The role of comorbidity indices and histochemical markers in surgically resected and non-resected primary central nervous system lymphoma.

The role of surgical resection in primary central nervous system lymphoma (PCNSL) was not recognized until recently. However, prognostic factors for surgically treated PCNSL remain unclear. In the present study, we aimed to identify and compare the prognostic value of comorbidity indices and immunohistochemical markers in patients with surgically and non-surgically treated PCNSL. This retrospective single-center study analyzed patients who underwent either surgical resection or stereotactic biopsy for newly diagnosed PCNSL between January 2012 and December 2021. Clinical demographics, comorbidity indices, and immunohistochemical markers were analyzed. We included 23 and 18 patients who underwent stereotactic biopsy and surgical resection, respectively. The median overall survival (OS) was 11.05 months. Using multivariate Cox regression, we identified pretreatment prognostic nutritional index (PNI) (p = 0.009), positive BCL2 staining (p = 0.026), and infratentorial involvement (p = 0.004) as independent prognostic factors of OS. Predictors of progression-free survival (PFS) included PNI (p = 0.040), infratentorial involvement (p = 0.021), and surgical resection for PCNSL (p = 0.048). Subgroup analyses revealed that positive BCL2 (p = 0.048) and PD-L1 (p = 0.037) staining were associated with worse OS in the biopsy group. PNI and infratentorial involvement could significantly impact both OS and PFS in patients with PCNSL. Surgical resection could predict favorable PFS but not OS. Moreover, BCL2 and PD-L1 expression can be employed as prognostic markers in these patients.

Mixed Mycobacterium kansasii and Mycobacterium smegmatis infection in an adult-onset immunodeficiency patient with anti-interferon-γ autoantibodies.

Anti-interferon-gamma autoantibody (AIGA) is a rare adult-onset immunodeficiency disease that increases the risk of occult infection. Nontuberculous mycobacteria (NTM) infections represent a diverse group of species and subspecies, and mixed infections with two or more NTM species have been reported. However, there is no consensus on the optimal antibiotics or immune modulator treatments for mixed NTM infections in AIGA patients. Here, we present the case of a 40-year-old female who initially presented with suspected lung cancer with obstructive pneumonitis. Tissue samples obtained through bronchoscopy, endoscopy, and bone marrow biopsy revealed disseminated mycobacterium infection. PCR-based testing confirmed a mixed pulmonary infection with Mycobacterium kansasii and Mycobacterium smegmatis, as well as M. kansasii bacteremia. The patient received 12 months of anti-NTM medications for M. kansasii, and the symptoms improved. Additionally, the images showed resolution after 6 months, even without the need for immune modulator treatment.

Recurrent spinal meningeal melanocytoma at lumbar spine level: a case report.

INTRODUCTION: Spinal meningeal melanocytoma is an extremely rare tumour with an estimated annual incidence of 1 per 10 million people. It usually arises from the intradural extramedullary compartment at the cervical levels. Although these tumours are histologically benign, they may behave aggressively. Local recurrence could occur even after total tumour excision. CASE REPORT: We report a case of a 33-year-old Asian male who developed progressive weakness and numbness of the bilateral lower extremities as well as urinary retention five years after complete tumour resection of lumbar spinal meningeal melanocytoma. Magnetic resonance imaging of the lumbar spine revealed a mass with thecal sac compression which was hypointense on T2-weighted images and hyperintense on T1-weighted images. The patient underwent total tumour removal. Histologic examination was compatible with recurrent meningeal melanocytoma. After a 4-week inpatient rehabilitation programme, he was able to ambulate without assistance and to do clean intermittent catheterisation for micturition on a regular basis. DISCUSSION: This is the first reported case of intradural extramedullary meningeal melanocytoma located at the lumbar region. Clinicians should consider the possibility of these rare tumours at any level of the spine, and be aware of sphincter dysfunction in addition to motor and sensory deficits of extremities.

SH3GLB1-related autophagy mediates mitochondrial metabolism to acquire resistance against temozolomide in glioblastoma.

