Isolated central nervous system relapse in two adolescents with primary mediastinal large B-cell lymphoma after treatment with R-DA-EPOCH.

The addition of rituximab to standard regimens for primary mediastinal large B-cell lymphoma (PMBCL) has significantly improved overall survival. However, the optimal management of isolated central nervous system (CNS) relapse and role of CNS prophylaxis remains undefined. We present cases of two adolescents with PMBCL who developed isolated CNS relapses. While isolated CNS relapse may be managed with high-dose chemotherapy and autologous stem cell transplant with or without CNS radiotherapy, review of these cases and the literature highlight the need for further work to define risk factors for CNS relapse, and identify patients who may benefit from CNS prophylaxis.

A first-in-class inhibitor of HSP110 to potentiate XPO1-targeted therapy in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma.

BACKGROUND: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations. METHODS: To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo. RESULTS: We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1wt as well as of XPO1E571K. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels. CONCLUSIONS: These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.

Patient with mediastinal carcinoma of unknown primary with RET fusion achieves durable response with RET inhibition.

Selective RET inhibitors have shown promise in thyroid cancer (TC) and nonsmall cell lung cancer (NSCLC) harboring RET fusions on next-generation sequencing (NGS), although rarity of the rearrangement has led to limited data for certain tumor types, such as carcinoma of unknown primary. We present a 65-year-old female with no history of malignancy, smoking or radiation exposure, who was found to have an anterior mediastinum malignancy of unknown primary, with metastases to supraclavicular lymph nodes. Core biopsy of the mediastinum revealed poorly differentiated carcinoma, while a biopsy of the thyroid revealed atypia of indeterminate significance (Bethesda III). PD-L1 immunohistochemistry was positive (90%), and liquid NGS revealed mutations in TP53 and the TERT promoter (c.-124C>T), as well as a CCDC6-RET fusion. This genetic profile resembled an anaplastic TC vs. NSCLC primary, although thymic primary and poorly differentiated TC remained on the differential. The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. At a reduced dosage, patient developed transaminitis, and selpercatinib was switched to pralsetinib. Brain MRI showed a nonenhancing temporal lobe signal abnormality, which on biopsy proved to be glioblastoma (GBM) with TERT promoter c.-124C>T mutation and FGFR3-TACC3 fusion by NGS. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.

Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study.

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51-75) in PMBCL versus 48% (95% CI: 41-57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78-95) in PMBCL versus 71% (95% CI: 64-79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.

[Progress in treatment of primary mediastinal large B-cell lymphoma].

Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive B-cell lymphoma originating from the thymus, which has different clinical and biological characteristics from diffuse large B-cell lymphoma, NOS. PMBCL tends to occur in young women, usually presenting as a large anterior mediastinal mass. Most patients are in stage Ⅰ-Ⅱ at the time of presentation. There is no standard prognostic scoring system for PMBCL. Immunochemotherapy is commonly used in the treatment of PMBCL, but the optimal first-line treatment has not been determined, and the status of radiotherapy is controversial. The value of PET-CT guided therapy needs to be further verified. Relapsed/refractory PMBCL has a poor prognosis, while novel therapies such as PD-1 inhibitors, brentuximab vedotin, and CAR-T can help improve survival in these patients.

Remarkable response to pazopanib plus vivolumab in a patient with pericardial synovial sarcoma carrying a novel genotype BRCA2 c.968dupT: A case report.

Pericardial synovial sarcomas (PSS) have a low incidence rate and are highly invasive with a dismal prognosis. Standard treatment includes surgery, radiotherapy and chemotherapy but with limited response. Here, we report the case of a 15-year-old nonsmoking youngster diagnosed with PSS who developed disease relapsed from surgery after 1 month. Next-generation sequencing (NGS) using baseline tissue was performed, and BRCA2 c.968dupT was detected. Then pazopanib (a multitargeted inhibitor) plus nivolumab (an immune checkpoint inhibitor) was administered, with a partial response and progression-free survival of 14 months. BRCA2 c.968dupT has not previously been reported in PSS and its response to targeted combination immunotherapy are not well characterized. Here, we report the efficacy of pazopanib combined with nivolumab in a PSS patient harboring BRCA2 c.968dupT and also provide the clinical evidence of the utility of NGS in exploring actionable mutations for solid tumor. Combination therapy based on immunotherapy may be a potential treatment choice for PSS harboring BRCA2 mutation.

