Ibrutinib as treatment for Bing-Neel syndrome reclassified as glioblastoma: a case report.

BACKGROUND: Glioblastoma is a highly malignant disease with limited treatment options. Ibrutinib, a covalent Bruton tyrosine kinase inhibitor, is an oral agent with manageable side effects used for hematological diseases including Waldenström macroglobulinemia. We present the case of a 69-year-old Caucasian male patient treated with ibrutinib for suspected Bing-Neel syndrome (BNS), which following a biopsy, was reclassified as glioblastoma. CASE PRESENTATION: In December 2018, a 69-year-old Caucasian male patient was diagnosed with Waldenström macroglobulinemia. As the patient was asymptomatic, without bone marrow failure or high M-component count, watchful waiting was initiated. Due to increasing neurological symptoms, the patient, based on magnetic resonance imaging, was diagnosed with Bing-Neel syndrome in May 2019. The patient received different treatments before starting ibrutinib monotherapy in August 2019 due to disease progression, both on magnetic resonance imaging and clinically. The patient remained clinically stable for 7 months. In March 2020, the patient developed headaches, and both magnetic resonance imaging and a biopsy revealed glioblastoma IDH-wildtype. Treatment was changed in line with the new diagnosis, but the patient died at the end of 2020. CONCLUSION: We present a case in which a patient with glioblastoma IDH-wildtype remained clinically stable for 7 months when treated with ibrutinib monotherapy, which is similar to what would be expected for the standard treatment for glioblastoma. To our knowledge, this is the first patient receiving ibrutinib for a glioblastoma IDH-wildtype with a meaningful clinical outcome. Our case may therefore support previous nonclinical findings, indicating a therapeutic value of ibrutinib in patients with glioblastoma and support for further investigation of ibrutinib as a possible treatment for glioblastoma.

Multiple myeloma: unplanned diagnostic pathways and association with risk factors and survival - a nationwide register-based cohort study in Denmark.

BACKGROUND: Multiple myeloma often presents with vague and non-specific symptoms. Many patients are diagnosed in unplanned rather than elective (planned) diagnostic pathways. This study investigates the diagnosis of multiple myeloma in unplanned pathways and the association with patient characteristics, disease profile, and survival. METHODS: We conducted a nationwide register-based study, including all patients diagnosed with multiple myeloma in Denmark in 2014-2018. Patients were categorised as diagnosed in an unplanned pathway if registered with an acute admission within 30 days prior to the multiple myeloma diagnosis and no other previously registered pathway to this diagnosis. Unplanned pathways were compared to all other pathways combined. RESULTS: We included 2,213 patients diagnosed with multiple myeloma, hereof 32% diagnosed in an unplanned pathway. Comorbidity, no prior cancer diagnosis, a history of few visits to the general practitioner (GP), multiple myeloma complications at diagnosis, high-risk cytogenetics, and advanced cancer stage were associated with a higher probability of being diagnosed in an unplanned pathway. For example, 24.4% (95% confidence interval (CI): 21.8-27.0) of patients with low comorbidity (Charlson Comorbidity Index (CCI) score 0) were diagnosed in an unplanned pathway as were 50.9% (95% CI: 45.6-56.1) of patients with high comorbidity (CCI score 3+). For patients with dialysis need at the time of diagnosis the probability was 66.0% (95% CI 54.2-77.8) and 30.9% (95% CI: 28.9-32.9) for patients with no dialysis need. Patients diagnosed in an unplanned pathway had inferior survival (hazard ratio 1.44 (95% CI: 1.26-1.64)). However, this association was not seen in analyses restricted to patients surviving for more than three years. CONCLUSIONS: High comorbidity level, few usual GP visits, advanced disease status at diagnosis, and complications were associated with diagnosis in an unplanned pathway. Further, patients diagnosed in an unplanned pathway had inferior survival. Promoting earlier diagnosis and preventing unplanned pathways may help improve survival in multiple myeloma.

