TURALIO® Risk Evaluation and Mitigation Strategy Program (tREMS): 3-year retrospective hepatic safety assessment.

Aim: Hepatic safety data assessment from the TURALIO® (pexidartinib) Risk Evaluation and Mitigation Strategy (tREMS) Program. Methods: Retrospective 3-year assessment (August 2019 to June 2022) of hepatic events from the TURALIO® (pexidartinib) Risk Evaluation and Mitigation Strategy Program. Results: A total of 451 patients, 369 prescribers, 2 wholesalers/distributors and 2 pharmacies were enrolled and certified. Twenty-one (4.7%) patients met the criteria for a hepatic adverse event or laboratory abnormality suggestive of serious and potentially fatal liver injury, all with onset within 2 months of therapy. No new hepatic safety signals were identified. Conclusion: Results are consistent with the phase 3 ENLIVEN trial data. Liver enzyme monitoring, combined with early intervention, including dose modification and discontinuation, conducted in patients treated with pexidartinib mitigate the risk of potential hepatotoxicity.

Safety findings from the 3-year data collected in the TURALIO^® Risk Evaluation and Mitigation Strategy ProgramPexidartinib (TURALIO^®) is an oral drug that is used to treat adults with tenosynovial giant cell tumor (TGCT) that cannot be fixed with surgery. TGCTs are rare, noncancerous tumors that cause pain, stiffness and difficulty moving. Pexidartinib works by blocking a protein that helps these tumors grow. Before pexidartinib, there were no good treatments for TGCT and surgery often could not remove all the tumors, so they would frequently grow back.Pexidartinib was approved in 2019 after a clinical trial showed it worked well in adults with TGCT. However, pexidartinib can sometimes cause serious liver harm for some patients. To handle this risk, a program called the tREMS (TURALIO^® Risk Evaluation and Mitigation Strategy) was established to ensure that pexidartinib is used safely.The tREMS Program teaches doctors, pharmacists and patients about the safe use of pexidartinib and potential liver risks and enrolls patients in a registry to watch their health. Doctors and pharmacies must be certified, and patients need regular liver tests. In the first 3 years, 451 patients and 369 doctors joined the program. Unintended liver issues were found in around 5% of patients, a rate that is about the same as that seen in pexidartinib clinical trials, and no new safety concerns were found. About half of patients with liver issues could reverse them by stopping pexidartinib. No patient had permanent liver damage, needed a transplant or died from liver problems. These results show that the tREMS Program is working well to keep patients with TGCT safe while taking pexidartinib.

Real-world drug utilization and treatment patterns in patients with tenosynovial giant cell tumors in the USA.

Aim: Real-world treatment patterns in tenosynovial giant cell tumor (TGCT) patients remain unknown. Pexidartinib is the only US FDA-approved treatment for TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Objective: To characterize drug utilization and treatment patterns in TGCT patients. Methods: In a retrospective observational study using IQVIA's linked prescription and medical claims databases (2018-2021), TGCT patients were stratified by their earliest systemic therapy claim (pexidartinib [N = 82] or non-FDA-approved systemic therapy [N = 263]). Results: TGCT patients treated with pexidartinib versus non-FDA-approved systemic therapies were predominantly female (61 vs 50.6%) and their median age was 47 and 54 years, respectively. Pexidartinib-treated patients had the highest 12-month probability of remaining on treatment (54%); 34.1% of pexidartinib users had dose reduction after their first claim. Conclusion: This study provides new insights into the unmet need, utilization and treatment patterns of systemic therapies for the treatment of TGCT patients.

Treatment patterns in patients with tenosynovial giant cell tumors in the USAThis database study is the first investigation of how drugs are used to treat patients with tenosynovial giant cell tumor (TGCT) in the real world. We researched adult TGCT patients from IQVIA's prescription and medical claims databases who started treatment with pexidartinib (N = 82) or other non-US FDA-approved systemic therapies (N = 263). The patients included in this analysis were mostly women (61.0 and 50.6%) and their median age was 47 and 54 years for pexidartinib and other non-FDA-approved systemic therapies, respectively. The patients treated with pexidartinib were most likely to remain on treatment (54.0%) at the end of the first year. Most patients (79.3%) started pexidartinib treatment at a total daily dose of 800 mg/day, as per the product label. Only 34.1% of patients had reduced medication dose during follow-up. Of note, this study found that TGCT patients were treated with other systemic therapies which remain unproven to be safe and effective in medical studies of TGCT. Given the unmet need, and with pexidartinib being the only approved systemic treatment in USA, there is an opportunity for the larger population of adult TGCT patients to benefit from its use. Further research is needed to identify barriers for access to pexidartinib and treatment of TGCT patients.

