Mutational burden and immune recognition of gliomas.

PURPOSE OF REVIEW: Recent evidence suggests high tumor mutational burden (TMB-H) as a predictor of response to immune checkpoint blockade (ICB) in cancer. However, results in TMB-H gliomas have been inconsistent. In this article, we discuss the main pathways leading to TMB-H in glioma and how these might affect immunotherapy response. RECENT FINDINGS: Recent characterization of TMB-H gliomas showed that 'post-treatment' related to mismatch repair (MMR) deficiency is the most common mechanism leading to TMB-H in gliomas. Unexpectedly, preliminary evidence suggested that benefit with ICB is rare in this population. Contrary to expectations, ICB response was reported in a subset of TMB-H gliomas associated with constitutional MMR or polymerase epsilon (POLE) defects (e.g., constitutional biallelic MMRd deficiency). In other cancers, several trials suggest increased ICB efficacy is critically associated with increased lymphocyte infiltration at baseline which is missing in most gliomas. Further characterization of the immune microenvironment of gliomas is needed to identify biomarkers to select the patients who will benefit from ICB. SUMMARY: Intrinsic molecular and immunological differences between gliomas and other cancers might explain the lack of efficacy of ICB in a subset of TMB-H gliomas. Novel combinations and biomarkers are awaited to improve immunotherapy response in these cancers.

Surgical approach to the treatment of pituicytoma. Report of five cases and a literature review.

Background: Pituicytoma (PTs) is a rare tumor of the sella and suprasellar region, derived from the pituicytes of the neurohypophysis, having distinct histological characteristics of glial neoplasms. We reported, the clinical data, neuroimaging studies, surgical approaches and pathology in five patients with PTs and also, we reviewed the literature. Methods: Retrospective chart from five consecutive patients with PTs treated at one University Hospital from 2016 to 2021 were reviewed. In addition, we conducted a search in PubMed/Medline databases using the term "Pituicytoma". Data regarding age, gender, pathological findings, and treatment modality applied were extracted. Results: All patients were female, aged 29-63, complaining of headaches, visual loss and field defects, dizziness and normal or abnormal levels of circulating pituitary hormones. Magnetic Resonance Imaging (MRI) showed in all patients a sellar and suprasellar mass, which was removed through an endoscopic transsphenoidal approach. Our third patient had a subtotal resection followed by close observation. Histopathology showed a glial non-infiltrative tumors with spindle cells, and a final diagnosis of pituicytoma was made. After surgery, visual field defects in all patients were normalized, and in two patients normal levels of plasma hormones were restored. After a mean of three years follow-up, the patients were managed post-operatively through close clinical observation and serial MRI. None of the patients had recurrence of the disease. Conclusion: PTs is a rare glial tumor of the sellar and suprasellar region that arises from neurohypophyseal pituicytes. Disease control may be achieved by total excision.

Prognostic Factors of Long-Term Outcomes after Primary Chemo-Radiotherapy in Non-Metastatic Anal Squamous Cell Carcinoma: An International Bicentric Cohort.

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with human papillomavirus (HPV) infection. The locally advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate the prognostic factors for ASCC after curative CRT. A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at two centers was performed. Complete response (CR), disease-free survival (DFS), and overall survival (OS) were analyzed by Kaplan-Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. The CR rate was 70% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated with shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77-18.81) in a univariate analysis. The median follow-up was 38 months, with a 3-year DFS of 71%. The prognostic factors for DFS were cT1-T2 (p = 0.0002), N0 (p = 0.035), HIV-positive (p = 0.047), HIV-HPV coinfection (p = 0.018), and well-differentiated tumors (p = 0.037). The three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.02) and well-differentiated tumors (p = 0.003) were associated with better OS. The unsupervised analysis demonstrated a clear segregation of patients in three clusters, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.74 95% CI = 1.25-2.42, p = 0.0008) were enriched with the locally advanced disease, anal canal location, HIV-HPV coinfection, and non-CR. In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

[Algorithm for the integrated diagnosis of gliomas 2021. Our experience]. / Algoritmo para el diagnóstico integrado de los gliomas 2021. Nuestra experiencia.