BACKGROUND: The mechanism by which glioblastoma evades temozolomide (TMZ)-induced cytotoxicity is largely unknown. We hypothesized that mitochondria plays a role in this process. METHODS: RNA transcriptomes were obtained from tumor samples and online databases. Expression of different proteins was manipulated using RNA interference or gene amplification. Autophagic activity and mitochondrial metabolism was assessed in vitro using the respective cellular and molecular assays. In vivo analysis were also carried out in this study. RESULTS: High SH3GLB1 gene expression was found to be associated with higher disease grading and worse survival profiles. Single-cell transcriptome analysis of clinical samples suggested that SH3GLB1 and the altered gene levels of oxidative phosphorylation (OXPHOS) were related to subsets expressing a tumor-initiating cell signature. The SH3GLB1 protein was regulated by promoter binding with Sp1, a factor associated with TMZ resistance. Downregulation of SH3GLB1 resulted in retention of TMZ susceptibility, upregulated p62, and reduced LC3B-II. Autophagy inhibition by SH3GLB1 deficiency and chloroquine resulted in attenuated OXPHOS expression. Inhibition of SH3GLB1 in resistant cells resulted in alleviation of TMZ-enhanced mitochondrial metabolic function, such as mitochondrial membrane potential, mitochondrial respiration, and ATP production. SH3GLB1 modulation could determine tumor susceptibility to TMZ. Finally, in animal models, resistant tumor cells with SH3GLB1 knockdown became resensitized to the anti-tumor effect of TMZ, including the suppression of TMZ-induced autophagy and OXPHOS. CONCLUSIONS: SH3GLB1 promotes TMZ resistance via autophagy to alter mitochondrial function. Characterizing SH3GLB1 in glioblastoma may help develop new therapeutic strategies against this disease in the future.

Muscle Biopsy: A Requirement for Precision Medicine in Adult-Onset Myopathy.

Muscle biopsy is a fundamental procedure to assist the final diagnosis of myopathy. With the recent advances in molecular diagnosis, serology tests, and mechanism-based classification in myopathy, the précised diagnosis for myopathy required the applications of multiple tools. This study intends to reappraise the benefit of muscle biopsy in adult-onset myopathy under the setting of an optimized muscle biopsy protocol and comprehensive serology tests. A one-group pretest-posttest study design was used. The pre- and post-biopsy diagnoses and treatments in 69 adult patients were compared. Muscle biopsy yielded 85.5% of definitive diagnoses, including changes in pre-biopsy diagnoses (40.6%) and narrowing down the suspicious myopathies (49.3%). The demographic data and clinical parameters between the group "with change" and "without change" after biopsy were not different. Among those with changes in diagnosis, 39.3% also had a corresponding shift in treatment, which benefits the patients significantly. Regarding the most common adult-onset myopathy, idiopathic inflammatory myopathy (IIM), 41% of patients with pre-biopsy diagnosis as IIM had changes in their IIM subtype diagnosis, and 53% was finally not IIM after muscle biopsy. Although there have been advances in molecular diagnosis recently, muscle biopsy still undoubtedly critically guided the diagnosis and treatment of adult-onset myopathy in the era of precision medicine.

FTY720 in resistant human epidermal growth factor receptor 2-positive breast cancer.

The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo.

Development of the CK-MB-1 trastuzumab-resistant HER2-positive breast cancer cell line and xenograft animal models.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who fail to respond to anti-HER2 treatments have poor prognoses. Most trastuzumab-resistant breast cancer cell lines available from biobanks feature either phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) mutation or the loss of phosphatase and tensin homolog (PTEN). However, PIK3CA mutations and/or PTEN loss do not account for most trastuzumab-resistant tumors in humans. METHODS: Breast cancer cells were collected from one patient's malignant ascites. These cells were cultured and maintained to develop a stable cell line, which we named CK-MB-1. We used western blotting to evaluate protein expression. The PIK3CA status of CK-MB-1 cells was analyzed using Sanger sequencing and validated using next-generation sequencing. In vivo, CK-MB-1 xenograft tumor models were developed in zebrafish and immunodeficient mice. RESULTS: CK-MB-1 cells maintained the major characteristics of the parental tumor including HER2 positivity and estrogen receptor negativity. The HER2 gene amplification of CK-MB-1 cells was detected by fluorescence in situ hybridization. The integrity of PTEN was confirmed by its positive protein expression and the absence of gene mutations. No common PIK3CA mutation was detected. Compared with the findings in two other HER2-positive trastuzumab-resistant cell lines, CK-MB-1 cells exhibited greater resistance to trastuzumab, chemotherapeutics, and small-molecule drugs. Trastuzumab resistance in CK-MB-1 cells was confirmed in vivo using the NOD SCID mouse model. CONCLUSIONS: CK-MB-1 cells represent a stable HER2-positive trastuzumab-resistant breast cancer cell line. The resistance of CK-MB-1 cells does not originate from the PTEN or phosphoinositide 3-kinase signaling pathway, which can provide an alternative approach for potential drugs.

Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood. CASE PRESENTATION: A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder. CONCLUSIONS: The increase of ß-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.