Experience With Tirabrutinib in the Treatment of Primary Central Nervous System Lymphoma that Is Difficult to Treat With Standard Treatment.

BACKGROUND/AIM: Standard treatment options for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based drug therapy and whole-brain radiation therapy. However, there are many cases in which these standard treatment options are not tolerated for various reasons. In the present study, five cases of refractory/relapsed PCNSL that are difficult to treat with standard treatment were successfully treated by tirabrutinib. PATIENTS AND METHODS: A total of 5 patients (4 women, 1 man) with refractory (n=3) and relapsed (n=2) PCNSL were included. The patients had a median age of 76 years and a median Karnofsky performance status (KPS) of 40. The reasons why standard treatment cannot be given to these patients are the low KPS, renal dysfunction, and resistance to HD-MTX. Administration of a drug via the oral route was challenging in three patients; thus, these patients were administered tirabrutinib in suspension through a nasogastric tube. RESULTS: Imaging findings showed that the patients achieved a 100% response rate to tirabrutinib, with a median survival of 8 months. As symptoms improved, 2 of the 3 patients who were initially administered tirabrutinib via a nasogastric tube were able to receive the drug via the oral route. Three patients developed adverse reactions; however, treatment was not interrupted because they were manageable. CONCLUSION: Tirabrutinib was effective in the treatment of patients who were unable to receive standard treatment options. Tirabrutinib may be considered one of the novel treatment strategies that could improve the prognosis of PCNSL patients in the future.

Experience with nasogastric tube administration of tirabrutinib in the treatment of an elderly patient with primary central nervous system lymphoma.

We report that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient's level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia.

Effectiveness of Palliative Cerebrospinal Fluid Shunting for Patients With Leptomeningeal Carcinomatosis-related Hydrocephalus.

BACKGROUND/AIM: Leptomeningeal carcinomatosis (LMC) with hydrocephalus is particularly difficult to treat, and its prognosis is extremely poor. The therapeutic outcomes of 14 patients with LMC-associated hydrocephalus who were treated with cerebrospinal fluid shunting are reported. PATIENTS AND METHODS: The study subjects were 14 LMC patients with solid primary cancer who had developed hydrocephalus. RESULTS: Postoperatively, both symptoms and Karnofsky performance status improved in 100% of patients. Postoperative therapy consisted of whole-brain radiotherapy in 4 cases and molecular targeted therapy in 4, with 6 patients not receiving any postoperative treatment. Median overall survival was 3.7 months, with no significant difference between those who underwent postoperative therapy and those who did not. However, two of those who received molecular targeted therapy survived for more than one year. CONCLUSION: Cerebrospinal fluid shunting for LMC-associated hydrocephalus is an effective therapeutic procedure from the palliative viewpoint. Patients for whom molecular targeted therapy is indicated may have better long-term survival.

Usefulness of presepsin / creatinine ratio as a new index that corrects for renal function.

Background : Presepsin (P-SEP) is a highly specific sepsis marker, and its fluctuation with respect to advanced renal impairment or sample agitation has not been fully investigated. We evaluated several renal function-corrected P-SEP indices to establish a simple index and its reference range. Methods : Blood samples for P-SEP measurement were collected with minimal agitation. P-SEP levels were measured using the rapid automated immunoanalyzer "PATHFAST." This study included 85 chronic kidney disease (CKD) patients, 65 healthy volunteers, and 4 sepsis patients. Results : Patients stratified by estimated glomerular filtration rate (GFR) had significantly higher P-SEP levels for CKD stage G3, especially the advanced GFR stage. We evaluated presepsin / creatinine (P-SEP / CRE) and P-SEP / eGFR ratios as possible indices for renal function. The P-SEP / CRE ratio exhibited no increase correlating with the GFR stage and was identical in the normal and CKD groups ;  P-SEP / eGFR decreased if GFR stage worsened. The P-SEP / CRE ratio became significantly higher in sepsis patients and was a more useful index with a reference range of 67-263. Conclusions : P-SEP levels were inversely correlated with renal function, indicating the necessity to consider the influence of renal impairment in CKD patients. The P-SEP / CRE ratio is helpful for sepsis diagnosis, even in patients with renal impairment. J. Med. Invest. 68 : 105-111, February, 2021.

The ADVIA2120i parameter Revised %MICRO is a surrogate marker of schistocyte formation after hematopoietic stem cell transplantation.

Objectives : Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an important early post-treatment condition. This study evaluated the Revised %MICRO, a parameter obtained from the ADVIA 2120i automated blood cell counter, as a surrogate marker of the schistocyte ratio. We hypothesized that individual differences between the %MICRO value and schistocyte ratio would remain constant. Design and Methods: EDTA-2K-treated peripheral blood samples were collected from 19 patients who underwent allogeneic HSCT from April 2014 to September 2018. First, the baseline difference, X, was calculated using a sample from the first day after HSCT as X = %MICRO (first day) - schistocyte ratio (first day). Next, the Revised %MICRO for each subsequent day was calculated as Revised %MICRO = %MICRO - X. We evaluated correlations of the schistocyte ratio with the calculated %MICRO and Revised %MICRO and the RBC fragment, RBC distribution width, %MICRO and Revised %MICRO data obtained from the ADVIA 2120i. Results : The mean schistocyte percentage and Revised %MICRO were both 0.4% ±â€…0.6. RBC fragments correlated weakly with the %MICRO and schistocyte ratio, respectively (r = 0.162 and r = 0.771, respectively), whereas the Revised %MICRO correlated strongly with the schistocyte ratio (r = 0.893). Conclusion : The Revised %MICRO appears to be a good surrogate of the schistocyte ratio in a clinical setting. J. Med. Invest. 67 : 250-254, August, 2020.

