Cancer Research and Treatment

Case Report

Long-term Complete Remission of Decitabine-Primed Tandem CD19/CD22 CAR-T Therapy with PD-1 and BTK Inhibitors Maintenance in a Refractory Primary Central Nervous System Lymphoma Patient: Rui Zou, Xiao Zhou, Hailing Liu, Peng Wang, Fan Xia, Liqing Kang, Lei Yu, Depei Wu, Zhengming Jin, Changju Qu; Cancer Res Treat. 2023;55(4):1363-1368. Published online June 14, 2023; DOI: https://doi.org/10.4143/crt.2023.371

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin’s lymphoma that affects the brain, eyes, cerebrospinal fluid, or spinal cord without systemic involvement. The outcome of patients with PCNSL is worse compared to patients with systemic diffuse large B-cell lymphoma. Given potential mortality associated with severe immune effector cell-associated neurotoxicity syndrome (ICANS), patients with PCNSL have been excluded from most clinical trials involving chimeric antigen receptor T-cell (CAR-T) therapy initially. Here, we report for the first time to apply decitabine-primed tandem CD19/CD22 dual-targeted CAR-T therapy with programmed cell death-1 (PD-1) and Bruton’s tyrosine kinase (BTK) inhibitors maintenance in one patient with multiline-resistant refractory PCNSL and the patient has maintained complete remission (CR) for a 35-month follow-up period. This case represents the first successful treatment of multiline resistant refractory PCNSL with long-term CR and without inducing ICANS under tandem CD19/CD22 bispecific CAR-T therapy followed by maintenance therapy with PD-1 and BTK inhibitors. This study shows tremendous potential in the treatment of PCNSL and offers a look toward ongoing clinical studies.

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Original Articles

CNS cancer

Hypo-trimethylation of Histone H3 Lysine 4 and Hyper-tri/dimethylation of Histone H3 Lysine 27 as Epigenetic Markers of Poor Prognosis in Patients with Primary Central Nervous System Lymphoma: Hoon Gi Kim, Minseok S. Kim, Young Sam Lee, Eun Hee Lee, Dae Cheol Kim, Sung-Hun Lee, Young Zoon Kim; Cancer Res Treat. 2022;54(3):690-708. Published online November 17, 2021; DOI: https://doi.org/10.4143/crt.2021.1121

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to investigate the methylation status of major histone modification sites in primary central nervous system lymphoma (PCNSL) samples and examine their prognostic roles in patients with PCNSL.
Materials and Method
Between 2007 and 2020, 87 patients were histopathologically diagnosed with PCNSL. We performed immunohistochemical staining of the formalin-fixed paraffin-embedded samples of PCNSL for major histone modification sites, such as H3K4, H3K9, H3K27, H3K14, and H3K36. After detection of meaningful methylation sites, we examined histone modification enzymes that induce methylation or demethylation at each site using immunohistochemical staining. The meaningful immunoreactivity was validated by western blotting using fresh tissue of PCNSL.
Results
More frequent recurrences were found in hypomethylation of H3K4me3 (p=0.004) and hypermethylation of H3K27me2 (p<0.001) and H3K27me3 (p=0.002). These factors were also statistically related to short PFS and overall survival in the univariate and multivariate analyses. Next, histone modification enzymes inducing the demethylation of H3K4 (lysine-specific demethylase-1/2 and Jumonji AT-rich interactive domain [JARID] 1A-D]) and methylation of H3K27 (enhancer of zeste homolog [EZH]-1/2) were immu- nohistochemically stained. Among them, the immunoreactivity of JARID1A inversely associated with the methylation status of H3K4me3 (R²=-1.431), and immunoreactivity of EZH2 was directly associated with the methylation status of H3K27me2 (R²=0.667) and H3K27me3 (R²=0.604). These results were validated by western blotting in fresh PCNSL samples.
Conclusion
Our study suggests that hypomethylation of H3K4me3 and hypermethylation of H3K27me2 and H3K27me3 could be associated with poor outcomes in patients with PCNSL and that these relationships are modified by JARID1A and EZH2.