Treatment of the elderly patient with haematological cancer.

During the last two decades, novel targeted therapies, in particular, ¼small molecules« for oral administration and monoclonal antibodies, have revolutionized the treatment and prognosis of haematological cancers. Generally, these treatments are well tolerated and therefore suitable for elderly patients. This review presents a short update on the current standard-of-care treatment of elderly patients with haematological cancer.

Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease.

Osteolytic bone disease is present in about 80% of patients with multiple myeloma at the time of diagnosis. Managing bone disease in patients with multiple myeloma is a challenge and requires a multi-faceted treatment approach with medication, surgery, and radiation. The established treatments with intravenous or subcutaneous antiresorptives can cause debilitating adverse events for patients, mainly osteonecrosis of the jaw, which, traditionally, has been difficult to manage. Now, oral surgery is recommended and proven successful in 60-85% of patients. Patients with spinal involvement may benefit from surgery in the form of vertebroplasty and kyphoplasty for pain relief, improved mobility, and reestablished sagittal balance, as well as the restoration of vertebral height. These procedures are considered safe, but the full therapeutic impact needs to be investigated further. Ixazomib, the first oral proteasome inhibitor, increases osteoblast differentiation, and recently published preliminary results in patients treated with Ixazomib maintenance have promisingly shown increased trabecular volume caused by prolonged bone formation activity. Other novel potential treatment strategies are discussed as well.

Increased Bone Volume by Ixazomib in Multiple Myeloma: 3-Month Results from an Open Label Phase 2 Study.

Multiple myeloma (MM) is an incurable bone marrow cancer characterized by the development of osteolytic lesions due to the myeloma-induced increase in osteoclastogenesis and decrease in osteoblastic activity. The standard treatment of MM often involves proteasome inhibitors (PIs), which can also have a beneficial off-target bone anabolic effect. However, long-term treatment with PIs is unadvised due to their high side-effect burden and inconvenient route of administration. Ixazomib is a new-generation, oral PI that is generally well tolerated; however, its bone effect remains unknown. Here, we describe the 3-month results of a single-center phase II clinical trial investigating the effect of ixazomib treatment on bone formation and bone microstructure. Thirty patients with MM in stable disease not receiving antimyeloma treatment for ≥3 months and presenting ≥2 osteolytic lesions received monthly ixazomib treatment cycles. Serum and plasma samples were collected at baseline and monthly thereafter. Sodium 18 F-Fluoride positron emission tomography (NaF-PET) whole-body scans and trephine iliac crest bone biopsies were collected before and after three treatment cycles. The serum levels of bone remodeling biomarkers suggested an early ixazomib-induced decrease in bone resorption. NaF-PET scans indicated unchanged bone formation ratios; however, histological analyses of bone biopsies revealed a significant increase in bone volume per total volume after treatment. Further analyses of bone biopsies showed unchanged osteoclast number and COLL1A1High -expressing osteoblasts on bone surfaces. Next, we analyzed the superficial bone structural units (BSUs), which represent each recent microscopic bone remodeling event. Osteopontin staining revealed that following treatment, significantly more BSUs were enlarged (>200,000 µm2 ), and the distribution frequency of their shape was significantly different from baseline. Overall, our data suggest that ixazomib induces overflow remodeling-based bone formation by decreasing the level of bone resorption and promoting longer bone formation events, making it a potentially valuable candidate for future maintenance treatment. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Clarithromycin added to bortezomib-cyclophosphamide-dexamethasone impairs health-related quality of life in multiple myeloma patients.

