Linfoma de Burkitt Primário de Mama: Relato de Caso / Primary Breast Burkitt Lymphoma: Case Report / Linfoma de Burkitt Primario de Mama: Relato de Caso

Introdução: O linfoma primário de mama (LPM) representa cerca de 0,5% das neoplasias mamárias, sendo considerado um tipo raro de tumor. Alguns dos tipos de LPM, por sua vez, possuem ligação intensa com o período gravídico e pós-parto em virtude do estímulo hormonal. O objetivo deste estudo é relatar um caso de LPM com apresentação rara de linfoma de Burkitt, considerando propostas terapêuticas eficazes para o seguimento. Relato do caso: Paciente do sexo feminino, 23 anos, portadora de tumoração periareolar em mama direita com aspecto de casca de laranja e crescimento rápido há um mês, queixas flogísticas no local da lesão, bom estado geral e sem outros sintomas associados. O quadro relatado iniciou-se sete meses após a expulsão fetal com feto morto. A paciente foi submetida à biópsia da lesão e encaminhada para seguimento ambulatorial sem sucesso, necessitando de retorno ao ambiente hospitalar por piora das condições clínicas e extensão da tumoração. Houve diagnóstico de linfoma de Burkitt, com tratamento multidisciplinar, sendo submetida a protocolo CODOX-M de quimioterapia, com óbito após 22 dias de acompanhamento hospitalar. Conclusão: Este relato demonstra uma situação rara em uma paciente jovem, ressaltando a importância de investigar as alterações mamárias, de maneira eficaz, para um diagnóstico precoce correto e um tratamento adequado, em todas as faixas etárias

Introduction: Primary breast lymphoma (PML) represents about 0.5% of breast cancers, being considered a rare type of tumor. Some of the types of PML, in turn, have an intense connection with the pregnancy and postpartum period due to hormonal stimulation. The aim of this study is to report a case of PML with a rare presentation of Burkitt's lymphoma, considering effective therapeutic proposals for follow-up. Case report: A 23-year-old female patient with a peri-areolar tumor in the right breast with orange peel aspect and rapid growth for one month, phlogistic complaints at the lesion site, good general condition and no other associated symptoms. The reported condition started seven months after fetal expulsion with a dead fetus. The patient underwent lesion biopsy and was referred to an outpatient follow-up with unsuccessful outcome, requiring return to the hospital due to worsening of clinical conditions and extension of the tumor. There was a diagnosis of Burkitt's lymphoma, with multidisciplinary treatment. She underwent the CODOX-M chemotherapy protocol, and died after 22 days of hospital follow-up. Conclusion: This report demonstrates a rare situation in a young patient, emphasizing the importance of effective investigation of breast changes so that correct early diagnosis and appropriate treatment can be made for all age groups

Introducción: El linfoma primario de mama (LMP) representa aproximadamente el 0,5% de los cánceres de mama, siendo considerado un tipo de tumor poco común. Algunos de los tipos de LPM, a su vez, tienen una conexión intensa con el embarazo y el posparto debido a la estimulación hormonal. El objetivo de este estudio es reportar un caso de LMP con rara presentación de linfoma de Burkitt, considerando propuestas terapéuticas efectivas para el seguimiento. Relato del caso: Paciente, 23 años, con un tumor periareolar en la mama derecha con aspecto de piel de naranja y rápido crecimiento durante un mes, quejas flogísticas en el sitio de la lesión, buen estado general y ningún otro. síntomas asociados. La condición reportada comenzó siete meses después de la expulsión fetal con un feto muerto. El paciente fue sometido a biopsia de la lesión y fue derivado sin éxito a seguimiento ambulatorio, requiriendo el retorno al entorno hospitalario por empeoramiento de la clínica y extensión del tumor. Hubo un diagnóstico de linfoma de Burkitt, con tratamiento multidisciplinario. Se sometió al protocolo de quimioterapia CODOX-M y murió a los 22 días de seguimiento hospitalario. Conclusión: Este informe demuestra una situación poco común en una paciente joven, enfatizando la importancia de investigar de manera efectiva los cambios en los senos para un diagnóstico temprano correcto y un tratamiento adecuado en todos los grupos de edad

[68Ga]Ga/[177Lu]Lu-BL01, a Novel Theranostic Pair for Targeting C-X-C Chemokine Receptor 4.

