Three-year follow-up analysis of phase 1/2 study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.

Background: The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up. Methods: Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions. Results: Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment. Conclusions: The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained.

A screw-type pacemaker lead implanted in the right atrium perforated the ascending aorta.

BACKGROUND: Perforation by pacemaker leads, although rare, is a complication reported since the introduction of pacemaker therapy. Although historically reported frequencies were as high as 5%, recent reports have cited frequencies ranging from 1 to 2%. We report a case where a screw-type atrial lead slightly penetrated the right atrial wall, causing chronic abrasion of the ascending aorta, resulting in shock. CASE PRESENTATION: A 54-year-old male presented with dilated cardiomyopathy diagnosed at 40 years of age when he developed decompensated heart failure. Despite ongoing treatment, his heart failure worsened, leading to hospitalization at the age of 54. During his hospital stay, he experienced cardiac arrest that required cardiopulmonary resuscitation, followed by a return of spontaneous circulation. He was subsequently transferred to our institution after initiation of venoarterial extracorporeal membrane oxygenation (VA-ECMO) and an intra-aortic balloon pump (IABP). Echocardiography revealed an ejection fraction of 25%, left ventricular end-diastolic diameter of 60 mm, and severe mitral regurgitation (MR). Transcatheter mitral valve repair was performed to treat severe MR, followed by implantation of a cardiac resynchronization therapy defibrillator (CRT-D). Three months later, the patient was brought to our emergency department by ambulance because of hypotension. Contrast-enhanced computed tomography revealed pericardial effusion causing cardiac tamponade, necessitating emergency pericardial decompression via left fourth intercostal mini-thoracotomy and drain placement. Upon transfer to the intensive care unit, 1200 mL of blood was drained from the chest tube, prompting a return to the operating room for a median sternotomy. It was discovered that the pacemaker lead on the left side of the right atrium had slowly eroded into the aorta, leading to perforation. The ascending aorta was repaired and hemostasis was achieved; the patient recovered uneventfully and was discharged on postoperative day 18. CONCLUSIONS: The pacemaker lead perforated the right atrium; chronic abrasion of the lead against the ascending aorta resulted in bleeding from the ascending aorta 3 months later.

Dosimetric impact of VMAT delivery angles for early glottic cancer treatment.

This study investigates the dosimetric effects of different gantry rotation angles used in volumetric modulated arc therapy (VMAT) for early glottic carcinoma. VMAT treatment plans using full-arc, half-arc, and partial-arc gantry rotation angles were generated from 22 computed tomography datasets of early-stage (T1-2N0) glottic laryngeal cancer. Dosimetric parameters associated with the planning target volume (PTV) and organs at risk (OARs), specifically the carotid arteries and thyroid, were compared. To assess the robustness of the VMAT plans, dose variations were analyzed by introducing positional shifts of 1, 3, and 5 mm from the isocenter of each plan along the superior-inferior, left-right, and anterior-posterior axes. Furthermore, we examined the size of the PTV, the air cavity volume within the PTV, and the variability of the beam path length through the gantry angles to investigate their correlations with PTV dose variations in the presence of positioning errors. Compared to full-arc and half-arc plans, the dosimetric parameters of partial-arc plans were found to be higher in PTV (D2%, D5%, D50%, and Dmean) and lower in OARs, while their dose variations of OAR parameters were greater for positioning errors. In addition, a correlation was observed between PTV size and PTV dose variations. Air cavity volume and depth variability were also correlated with some PTV parameters, depending on the arc plan. The results presented in this study suggest that the partial-arc gantry angles can allow higher PTV doses while minimizing OAR doses in VMAT treatment planning for early glottic cancer. However, the small delivery angles may lead to greater dose variations in the OARs when positioning errors occur.

Adverse plasma branched-chain amino acid profile mirrors fatty muscle degeneration in diabetic heart failure patients.