Tenosynovial Giant Cell Tumor Observational Platform Project (TOPP) Registry: A 2-Year Analysis of Patient-Reported Outcomes and Treatment Strategies.

BACKGROUND: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies. MATERIAL AND METHODS: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment). RESULTS: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy. CONCLUSION: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088).

Breaking the Mold: Epigenetics and Genomics Approaches Addressing Novel Treatments and Chemoresponse in TGCT Patients.

Testicular germ-cell tumors (TGCT) have been widely recognized for their outstanding survival rates, commonly attributed to their high sensitivity to cisplatin-based therapies. Despite this, a subset of patients develops cisplatin resistance, for whom additional therapeutic options are unsuccessful, and ~20% of them will die from disease progression at an early age. Several efforts have been made trying to find the molecular bases of cisplatin resistance. However, this phenomenon is still not fully understood, which has limited the development of efficient biomarkers and precision medicine approaches as an alternative that could improve the clinical outcomes of these patients. With the aim of providing an integrative landscape, we review the most recent genomic and epigenomic features attributed to chemoresponse in TGCT patients, highlighting how we can seek to combat cisplatin resistance through the same mechanisms by which TGCTs are particularly hypersensitive to therapy. In this regard, we explore ongoing treatment directions for resistant TGCT and novel targets to guide future clinical trials. Through our exploration of recent findings, we conclude that epidrugs are promising treatments that could help to restore cisplatin sensitivity in resistant tumors, shedding light on potential avenues for better prognosis for the benefit of the patients.

Role of colony-stimulating factor 1 in the neoplastic process of tenosynovial giant cell tumor.

Tenosynovial giant cell tumors (TGCTs) are rare, locally aggressive, mesenchymal neoplasms, most often arising from the synovium of joints, bursae, or tendon sheaths. Surgical resection is the first-line treatment, but recurrence is common, with resulting impairments in patients' mobility and quality of life. Developing and optimizing the role of systemic pharmacologic therapies in TGCT management requires an understanding of the underlying disease mechanisms. The colony-stimulating factor 1 receptor (CSF1R) has emerged as having an important role in the neoplastic processes underlying TGCT. Lesions appear to contain CSF1-expressing neoplastic cells derived from the synovial lining surrounded by non-neoplastic macrophages that express the CSF1R, with lesion growth stimulated by both autocrine effects causing proliferation of the neoplastic cells themselves and by paracrine effects resulting in recruitment of CSF1 R-bearing macrophages. Other signaling pathways with evidence for involvement in TGCT pathogenesis include programmed death ligand-1, matrix metalloproteinases, and the Casitas B-cell lymphoma family of ubiquitin ligases. While growing understanding of the pathways leading to TGCT has resulted in the development of both regulatory approved and investigational therapies, more detail on underlying disease mechanisms still needs to be elucidated in order to improve the choice of individualized therapies and to enhance treatment outcomes.

A prospective real-world study of the diffuse-type tenosynovial giant cell tumor patient journey: A 2-year observational analysis.

BACKGROUND AND OBJECTIVES: Diffuse-tenosynovial giant cell tumor (D-TGCT) is a rare, locally aggressive, typically benign neoplasm affecting mainly large joints, representing a wide clinical spectrum. We provide a picture of the treatment journey of D-TGCT patients as a 2-year observational follow-up. METHODS: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study at tertiary sarcoma centers spanning seven European countries and two US sites. Histologically confirmed D-TGCT patients were categorized as either those who remained on initial treatment strategy (determined at baseline visit) or those who changed treatment strategy with specific changes documented (e.g., systemic treatment to surgery) at the 1-year and/or 2-year follow-up visits. RESULTS: A total of 176 patients were assessed, mean diagnosis age was 38.4 (SD ± 14.6) years; most patients had a knee tumor (120/176, 68.2%). For the 2-year observation period, most patients (75.5%) remained on the baseline treatment strategy throughout, 54/79 patients (68.4%) remained no treatment, 30/45 patients (66.7%) remained systemic treatment, 39/39 patients (100%) remained surgery. Those who changed treatment strategy utilized multimodal treatment options. CONCLUSIONS: This is the first prospectively collected analysis to describe D-TGCT patient treatments over an extended follow-up and demonstrates the need for multidisciplinary teams to determine an optimal treatment strategy.

Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT).

Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.

Long-term outcomes of pexidartinib in tenosynovial giant cell tumors.

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. RESULTS: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). CONCLUSIONS: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

SPOP suppresses testicular germ cell tumors progression through ubiquitination and degradation of DPPA2.

Dysregulation of the ubiquitin-proteasome pathway is strongly associated with cancer initiation and progression. Speckle-type POZ(pox virus and zinc finger protein) protein(SPOP) is an adapter protein of CUL3-based E3 ubiquitin ligase complexes. Gene expression profiling from the Cancer Genome Atlas (TCGA) suggests that SPOP is downregulated in testicular germ cell tumors (TGCTs), but the specific contribution of this protein remains to be explored. In this study, we show that the germ line-specific factor DPPA2 was identified as a proteolytic substrate for the SPOP-CUL3-RBX1 E3 ubiquitin-ligase complex. SPOP specifically binds to a SPOP-binding consensus (SBC) degron located in DPPA2 and targets DPPA2 for degradation via the ubiquitin-proteasome pathway. SPOP downregulation increases the expression of pluripotency markers OCT4 and Nanog but decreases that of early differentiation marker gene Fst. This effect is partly dependent on its activity toward DPPA2. In addition, the dysregulation of SPOP-DPPA2 axis contributes to the malignant transformation phenotypes of TGCT cells.

Distinct telomere length and molecular signatures in seminoma and non-seminoma of testicular germ cell tumor.

Testicular germ cell tumors (TGCTs) are classified into two main subtypes, seminoma (SE) and non-seminoma (NSE), but their molecular distinctions remain largely unexplored. Here, we used expression data for mRNAs and microRNAs (miRNAs) from The Cancer Genome Atlas (TCGA) to perform a systematic investigation to explain the different telomere length (TL) features between NSE (n = 48) and SE (n = 55). We found that TL elongation was dominant in NSE, whereas TL shortening prevailed in SE. We further showed that both mRNA and miRNA expression profiles could clearly distinguish these two subtypes. Notably, four telomere-related genes (TelGenes) showed significantly higher expression and positively correlated with telomere elongation in NSE than SE: three telomerase activity-related genes (TERT, WRAP53 and MYC) and an independent telomerase activity gene (ZSCAN4). We also found that the expression of genes encoding Yamanaka factors was positively correlated with telomere lengthening in NSE. Among them, SOX2 and MYC were highly expressed in NSE versus SE, while POU5F1 and KLF4 had the opposite patterns. These results suggested that enhanced expression of both TelGenes (TERT, WRAP53, MYC and ZSCAN4) and Yamanaka factors might induce telomere elongation in NSE. Conversely, the relative lack of telomerase activation and low expression of independent telomerase activity pathway during cell division may be contributed to telomere shortening in SE. Taken together, our results revealed the potential molecular profiles and regulatory roles involving the TL difference between NSE and SE, and provided a better molecular understanding of this complex disease.

Management of Pigmented Villonodular Synovitis (PVNS): an Orthopedic Surgeon's Perspective.