C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in hematological and solid malignancies. LY2510924 is a potent peptide antagonist of CXCR4. A derivative of LY2510924, BL01, was evaluated for theranostic applications targeting CXCR4. Methods: BL01 was synthesized by solid phase approach. A Lys(ivDde) residue was added at the C-terminus of LY2510924 (cyclo[Phe-Tyr-Lys(iPr)-d-Arg-2-Nal-Gly-d-Glu]-Lys(iPr)-NH2). A DOTA chelator was conjugated to the side chain of the deprotected exogenous Lys residue. The binding affinity of Ga/Lu-BL01 was determined by competitive radioligand binding assays. BL01 was radiolabeled with 68GaCl3 or 177LuCl3. Biodistribution studies were performed in mice bearing Daudi Burkitt's lymphoma tumor xenografts at selected time points. PET imaging studies were performed with [68Ga]Ga-BL01, with blocking experiments performed with preinjection of LY2510924. The stability of [68Ga]Ga/[177Lu]Lu-BL01 was assessed in mouse plasma. Results: Ga-BL01 and Lu-BL01 have nanomolar affinity for CXCR4. [68Ga]Ga-BL01 was obtained in 58 ± 5% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 40 ± 11 GBq/µmol, while [177Lu]Lu-BL01 was obtained in 65 ± 6% decay-corrected radiochemical yields and >99% radiochemical purity with a molar activity of 120 ± 21 GBq/µmol. [68Ga]Ga-BL01 and [177Lu]Lu-BL01 were excreted primarily through the renal pathway. Daudi xenografts were clearly delineated in PET images with good contrast. On the basis of biodistribution data, tumor uptake of [68Ga]Ga-BL01 was 10.2 ± 2.56% injected dose per gram (%ID/g) at 1 h postinjection (p.i.). Spleen (12.6 ± 2.36 %ID/g) and lungs (13.2 ± 2.98 %ID/g), organs that express CXCR4, had high uptake as well. Preinjection of LY2510924 reduced average uptake of [68Ga]Ga-BL01 in tumors by 88%, demonstrating target specificity. The uptake of [68Ga]Ga-BL01 in tumor increased to 15.3 ± 1.86 %ID/g at 2 h p.i., with improved contrast. [177Lu]Lu-BL01 has similar pharmacokinetics as [68Ga]Ga-BL01 at 1 h p.i. The highest uptake was observed in tumor (14.0 ± 1.11 %ID/g), followed by the lungs (13.0 ± 1.27 %ID/g) and spleen (11.6 ± 1.78 %ID/g). The tumor uptake increased to 16.2 ± 2.69 %ID/g at 4 h p.i., before declining slightly to 10.1 ± 1.41 %ID/g at 24 h p.i. Both compounds were stable in vivo, as no metabolites were observed at 5 min p.i. Conclusions: [68Ga]Ga-BL01 and [177Lu]Lu-BL01 are a promising theranostic pair for imaging and endoradiotherapy of CXCR4-expressing malignancies.

Hyperfractionated radiation therapy in Burkitt's lymphoma: a reconsideration aspect.

Burkitt's lymphoma (BL) is an aggressive non-Hodgkin's B-cell lymphoma with an extremely short doubling time that often presents in extra nodal sites or as an acute leukaemia. Nowadays, with the rapid response to chemotherapy and the diffuse nature of BL, there is no established role for radiation therapy (RT) even in localized disease. Regarding the relapsed/refractory BL, the treatment recommendations remain undefined. We present a 56-year-old woman, diagnosed with BL refractory to 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), who had disease progression on R-DHAP (rituximab, dexamethasone, high dose cytarabine and cisplatin) with intrathecal methotrexate, then a partial response on RICE (rituximab, ifosfamide, carboplatin and etoposide). Patient received high dose chemotherapy and autologous haematopoietic stem cell transplantation. Then, she was treated with hyperfractionated involved-field RT regimen. Currently, the patient remains disease free for around 2 years after remission. We acknowledge that RT is not a standard treatment of BL, especially in patients who attain complete response (CR) after first-line multi-agent chemotherapy or even in those who have a CR after second-line chemotherapy pre-transplant. Yet, the use of a superfractionated regimen of consolidative radiation could be justified in the treatment of recurrent/refractory localized BL who do not achieve a CR even with second-line salvage chemotherapy. Radiation therapy in this context, given that it is a well-tolerated treatment, is a modality worthy of being re-considered in relapsed/refractory BL. Copyright © 2016 John Wiley & Sons, Ltd.

Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model.

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy ß-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.

High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a (177)Lu-based CD22-specific radioimmunoconjugate and rituximab.

PURPOSE: Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy ß-emitter (177)Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. METHODS: The binding activity of CHX-A″-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of (177)Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1 (null) ) interleukin-2 receptor common gamma chain (IL2rγ (null) ) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. (177)Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. RESULTS: Conjugation of CHX-A"-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the (177)Lu-labelled anti-CD22 IgG than of (177)Lu-labelled rituximab. Treatment with (177)Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with (177)Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. CONCLUSION: These findings suggest that dual targeting with (177)Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.

Liposomal cytarabine in prophylaxis or curative treatment of central nervous system involvement in Burkitt leukemia/lymphoma.

In recent years, the outcome of Burkitt leukemia/lymphoma (BL) has improved significantly. Central nervous system (CNS) involvement continues to be a poor prognostic indicator. High doses of intravenous polychemotherapy, intrathecal chemotherapy, and cranio-spinal radiation therapy are used by numerous groups. Majority of patients are cured after this strategy. The next challenge is to decrease toxicities of treatment, including long-term toxicities secondary to cranio-spinal radiation therapy observed in these cured patients. Liposomal cytarabine could be a good alternative to cranio-spinal radiation therapy as already reported in acute lymphoblastic leukemia. We report here eleven patients treated in our center for BL, with liposomal cytarabine instead of cranio-spinal radiation therapy as prophylactic or curative treatment for CNS involvement. Treatment was safe with no short-term grade >3 adverse events. Moreover, no long-term side effects and no impact on outcome were observed. We conclude that LC could be a good option to decrease short/long-term side effects of cranio-spinal radiation therapy in BL and could be evaluated in a future clinical trial.

Doxorubicin enhances (131)I-rituximab induced cell death in Raji cells.

AIM: There are various therapeutic modalities of treatment for non-Hodgkin's lymphoma, but with certain limitations, hence, investigating the scope of combined therapeutic approach. MATERIALS AND METHODS: In this article, cellular toxicity, apoptosis and expression of mitogen-activated protein kinase signaling pathway proteins were investigated in Raji cells preincubated with doxorubicin followed by (131)I-rituximab (rituximab radiolabeled with Iodine-131) treatment. RESULTS: It was found that the (131)I-rituximab in combination with doxorubicin showed a higher amount of cell toxicity and apoptosis compared to respective controls. Expression of anti-apoptotic protein (B-cell lymphoma-extra-large) was downregulated and cleavage of poly (ADP-ribose) polymerase, a marker of apoptosis was higher in cells treated with doxorubicin (2 µg/mL) and 131 I-rituximab (P ≤ 0.05). Moreover, in these cells the basal level of expression of p42/44 and p38 were increased while its phosphorylation was decreased. CONCLUSION: These results suggest that doxorubicin has the potential to sensitize (131)I-rituximab induced cell death in Raji cells.

A rare neoplasm of the thyroid gland.

Burkitt's lymphoma of the thyroid gland is a rare malignancy. We present a case of a 58-year-old female who developed a rapid enlargement of her thyroid gland. Core biopsy confirmed the diagnosis of Burkitt's lymphoma. The tumour resolved after three cycles of chemotherapy. This case report emphasises the importance of considering lymphoma when dealing with thyroid nodules and goitres, as its management is different from that of other thyroid pathologies and delaying treatment has an impact on prognosis.

Sulfation of keratan sulfate proteoglycan reduces radiation-induced apoptosis in human Burkitt's lymphoma cell lines.

This study focuses on clarifying the contribution of sulfation to radiation-induced apoptosis in human Burkitt's lymphoma cell lines, using 3'-phosphoadenosine 5'-phosphosulfate transporters (PAPSTs). Overexpression of PAPST1 or PAPST2 reduced radiation-induced apoptosis in Namalwa cells, whereas the repression of PAPST1 expression enhanced apoptosis. Inhibition of PAPST slightly decreased keratan sulfate (KS) expression, so that depletion of KS significantly increased radiation-induced apoptosis. In addition, the repression of all three N-acetylglucosamine-6-O-sulfotransferases (CHST2, CHST6, and CHST7) increased apoptosis. In contrast, PAPST1 expression promoted the phosphorylation of p38 MAPK and Akt in irradiated Namalwa cells. These findings suggest that 6-O-sulfation of GlcNAc residues in KS reduces radiation-induced apoptosis of human Burkitt's lymphoma cells.