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Nationwide Population-Based Incidence and Survival Rates of Malignant Central Nervous System Germ Cell Tumors in Korea, 2005-2012: Seung Hoon Lee, Kyu-Won Jung, Johyun Ha, Chang-Mo Oh, Hyeseon Kim, Hyeon Jin Park, Heon Yoo, Young-Joo Won; Cancer Res Treat. 2017;49(2):494-501. Published online August 24, 2016; DOI: https://doi.org/10.4143/crt.2016.129

Abstract PDF PubReader ePub

Purpose
Malignant central nervous system (CNS) germ cell tumors (GCTs), although rare, are thought to occur more frequently among Asians. However, a recent population-based study revealed no differences in GCT incidence between Asians and Caucasians. Therefore, this study was conducted to determine the incidence and survival rates of CNS GCTs using the national cancer incidence database, and to compare these rates to those in the United States and Japan.
Materials and Methods
We extracted CNS GCT patients diagnosed between 2005 and 2012 from the Korea Central Cancer Registry database. Age-standardized rates (ASRs), annual percentage change, and the male-female incidence rate ratios (IRRs) were calculated. To estimate the survival rate, we used data for patients diagnosed between 2005 and 2010 and followed their cases until December 31, 2013.
Results
The ASR for CNS GCT between 2005 and 2012 was 0.179 per 100,000 (95% confidence interval, 0.166 to 0.193), with an overall male-to-female (M:F) IRR of 2.95:1. However, when stratified by site, the M:F IRR was 13.62:1 for tumors of the pineal region and 1.87:1 for those located in nonpineal regions. The most frequent histologic type was germinoma (76.0%), and the most frequent location was the suprasellar region (48.5%). The 5-year survival rate of germinoma patients was 95.3%.
Conclusion
The incidence rate of CNS GCTs in Korea during 2005-2012 was 0.179 per 100,000, which was similar to that of the Asian/Pacific Islander subpopulation in the United States. Moreover, the CNS GCT survival rate in Korea was similar to rates in Japan and the United States.

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Population-based Incidence and Survival for Primary Central Nervous System Lymphoma in Korea, 1999-2009: Sang-Hoon Shin, Kyu-Won Jung, Johyun Ha, Seung Hoon Lee, Young-Joo Won, Heon Yoo; Cancer Res Treat. 2015;47(4):569-574. Published online February 12, 2015; DOI: https://doi.org/10.4143/crt.2014.085

Abstract PDF PubReader ePub

Purpose
Primary central nervous system lymphoma (PCNSL) is an uncommon brain tumor accounting for 2%-5% of all primary brain tumors. Few population-based analyses of survival for patients with PCNSL have been conducted, particularly in Asian countries. Materials and Methods Using the Korea National Cancer Incidence Database, 1,062 cases of PCNSL newly diagnosed from 1999 to 2009 were analyzed. The crude rate, age-standardized rate (ASR), and annual percent change were calculated. To estimate the observed survival, we restricted the data to between 1999 and 2007 and followed the cases until December 2010. The overall survival was estimated using the Kaplan-Meier method, and piecewise Poisson regression model.
Results
The ASR for PCNSL between 1999 and 2009 was 0.17 per 100,000, and the annual percent change from 1999 to 2009 was 8.8% (p < 0.001). The ASR of males was higher than that of females, and the older groups (60s or over) showed the largest increase in incidence rates. For all ages, the five-year survival from PCNSL was 29.9% between 1999 and 2007. Survival from PCNSL is known to show strong association with age at diagnosis. Conclusion These results are similar to those of previous studies. Our findings may be helpful to clinicians and patients in determining long-term prognoses for PCNSL.

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Case Reports

Primary Histiocytic Sarcoma of the Central Nervous System: Hoonsub So, Sun A Kim, Dok Hyun Yoon, Shin Kwang Khang, Jihye Hwang, Chong Hyun Suh, Cheolwon Suh; Cancer Res Treat. 2015;47(2):322-328. Published online August 29, 2014; DOI: https://doi.org/10.4143/crt.2013.163

Abstract PDF PubReader ePub

Histiocytic sarcoma is a type of lymphoma that rarely involves the central nervous system (CNS). Its rarity can easily lead to a misdiagnosis. We describe a patient with primary CNS histocytic sarcoma involving the cerebral hemisphere and spinal cord, who had been initially misdiagnosed as demyelinating disease. Two biopsies were necessary before a correct diagnosis was made. A histologic examination showed bizarre shaped histiocytes with larger nuclei and nuclear atypia. The cells were positive for CD68, CD163, and S-100 protein. As a resection was not feasible due to multifocality, he was treated with highdose methotrexate, but showed no response. As a result, he was switched to high dose cytarabine; but again, showed no response. The patient died 2 months from the start of chemotherapy and 8 months from the onset of symptoms. Since few patients with this condition have been described and histopathology is difficult to diagnose, suspicion of the disease is essential.

