Clinical markers of immunotherapy outcomes in advanced sarcoma.

BACKGROUND: Despite immunotherapy's promise in oncology, its use for sarcoma remains challenging. There are no sarcoma-specific biomarkers for immune checkpoint inhibitors (ICI). Previously, we reported our institutional experience highlighting ICI activity in 29 patients with sarcoma. In this study, we explore responses to ICI based on ICI regimen and other covariates to identify significant clinical factors in advanced sarcoma outcomes. METHODS: Patients in The Ohio State University Sarcoma Clinics were enrolled in the Sarcoma Retrospective ICI database from January 1, 2015 through November 1, 2021. Data included treatment regimen (single-agent ICI or ICI + combination) along with clinical covariates. ICI + combination was further categorized into ICI + medication, ICI + radiation, ICI + surgery, or ICI + multiple (more than 2 modalities). Statistical analysis included log-rank tests and proportional hazard regression. The primary objective was to evaluate overall survival (OS) and progression-free survival (PFS). RESULTS: Of the patients in the database, 135 met inclusion criteria. We demonstrated improved OS in patients treated with ICI + combination (p = 0.014, median 64 weeks), but no effect on PFS (p = 0.471, median 31 weeks). Patients with a documented immune-related adverse event (irAE) of dermatitis had improved OS, but only in the ICI + combination cohort (p = 0.021). Patients who received single-agent ICI and whose change in the neutrophil-to-lymphocyte ratio (NLR) was less than 5 had an improved OS (p = 0.002); this was not seen in patients who received ICI + combination therapy (p = 0.441). There were no differences in OS based on age, gender, histology, or subcategories of ICI + combination. This was not the case for PFS; patients who received any ICI regimen and were younger than 70 had a worse PFS (p = 0.036) compared with their older counterparts in this dataset. Patients who developed an irAE, specifically colitis (p = 0.009), hepatitis (p = 0.048), or dermatitis (p = 0.003), had an improved PFS. There were no differences in PFS based on ICI regimen (or subcategories of ICI + combination), gender, histology, change in NLR, or grade of irAE. CONCLUSIONS: This retrospective study demonstrates that ICI + combination therapy can improve OS in some patients with advanced sarcoma. This is consistent with our prior results of ICI in sarcoma.

Activity of PD1 inhibitor therapy in advanced sarcoma: a single-center retrospective analysis.

BACKGROUND: Sarcomas constitute a heterogeneous group of tumors with different clinical behaviors and variable responses to systemic therapies. Recent immunotherapy studies with PD1 inhibitors (PD1i) show promising results with use in certain soft-tissue sarcomas; however, the clinical and molecular features that best predict response to PD1i remain unclear. METHODS: Demographic, imaging, histologic, and genetic sequencing data was collected for sarcoma patients who received nivolumab or pembrolizumab (PD1i) treatment at our institution between January 1st 2015 and April 23rd 2018. The primary objective was to determine progression-free survival (PFS) in patients with advanced sarcomas receiving PD1i. Secondary objectives included determining overall survival (OS) and assessment of characteristics associated with response to PD1i. Fifty-six patients who were treated with PD1i therapy met inclusion criteria for this study. RESULTS: Partial response towards PD1i treatment was seen in 3 in 26 evaluable patients, but no complete responses were observed (overall response rate 11.5%). Within this group of patients, the 90 day PFS was found to be 48.8%. In patients in whom PD1 expression was known, there was a statistically significant positive correlation between expression of PD1 and longer PFS and OS rates. Patients that were treated with more than four cycles of PD1i therapy were also more likely to have a greater OS. CONCLUSIONS: This study suggests activity of PD1i in a pretreated cohort of advanced sarcoma patients, particularly for the subset of patients with PD1 positive tumors. Our results highlight the importance of further research to better target the optimal patient population and markers of response.

Patient-Derived Conditionally Reprogrammed Cells in Prostate Cancer Research.

Prostate cancer (PCa) remains a leading cause of mortality among American men, with metastatic and recurrent disease posing significant therapeutic challenges due to a limited comprehension of the underlying biological processes governing disease initiation, dormancy, and progression. The conventional use of PCa cell lines has proven inadequate in elucidating the intricate molecular mechanisms driving PCa carcinogenesis, hindering the development of effective treatments. To address this gap, patient-derived primary cell cultures have been developed and play a pivotal role in unraveling the pathophysiological intricacies unique to PCa in each individual, offering valuable insights for translational research. This review explores the applications of the conditional reprogramming (CR) cell culture approach, showcasing its capability to rapidly and effectively cultivate patient-derived normal and tumor cells. The CR strategy facilitates the acquisition of stem cell properties by primary cells, precisely recapitulating the human pathophysiology of PCa. This nuanced understanding enables the identification of novel therapeutics. Specifically, our discussion encompasses the utility of CR cells in elucidating PCa initiation and progression, unraveling the molecular pathogenesis of metastatic PCa, addressing health disparities, and advancing personalized medicine. Coupled with the tumor organoid approach and patient-derived xenografts (PDXs), CR cells present a promising avenue for comprehending cancer biology, exploring new treatment modalities, and advancing precision medicine in the context of PCa. These approaches have been used for two NCI initiatives (PDMR: patient-derived model repositories; HCMI: human cancer models initiatives).