PURPOSE OF REVIEW: Pigmented villonodular synovitis (PVNS) or tenosynovial giant cell tumor (TGCT) encompasses a wide spectrum of disease and is divided into localized and diffuse variants. Surgical resection remains the principal treatment for nearly all localized type disease and most diffuse type. Recent mechanistic understanding of the disease led to drug discovery that has opened new avenues for patients with recalcitrant disease. In this manuscript, we review the current treatment options for TGCT, presenting outcomes from traditional surgical approaches as well as those from nonsurgical approaches. RECENT FINDINGS: Arthroscopic and/or open surgery remains the mainstay of treatment for TGCT for the vast majority of patients. While radiosynoviorthesis and external beam radiation have been used for recalcitrant disease, recent understanding of the colony stimulating factor 1 receptor (CSF1R) pathway and its paracrine and autocrine role in TGCT has led to the development of targeted inhibitors. Their optimal role and efficacy are unclear due to limited number of high-quality studies and contradictory results; however, recent and ongoing studies suggest there may be a role for their use, especially in diffuse and/or refractory disease. Surgery remains the most common treatment for TGCT, however, there may be an increasing role for adjuvant therapies, including the new targeted agents. Weighing the side effects of these treatments against the symptomatic benefit on a patient-by-patient basis in this benign disease remains critical.

Pexidartinib: first approved systemic therapy for patients with tenosynovial giant cell tumor.

Pexidartinib is an orally administered small molecule tyrosine kinase inhibitor. Phase III ENLIVEN study results provided clinical evidence for US FDA approval for treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Recommended dosage is 400 mg orally twice daily on an empty stomach. Long-term follow-up in pooled analyses showed increased response rates compared with those observed in ENLIVEN. Patients on pexidartinib also experience meaningful improvements in range of motion. Side effects associated with pexidartinib are generally manageable; however, there is a risk of potentially life-threatening mixed or cholestatic hepatotoxicity and pexidartinib has a Risk Evaluation and Mitigation Strategy (REMS) program to ensure appropriate monitoring.

Maternal use of personal care products during pregnancy and risk of testicular germ cell tumors in sons.

BACKGROUND: The etiology of testicular germ cell tumors (TGCT) is poorly understood, however, exposure to endocrine disrupting chemicals (EDCs) may be related to increased risk. Personal care products, some of which contain EDCs, are widely used on a daily basis and are known to cross the placenta, be present in breastmilk, and are capable of inducing reproductive tract abnormalities. To determine the association between personal care product use during pregnancy and breastfeeding and TGCT risk, an analysis among mothers of TGCT cases and controls was conducted. METHODS: The US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study enrolled TGCT cases and controls and their mothers between 2002 and 2005. The current analysis examined personal care product use during pregnancy among 527 mothers of TGCT cases and 562 mothers of controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for identified covariates. RESULTS: Maternal use of face lotion more than one time per week was associated with a significantly increased risk of TGCT (OR: 1.42, 95% CI: 1.08-1.86, p-trend: 0.01). None of the other products examined (perfume, hairspray, nail polish, hair dye, permanent wave, body lotion, deodorant, sunscreen) were associated with TGCT risk. CONCLUSIONS: Frequent exposure to face lotion during pregnancy and while breastfeeding may be associated with increased TGCT risk. Further investigation into the endocrine disrupting effects of personal care products is warranted.

Future of testicular germ cell tumor incidence in the United States: Forecast through 2026.

BACKGROUND: Testicular germ cell tumors (TGCTs) are rare tumors in the general population but are the most commonly occurring malignancy among males between ages 15 and 44 years in the United States (US). Although non-Hispanic whites (NHWs) have the highest incidence in the US, rates among Hispanics have increased the most in recent years. To forecast what these incidence rates may be in the future, an analysis of TGCT incidence in the Surveillance, Epidemiology, and End Results program and the National Program of Cancer Registries was conducted. METHODS: TGCT incidence data among males ages 15 to 59 years for the years 1999 to 2012 were obtained from 39 US cancer registries. Incidence rates through 2026 were forecast using age-period-cohort models stratified by race/ethnicity, histology (seminoma, nonseminoma), and age. RESULTS: Between 1999 and 2012, TGCT incidence rates, both overall and by histology, were highest among NHWs, followed by Hispanics, Asian/Pacific Islanders, and non-Hispanic blacks. Between 2013 and 2026, rates among Hispanics were forecast to increase annually by 3.96% (95% confidence interval, 3.88%-4.03%), resulting in the highest rate of increase of any racial/ethnic group. By 2026, the highest TGCT rates in the US will be among Hispanics because of increases in both seminomas and nonseminomas. Rates among NHWs will slightly increase, whereas rates among other groups will slightly decrease. CONCLUSIONS: By 2026, Hispanics will have the highest rate of TGCT of any racial/ethnic group in the US because of the rising incidence among recent birth cohorts. Reasons for the increase in younger Hispanics merit further exploration. Cancer 2017;123:2320-2328. © 2017 American Cancer Society.