[Therapeutics of Burkitt lymphoma in adults - review].

Burkitt lymphoma is a highly aggressive non-Hodgkin's lymphoma. As Burkitt lymphoma cells are very sensitive to chemotherapy, chemotherapy is the major therapeutic schedule for this disease. Rituximab raised the overall survival rate markedly. Bone marrow transplant, surgery and radiotherapy also demonstrated to have a supporting role for patients with Burkitt lymphoma. This review focus on research progress of the therapeutics and major regimens for the disease.

Influx of extracellular calcium participates in rituximab-enhanced ionizing radiation-induced apoptosis in Raji cells.

We have previously shown that rituximab has a significant radiosensitizing effect on Raji cells in vitro. To investigate whether calcium signals participate in rituximab- and radiation-induced cell death in Raji cells, confocal laser scanning microscopy was used to detect kinetic changes in intracellular free calcium concentration ([Ca2+]i). Cell survival, the rates of apoptosis in Raji cells and the kinetics of γ-H2AX foci induction and loss were also evaluated. X-irradiation of Raji cells induced an initial increase of [Ca2+]i in both the presence and absence of extracellular calcium, followed by a decrease in [Ca2+]i over time. Rituximab enhanced both the amplitude and the duration of intracellular calcium signals in the irradiated cells. EGTA significantly inhibited radiation- or radiation/rituximab combination treatment-induced apoptosis. However, the calcium chelators EGTA and BAPTA/AM conferred no survival advantage on the irradiated cells. Furthermore, although no significant difference was seen after 1h, the treatment of cells with a combination of irradiation and rituxiamb caused an increase of γ-H2AX foci when compared with irradiated cells after 8h. Both EGTA and BAPTA/AM suppressed the number of γ-H2AX foci induced by either radiation or radiation combined with rituximab. Our results suggest that rituximab increases the level of [Ca2+]i in irradiated Raji cells. The entry of calcium from the extracellular space plays an essential role in [Ca2+]i-dependent radiation-induced apoptosis in Raji cells. The calcium chelators inhibited the formation of γ-H2AX foci, which are thought to prevent the activation of Ca2+/Mg(2+)-dependent endonucleases and subsequent DNA fragmentation. The calcium chelators most likely modulate only particular features of apoptosis and fail to change the fates of cells that are already committed to die.

Curcumin improves the antitumor effect of X-ray irradiation by blocking the NF-κB pathway: an in-vitro study of lymphoma.

Curcumin, a phenolic compound from the rhizomes of Curcuma longa, inhibits the growth of a variety of malignant cell types including lymphoma cells. We investigated the role of curcumin in modulating the response of Burkitt's lymphoma cells to ionizing radiation (IR) in vitro and explored the mechanisms that mediated this effect. We treated three Burkitt's lymphoma cell lines with vehicle, curcumin, IR, and curcumin in combination with IR. Cell viability, apoptosis, and cell cycle distribution were determined to ascertain the radiosensitization effect of curcumin. Nuclear factor-kappa B (NF-κB) activation was assessed by nuclear translocation of p65. Apoptosis-related proteins were monitored by western blot assay and real-time RT-PCR. Pretreatment of curcumin sensitized lymphoma cells to IR-induced apoptosis and increased G2/M phase arrest in the cell cycle distribution. Accordingly, the antiapoptotic Bcl-xL protein, cell cycle modulating protein CDC2, and cyclin B1 were downregulated by the curcumin treatment. IR activated NF-κB as evidenced by an increased nuclear p65 translocation and cytoplasmic IκBα expression. However, pretreatment with curcumin significantly decreased the nuclear translocation of p65 and cytoplasmic IκBα degradation. Survivin and hexokinase II, downstream effectors of NF-κB that mediate the antiapoptotic effect of NF-κB, were suppressed by the pretreatment of curcumin. These observations suggest that the activated NF-κB pathway plays a prosurvival role in Burkitt's lymphoma in response to IR. Curcumin blocks this pathway and has therapeutic potential for improving the antitumor effects of radiotherapy.

Primary gastrointestinal tract lymphoma in the pediatric patient: review of 265 patients from the SEER registry.

