Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses:A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients

Benign and low-grade cartilaginous tumors: an update on differential diagnosis

Cartilaginous neoplasms hold considerable share in the routine diagnostics of bone tumor pathology. Benign cartilage forming tumors, that are in general more frequent than their malignant counterparts, may often pose diagnostic challenges. Distinction of a benign cartilaginous lesion from a low-grade malignant tumor can render difficulties especially in a small biopsy material. Considering the divergent therapeutic and prognostic implications, a careful assessment of histologic, radiologic and clinical findings/features is very important, and an experienced multidisciplinary team is indispensable to achieve an accurate diagnosis. This mini review focuses on the histomorphological findings of benign, locally aggressive and low-grade cartilaginous tumors referring to the latest edition of WHO Classification of Tumors of Soft Tissue and Bone Tumors (fifth edition, 2020). The focus of this article is on the differential diagnosis of benign cartilaginous lesions and their distinction from other cartilaginous lesions, especially their malignant counterparts. Histomorphology, in correlation with imaging findings, serve as the cornerstone in the diagnosis of cartilaginous tumors. Based on overlapping morphological and radiological features between the tumor types, including benign and malignant ones, their diagnosis can be challenging. Emerging molecular findings play a notable role in understanding the underlying mechanisms involved in their development, though their routine use in molecular diagnostics is limited to few indications. Likewise, the role of immunohistochemistry remains limited in the differential diagnosis of the cartilaginous tumors, emphasizing the need for joined histological and radiological evaluation

Treatment of Progressive Cherubism during the Second Dental Transitional Phase with Calcitonin

Cherubism is an autosomal dominant disease with variable expression. Aggressive forms of untreated cherubism may lead to severe malformation of the maxillofacial skeleton, developing tooth germs and teeth. Scarcely described and empirically applied interventional therapies during active stages of the disease try to limit the damage and deformation caused by progression of expanding intraosseous lesions. The final goal is to minimize the need for corrective surgeries once progressive growth has halted and disease enters its quiescent phase. New insights into the pathophysiology of cherubism hypothesize a potential role for dental development and jaw growth in the (hyper)activation of the disease. Theoretically, this could guide the ideal moment of pharmacological interventions. In this case report, the off-label use of systemic calcitonin treatment is described, stressing particularly the potential importance of its appropriate timing and duration of treatment.</p

Efficacy and Toxicity of Calcitonin Treatment in Children with Cherubism:A Single-Center Cohort Study

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range &lt;1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols.</p

Efficacy and Toxicity of Calcitonin Treatment in Children with Cherubism:A Single-Center Cohort Study

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range &lt;1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols.</p

Efficacy and Toxicity of Calcitonin Treatment in Children with Cherubism:A Single-Center Cohort Study

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range &lt;1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols.</p

No NFATC2 fusion in simple bone cyst of the jaw

Aims: Simple Bone Cysts (SBCs) predominantly occur in long bones and 59% harbour NFATC2 rearrangements. Jaw SBC is rare and was previously referred to as traumatic bone cyst. It can rarely occur in association with cemento-osseous dysplasia (COD). To determine whether jaw SBCs represent the same entity as SBC of the long bones, or if they have a different molecular signature, we collected 48 jaw SBC cases of 47 patients to assess NFATC2 rearrangement. Methods and results: Out of the 48 cases, 36 could be used for fluorescence in-situ hybridization (FISH), of which nine (two of which associated with COD) were successful using an NFATC2 split probe. The remaining cases failed to show adequate FISH signals. All nine cases lacked NFATC2 rearrangement and five of these showed no detectable gene fusions using Archer FusionPlex. Conclusion: In our study, NFATC2 rearrangement is absent in solitary jaw SBC (n = 7) and COD-associated SBC (n = 2). Our findings suggest that SBC presenting in the jaw is molecularly different from SBC in long bones. Future molecular studies may confirm the absence of clonal molecular aberrations in SBC of the jaw which would support a non-neoplastic, reactive origin.</p

Efficacy and Toxicity of Calcitonin Treatment in Children with Cherubism:A Single-Center Cohort Study

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range &lt;1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols.</p

RANKL inhibition for giant cell lesions of the jaw: A retrospective cohort analysis

Background: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). Methods: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. Results: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0–62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8–43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0–50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. Conclusion: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