Clinical Outcomes of Surgical Resection for Brain Metastases from Non-small Cell Lung Cancer.

BACKGROUND/AIM: Recent advances in systemic chemotherapy, including molecularly targeted therapy, have dramatically improved survival for patients with advanced non-small cell lung cancer. We retrospectively analyzed the clinical outcomes of surgical resection for brain metastases of non-small cell lung cancer cases performed at the Department of Neurosurgery of Kindai University Hospital, Osaka, Japan. PATIENTS AND METHODS: Craniotomy and tumor resection were performed for 56 patients with brain metastases of non-small cell lung cancer. Adenocarcinoma was the most common histological type, appearing in 40 cases, of which 18 were positive for driver gene mutations. RESULTS: Median survival for all 56 patients was 14.5 months, and single brain metastasis and adenocarcinoma were identified as favorable prognostic factors. Analysis limited to the 40 cases of adenocarcinoma identified single brain metastasis as a favorable prognostic factor. Although no significant difference was found for systemic chemotherapy, patients who received molecularly targeted therapy showed a better prognosis than those who received cytotoxic chemotherapy. Analyses of both the entire group and of adenocarcinoma patients alone found that whole-brain radiotherapy showed no significant association with survival. CONCLUSION: Single brain metastasis and adenocarcinoma were identified as favorable prognostic factors, but did not confirm any benefit from whole-brain radiotherapy. These results suggest that multimodal treatment strategies utilizing various methods of treatment, including systemic chemotherapy, may help prolong patient survival in the future.

[A Case of Primary Central Nervous System Lymphomatoid Granulomatosis that was Completely Ameliorated by Corticosteroid Treatment].

Lymphomatoid granulomatosis (LYG) is an angiocentric, angiodestructive lymphoreticular proliferative disease that usually affects the lungs but it has been speculated to also effect the central nervous system (CNS). However, unique primary LYG of the CNS has rarely been reported in the literature. Herein, we describe a clinical case of a 37-year-old female patient with grade 1 primary CNS-LYG having a good prognosis owing to corticosteroid treatment. The aforesaid patient, presented with a headache and left leg weakness with no evidence of a systemic disease. MRI revealed multiple small enhancing nodules in the right hemisphere with diffuse high-intensity lesions on T2/ FLAIR image. A brain biopsy showed lymphohistiocytic cells with blood vessels infiltrated with CD3+ and CD20+. The Epstein-Barr virus encoded small RNA-ISH test was negative. Based on the above findings, grade 1 primary CNS-LYG was diagnosed. Following the administration of oral corticosteroids, a systemic high-dose corticosteroid therapy was administrated. Complete remission was achieved and maintained for 24 months following treatment. Grade 1 primary CNS-LYG is a rare disease that is not apparently associated with the Epstein-Barr virus (EBV) and possibly yields much better prognosis than the frequently EBV-positive systemic LYG with CNS localization. (Received November 5, 2019; Accepted November 20, 2019; Published February 1, 2020).

A case of leptomeningeal metastases of human epidermal growth factor receptor 2-positive breast cancer that responded well to lapatinib plus capecitabine.

BACKGROUND: Leptomeningeal metastases (LM) pose the most difficult form of cancer metastasis to treat and portend a poor prognosis. Standard treatment has yet to be established, and intrathecal chemotherapy and whole- brain radiotherapy are administered on an empirical basis. CASE DESCRIPTION: We report on a 46-year-old woman with LM from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. She was suffering from intractable headaches, severe nausea and vomiting, and cerebellar ataxia. Contrast-enhanced magnetic resonance imaging (MRI) revealed diffuse enhancement of the meninges, mainly in the posterior cranial fossa, and compression of the cerebellum by the profoundly thickened meninges. The first step in the treatment was decompression of the posterior cranial fossa to relieve intracranial hypertension. After surgery, her symptoms immediately improved. The second step was treatment with lapatinib at 1250 mg and capecitabine 1200 mg, which dramatically improved her symptoms and disappeared diffuse abnormal signal enhancement on MRI. CONCLUSION: We treated a patient with LM from primary HER2-positive breast cancer who responded well to lapatinib plus capecitabine.

Clinical evaluation of presepsin considering renal function.