The utilization of the different molecular techniques for the diagnosis of gliomas according to the WHO classification is still not available to everyone in our country. Our objective was to describe the diagnostic algorithm developed based on available resources, in accordance with the current classification (2021). Also, to describe the epidemiological profile of gliomas diagnosed between 2018-2021 at the Roffo Institute and compare it with the international literature. IDH1-R132H and ATRX mutation, as well as 1p19q status, CDKN2A, EGFR, and p53 were evaluated. 94 patients were included, 53.2% were male, with a mean age of 50.9 years. The most frequent diagnosis was GB IDH1-wild type (63.8%). Considering only grade 2 and 3 gliomas, diffuse astrocytoma IDH1-Mutated / ATRX-Mutated / p53-overexpressed, grade 2 (11.7%) was the most frequent diagnosis. Regarding their location, 67% of the tumors were located in the neocortical telencephalon: 24.5% of the total in the frontal lobe. In 95.7% of cases, a conclusive integrated diagnosis was reached following the proposed algorithm. The epidemiological characteristics coincide with what has been published in the literature. Molecular biology allowed us to clearly differentiate pathologies that we assumed were related from a histological point of view, but which, observing their natural history, their genetics and their response to established treatments were different tumors, although they were all called "gliomas". International standards do not conceive CNS tumor diagnosis without molecular biology. It is not acceptable to continue to diagnose only with histological standards. The proposed algorithm could be a viable and reliable alternative.

La aplicación de las diferentes técnicas moleculares para el diagnóstico de los gliomas según la clasificación de la OMS, sigue sin estar al alcance de todos en nuestro país. Nuestro objetivo fue describir el protocolo diagnóstico desarrollado en función de los recursos disponibles, conforme con la clasificación vigente (2021). También, describir el perfil epidemiológico de los gliomas diagnosticados entre 2018-2021 en el Instituto Roffo y contrastarlo con la literatura. Se evaluó la mutación en IDH1-R132H, ATRX, el estado del 1p19q, CDKN2A, EGFR y del p53. Se incluyeron 94 pacientes, 53.2% fueron masculinos, con una edad promedio de 50.9 años. El diagnóstico más frecuente fue el de GB IDH1-no mutado (63.8%). Considerando únicamente a los gliomas grado 2 y 3, el astrocitoma difuso IDH1-Mutado/ATRX-Mutado/p53-sobreexpresado, grado 2 (11.7%) fue el más frecuente. En cuanto a su localización, el 67% de los tumores se ubicaron en el telencéfalo neocortical: 24.5% del total en el lóbulo frontal. En el 95.7% de los casos se arribó a un diagnóstico integrado concluyente siguiendo el algoritmo propuesto. Las características epidemiológicas coinciden con lo publicado en la literatura. La biología molecular nos permitió diferenciar nítidamente enfermedades que suponíamos emparentadas desde un punto de vista histológico, pero que observando su historia natural, su genética y su respuesta a tratamientos instaurados eran tumores distintos, aunque todos fueran llamados "gliomas". Los estándares internacionales no conciben su diagnóstico sin la biología molecular. No es aceptable que se siga diagnosticando únicamente con estándares histológicos. El algoritmo propuesto podría ser una alternativa viable y confiable.

Preoperative imaging features: Are they useful tools for predicting IDH1 mutation status in gliomas Grades II-IV?

Background: It is already known that gliomas biomolecular parameters have a reliable prognostic value. However, an invasive procedure is required to determine them. Our aim was to better understand the clinical characteristics of gliomas Grades II-IV and to assess the usefulness of imaging features in magnetic resonance imaging (MRI) to predict the isocitrate dehydrogenase one (IDH1) mutation. Methods: Preoperative MRI characteristics were retrospectively reviewed and molecular diagnosis of gliomas was tested in adult patients between 2014 and 2021 in two institutions. We applied a biological criterion to divide the brain in cerebral compartments. Results: A total of 108 patients met the inclusion criteria. Contrast enhancement (CE) in MRI was significantly associated with wild-type IDH1 (IDH1-Wt) (P < 0.00002). Furthermore, the positive predictive value of CE for IDH1-Wt was of 87.1%. On the other hand, the negative predictive value of non-CE for mutated IDH1 (IDH1-Mut) was of 52.6%; 60.2% of gliomas were located in the neocortical and 24.1% in the allocortical/mesocortical telencephalon. Considering gliomas Grades II-III, 66.7% of IDH1-Mut and 28.6% of IDH1-Wt gliomas were located in the neocortex, without statistical significance. Conclusion: Our research revealed that CE is useful for predicting IDH1-Wt in gliomas. On the contrary, nonCE is not useful for predicting IDH1-Mut gliomas. Thus, the traditional concept of associating non-CE MRI with a low-grade glioma should be reviewed, as it can lead to an underestimation of the potential aggressiveness of the tumor. If this association was validated with the future prospective studies, a noninvasive tool would be available for predicting gliomas IDH1 mutation status.