Resection of a Large Growing Mediastinal Germ Cell Tumor Using a Multidisciplinary Approach.

Mediastinal germ cell tumors (GCTs) are rare. Post-chemotherapy residual masses in patients with a nonseminomatous GCT require resection. A patient with a large mediastinal GCT involving the left subclavian artery, superior vena cava (SVC) and hilum of the right lung is presented. Despite a biochemical response to chemotherapy, the tumor enlarged on serial imaging. With guidance from medical oncology, a multidisciplinary surgical team, including cardiac anesthesia, cardiac surgery and thoracic surgery resected the tumor with a staged reconstruction of the SVC. The procedure was well tolerated and yielded clear margins. The final pathology showed a significant associated component of rhabdomyosarcoma.

Plasmocitoma extramedular: una rara causa de masa mediastínica / Extramedullary mediastinal plasmacytoma: report of one case

Solitary extramedullary plasmacytomas represent 3% of plasma cell neoplasms. Their most common locations are the upper gastrointestinal and respiratory tract. We report a 70-year-old male presenting with progressive dyspnea and cough. A chest radiography showed widened mediastinum. Chest computed tomography showed a mediastinal mass. A bronchoscopy showed an extrinsic compression and complete occlusion of the primary bronchus. A self-expandable prosthesis was installed in left bronchus. A population of plasmacytoid cells was evidenced in the mass biopsy. Immunohistochemistry revealed CD20+ and CD138+. These tumor cells stained positively for lambda light chains, but negatively for kappa chains. Therefore an extramedullary plasmacytoma was diagnosed. A multiple myeloma was discarded with a normal blood count, serum calcium and creatinine levels. Serum protein electrophoresis had a monoclonal spike, serum IgG was 1963 mg/dl. Bone marrow aspiration had 1% of plasma cells. Bone x-rays were normal. Computed tomographies of the neck, thorax, abdomen and pelvis ruled out other plasmacytomas. Eight cycles of chemotherapy with thalidomide, melphalan and prednisone were indicated, obtaining complete remission of the tumor. The review of the literature shows that mediastinal extramedullary plasmacytomas are extremely rare. They generally appear in men aged between 50 and 60 years. The treatment of choice is radiotherapy, but given the location in the present case, chemotherapy was considered the best option. Recurrence is approximately 10 to 30% and 10% of patients progress to myeloma, thus requiring close monitoring.

Tumores de células germinales del mediastino: experiencia con 29 pacientes / Mediastinal germ cell tumors: surgical experience with twenty nine patients

Objetivo: revisar e informar la experiencia adquirida con el manejo de tumores de células germinales del mediastino, en el Hospital Calderón Guardia. Metodología: previa autorización acumulada en la base de datos del Servicio de Cirugía de Tórax y los expedientes clínicos de 29 pacientes con tumores de células germinales del mediastino, operados entre 1986 y 2012. Resultados: se encontró mayor frecuencia en hombres jóvenes con una relación por género de 13.5:1, y edad promedio de 26 años. La localización correspondió en 28 casos al mediastino antero superior y 1 al medio. La presentación en 27 casos fue una radiografía de tórax con ensanchamiento del mediastino, uno con derrame pleural y uno con derrame pleural y mediastino ensanchado. Los síntomas más frecuentes fueron: disnea, dolor retrosternal, fiebre, tos, pérdida de peso, síndrome de vena cava superior, hemoptisis y ginecomastía en un varón con coriocarcinoma. La muestra para diagnóstico se obtuvo por mediastinotomía en 14 casos, toracotomía en 8, videotoracoscopía en 4 esternotomía en 1, mediastinoscopía en 1 y broncoscopía en 1. Conclusión: los tumores germinales del mediastino son infrecuentes; la extirpación quirúrgica es el tratamiento de elección para los técnicamente resecables y se acompaña de curación de los benignos. En los malignos, la aparente resección completa no es garantía de curación, por lo que debe considerarse la quimioterapia adyuvante, que demostró ser de gran utilidad, por cuanto varios tumores parcialmente resecados se curaron con quimioterapia, y algunos con aparente resección completa recidivaron...

