Intracranial non-germinomatous germ cell tumors in children and adolescents: how can the experience from an uppermiddle-income country contribute to the worldwide effort to improve outcomes?

Background: Non-germinomatous germ cell tumors (NGGCT) accounts for one third of intracranial GCT. While the germinoma group have an excellent overall survival, the standard of practice for children with NGGCT is still under evaluation. Aims: Describe the results of the of the Brazilian consortium protocol. Methods: Since 2013, 15 patients with a diagnosis of NGGCT by histopathology and/or serum/cerebrospinal fluid (CSF) tumor markers, ßHCG >200mlU/ml and/or positive alpha-fetoprotein were treated with neoadjuvant chemotherapy with carboplatin, cyclophosphamide and etoposide followed by ventricular radiotherapy (RTV) of 18Gy with boost (32Gy) to the primary site. Metastatic patients underwent craniospinal irradiation (CSI) and "slow responders" to the four initial cycles of CT, to autologous stem cell transplantation (ASCT) followed by CSI. Results: Mean age, 13.1 years. Thirteen males. Primary sites: pineal (n=12), suprasellar (n=2) and bifocal (n=1). Four patients were metastatic at diagnosis. Eight patients had CSF and/or serum alpha-fetoprotein levels > 1,000ng/ml. Tumor responses after chemotherapy demonstrated complete in six cases and partial in seven, with "second-look" surgery being performed in five cases, and two patients presenting viable lesions being referred to ASCT. The main toxicity observed was hematological grades 3/4. Two patients with metastatic disease, one with Down Syndrome and AFP > 1,000ng/ml and the other with choriocarcinoma and pulmonary metastases, developed progressive disease resulting in death, as well as two other patients without evidence of disease, due to endocrinological disorders. Event-free and overall survival at 2 and 5 years were 80% and 72.7%, respectively, with a mean follow-up of 48 months (range, 7-107). Conclusions: Despite the small number of patients, in our series, treatment with six cycles of chemotherapy and RTV with focal boost for localized disease (n=11) and ACST for identified slow responders (n=2) seem to be effective strategies contributing to the overall effort to improve outcomes of this group of patients.

Up-Front ASCT Overcomes the Survival Benefit Provided by HDAC-Based Induction Regimens in Mantle Cell Lymphoma: Data from a Real-Life and Long-Term Cohort.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare malignancy with heterogeneous behavior. Despite the therapeutic advances recently achieved, MCL remains incurable. Currently, the standard of care for young and fit patients involves induction immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). However, the role of more intensive induction regimens, such as those based on high doses of cytarabine (HDAC), remains controversial in the management of ASCT-eligible patients. METHODS: This retrospective, observational, and single-center study involved 165 MCL patients treated at the largest oncology center in Latin America from 2010 to 2022. We aimed to assess outcomes, determine survival predictors, and compare responses between different primary therapeutic strategies, with a focus on assessing the impact of HDAC-based regimens on outcomes in ASCT-eligible patients. RESULTS: The median age at diagnosis was 65 years (38-89 years), and 73.9% were male. More than 90% of the cases had a classic nodal form (cnMCL), 76.4% had BM infiltration, and 56.4% presented splenomegaly. Bulky ≥ 7 cm, B-symptoms, ECOG ≥ 2, and advanced-stage III/IV were observed in 32.7%, 64.8%, 32.1%, and 95.8%, respectively. Sixty-four percent of patients were categorized as having high-risk MIPI. With a median follow-up of 71.1 months, the estimated 2-year OS and EFS were 64.1% and 31.8%, respectively. Patients treated with (R)-HDAC-based regimens had a higher ORR (85.9% vs. 65.7%, p = 0.007) compared to those receiving (R)-CHOP, as well as lower POD-24 rates (61.9% vs. 80.4%, p = 0.043) and lower mortality (43.9% vs. 68.6%, p = 0.004). However, intensified induction regimens with (R)-HDAC were not associated with a real OS benefit in MCL patients undergoing up-front consolidation with ASCT (2-year OS: 88.7% vs. 78.8%, p = 0.289). Up-front ASCT was independently associated with increased OS (p < 0.001), EFS (p = 0.005), and lower POD-24 rates (p < 0.001) in MCL. Additionally, CNS infiltration, TLS, hypoalbuminemia, and the absence of remission after induction were predictors of poor OS. CONCLUSIONS: In the largest Latin American cohort of MCL patients, we confirmed the OS benefit promoted by up-front consolidation with ASCT in young and fit patients, regardless of the intensity of the immunochemotherapy regimen used in the pre-ASCT induction. Although HDAC-based regimens were not associated with an unequivocal increase in OS for ASCT-eligible patients, it was associated with higher ORR and lower rates of early relapses for the whole cohort.