Which biological pathways are responsible for the late appearance of brain metastases in renal cell carcinoma? Analysis of eight cases.

Background: Renal cell carcinoma (RCC) represents 1% of all cancers and its brain metastases amount to 8.1% of all metastatic tumors. Late brain metastases are defined as tumors that appear 10 years after diagnosis of the primary lesion. The objective of this work is to discuss which biological pathways are responsible for the late appearance of these metastases analyzing eight cases. Case Description: We report here eight cases of late brain metastases of RCC treated between 2018 and 2021. Patients consulted for different clinical complaints. Brain magnetic resonance imaging and computed tomography scan were performed on all patients. They were treated by complete surgical resection plus radiosurgery or by radiosurgery alone. The histology of most metastases showed clear cell RCC. Conclusion: In the presence of a patient with an intracranial tumor and a history of RCC with more than 10 years of evolution, the presence of late metastasis should always be considered. There are many theories described in the literature that try to explain the late appearance of brain metastases from RCC (low mitotic index, impaired immune system, cross talk, self-seeding, and among others).

Effects of time to chemoradiation on high-grade gliomas from the Buenos Aires Metropolitan Area.

High-Grade Gliomas (HGG) are the most frequent brain tumor in adults. The gold standard of clinical care recommends beginning chemoradiation within 6 weeks of surgery. Disparities in access to healthcare in Argentina are notorious, often leading to treatment delays. We conducted this retrospective study to evaluate if time to chemoradiation after surgery is correlated with progression-free survival (PFS). Our study included clinical cases with a histological diagnosis of Glioblastoma (GBM), Anaplastic Astrocytoma (AA) or High-Grade Glioma (HGG) in patients over 18 years of age from 2014 to 2020. We collected data on clinical presentation, type of resection, time to surgery, time to chemoradiation, location within the Buenos Aires Metropolitan Area (BAMA) and type of health insurance. We found 63 patients that fit our inclusion criteria, including 26 (41.3%) females and 37 (58.7%) males. Their median age was 54 years old (19-86). Maximal safe resection was achieved in 49.2% (n = 31) of the patients, incomplete resection in 34.9% (n = 22) and the other 15.9% (n = 10) received a biopsy, but no resection. The type of health care insurance was almost evenly divided, with 55.6% (n = 35) of the patients having public vs. 44.4% (n = 28) having private health insurance. Median time to chemoradiation after surgery was 8 (CI 6.68-9.9) weeks for the global population. When we ordered the patients PFS by time to chemoradiation we found that there was a statistically significant effect of time to chemoradiation on patient PFS. Patients had a PFS of 10 months (p = 0.014) (CI 6.89-13.10) when they received chemoradiation <5 weeks vs a PFS of 7 months (CI 4.93-9.06) when they received chemoradiation between 5 to 8 weeks and a PFS of 4 months (CI 3.76-4.26 HR 2.18 p = 0.006) when they received chemoradiation >8 weeks after surgery. Also, our univariate and multivariate analysis found that temporal lobe location (p = 0.03), GMB histology (p = 0.02) and biopsy as surgical intervention (p = 0.02) all had a statistically significant effect on patient PFS. Thus, time to chemoradiation is an important factor in patient PFS. Our data show that although an increase in HGG severity contributes to a decrease in patient PFS, there is also a large effect of time to chemoradiation. Our results suggest that we can improve patient PFS by making access to healthcare in Buenos Aires more equitable by reducing the average time to chemoradiation following tumor resection.