Seminoma primário do mediastino / Primary mediastinal seminoma

O seminoma é um tumor maligno de células germinativas que possui como sitio primário preferencial os testículos, embora existam raros casos de localização extra-gonadal. Os autores relatam caso de seminoma primário de mediastino em paciente masculino, 26 anos de idade, que apresentava dispnéia progressiva, tosse seca, rouquidão, dor torácica eventual, obstrução óbvia da veia cava superior e massa volumosa e palpável no mediastino ântero-superior. O diagnóstico etiológico foi suspeitado pelos exames de imagem, anatomopatológico e marcadores séricos e firmado pelo estudo imuno-histoquimico. Não havia evidência de metástase à distância, mas o tumor estava localmente avançado. O tratamento proposto foi poliquimioterápico com esquema PEB (cispiatina, etoposide e bleomicina) e o paciente evoluiu sem maiores intercorrências.

The seminoma is a malignant germ cell tumor that is rarely placed in an extra-testicular position. A 26 years old male patient with primary mediastinal seminoma was studied. His symptoms were: progressive dyspnea, unproductive cough, hoarseness, occasional chest pain, obvious superior vena cava obstruction, and a huge and palpable mass located in the upper anterior mediastinum. Image exams, serum markers and histological study led to diagnosis, of seminoma which was confirmed by immunohistochemical study. There was no evidence of distant metastatic disease although it was locally advanced. After the beginning of the treatment with chemotherapy, the patient's symptoms were improved.

Tumores primarios del mediastino en la infancia / Primary mediastinal tumors in childhood

Sesenta y seis pacientes en edades comprendidas entre 16 horas y 15 años recibieron tratamiento en el Hospital Pediátrico Docente "William Soler" de 1967 a 1988. Las lesiones encontradas fueron las siguientes: neuroblastoma, 11; ganglioneuroma, 6; ganglioneuroblastoma, 5; quiste broncógeno, 6; quiste enterógeno, 5;higroma quístico, 3;teratoma, 3; lipoma, 2; timoma linfocítico, 1; timoma teratomatosa, 1; timoma granulomatoso, 1; carcinoma indiferenciado del timo, 1; timolipoma, 12; hiperplasia del timo, 5; enfermedad de Hodgkin, 9 y linfosarcoma, 6.Veinte y ocho (42,4 %) tenían de 0 a 2 años y 38 (57,7 %) entre 3 y 15 años. En 31 pacientes (47%) la lesión se localizó en el mediastino posterior; en 14 (21 %) en el medio: en 16 (25,7%) se localizó en el anterior y en 5 (6%) ocupó más de un comportamiento mediastínico. Veinte y cuatro pacientes (36%) se mostraron asintomáticos. En los pacientes sintomáticos predominaron los sintomas respiratorios, entre ellos disnea, tos, cianosis e infecciones respiratorias repetidas. Hubo 29 tumores benignos (44 %) y 37 lesiones malignas (56%). Entre la lesiones benignas sobrevivieron 26 (90%) y entre las malignas 23 (62%). El diagnóstico se comprobó por toracotomía en 53 pacientes, por biopsia ganglionar en 12 y por necropsia en uno. El tratamiento de elección fue la cirugía, excepto en los linfomas. En los tumores malignos se usó radioterapia y poliquimioterapia

Tumores do mediastino: diagnóstico e terapêutica / Mediastinal tumors: diagnosis and therapeutics

Entre janeiro de 1980 e dezembro de 1987 admitimos em nosso serviço 49 pacientes portadores de tumores do mediastino, primários e secundários. Trinta eram do sexo masculino e 19 do sexo feminino. A maior incidência se deu na terceira década de vida. Os tumores malignos predominaram, ocorrendo em 28 pacientes (57%). A localizaçäo preferencial foi o mediastino anterior (51%), a seguir o compartimento visceral (31%) e depois o mediastino posterior (18%). Os sintomas estavam presentes em 34 pacientes (69,4%), 13 com tumores benignos (26,5%) e 21 com tumores malignos (42,9%). O sintoma mais freqüente foi a dor torácica (31%), seguido pelos sinais de compressäo de veia cava superior (19%). A toracotomia foi realizada em 26 pacientes, conseguindo-se a ressecçäo completa do tumor em 20 casos, dos quais quatro submetidos a quimioterapia prévia. Nos seis pacientes restantes, a toracotomia foi utilizada para obtençäo do diagnóstico histopatológico. A mediastinoscopia cervical e a mediastinotomia anterior foram empregadas em 10 e 8 casos, para biopsia tumoral em lesöes sabidamente irressecáveis. Näo houve mortalidade operatória. Concluimos que a toracotomia com ressecçäo é curativa nos tumores benignos e tem destaque no manuseio das lesöes malignas