Presepsin, a glycoprotein produced during bacterial phagocytosis, is used as a sepsis marker for bacterial infections. However, presepsin levels are affected by renal function, and the evaluation criteria according to kidney function or in chronic kidney diseases remain controversial. Furthermore, presepsin may be increased by sample stirring, but no studies have evaluated this effect.In this study, we excluded the effect of stirring by standardizing the blood collection conditions, analyzed the influence of kidney function on presepsin concentrations, and recalculated the reference range based on the findings. EDTA-whole blood from 47 healthy subjects and 85 patients with chronic kidney disease was collected to measure presepsin by PATHFAST. Presepsin was found to be significantly correlated with the levels of creatinine (r = 0.834), eGFRcreat (r = 0.837), cystatin-C (r = 0.845), and eGFRcys (r = 0.879). Furthermore, in patients with CKD, presepsin levels stratified by eGFRcys showed a significant increase in the CKD G2 patient group and with advancing glomerular filtration rate stage. The following values were obtained: Normal: 97.6 ± 27.4 pg/mL, CKD G1: 100.2 ± 27.6 pg/mL, CKD G2: 129.7 ± 40.7 pg/mL, CKD G3: 208.1 ± 70.2 pg/mL, CKD G4: 320.2 ± 170.1 pg/mL, CKD G5: 712.8 ± 336.3 pg/mL. The reference range, calculated by a nonparametric method using 67 cases of healthy volunteers and patients with chronic kidney disease G1, was found to be 59-153 pg/mL, which was notably lower than the standard reference range currently used. Presepsin concentrations were positively correlated with a few biomarkers of renal function, indicating the necessity to consider the effect of renal function in patients with renal impairment. Using the recalculated reference range considering kidney function may improve the accuracy of evaluating presepsin for diagnosis of sepsis compared to the standard reference currently in use.

Cut-off value of total adiponectin for managing risk of developing metabolic syndrome in male Japanese workers.

AIM: To determine the optimal cut-off value of serum total adiponectin for managing the risk of developing metabolic syndrome (MetS) in male Japanese workers. METHODS: A total of 365 subjects without MetS aged 20-60 years were followed up prospectively for a mean of 3.1 years. The accelerated failure-time model was used to estimate time ratio (TR) and cut-off value for developing MetS. RESULTS: During follow-up, 45 subjects developed MetS. Age-adjusted TR significantly declined with decreasing total adiponectin level (≤ 4.9, 5.0-6.6, 6.7-8.8 and ≥ 8.9 µg/ml, P for trend = 0.003). In multivariate analyses, TR of MetS was 0.12 (95% CI 0.02-0.78; P = 0.03) in subjects with total adiponectin level of 5.0-6.6 µg/ml, and 0.15 (95% CI 0.02-0.97; P = 0.047) in subjects with total adiponectin level ≤ 4.9 µg/ml compared with those with total adiponectin level ≥ 8.9 µg/ml. The accelerated failure-time model showed that the optimal cut-off value of total adiponectin for managing the risk of developing MetS was 6.2 µg/ml. In the multivariate-adjusted model, the mean time to the development of MetS was 78% shorter for total adiponectin level ≤ 6.2 µg/ml compared with > 6.2 µg/ml (TR 0.22, 95% CI: 0.08-0.64, P = 0.005). CONCLUSION: Our findings suggest that the cut-off value for managing the risk of developing MetS is 6.2 µg/ml in male Japanese workers. Subjects with total adiponectin level ≤ 6.2 µg/ml developed MetS more rapidly than did those with total adiponectin level > 6.2 µg/ml.

An X-ray absorption spectroscopic study on mixed conductive La0.6Sr0.4Co0.8Fe0.2O(3-δ) cathodes. I. Electrical conductivity and electronic structure.

The electrical conduction mechanism of mixed conductive perovskite oxides, La(0.6)Sr(0.4)Co(0.8)Fe(0.2)O(3-δ), for cathode materials of solid oxide fuel cells has been investigated from electronic structural changes during oxygen vacancy formation. La(0.6)Sr(0.4)Co(0.8)Fe(0.2)O(3-δ) was annealed under various oxygen partial pressures p(O(2))s at 1073 K and quenched. Iodometric titration indicated that the oxygen nonstoichiometry of La(0.6)Sr(0.4)Co(0.8)Fe(0.2)O(3-δ) depended on the annealing p(O(2)), with more oxygen vacancies introduced at lower than at higher p(O(2))s. X-Ray absorption spectroscopic measurements were performed at the O K-, Co L-, Fe L-, Co K-, and Fe K-edges. The valence states of the Co and Fe ions were investigated by the X-ray absorption near edge structure (XANES) at the Co and Fe L(III)-edges. While the Fe average valence was almost constant, the valence of the Co ions decreased with oxygen vacancy introduction. The O K-edge XANES spectra indicated that electrons were injected into the Co 3d/O 2p hybridization state with oxygen vacancy introduction. Both absorption edges at the Co and Fe K-edge XANES shifted towards lower energies with oxygen vacancy introduction. The shift at the Co K-edge resulted from the decrease in the Co average valence and that at the Fe K-edge appeared to be caused by changes in the coordination environment around the Fe ions. The total conductivity of La(0.6)Sr(0.4)Co(0.8)Fe(0.2)O(3-δ) decreased with decreasing p(O(2)), due to a decreasing hole concentration.