AIMS: Elevated plasma branched-chain amino acids (BCAAs) are tightly linked to incident diabetes and its complications, while lower BCAAs are associated with adverse outcomes in the elderly and heart failure (HF) patients. The interplay between body compositions and plasma BCAAs, especially under the influence of co-morbid diabetes in HF patients, is not well understood. Here, we examined the impact of diabetes on the prognostic value of plasma BCAA and its association with body compositions in HF patients. METHODS AND RESULTS: We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male), among which 36% had diabetes. Blood samples for plasma BCAA measurements were collected in a fasting state after stabilization of HF and analysed using ultraperformance liquid chromatography. A dual-energy X-ray absorptiometry scan assessed regional body compositions, and muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.00 and <5.40 kg/m2 for males and females, respectively, according to the criteria of the Asian Working Group for Sarcopenia. Although analyses of covariance revealed that plasma BCAAs were significantly higher in diabetic patients, low valine (<222.1 nmol/mL) similarly predicted adverse events defined by HF hospitalization, lethal arrhythmia, or all-cause death in both diabetic and non-diabetic patients independently of age, sex, and NT-proBNP (adjusted hazard ratio [HR] 3.1, 95% confidence interval [CI] of 1.1-8.6 and adjusted HR 2.67, 95% CI 1.1-6.5, respectively; P for interaction 0.88). In multivariate linear regression analyses comprising age, sex, and regional body compositions as explanatory variables, plasma BCAAs were positively correlated with visceral adipose tissue area in non-diabetic patients (standardized ß coefficients [ß] = 0.44, P < 0.001). In contrast, in diabetic patients, plasma BCAAs were correlated positively with ASMI (ß = 0.49, P = 0.001) and negatively with appendicular fat mass index (AFMI; ß = -0.42, P = 0.004). Co-morbid diabetes was independently associated with muscle wasting (adjusted odds ratio 2.1, 95% CI 1.1-4.0) and significantly higher plasma 3-methylhistidine level, a marker of myofibrillar degradation. In diabetic patients, ASMI uniquely showed a J-shaped relationship with AFMI, and in a subgroup of HF patients with muscle wasting, diabetic patients showed 12% higher AFMI than non-diabetic patients despite comparable ASMI reductions. CONCLUSIONS: Despite higher plasma BCAA levels in HF patients with diabetes, the prognostic value of low valine remained consistent regardless of diabetes status. However, low BCAAs were distinctly associated with fatty muscle degeneration in the extremities in diabetic patients, suggesting the importance of targeted interventions to prevent such tissue remodelling in this population.

Successful Multimodal Treatment of Intracranial Growing Teratoma Syndrome with Malignant Features.

Molecular analysis of the growing teratoma syndrome has not been extensively studied. Here, we report a 14-year-old boy with a growing mass during treatment for a mixed germ cell tumor of the pineal region. Tumor markers were negative; thus, growing teratoma syndrome was suspected. A radical resection via the occipital transtentorial approach was performed, and histopathological examination revealed a teratoma with malignant features. Methylation classifier analysis confirmed the diagnosis of teratoma, and DMRT1 loss and 12p gain were identified by copy number variation analysis, potentially elucidating the cause of growth and malignant transformation of the teratoma. The patient remains in remission after intense chemoradiation treatment as a high-risk germ cell tumor.

Using artificial intelligence to improve human performance: efficient retinal disease detection training with synthetic images.

BACKGROUND: Artificial intelligence (AI) in medical imaging diagnostics has huge potential, but human judgement is still indispensable. We propose an AI-aided teaching method that leverages generative AI to train students on many images while preserving patient privacy. METHODS: A web-based course was designed using 600 synthetic ultra-widefield (UWF) retinal images to teach students to detect disease in these images. The images were generated by stable diffusion, a large generative foundation model, which we fine-tuned with 6285 real UWF images from six categories: five retinal diseases (age-related macular degeneration, glaucoma, diabetic retinopathy, retinal detachment and retinal vein occlusion) and normal. 161 trainee orthoptists took the course. They were evaluated with two tests: one consisting of UWF images and another of standard field (SF) images, which the students had not encountered in the course. Both tests contained 120 real patient images, 20 per category. The students took both tests once before and after training, with a cool-off period in between. RESULTS: On average, students completed the course in 53 min, significantly improving their diagnostic accuracy. For UWF images, student accuracy increased from 43.6% to 74.1% (p<0.0001 by paired t-test), nearly matching the previously published state-of-the-art AI model's accuracy of 73.3%. For SF images, student accuracy rose from 42.7% to 68.7% (p<0.0001), surpassing the state-of-the-art AI model's 40%. CONCLUSION: Synthetic images can be used effectively in medical education. We also found that humans are more robust to novel situations than AI models, thus showcasing human judgement's essential role in medical diagnosis.