[Polymorphisms of KITLG, SPRY4, and BAK1 genes in patients with testicular germ cell tumors and individuals with infertility associated with AZFc deletion of the Y chromosome].

Testicular cancer is the most common form of solid cancer in young men. Testicular cancer is represented by testicular germ cell tumors (TGCTs) derived from embryonic stem cells with different degrees of differentiation in about 95% of cases. The development of these tumors is related to the formation of a pool of male germ cells and gametogenesis. Clinical factors that are predisposed to the development of germ-cell tumors include cryptorchidism and testicular microlithiasis, as well as infertility associated with the gr/gr deletion within the AZFс locus. KITLG, SPRY4, and BAK1 genes affect the development of the testes and gametogenesis; mutations and polymorphisms of these genes lead to a significant increase in the risk of the TGCT development. To determine the relationship between gene polymorphisms and the development of TGCTs, we developed a system for detection and studied the allele and genotype frequencies of the KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), and BAK1 (rs210138) genes in fertile men, patients with TGCTs, and patients with infertility that have the AZFс deletion. A significant association of rs995030 of the KITLG gene with the development of TGCTs (p = 0.029 for the allele G, p = 0.0124 for the genotype GG) was revealed. Significant differences in the frequencies of the studied polymorphisms in patients with the AZFc deletion and the control group of fertile men were not found. We showed significant differences in the frequencies for the combination of all high-risk polymorphisms in the control group, patients with the AZFc deletion and patients with TGCTs (p (TGCTs-AZF-control) = 0.0207). A fivefold increase in the frequency of the combination of all genotypes in the TGCT group (p = 0.0116; OR = 5.25 [1.44-19.15]) and 3.7-fold increase was identified in patients with the AZFc deletion (p = 0.045; OR = 3.69 [1.11-12.29]) were revealed. The genotyping of patients with infertility caused by the AZFc deletion can be used to identify individuals with an increased risk of TGCTs.

Incidence of testicular germ cell tumors among US men by census region.

BACKGROUND: The incidence of testicular germ cell tumors (TGCTs) in the United States is notably higher among white men versus other men. Previously, however, it was reported that rates were rising among Hispanics in certain areas. To determine whether this finding was evident in a wider area of the United States, data from 39 US cancer registries were examined. METHODS: Racial/ethnic-specific incidence rates per 100,000 man-years were calculated overall and by census region for the period of 1998-2011. Annual percentage changes (APCs) were estimated, and joinpoint models were fit. Differences in incidence by region were examined with the Wald test. RESULTS: From 1998 to 2011, 88,993 TGCTs were recorded. The TGCT incidence was highest among non-Hispanic whites (6.57 per 100,000), who were followed by Hispanics (3.88), American Indians/Alaska Natives (2.88), Asians/Pacific Islanders (A/PIs; 1.60), and non-Hispanic blacks (1.20). The incidence significantly increased among Hispanics (APC, 2.31; P < .0001), with rates rising in all regions except the South. Rates rose slightly among non-Hispanic whites (APC, 0.51; P = .0076). Significant differences in rates by region were seen for Hispanics (P = .0001), non-Hispanic whites (P < .0001), and A/PIs (P < .0001), with the highest rates among Hispanics in the West and with the highest rates among non-Hispanic whites and A/PIs in the Northeast. CONCLUSIONS: Although the incidence of TGCTs remained highest among non-Hispanic whites between 1998 and 2011, the greatest increase was experienced by Hispanics. Rising rates of TGCTs among Hispanics in the United States suggest that future attention is warranted. Reasons for the increase may include variability in birthplace, changing exposures, genetic susceptibility, and the length of US residence.

The expression of programmed cell death ligand 1 (PD-L1) involves in the clinicopathologic characteristics and prognostic implications of testicular germ cell tumor (TGCT): a systematic review and meta-analysis.