Linfoma No Hodgkin en niños / Non-Hodgkin's Lymphoma in children

El presente trabajo es una evaluación de 250 pacientes en edad pediátrica, con Linfoma no Hodgkin (LNH), tratados en el Instituto Nacional de Enfermedades Neoplásicas (I.N.E.N.) en un período de 35 años, entre 1952 y 1986. La edad mediana del grupo evaluado fue de 90 meses, siendo el 75 por ciento de los pacientes menores de 10 años y el pico de incidencia de 4 a 6 años.El sexo masculino tuvo preponderancia sobre el femenino, con una relación M/F de 2.1:1 en todas las presentaciones. El tiempo promedio de enfermedad hasta el diagnóstico fue de 2 meses, encontrándose que en el 72 por ciento de los casos, la evolución de los síntomas fue de 3 meses. El 75.2 por ciento de los pacientes fue diagnosticado en estadíos avanzados (III-IVA/B) y solo el 24.8 por ciento en estadíos I-II. En el 65 por ciento de los pacientes, el linfoma primario fue extraganglionar (abdomen, subcutáneo, cabeza y cuello) y en el 35 por ciento de los casos fue ganglionar (mediastino y ganglios periféricos). La localización primaria más frecuente fue la abdominal (37 por ciento), seguida por la ganglionar (21 por ciento), en cabeza y cuello (18 por ciento), mediastinal (14 por ciento) y subcutánea (9 por ciento). El 98 por ciento de los pacientes presentaron histología de alto grado de malignidad y de patrón difuso, siendo el tipo histológico más frecuente el linfoma indiferenciado (Burkitt y No Burkitt), con 30.8 por ciento de los casos, seguido en frecuencia por el histiocítico y el linfocítico poco diferenciado. La localización más frecuente de los linfomas indiferenciados fue en el abdomen, los linfoblásticos en el mediastino, los linfocíticos poco diferenciados difusos en el abdomen y ganglios periféricos y los histiocíticos en el abdomen y ganglios. En la presentación abdominal, el tumor fue irresecable en el 90 por ciento de los casos, siendo el íleon terminal la localización intraluminal más frecuente. La intususcepción intestinal fue el hallazgo más frecuente en los pacientes que presentaron abdomen agudo. En el 14 por ciento de los pacientes se detectó compromiso de la M.O. al diagnóstico. En la presentación ganglionar, el 43 por ciento de los pacientes tuvo compromiso de M.O. al diagnóstico. En la presentación de cabeza y cuello, la localización más frecuente fue el seno maxilar. En el 63 por ciento de los casos la enfermedad se encontraba en estadío avanzado al diagnóstico, presentando 24 por ciento de los pacientes compromiso de M.O. al diagnóstico. En la presentación media

Linfomas näo-Hodgkin de localizaçäo mediastinal na infância: relato de dois casos com insuficiência respiratória aguda; referência ao diagnóstico com punçäo mediastinal com agulha e exame citológico e ao tratamento com poliquimioterapia / Mediastinal non-Hodgkin lymphomas in infancy: report of 2 cases with acute respiratory failure; reference to the diagnosis with mediastinal puncture and cytologic examination with polichemotherapy

Apresenta-se relato de dois casos de linfomas de mediastino na infância, que apresentaram insuficiência respiratória aguda. Chama-se atençäo para o valor da punçäo diastinal e o exame citológico do material aspirado como método diagnóstico de valor nos casos de emergência e realça-se o valor da poliquimioterapia no tratamento com resoluçäo do problema respiratório e hematológico