Reliable detection of genetic alterations in cyst fluid DNA for the diagnosis of brain tumors.

PURPOSE: Liquid biopsy of cyst fluid in brain tumors has not been extensively studied to date. The present study was performed to see whether diagnostic genetic alterations found in brain tumor tissue DNA could also be detected in cell-free DNA (cfDNA) of cyst fluid in cystic brain tumors. METHODS: Cyst fluid was obtained from 22 patients undergoing surgery for a cystic brain tumor with confirmed genetic alterations in tumor DNA. Pathological diagnoses based on WHO 2021 classification and diagnostic alterations in the tumor DNA, such as IDH1 R132H and TERT promoter mutation for oligodendrogliomas, were detected by Sanger sequencing. The same alterations were analyzed by both droplet digital PCR (ddPCR) and Sanger sequencing in cyst fluid cfDNA. Additionally, multiplex ligation-dependent probe amplification (MLPA) assays were performed to assess 1p/19q status, presence of CDKN2A loss, PTEN loss and EGFR amplification, to assess whether differentiating between astrocytomas and oligodendrogliomas and grading is possible from cyst fluid cfDNA. RESULTS: Twenty-five genetic alterations were found in 22 tumor samples. All (100%) alterations were detected in cyst fluid cfDNA by ddPCR. Twenty of the 25 (80%) alterations were also detected by Sanger sequencing of cyst fluid cfDNA. Variant allele frequency (VAF) in cyst fluid cfDNA was comparable to that of tumor DNA (R = 0.62, Pearson's correlation). MLPA was feasible in 11 out of 17 (65%) diffuse gliomas, with close correlation of results between tumor DNA and cyst fluid cfDNA. CONCLUSION: Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors.

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes.

AIMS: Iron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM. METHODS AND RESULTS: We enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of <10 points as individuals with SPPB scores of <10 points are most likely to be classified as frail and are at high risk for disability and future adverse events, including death. ID was defined as serum ferritin < 100 or 100-299 ng/mL when transferrin saturation (TSAT) was <20% according to the HF guidelines. Among the 562 HF patients (72 ± 14 years old; 56% male), 329 patients (58%) and 191 patients (34%) had ID and low physical function, respectively. Multivariate logistic regression analysis showed that TSAT as a continuous variable, but not ID, was a predictor of low physical function (odds ratio: 0.980, P = 0.024). Subgroup analysis showed that a significant association between low TSAT and low physical function was lost in HF patients with DM (P for interaction < 0.001). A spline dose-response curve for the relationship between TSAT and risk of low physical function with adjustments for covariates associated with low physical function in non-DM patients was almost linear with an increase in the risk of low physical function as the TSAT increased, but such a relationship was not found in the analyses of DM patients. A lack of close TSAT-SPPB relationship in HF patients with DM was confirmed also in a propensity-score-matched cohort. CONCLUSIONS: TSAT as a continuous variable, but not ID, was independently associated with physical function in HF patients, and a significant association was lost in patients with HF and DM, suggesting a limited impact of iron supplementation therapy in HF patients with DM.

Coexistence of sarcopenia and self-reported weight loss is a powerful predictor of mortality in older patients with heart failure.