Algoritmo para el diagnóstico integrado de los gliomas 2021. Nuestra experiencia / Algorithm for the integrated diagnosis of gliomas 2021. Our experience

Resumen La aplicación de las diferentes técnicas moleculares para el diagnóstico de los gliomas según la clasificación de la OMS, sigue sin estar al alcance de todos en nuestro país. Nuestro objetivo fue describir el protocolo diagnóstico desarrollado en función de los recursos disponibles, conforme con la clasificación vigente (2021). También, describir el perfil epidemiológico de los gliomas diagnosticados entre 2018-2021 en el Instituto Roffo y contrastarlo con la literatura. Se evaluó la mutación en IDH1-R132H, ATRX, el estado del 1p19q, CDKN2A, EGFR y del p53. Se incluyeron 94 pacientes, 53.2% fueron masculinos, con una edad promedio de 50.9 años. El diagnóstico más frecuente fue el de GB IDH1-no mutado (63.8%). Considerando únicamente a los gliomas grado 2 y 3, el astrocitoma difuso IDH1-Mutado/ATRX-Mutado/p53-sobreexpresado, grado 2 (11.7%) fue el más frecuente. En cuanto a su localización, el 67% de los tumores se ubicaron en el telencéfalo neocortical: 24.5% del total en el lóbulo frontal. En el 95.7% de los casos se arribó a un diagnóstico integrado concluyente siguiendo el algoritmo propuesto. Las características epidemiológicas coinciden con lo publicado en la literatura. La biología molecular nos permitió diferenciar nítidamente enfermedades que suponíamos emparentadas desde un punto de vista histológico, pero que observando su historia natural, su genética y su respuesta a tratamientos instaurados eran tumores distintos, aunque todos fueran llamados "gliomas". Los estándares internacionales no conciben su diagnóstico sin la biología molecular. No es aceptable que se siga diagnosticando únicamente con estándares histológicos. El algoritmo propuesto podría ser una alternativa viable y confiable.

Abstract The utilization of the different molecular techniques for the diagnosis of gliomas according to the WHO classification is still not available to everyone in our country. Our objective was to describe the diagnostic algorithm devel oped based on available resources, in accordance with the current classification (2021). Also, to describe the epidemiological profile of gliomas diagnosed between 2018-2021 at the Roffo Institute and compare it with the international literature. IDH1-R132H and ATRX mutation, as well as 1p19q status, CDKN2A, EGFR, and p53 were evaluated. 94 patients were included, 53.2% were male, with a mean age of 50.9 years. The most frequent diagnosis was GB IDH1-wild type (63.8%). Considering only grade 2 and 3 gliomas, diffuse astrocytoma IDH1- Mutated / ATRX-Mutated / p53-overexpressed, grade 2 (11.7%) was the most frequent diagnosis. Regarding their location, 67% of the tumors were located in the neocortical telencephalon: 24.5% of the total in the frontal lobe. In 95.7% of cases, a conclusive integrated diagnosis was reached following the proposed algorithm. The epidemiological characteristics coincide with what has been published in the literature. Molecular biology allowed us to clearly differentiate pathologies that we assumed were related from a histological point of view, but which, observing their natural history, their genetics and their response to established treatments were different tumors, although they were all called "gliomas". International standards do not conceive CNS tumor diagnosis without molecular biology. It is not acceptable to continue to diagnose only with histological standards. The proposed algorithm could be a viable and reliable alternative.

Manejo de toxicidades por inmunoterapias / Management of toxicities by immunotherapies

La inmunoterapia vino para quedarse. Partiendo desde el melanoma, fue ganando terreno en tratamiento de otros tumores más prevalentes, razón por la cual actualmente es ineludible para el personal de la salud involucrado en el cuidado de pacientes oncológicos, conocer el manejo de los eventos adversos asociados a las drogas empleadas (AU)

Immunotherapy is here to stay. Moving from melanoma to the most prevalent tumors, in just a few years it becomes one of the first choices for the medical oncologist. It is for this reason that all the health care staff should be aware of the management of the adverse effects of the drugs involved (AU)

Experiencia de una institución Argentina en tumores neuroendocrinos de cérvix / Experience of an Argentine institution in neuroendocrine tumors of the cervix

El cáncer de cuello uterino es de alta prevalencia en nuestra comunidad. El subtipo escamoso tiene directa relación con factores socioeconómicos. Los tumores neuroendocrinos son la variedad menos frecuente y no presentan un claro agente causal. En este trabajo se analizan los casos identificados en nuestro instituto en la última década, enfocándonos en los aspectos de presentación de la enfermedad y rasgos sociales (AU)

The cervical cancer has a high prevalence in our comunity. It is a disease with a direct correlation to socio-economic factors in cases of squamous subtype. Neuroendocrine tumors are the least frequent subtype, and do not present a clear cause. In this study, we present the cases identified in our institution in the last decade, focusing on the clinical presentation aspects of the disease and its social traits (AU)