Incidence and risk factors for bone metastases at presentation in solid tumors.

Introduction: Bone metastases are associated with increased morbidity and decreased quality of life in patients with solid tumors. Identifying patients at increased risk of bone metastases at diagnosis could lead to earlier interventions. We sought to retrospectively identify the incidence and predictive factors for bone metastases at initial diagnosis in a large population-based dataset. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients 18 years-old or older diagnosed with solid cancers from 2010 to 2019. Patients with hematologic malignancies and primary tumors of the bone were excluded. We calculated the incidence and predictive factors for bone metastases according to demographic and tumor characteristics. Results: Among 1,132,154 patients identified, 1,075,070 (95.0%) had known bone metastasis status and were eligible for the study. Bone metastases were detected in 55,903 patients (5.2% of those with known bone metastases status). Among patients with bone metastases, the most common primary tumors arose from lung (44.4%), prostate (19.3%), breast (12.3%), kidney (4.0%), and colon (2.2%). Bone metastases at presentation were most common in small cell lung cancer (25.2%), non-small cell lung cancer (18.0%), and esophageal adenocarcinoma (9.4%). In addition to stage classification, predictors for bone metastases included Gleason score (OR 95.7 (95% CI 73.1 - 125.4) for Grade Group 5 vs 1 and OR 42.6 (95% CI 32.3 - 55.9) for Group 4 vs 1) and PSA (OR 14.2 (95% CI 12.6 - 16.0) for PSA > 97 vs 0 - 9.9) for prostate cancer, HER2 and hormonal receptor (HR) status (OR 2.2 (95% CI 1.9 - 2.6) for HR+/HER2+ vs HR-/HER2-) for breast cancer, histology (OR 2.5 (95% CI 2.3 - 2.6) for adenocarcinoma vs squamous) for lung cancer, and rectal primary (OR 1.2 (95% 1.1 - 1.4) vs colon primary) and liver metastases (OR 8.6 (95% CI 7.3 - 10.0) vs no liver metastases) for colorectal tumors. Conclusions: Bone metastases at presentation are commonly seen in solid tumors, particularly lung, prostate, breast, and kidney cancers. Clinical and pathologic factors are associated with a significantly increased risk for bone metastases.

The Association of Agent Orange Exposure with the progression of monoclonal gammopathy of undetermined significance to multiple myeloma: a population-based study of Vietnam War Era Veterans.

Herbicide and pesticide exposure [e.g., agent orange (AO)] is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, it is unclear whether TCDD/AO exposure (AO exposure hereafter) increases the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. We sought to evaluate the association in a nationwide study of US Veterans. A natural language processing algorithm was used to confirm MGUS and progression to MM. We included Veterans who were diagnosed with MGUS from 10/1/1999 to 12/31/2021 and served during the Vietnam War Era from 1/9/1962 to 5/7/1975. AO exposure was stratified according to three TCDD exposure levels: high (1/9/1962-11/30/1965), medium (12/1/1965-12/31/1970), or low (1/1/1971-5/7/1975). The association between AO exposure and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. The analytic cohort included 10,847 Veterans with MGUS, of whom 26.3% had AO exposure and 7.4% progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, high exposure was associated with an increased progression rate (multivariable-adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. This information is critical to inform progression risk in patients diagnosed with MGUS and prior AO exposure. It is also applicable to MGUS patients with occupational TCDD exposure from herbicides and pesticides.

Evolving Barriers to Clinical Trial Enrollment and Clinical Care in Neuro-oncology in the Face of COVID-19.

The lack of treatments with durable response in neuro-oncology highlights the critical need for clinical trials to advance patient care. The intersection of relatively low incidence, evolving classification schema, and entrenched community, healthcare provider, and organizational factors have been historic challenges against successful trial enrollment and implementation. The additional need for multidisciplinary, often tertiary-level care, further magnifies latent national and international health inequities with rural and under-served populations. The COVID-19 pandemic both unveiled fundamental weaknesses in historical approaches and prompted the necessity of new approaches and systems for conducting clinical trials. Here, we provide an overview of traditional barriers to clinical trial enrollment in neuro-oncology, the effect of COVID-19 on these barriers, and the discovery of additional systemic weaknesses. Finally, we discuss future directions by reflecting on lessons learned with strategies to broaden access of care and streamline clinical trial integration into clinical practice.

The Association of Agent Orange (AO) Exposure with Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma (MM) Progression: A Population-based Study of Vietnam War Era Veterans.