AIM: We examined whether the addition of self-reported weight loss improves the accuracy of prediction of mortality caused by sarcopenia in heart failure (HF) patients. METHODS: We enrolled 477 HF patients (mean age 77 years) who received combined assessment of sarcopenia and self-reported weight loss. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia. If the patients answered "yes" to the question "have you lost 2 kg or more in the past 6 months?", they were diagnosed as having self-reported weight loss. RESULTS: Sarcopenia and self-reported weight loss coexisted in 32% of patients. During a median follow-up period of 763 days, 65 patients (15%) died. Kaplan-Meier curves showed a significantly higher rate of mortality in HF patients with both sarcopenia and self-reported weight loss than in HF patients with sarcopenia alone. Multivariate Cox proportional hazards analysis showed that the coexistence of sarcopenia and self-reported weight loss is an independent predictor of mortality in HF patients. Inclusion of the coexistence of sarcopenia and self-reported weight loss in the baseline model consisting of established prognostic markers significantly improved both the net reclassification index and the integrated discrimination index. CONCLUSIONS: The coexistence of sarcopenia and self-reported weight loss is a powerful predictor of mortality in HF patients. Geriatr Gerontol Int 2024; 24: 95-101.

Circulating level of ß-aminoisobutyric acid (BAIBA), a novel myokine-like molecule, is inversely associated with fat mass in patients with heart failure.

Results of experimental studies have shown that ß-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule, is an endogenous negative regulator of fat mass in mice, but it remains unclear whether that is the case in humans, though an enhanced BAIBA concentration in patients receiving sodium-glucose cotransporter 2 inhibitors was found in our recent study. The objective of this study was to analyze the determinants of circulating BAIBA concentration in humans, with focus on the possible link between circulating BAIBA and body composition including fat mass. Data for 188 consecutive patients with heart failure (HF, 64 ± 13 years; 70% male) who received a dual energy X ray absorptiometry (DEXA) scan for assessment of body composition including fat mass index (FMI) and appendicular skeletal muscle mass index (ASMI) were used in this study. Plasma BAIBA concentration in a fasting state after stabilization of HF was determined using ultraperformance liquid chromatography. Plasma BAIBA was detected in 66% of the patients. In simple linear regression analyses of data from patients in whom plasma BAIBA was detected, plasma BAIBA concentration was positively correlated with uric acid and was negatively correlated with body mass index (BMI), estimated glomerular filtration rate (eGFR), FMI, and % body fat. There were no correlations between plasma BAIBA concentration and indexes of muscle mass and bone mass. The results of multiple linear regression analyses showed that FMI and % body fat in addition to BMI, but not ASMI, were independent explanatory factors for plasma BAIBA concentration. In conclusion, plasma BAIBA concentration is inversely correlated with indexes of fat mass, indicating that BAIBA may be a therapeutic target for excessive fat accumulation.

Neuropil-like islands are a possible pathogenetic link between glioblastoma and gangliocytoma/ganglioglioma in a case of synchronous bilateral brain tumors.

Neuropil-like islands (NIs) are a histologic hallmark of glioneuronal tumors with neuropil-like islands (GTNIs), but GTNIs are presently not considered a homogeneous entity. The essence of GTNI is likely its glial component, and NIs are now considered aberrant neuronal differentiation or metaplasia. The case we report herein is a 41-year-old woman who was synchronously affected by two brain tumors: one was a glioblastoma (glioblastoma multiforme, GBM), of isocitrate dehydrogenase (IDH)-wild type, with NIs in the left parietal lobe, and the other was histologically a composite gangliocytoma (GC)/anaplastic ganglioglioma (GG) with NIs in the right medial temporal lobe. While both tumors were genetically wild type for IDH, histone H3, and v-raf murine sarcoma viral oncogene homolog B1 (BRAF), the former tumor, but not the latter, was mutated for telomerase reverse transcriptase promoter gene (TERT). A recent systematic study using DNA methylation profiling and next-generation sequencing showed that anaplastic GG separate into other WHO tumor types, including IDH-wild-type GBM. It suggested a diagnostic scheme where an anaplastic GG is likely an IDH-wild-type GBM if it is a BRAF wild type, IDH wild type, and TERT promoter mutant tumor. The likely scenario in this patient is that the GBM results from the progression of GC/anaplastic GG due to the superimposed TERT promoter mutation and the propagation of newly generated GBM cells in the contralateral hemisphere. A systematic analysis using DNA methylation profiling and next-generation sequencing was not available in this study, but the common presence of NIs histologically noted in the two tumors could support this scenario. Although a sufficient volume of molecular and genetic testing is sine qua non for the accurate understanding of brain tumors, the importance of histologic observation cannot be overemphasized.