Background: Testicular germ cell tumor (TGCT) is a type of tumor with relatively lower incidence but being more prevalent in young men. The expression of programmed cell death ligand 1 (PD-L1) serves as a potential biomarker for predicting the survival outcomes of other tumors. Some studies discovered higher prevalence of PD-L1 in TGCT patients who achieved favorable treatment outcomes, while other studies showed lower or absent expression of PD-L1 in TGCT with the better prognosis as well. Therefore, in order to address this controversy and clarify the association between the expression of PD-L1 and pathological features and prognosis of TGCT, this meta-analysis was conducted. Methods: A comprehensive literature search was performed using following search terms: "testis", "testicle", "testicular", "cancer", "carcinoma", "tumor", "neoplasm", "programmed cell death ligand 1", "programmed death ligand 1", "PD-L1", "PDL1", "B7 homolog 1", "B7-H1", "B7H1" and "CD274". Relevant studies were retrieved according to the inclusion criteria from reputable databases including PubMed, Embase, Web of Science, Cochrane Library and China National Knowledge Infrastructure (CNKI). These studies investigated the expression of PD-L1 in both tumor cells and tumor infiltrating immune cells (TIICs) in TGCT. The overall proportion of PD-L1 positivity was assessed using R programming. Pooled hazard ratio (HR) and odds ratio (OR) with corresponding 95% confidence interval (CI) were calculated using Revman software to evaluate the involvement of PD-L1 expression in TGCT. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality assessment of included studies. Sensitivity analysis and publication bias evaluation were subsequently performed. Results: A total of eight eligible studies compromising 1,589 patients diagnosed with TGCT were finally included in this study. PD-L1 positivity was detected in 31% and 41% of TGCT patients' tumor cells and TIICs, respectively. The pooled data demonstrated a significant association between elevated PD-L1 expression levels in TIICs and a favorable prognosis characterized by the reduced disease progression and relapse events (HR =0.21, 95% CI: 0.13-0.33). Furthermore, PD-L1+ TIICs exhibited higher prevalence rates in seminoma (OR =2.11, 95% CI: 1.57-2.84) and embryonal carcinoma (OR =6.23, 95% CI: 2.42-16.02) patients. Notably, PD-L1 expression in TIICs displayed a tendency to increase in TGCT patients with lower stages or without lymph node metastasis. Conclusions: PD-L1 expression was observed in choriocarcinoma tumor cells, while yolk sac tumor and teratoma tumor cells exhibited lower or absent expression of PD-L1. Conversely, PD-L1 expression in TIICs was associated with seminoma and embryonal carcinoma, which was more commonly observed in TGCT patients with lower stages and better prognosis, thereby providing a theoretical foundation for the application of immunotherapy in relapsed/refractory TGCT patients.

Pexidartinib Upfront in a Case of Tenosynovial Giant Cell Tumor: Proof of Concept for a Treatment Paradigm Shift.

BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive tumor of the joints, bursa, and tendon sheath that can cause considerable pain and substantial morbidity. Although surgery is the primary treatment for patients with TGCT, surgical resection is associated with high rates of recurrence, particularly for patients with diffuse TGCT. Pexidartinib, a colony-stimulating factor 1 receptor inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. CASE DESCRIPTION: A 32-year-old man presented with intra-articular diffuse TGCT with pain and received noncurative treatment for 5 years (2014-2019). In 2019, the patient was found to have extensive disease accompanied by pain and limited range of motion. The patient's case was presented to a sarcoma multidisciplinary tumor board, who determined that surgery would cause significant morbidity and macroscopic residual tumor. As a result of the extent of disease, young age, and otherwise good health, treatment with pexidartinib was started through a compassionate use program at 800 mg/day. After dose reductions to pexidartinib at 400 mg/day and then 200 mg/day as a result of creatine phosphokinase elevations, the patient achieved a complete response after 2 years of treatment; pain was reduced and mobility was restored. The patient reported no side effects related to pexidartinib treatment. Treatment was stopped in 2022 for future family planning. After pexidartinib therapy was interrupted, the patient's wife had a successful pregnancy and delivery; however, the disease showed a slow but constant clinical deterioration, with a reduction in the range of movement of the affected knee and an apparent increase in widespread TGCT nodules. CONCLUSION: Our case is unique because it provides support for pexidartinib use as upfront therapy for TGCT, instead of surgery, in selected cases.