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A Rare Presentation of Follicular Lymphoma: Cerebellar Involvement, Successfully Treated with a Combination of Radiotherapy and Chemotherapy: Nuri Karadurmus, Selmin Ataergin, Gokhan Erdem, Mustafa Cakar, Ozdes Emer, Sukru Ozaydin, Mustafa Ozturk, Mukerrem Safali, Fikret Arpaci; Cancer Res Treat. 2013;45(3):234-238. Published online September 30, 2013; DOI: https://doi.org/10.4143/crt.2013.45.3.234

Abstract PDF PubReader ePub

The central nervous system (CNS) is an important area of involvement for both high-grade, aggressive primary and secondary lymphomas. Although follicular lymphoma represents a low-grade histology, it may rarely present with CNS involvement. Here, we describe a patient diagnosed with follicular lymphoma who was presented with cerebellar involvement.

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Rare central nervous system lymphomas
Furqaan Ahmed Kaji, Nicolás Martinez‐Calle, Vishakha Sovani, Christopher Paul Fox
British Journal of Haematology.2022; 197(6): 662. CrossRef
Secondary parenchymal CNS involvement by lymphoma including rare types: Follicular and EBV-positive NK/T cell lymphoma, nasal type
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Cerebral Amyloidoma Resulting from Central Nervous System Lymphoplasmacytic Lymphoma: A Case Report and Literature Review
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Sites of extranodal involvement are prognostic in patients with stage 1 follicular lymphoma
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Follicular Lymphoma Presenting with Leptomeningeal Disease
Rubens Costa, Ricardo Costa, Renata Costa
Case Reports in Hematology.2014; 2014: 1. CrossRef

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Original Articles

Combined Chemotherapy and Radiotherapy for Primary CNS Lymphoma: Jeong Eun Lee, Dae Yong Kim, Yong Chan Ahn, Do Hoon Lim, Seung Jae Huh, Seong Soo Shin, Won Seok Kim, Won Ki Kang, Do Hyun Nam, Jung Il Lee, Jong Hyun Kim; Cancer Res Treat. 2001;33(5):398-403. Published online October 31, 2001; DOI: https://doi.org/10.4143/crt.2001.33.5.398

Abstract PDF: PURPOSE
This study was performed in order to evaluate the effectiveness of combined chemotherapy and radiotherapy (RT) in primary central nervous system lymphoma (PCNSL).
MATERIALS AND METHODS
From January 1995 to August 1999, 21 patients with a diagnosis of PCNSL were treated with combined chemotherapy and radiotherapy. Their median age was 47 years with range of 19 to 78 years. Twelve patients were male and nine patients were female. All patients were immunocompetent and they had no evidence of systemic lymphoma. All patients underwent placement of an Ommaya reservoir and recieved a combination regimen using pre-RT systemic and intra-Ommaya methotrexate (MTX), 40 Gy whole-brain RT with a 14.4 Gy boost, and 2 courses of post-RT high-dose cytarabine. The median follow-up period of all patients and survived patients were 22 months and 36 months, respectively.
RESULTS
The median overall survival duration was 21 months and the overall two- and four-year survival rates were 51% and 43%, respectively. Complete response (CR), partial response, stable disease, and progressive disease were achieved in 12, 3, 1, and 5 patients, respectively. All nine patients without CR expired within 1-31 months (median 6 months). Two patients among the patients with CR developed recurrence after 13 and 14 months, respectively. The location of recurrent disease was within the port of radiation boost. Survival was influenced by age, performance status, and CR. There was one episode of MTX neurotoxicity and hepatotoxicity,respectively.
CONCLUSION
Combined chemotherapy and radiotherapy was an effective treatment for PCNSL, and was associated with a minimum toxicity. However, we must pay attention to the recurrence and late toxicity, particularly within two years following treatment.

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A Case of Relapse in Central Nervous System during the Chemotherapy of Testicular Lymphoma Stage 1: Wook Sun Choi, Si Young Kim, Jeong Hee Kim, Hwi Joong Yoon, Kyung Sam Cho; J Korean Cancer Assoc. 1996;28(6):1133-1139.

Abstract PDF: Primary testicular non-Hodgkin's Lymphoma is very rare. It may be the systemic manifestation of nodular lymphoma. The most common symptom of primary testicular lymphoma is the painless enlargement of testis. It frequently involves Waldeyer's ring, skin and central nervous system. The combination chemotherapy and CNS prophlylaxis may be needed in the treatment of early stage primary testicular non-Hodgkin's lymphoma. We are reporting a case of primary testicular non-Hodgkin's 1ymphoma stage I, which relapsed in central nervous system during combination chemotherapy.

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