Miliary Tuberculosis during R-MPV Therapy in an Elderly Patient with Primary Central Nerve System Lymphoma: A Case Report.

Most elderly patients with tuberculosis (TB) have previously been infected with Mycobacterium tuberculosis, which remains dormant in the body for decades and may reactivate when their immunity declines due to underlying diseases. Elderly cancer patients are at a high risk for TB, and the treatment of TB reactivation in these patients is challenging. Among cancer patients, the incidence of TB reactivation is the highest in lymphoma patients. However, the impact of chemotherapy on TB reactivation in lymphoma patients is unknown. We report the case of an immunocompetent elderly patient with primary central nervous system lymphoma (PCNSL) having no prior history of TB, who developed miliary TB during multiagent chemotherapy consisting of rituximab, high-dose methotrexate, procarbazine, and vincristine (R-MPV therapy). Retrospectively, the chest computed tomography showed calcification of the pleura, suggesting that the patient had a latent tuberculosis infection (LTBI) and developed miliary TB from the reactivation of TB triggered by the R-MPV therapy. Our case emphasizes that when chemotherapy is administered to patients with PCNSL, interferon-gamma release assay (IGRA) should be performed if there are findings on chest examination suggestive of LTBI, such as pleural calcification, and if IGRA is positive, chemotherapy should be given concurrently with LTBI treatment.

Karnofsky Performance Status and quality of life in patients with relapsed or refractory primary CNS lymphoma from a phase I/II study of tirabrutinib.

Background: Tirabrutinib, a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL) based on phase I/II studies in Japan. We previously reported the overall response rate and safety profile. We describe Karnofsky Performance Status (KPS) and the quality of life (QoL) in patients with r/r PCNSL receiving tirabrutinib based on more than 1-year follow-up data. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with tirabrutinib once daily at a dose of 320, 480, or 480 mg under fasted conditions. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely EORTC QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L) along with KPS. Results: Forty-four patients (mean age, 60 years [range 29-86]) were enrolled. The median follow-up period was 14.9 months (range, 1.4-27.7). The median KPS of the patients at baseline was 80.0 (range, 70-100), and this remained constant during the treatment. The global health status/QoL in the QLQ-C30 showed significant improvements from baseline through cycles 3-17 and remained relatively constant thereafter until cycle 23. Improvements were also seen in emotional functioning and constipation in the QLQ-C30 segments. Other items of QLQ-C30 and QLQ-BN20, EQ-5D visual analog scales, and EQ-5D index were maintained during the treatment. Conclusions: Tirabrutinib generally maintains KPS and QoL scores with some improvements in specific QoL items in patients with r/r PCNSL.

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study.

BACKGROUND: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI. RESULTS: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38-99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p value 0.044 for overall survival). CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

Distinct patterns of copy number alterations may predict poor outcome in central nervous system germ cell tumors.

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

A clinicopathological analysis of supratentorial ependymoma, ZFTA fusion-positive: utility of immunohistochemical detection of CDKN2A alterations and characteristics of the immune microenvironment.