Evaluation of cytokine profile in the different phases of the autologous hematopoietic stem cell transplantation in patients with multiple myeloma.

BACKGROUND: The autologous hematopoietic stem cell transplantation (ASCT) is of fundamental importance in the treatment of patients with multiple myeloma (MM). Nevertheless, due to its toxicity, it decreases the number of bone marrow cells available, altering the cell interactions and causing an imbalance between pro- and anti-inflammatory cytokines. METHODS: Thus, we determined the serum levels of pro- and anti-inflammatory cytokines in samples of patients with MM obtained from the different phases of ASCT. RESULTS: In summary, the cytokines levels varied considering the different phases of ASCT. The levels of IL-1ra tend to increase in the post-apheresis period suggesting an anti-inflammatory role induced by the apheresis process. A response characterized by the increase in the concentrations of IL-5 and IL-8 was observed in the post-conditioning bone marrow aplasia phase. The rise in IL-5 levels was not correlated with any clinical or laboratory event in this framework; IL-8 was associated with positive blood cultures and seems to have an effect against microbial agents. The increase in the levels of IL-10 and IL-12 suggests a possible regulatory effect of the inflammatory response in the period of bone marrow recovery and IL-12 seems to be inversely associated with the presence of minimal residual disease. CONCLUSIONS: Apheresis process seems to induce an anti-inflammatory response, followed by a pro-inflammatory response and a stimulus for granulocytes differentiation.

The expression of the aminoacid transporters ASCT2 (SLC1A5) and LAT1 (SLC7A5) in astrocytomas / Expressão dos transportadores de aminoácidos ASCT2 (SLC1A5) e LAT1 (SLC7A5) em astrocitomas

OBJECTIVE: ASCT2 and LAT1 are aminoacid transporters involved in glutamine transport and play a role in tumor growth. Previous studies have shown an association of ASCT2 to cell proliferation through the mechanistic Target of Rapamycin (mTOR) translational machinery; LAT1 has been shown as a prognostic marker due to its relation to tumor invasion, microscopic vascular invasion and metastasis. This study analyzed the gene expression of ASCT2 and LAT1 in astrocytomas of different grades and how this correlates to clinical outcome in glioblastoma patients. METHOD: This is an observational study with ASCT2 and LAT1 mRNA expression analysis in 153 samples of human astrocytomas, distributed in different World Health Organization (WHO) grades of malignancy (23 at grade I or pilocytic astrocytoma, 26 at grade II or low-grade astrocytoma, 18 at grade III or anaplastic astrocytoma, 86 at grade IV astrocytoma or glioblastoma (AGIV or GBM)); these were compared to 22 non-neoplastic brain samples. RESULTS: Significant hyperexpression of both genes was observed particularly in malignant astrocytomas (GIII & GBM). Moreover, LAT1 hyperexpression impacted negatively in the overall survival in a subset of GBM patients. CONCLUSION: LAT1 is more expressed in higher grade astrocytomas. It leads to a poorer prognosis among GBM patients and may be a potential therapeutical target.

OBJETIVO: ASCT2 e LAT1 são transportadores de aminoácidos envolvidos no transporte de glutamina e desempenham um papel no crescimento tumoral. Estudos prévios mostraram uma associação de ASCT2 com proliferação celular através da maquinaria de tradução do mTOR; tem sido mostrado que o LAT1 é um marcador prognóstico devido à sua relação com invasão tumoral, invasão vascular microscópica e metástase. Este estudo analisou a expressão gênica de ASCT2 e LAT1 em astrocitomas de diferentes graus e sua correlação com desfecho clínico em pacientes com glioblastoma. METODO: Este é um estudo observacional com análise de expressão de RNAm de ASCT2 e LAT1 em 153 amostras de astrocitomas humanos, distribuídas em diferentes graus de malignidade segundo a OMS (23 astrocitomas de grau I ou astrocitoma pilocítico, 26 de astrocitoma de grau II ou astrocitoma de baixo grau, 18 de astrocitoma de grau III ou astrocitoma anaplásico, 86 de astrocitoma de grau IV ou glioblastoma (AGIV ou GBM); estes foram comparados com 22 amostras cerebrais não neoplásicas. RESULTADOS: Foi observada uma hiperexpressão de ambos os genes, particularmente nos astrocitomas malignos (GIII & GBM). Além disso, a hiperexpressão LAT1 impactou negativamente na sobrevida global em um grupo de pacientes com GBM. CONCLUSÃO: LAT1 é mais expresso em astrocitomas de grau maior. Isso leva a um pior prognóstico entre os pacientes com GBM e pode ser um potencial alvo terapêutico.