Background: Herbicide and pesticide exposure (e.g., agent orange [AO]) is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Monoclonal gammopathy of undetermined significance (MGUS) is the precursor state to MM; however, not all patients with MGUS progress to MM. It is unclear whether AO exposure increases the risk of progression of MGUS to MM. Purpose: We aimed to determine the association between AO exposure and progression to MM in a nation-wide study of U.S. Veterans with MGUS. Patients and Methods: This is a population-based cohort study of Vietnam Era Veterans diagnosed with MGUS. A natural language processing (NLP) algorithm was used to confirm MGUS and progression to MM. The association between AO and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. Veterans who served during the Vietnam War Era from 1/9/1962-5/7/1975 and were diagnosed with MGUS between 10/1/1999-12/31/2021 were included. We excluded patients with missing BMI values, progression within 1 year after MGUS diagnosis date, non-IgG or IgA MGUS, or birth years outside of the range of the AO exposed group, and race other than Black and White. AO exposure and service during 1/9/1962-;5/7/1975 and stratified according to TCDD exposure levels by three time periods: 1/9/1962-11/30/1965 (high), 12/1/1965-12/31/1970 (medium), or 1/1/1971-5/7/1975 (low). The association between AO and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. Results: We identified 10,847 Veterans with MGUS, of whom 7,996 had AO exposure. Overall, 7.4% of MGUS patients progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, AO exposure from 1/9/1962-11/30/1965, high TCDD exposure, was associated with an increased risk of progression (adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. Conclusions: In patients with MGUS, the high Agent Orange exposure time period is associated with a 48% increased risk of progression to multiple myeloma. This suggests that patients with MGUS and prior Agent Orange exposure or occupational exposure to TCDD (eg. Agricultural workers) may require thorough screening for plasma cell dyscrasias.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas.

BACKGROUND: With advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC. METHODS AND MATERIALS: Patients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration. RESULTS: One hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0-1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups. CONCLUSIONS: Higher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

The Impact of TSC-1 and -2 Mutations on Response to Therapy in Malignant PEComa: A Multicenter Retrospective Analysis.

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.

Evaluation of the Effectiveness of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Chronic Low Back Pain Due to Severe Lumbar Spinal Degeneration: A 12-Month, Open-Label, Prospective Controlled Trial.

BACKGROUND: 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. OBJECTIVES: 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. STUDY DESIGN: Prospective, open-label, nonrandomized, parallel-controlled, 2-arm exploratory study. SETTING: A private, specialized, interventional pain management and regenerative medicine clinic. METHODS: 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 ASSESSMENT: 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. RESULTS: 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. LIMITATIONS: Single center, nonrandomized study. CONCLUSIONS: 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.

Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus.

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.

Anti-Cancer Tumor Cell Necrosis of Epithelial Ovarian Cancer Cell Lines Depends on High Expression of HDM-2 Protein in Their Membranes.

OBJECTIVE: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: 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.

Cost-effectiveness Applications of Patient-reported Outcome Measures (PROMs) in Spine Surgery.

Because of the rising health care costs in the United States, there has been a focus on value-based care and improving the cost-effectiveness of surgical procedures. Patient-reported outcome measures (PROMs) can not only give physicians and health care providers immediate feedback on the well-being of the patients but also be used to assess health and determine outcomes for surgical research purposes. Recently, PROMs have become a prominent tool to assess the cost-effectiveness of spine surgery by calculating the improvement in quality-adjusted life years (QALY). The cost of a procedure per QALY gained is an essential metric to determine cost-effectiveness in universal health care systems. Common patient-reported outcome questionnaires to calculate QALY include the EuroQol-5 dimensions, the SF-36, and the SF-12. On the basis of the health-related quality of life outcomes, the cost-effectiveness of various spine surgeries can be determined, such as cervical fusions, lumbar fusions, microdiscectomies. As the United States attempts to reduce costs and emphasize value-based care, PROMs may serve a critical role in spine surgery moving forward. In addition, PROM-driven QALYs may be used to analyze novel spine surgical techniques for value-based improvements.

Statistics for the Practicing Spine Surgeon: Fundamental Measurements.

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.

Statistics for the Practicing Spine Surgeon: Supplementary Data Analysis Measurements.

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.

Pancreaticoduodenectomy outcomes for locally advanced right colon cancers: A systematic review.

BACKGROUND: Pancreaticoduodenectomy (PD) with right hemicolectomy (RH) to treat locally advanced right colon cancer (LARCC) has been rarely reported in the literature. Herein, we characterize clinicopathologic factors and evaluate outcomes of en bloc PD and RH for LARCC. METHODS: A systematic review of the literature was conducted on PubMed using MeSH terms ("pancreaticoduodenectomy" or "pancreas/surgery" or "duodenum/surgery" or "colectomy") and ("colonic neoplasms"). Data was extracted from patients who underwent en bloc PD and RH for LARCC. Factors investigated included patient demographics, surgical and pathologic parameters, postoperative complications, disease recurrence, and survival. RESULTS: Our search yielded 27 articles (106 patients), including 1 case from our institution. Most patients were male (62.1%), median age 58 years (range 34-83). Surgical procedures performed included en bloc RH with PD (n = 91, 85.8%) and en bloc RH with pylorus-preserving PD (n = 15, 14.2%). Among reported, 95.5% of patients (n = 63), underwent R0 resection. One or more complications were reported in 33 patients (52.4%). Median survival was 168 months. Survival after resection was 75.9% at 2 years and 66.3% at 5 years. Overall survival was greater in patients with no lymph node involvement (IIC versus IIIC, hazard ratio 8.4, P = .003). Five-year survival for patients was 84.9% in patients with stage IIC versus 46.4% in patients with stage IIIC. There were 3 postoperative mortalities. CONCLUSION: This data demonstrates that en bloc PD and RH is rarely performed yet can be a potentially safe treatment option in patients with LARCC. Lymph node involvement was the only independent prognostic factor.