OBJECTIVES: The Danish Myeloma Study Group initiated a randomized, placebo-controlled, double-blinded phase II study to investigate the efficacy of adding clarithromycin to cyclophosphamide-bortezomib-dexamethasone (VCD) induction therapy in transplant eligible, newly diagnosed multiple myeloma patients. The study was prematurely terminated due to severe complications, and no effect of adding clarithromycin was found. The aim of this study was to compare health-related quality of life (HRQoL) between the two groups and to explore the coherence hereof with adverse event (AE) registration by clinicians. METHODS: Patients completed three validated HRQoL questionnaires at inclusion, before cyclophosphamide priming, and two months after high-dose therapy (HDT). The mean score difference was interpreted by clinically relevant differences between groups. Spearman's correlation analysis was used to compare patient-reported toxicities with AEs. RESULTS: Of 58 included patients, 55 participated in the HRQoL reporting. Before cyclophosphamide priming, patients in the clarithromycin group reported clinically relevant reduced HRQoL for eleven domains with persistent reduction in four domains two months after HDT. Poor correlation between patient-reported toxicities and clinician-reported AEs was observed. CONCLUSIONS: Despite the premature study termination, our data demonstrate impaired HRQoL when clarithromycin was added to the VCD regimen. We found clear underreporting of toxicities by clinicians. ClinicalTrials.gov number NCT02573935.

A randomized placebo-controlled phase II study of clarithromycin or placebo combined with VCD induction therapy prior to high-dose melphalan with stem cell support in patients with newly diagnosed multiple myeloma.

BACKGROUND: The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy. METHODS: Patients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo. RESULTS: The study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5-64.7) and in 16 patients (51.6%, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group. CONCLUSION: The study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy.Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).

Chemerin is elevated in multiple myeloma patients and is expressed by stromal cells and pre-adipocytes.

Chemerin is a recently discovered adipokine shown to be involved in both inflammatory and metabolic processes. Here, we demonstrate that chemerin serum levels are elevated in patients with multiple myeloma and that it increases with disease progression. We found that chemerin is expressed by stromal cells and preadipocytes, whereas its receptor CCRL2 is expressed by primary myeloma cells, suggesting a paracrine signaling loop between bone marrow stromal cells/adipocytes and myeloma cells. This is the first study exploring chemerin and its receptors in multiple myeloma.

Muscle after spinal cord injury.

The morphological and contractile changes of muscles below the level of the lesion after spinal cord injury (SCI) are dramatic. In humans with SCI, a fiber-type transformation away from type I begins 4-7 months post-SCI and reaches a new steady state with predominantly fast glycolytic IIX fibers years after the injury. There is a progressive drop in the proportion of slow myosin heavy chain (MHC) isoform fibers and a rise in the proportion of fibers that coexpress both the fast and slow MHC isoforms. The oxidative enzymatic activity starts to decline after the first few months post-SCI. Muscles from individuals with chronic SCI show less resistance to fatigue, and the speed-related contractile properties change, becoming faster. These findings are also present in animals. Future studies should longitudinally examine changes in muscles from early SCI until steady state is reached in order to determine optimal training protocols for maintaining skeletal muscle after paralysis.

Myeloid sarcoma developing in pre-existing pyoderma gangrenosum.

We report here a case of pyoderma gangrenosum in a patient with myelodysplastic syndrome developing into myeloid sarcoma as a sign of transformation to acute leukaemia. The patient was treated successfully with intensive chemotherapy and achieved complete remission, and her otherwise expanding ulcers started to heal. This is the first reported case of secondary blastic infiltration in pyoderma gangrenosum, and it underlines the importance of performing re-biopsy of non-healing ulcers, especially in patients with an underlying haematological disease.

[Epithelial inclusion cyst of the clitoris as a late complication of childhood female circumcision]. / Epitelial inklusionscyste ved clitoris som senkomplikation i forbindelse med kvindelig omskaering.

Two cases of epithelial inclusion cyst as a late complication of childhood female circumcision in patients aged 39 and 27 years are reported. Symptoms were interference with sexual intercourse and discomfort during sitting. Surgical treatment of the condition is known to be effective with few complications and gave correct aesthetic and functional results. Histology confirmed the diagnosis of epithelial inclusion cyst.