67-0.95). Further multivariable analyses showed that metformin use was associated with a significant reduction in progression rate in white patients (aHR 0.73; 95% CI 0.58-0.91) but not in black patients (aHR 0.90; 95% CI 0.69-1.17). Conclusions: For patients with DM and MGUS, ≥4 years of metformin use was associated with a reduced risk of progression of MGUS to MM in white patients but not in black patients. Citation Format: Lawrence W. Liu, Nikhil Grandhi, Mei Wang, Theodore Thomas, Akhil Kumar, Kristin Vargo, Kristen M. Sanfilippo, Graham Colditz, Su-Hsin Chang. Racial differences in the association of metformin use with progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1960.

Regenerative medicine interventions are applied to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous/allogenic biologics and it continues to expand. The anti-inflammatory, immunomodulatory, and regenerative properties of bone marrow mesenchymal stem cells (BM-MSCs), and investigation into their therapeutic efficacy and safety in patients with severe chronic low back pain, have not been demonstrated in controlled studies. Multiple pain generators have been hypothesized to be responsible in severe spinal degeneration and it is difficult to identify a single pain generator; consequently, resulting in inadequate therapeutic results.The study was undertaken to evaluate the effectiveness of autologous bone marrow MSCs in the treatment of chronic low back pain due to severe lumbar spinal degeneration with involvement of multiple structures.Prospective, open-label, nonrandomized, parallel-controlled, 2-arm exploratory study.A private, specialized, interventional pain management and regenerative medicine clinic.The treatment group patients received a one-time bone marrow concentrate injection into spinal structures (i.e., discs, facets, spinal nerves, and sacroiliac joints), along with conventional treatment, whereas, the control group received conventional treatment with nonsteroid anti-inflammatory drugs, over-the-counter drugs, structured exercise programs, physical therapy, spinal injections and opioids, etc., as indicated.Outcomes were assessed utilizing multiple instruments, including the Oswestry Disability Index (ODI), Numeric Rating Scale (NRS-11), EuroQOL 5-Dimensional Questionnaire (EQ-5D-3L), Global Mental Health (GMH), and Global Physical Health (GPH). Multiple outcomes were assessed with primary outcomes being minimal clinically important differences (MCID) in ODI scores between the groups and/or a 2-point reduction in pain scores. In the study group, total nucleated cells, colony forming units-fibroblast, CD34-positive cell numbers and platelets were also recorded, along with post-procedure magnetic resonance imaging changes. Outcomes were assessed at 1, 3, 6, and 12 months.Significant improvement was achieved in functional status measured by ODI, pain relief measured by NRS-11, and other parameters measured by EQ-5D-3L, GMH, and GPH, in the study group relative to the control group at all time periods. The results showed significant improvements at 12-month follow-up with 67% of the patients in the study group achieving MCID utilizing ODI when compared to 8% in the control group. Greater than 2-point pain reduction was seen in 74% of the patients at 3 months, 66% of the patients at 6 months, and 56% of the patients at 12 months. Both MCID and pain relief of 2 points were significantly different compared to the control group. Opioid use decreased in the investigational group, whereas, there was a slight increase in the control group. Age, gender, opioid use, and body mass index did not affect the outcomes in the stem cell group.Single center, nonrandomized study.The first available controlled study utilizing BM-MSCs in severe degenerative spinal disease with interventions into multiple structures simultaneously, including disc, facet joints, nerve roots, and sacroiliac joint based on symptomatology, showed promising results.

Background: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy. Methods: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. Results: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1/-2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies. Conclusions: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.

Patients with epithelial ovarian cancers experience the highest fatality rates among all gynecological malignancies which require development of novel treatment strategies. Tumor cell necrosis was previously reported in a number of cancer cell lines following treatment with a p53-derived anti-cancer peptide called PNC-27. This peptide induces necrosis by transmembrane pore formation with HDM-2 protein that is expressed in the cancer cell membrane. We aimed to extend these studies further by investigating expression of membrane HDM-2 protein in ovarian cancer as it relates to susceptibility to PNC-27.Herein, we measured HDM-2 membrane expression in two ovarian cancer cell lines (SKOV-3 and OVCAR-3) and a non-transformed control cell line (HUVEC) by flow cytometric and western blot analysis. Immunofluorescence was used to visualize colocalization of PNC-27 with membrane HDM-2. Treatment effects with PNC-27 and control peptide were assessed using a MTT cell proliferation assay while direct cytotoxicity was measured by lactate dehydrogenase (LDH) release and induction of apoptotic markers; annexin V and caspase-3.HDM-2 protein was highly expressed and frequently detected in the membranes of SKOV-3 and OVCAR-3 cells; a prominent 47.6 kDa HDM-2 plasma membrane isoform was present in both cell lines whereas 25, 29, and 30 kDa isoforms were preferentially expressed in OVCAR-3. Notably, PNC-27 colocalized with HDM-2 in the membranes of both cancer cell lines that resulted in rapid cellular necrosis. In contrast, no PNC-27 colocalization and cytotoxicity was observed with non-transformed HUVEC demonstrating minimal expression of membrane HDM-2.Our results suggest that HDM-2 is highly expressed in the membranes of these ovarian cancer cell lines and colocalizes with PNC-27. We therefore conclude that the association of PNC-27 with preferentially expressed membrane HDM-2 isoforms results in the proposed model for the formation of transmembrane pores and epithelial ovarian cancer tumor cell necrosis, as previously described in a number of solid tissue and hematologic malignancies.

There are vast numbers of evidenced-based clinical trials produced each year, making it increasingly difficult to stay up to date with new treatments and protocols designed to provide the most optimal patient care. A physician's ability to combine existing knowledge with new data is limited by a basic understanding of the background statistics used in these studies. Our goal is to not only define the basic statistics commonly used in clinical trials but to also ensure that practitioners are able to have a working understanding of these statistical measurements to effectively make the most informed and efficacious decisions regarding patient management. On the basis of the recent growth of empirical spine literature, it is becoming more important for spine surgeons to have the basic statistical background necessary to efficiently interpret new data, which may affect clinical decision making regarding patient care.

Purpose Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. Materials and Methods We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. Results A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). Conclusions Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

With the rapid rise of clinical spine surgery literature in the last few decades, there is a greater need for practicing spine surgeons to confidently analyze and critique published literature within the field. The conclusions drawn from published studies are often integrated into a physician's clinical decision-making. A strong knowledge in the fundamental statistical measurements used most frequently in spine surgery literature can enhance the ability to properly interpret the meaning of a study's results. However, medical education often lacks the incorporation of clinically relevant statistical analysis. The purpose of this review is to provide an overview of some of the most commonly used statistical measurements in spine surgery, specifically intraclass correlation coefficient, diagnostic testing analyses, Kaplan-Meier curves, hazard ratios, distribution, and variance.

Cervical spine fractures in athletes can be devastating injuries, and patients with underlying stenosis are at an increased risk of a spinal cord injury. Early recognition and treatment are paramount in these injuries. The number of catastrophic injuries has decreased over the years with better coaching, equipment, and player techniques. These injuries can present with an array of symptoms and radiographic findings, but the key components of stability and decompressed neural elements remain critical in the development of a diagnosis and treatment. Return to play after a cervical spine injury is determined on a player-by-player basis. This decision is dependent upon the nature of the injury, the patient’s underlying spinal anatomy, the patient’s neurological symptoms and examination, and the effects of surgical or nonsurgical treatment on the stability and mobility of the spine.