OBJECTIVE: The objective of this study is to determine outcomes of pediatric patients with primary gastrointestinal tract lymphoma (PGTL) and the impact of surgery or radiation on survival. METHODS: The Surveillance, Epidemiology, and End Result database was queried from 1973 to 2006 for patients younger than 20 years with PGTL. RESULTS: 265 patients with PGTL were identified. Overall 5- and 10-year survivals were 84% and 83%, respectively. Tumors of the stomach (9%) and rectum/anus (2%) had the worst and best 10-year survivals, respectively (59% vs 100%, P = .023). There was no significant difference in 10-year survival for patients younger than 10 years of age who had surgical extirpation (83% vs 85% no surgery, P = .958) or radiotherapy (76% vs 85% no radiotherapy, P = .532). However, there was a significantly decreased 10-year survival in patients 10 years or older who had surgical extirpation (79% vs 100% no surgery, P = .013) or radiotherapy (49% vs 87% no radiotherapy, P = .001). Under multivariate analysis, tumor location was an independent predictor of improved survival (small bowel, HR 0.21, P = .002; large bowel, HR 0.23, P = .004). CONCLUSION: We found no significant survival advantage for surgical extirpation or radiotherapy in patients younger than 10 years with PGTL, whereas either treatment modality was associated with lower survival in patients 10 years or older.

Secondary choroidal lymphoma in a child treated for Burkitt lymphoma.

A 9-year-old girl presented with a choroidal tumor 6 years after remission of Burkitt lymphoma with no evidence of systemic recurrence. The tumor regressed after plaque radiotherapy. The second tumor could have been related to previous chemotherapy, caused by Epstein-Barr virus infection, or the result of independent lymphoma cell growth.

Case report. Primary hypothalamic third ventriclular Burkitt's lymphoma: a case report with emphasis on differential diagnosis.

A patient with primary Burkitt-type lymphoma of the central nervous system is presented. A hypothalamic-third ventricular tumour in a man 71 years of age was diagnosed histologically as Burkitt's lymphoma. Primary Burkitt's lymphoma of the hypothalamic region is extremely rare and has not been previously reported in adults.

Follicular lymphoma transformation to dual translocated Burkitt-like lymphoma: improved disease control associated with radiation therapy.

Dual translocated (or "dual hit") lymphomas are highly aggressive B cell neoplasms associated with an extremely poor prognosis. The optimal treatment for these lymphomas remains undefined. We present two cases of follicular lymphoma with transformation to Burkitt-like lymphoma. In both cases dual translocations involving both the bcl-2 and c-myc loci were present. Each patient underwent intensive induction immunochemotherapy followed by autologous stem cell transplantation and radiation therapy. The first patient received post-transplant mediastinal radiation and developed recurrence in multiple areas outside of the radiation field. The second patient received total body irradiation as part of the conditioning regimen, and is without recurrence 18 months after transplant, and 24 months after diagnosis of the dual translocated lymphoma. We review dual translocation B cell lymphoma in the setting of transformation from follicular lymphoma, and suggest a potential role for total body irradiation in the management of this highly aggressive non-Hodgkin lymphoma.

Rituximab sensitizes a Burkitt lymphoma cell line to cell killing by X-irradiation.

Clinical trials with rituximab in combination with chemotherapeutic regimens have shown promising results. Data on the effects of rituximab treatment in combination with irradiation are, however, limited and inconsistent. This study aims to investigate the effects of rituximab (R) on cell death induced by X-irradiation in Raji lymphoma cells and to evaluate its mechanisms. We found the cell growth inhibition by irradiation was enhanced by additional rituximab exposure both in cells precultured with rituximab followed by irradiation (R + irradiation) or in cells treated in the reverse sequence (irradiation + R). R + irradiation combination treatment induced more apoptotic cells than irradiation and irradiation + R treatment as early as 12 h after treatment. At 24 h, both combination treatments, R + irradiation and irradiation + R, showed apoptotic cells, which were significantly different from irradiation alone. G2/M cell cycle arrest was observed after irradiation alone and the combination treatment. The combination treatment revealed an elevation in reactive oxygen species (ROS) generation in a radiation dose-dependent manner. In addition, rituximab enhanced the cell growth inhibition and apoptotic cell death induced by the oxidative agent, H(2)O(2). We propose that rituximab mediates a significant in vitro radiosensitizing effect and induces cell cycle changes and apoptosis in Raji cells. ROS probably play an important role in these events.