EPN-ZFTA is a rare brain tumor where prognostic factors remain unclear and no effective immunotherapy or chemotherapy is currently available. Therefore, this study investigated its clinicopathological features, evaluated the utility of MTAP and p16 IHC as surrogate markers of CDKN2A alterations, and characterized the immune microenvironment of EPN-ZFTA. Thirty surgically removed brain tumors, including 10 EPN-ZFTA, were subjected to IHC. MLPA was performed for CDKN2A HD in 20 ependymal tumors, including EPN-ZFTA. The 5-years OS and PFS of EPN-ZFTA were 90% and 60%, respectively. CDKN2A HD was detected in two cases of EPN-ZFTA; these cases were immunohistochemically negative for both MTAP and p16 and recurred earlier after surgery. As for the immune microenvironment of EPN-ZFTA, B7-H3, but not PD-L1, was positive in all cases of EPN-ZFTA; Iba-1-positive or CD204-positive macrophages were large, while infiltrating lymphocytes were small, in number in EPN-ZFTA. Collectively, these results indicate the potential of MTAP and p16 IHC as useful surrogate markers of CDKN2A HD in EPN-ZFTA, and tumor-associated macrophages, including the M2 type, may contribute to its immune microenvironment. Furthermore, the expression of B7-H3 in EPN-ZFTA may indicate the usefulness of B7-H3 as a target of immune checkpoint chemotherapy for EPN-ZFTA via B7-H3 pathway.

Independent Association Between Use of Proton Pump Inhibitors and Muscle Wasting in Patients with Heart Failure: A Single-Center, Ambispective, Observational Study.

BACKGROUND: Although proton pump inhibitors (PPIs) play a pivotal role in the prevention and treatment of gastric acid-related diseases and gastrointestinal adverse events caused by antiplatelet therapies, the safety of long-term use of PPIs has been questioned. OBJECTIVE: The aim of this study was to determine the effects of use of PPIs on muscle mass and bone mineral density in heart failure (HF) patients. METHODS: This was a single-center, ambispective (combined retrospective and prospective), observational study. HF patients (n = 747; 72 years of age; males, 54%) who received a dual-energy x-ray absorptiometry scan were enrolled. Muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.0 kg/m2 in males and <5.4 kg/m2 in females. Propensity scores for the use of PPIs were calculated using a multivariate logistic regression model to minimize selection bias. RESULTS: Before propensity score matching, ASMI was significantly lower in patients receiving PPIs than in patients not receiving PPIs, resulting in a higher prevalence of muscle wasting in the PPI group. Such a relationship between use of PPIs and muscle wasting remained after propensity score matching. In multivariate Cox regression analyses, use of PPIs was independently associated with presence of muscle wasting (hazard ratio 1.68, 95% confidence interval 1.05-2.69) after adjustment for established risk factors of sarcopenia. On the other hand, there were no differences in bone mineral density between the PPI group and the no-PPI group. CONCLUSION: Use of PPIs is associated with a high risk of muscle wasting in HF patients. Caution is warranted when long-term PPI treatment is performed in sarcopenic HF patients and HF patients with several risk factors for muscle wasting.

Impact of tumor markers on diagnosis, treatment and prognosis in CNS germ cell tumors: correlations with clinical practice and histopathology.

Tumor markers in CNS germ cell tumors (GCTs) include human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP), which have significant diagnostic implications, as elevation of either one leads to clinical diagnosis of non-germinomatous GCTs without histopathological confirmation, justifying intensified chemotherapy and irradiation. The current study, based on an international cohort of histopathologically verified GCTs that underwent biopsy (n = 85) or resection (n = 76), sought to better define the clinical role and prognostic significance of tumor markers from serum and CSF in this challenging patient population. We found that HCG was elevated only in cases with a germinoma or choriocarcinoma component, and there existed a clear cut-off HCG value between the two. AFP was often elevated in GCTs without a yolk sac tumor component, especially immature teratoma. HCG was elevated only in CSF in 3-of-52 cases, and AFP was elevated only in serum in 7-of-49 cases, emphasizing the potential utilization of both serum and CSF studies. Immature teratoma demonstrated unfavorable prognosis independent of tumor marker status, with 56% 5-year overall survival; however, co-existent germinoma components indicated a more favorable prognosis. Taken together, the study findings emphasize the importance for routine assessment and guarded interpretation of tumor markers in CNS GCTs.