Prospective Evaluation of the Concordance of Commercial Circulating Tumor DNA Alterations with Tumor-Based Sequencing across Multiple Soft Tissue Sarcoma Subtypes.

Soft tissue sarcomas (STS) are diverse tumors with heterogenous alterations. Platforms to detect circulating tumor DNA (ctDNA) have rapidly increased in popularity as they may avoid invasive biopsy morbidity. However, ctDNA profiling concordance with standard solid tumor comprehensive genomic profiling (CGP) is poorly characterized. Here, we report the outcomes of a single-institution experience comparing mutational results from commercial ctDNA and solid tumor CGP in advanced STS subjects. We identified STS subjects who had undergone solid tumor based CGP in four distinct cohorts: Dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), and gastrointestinal stromal tumor (GIST). Subjects with radiographically measurable tumor were profiled using a commercial ctDNA CGP panel. Overlapping genes/exons on both biopsy panels were analyzed. Twenty-four subjects completed both ctDNA and solid tumor CGP. ctDNA was detected in 18/24 subjects. Subject level concordance rates in all overlapping genes were: LMS = 4/6; UPS = 2/6; DDLPS = 1/6; GIST = 0/6. Copy number alterations were notably poorly concordant. For subjects with short variant alterations and detectable tumor fractions, concordance with solid tumor CGP was 76% (13/17). LMS subjects had the highest median tumor fraction and concordance. No correlation was seen between tumor fraction or radiographic tumor volume largely driven by low estimated tumor fraction. A limitation of the study is that only targeted sequencing was performed. However, given the poor concordance in commonly altered genes, ctDNA panels in sarcoma cannot be broadly applied. Further, more extensive studies will need to be performed.

Smoking is Associated With 1-year Suboptimal Patient-reported Outcomes After 2-level Anterior Cervical Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To study the impact of smoking on patient-reported outcomes after primary 2-level anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Previous studies have found suboptimal outcomes after multilevel ACDF in smoking patients. There is contrasting evidence on the negative effects of smoking in single-level ACDF, while there are no specific reports in 2-level ACDF. Adding knowledge of smoking's impact on patient-reported outcomes (PRO) will help in tailored patient counseling and preoperative education. METHODS: Patients 18 years of age or older at a single academic institution who underwent 2-level ACDF to treat cervical radiculopathy and/or myelopathy between September 2013 and September 2015 were included. PRO was studied using the neck disability index (NDI) preoperatively, and at 3, 6, 12 months. χ test for qualitative variables, and one-way analysis of variance (ANOVA) and unpaired t test for quantitative variables were used for statistical analysis. RESULTS: A total of 61 patients, of which 23 (37.7%) were classified as smokers were included. Demographic and clinical profile of patients was similar both groups. Preoperatively, smokers had a mean NDI of 62.8±12.7 with a 17.5%, 18.7%, and 27.7% decrease at 3, 6, and 12-months, respectively. Nonsmokers had a mean preoperative NDI of 45.9±15.3, with a 36.4%, 61.2% and 65.4% decrease at 3, 6, and 12-months, respectively. Despite higher baseline NDI in smokers, improvement in NDI reached significance at 3-months in nonsmokers. In smokers, the improvement in NDI was slower and reached significance at 12-months. The radiographic fusion status at latest follow-up was similar in smokers and nonsmokers (P=0.67). CONCLUSIONS: Smokers had lower improvements in NDI scores compared to nonsmokers after a 2-level ACDF. Preoperative counseling before 2-level ACDF should include education about risks of inferior clinical outcomes in smokers independent of fusion status.

Posterior rectus sheath hernia causing intermittent small bowel obstruction.

A posterior rectus sheath hernia is an abdominal wall hernia that is rarely encountered. Owing to its rarity, it can be easily overlooked in the setting of a patient presenting with abdominal pain. We report a case of a posterior rectus sheath hernia that caused intermittent small bowel obstruction. The unusual aspects of this case are that the defect was large, measuring 6 cm in the transverse diameter, and that it contained small bowel within a large portion of the rectus sheath. Because the defect was large and affected nearly the entire posterior rectus sheath, it was difficult to discern on computed tomography until a small bowel obstruction developed. In this case, a limited awareness of this clinical entity contributed to the delay in diagnosis.