Hepatotoxicidad colestásica asociada al uso de quimioterapia en esquema con lomustina: reporte de un caso y revisión de la literatura / Colestasic hepatotoxicity associated with the use of chemotherapy in scheme with lomustine: case report and literature review

Drug-induced liver injury (DILI) is a rare entity associated with high morbidity and mortality. It includes a broad spectrum of clinical patterns, from acute hepatitis to cirrhosis. Among the common associated drugs are antimicrobial like anti-TBC, antineoplastic, CNS agents and non-steroidal anti-inflammatory drugs. Establishing causality between DILI and a certain drug is a challenge. Some scoring systems have been evaluated, considering RUCAM score as the gold standard. We present the case of a 35-year-old woman with a history of a high-grade glioma treated with surgery and chemotherapy with lomustine, procarbazine and vincristine. She evolved with altered liver tests, predominantly cholestatic pattern, but asymptomatic. Etiologic study negative and abdominal imaging were normal. The liver biopsy was compatible with 40% ductopenia, without inflammatory elements. We consider DILI associated with the use of lomustine, with RUCAM score suggesting. After discontinuing chemotherapy and using ursodeoxycholic acid for the treatment of cholestasis there was an improvement in liver tests. There is limited evidence in the literature regarding hepatotoxicity associated with lomustine, mainly in experimental animal models. Cases of cholestatic hepatotoxicity have been described with the use of other similar nitrosureas. In relation to procarbazine and vincristine, DILI is reported mainly reversible and predominantly with hepatocellular pattern, not consistent with our case. We find it interesting to communicate with review of the literature about it.

El daño hepático inducido por drogas (DILI) es una entidad poco frecuente, con alta morbimortalidad asociada. Incluye un amplio espectro de patrones clínicos, desde hepatitis aguda a cirrosis. Dentro de los fármacos frecuentemente asociados se encuentran antibióticos como anti-TBC, agentes antineoplásicos, de acción en el SNC y anti-inflamatorios no esteroidales. Establecer una causalidad entre DILI y una determinada droga constituye un desafío. Para ello, se han evaluado diversos sistemas de puntuación, considerándose gold estándar el RUCAM score. Se presenta el caso de una mujer de 35 años de edad con antecedentes de glioma de alto grado operado y en quimioterapia con lomustina, procarbazina y vincristina. En su evolución presenta alteración de pruebas hepáticas de predominio colestásico de manera asintomática, con estudio etiológico causal negativo e imagenológico normal. La biopsia hepática fue compatible con ductopenia de 40% sin elementos inflamatorios. Se plantea DILI asociado al uso de lomustina con un score de RUCAM sugerente, decidiéndose interrumpir sus ciclos de quimioterapia e inicia tratamiento con ácido ursodesoxicólico, presentando mejoría progresiva de pruebas hepáticas. Existe evidencia limitada en la literatura en relación a hepatotoxicidad asociada a este fármaco, principalmente en modelos experimentales, y con el uso de otras nitrosureas similares se han descrito casos de hepatotoxicidad de predominio colestásico. En relación con procarbazina y vincristina existen reportes de DILI principalmente reversible y con patrón de predominio hepatocelular, lo que no es concordante con nuestro caso, por lo cual nos parece de interés comunicarlo con revisión de la literatura al respecto.

Cutaneous lymphoma of the tarsus in a cat - case study / Linfoma cutáneo tarsal en gato - estudio de caso

ABSTRACT Lymphoma is the most common lymphoproliferative disorder in cats. Cutaneous lymphoma, however, is a rare form of extranodal lymphoma. Recently, several cutaneous lymphomas at the tarsal region have been reported in cats. As it differs clinically and histopathologically from the common cutaneous lymphoma, it was denominated cutaneous tarsal lymphoma. The present study describes the case of a 13-year-old male domestic longhair cat that presented with a subcutaneous mass, of 30-days evolution, at the tarsal region of the right pelvic limb. Histopathology analysis showed malignant neoplasia of round cells, morphologically suggestive of large cell lymphoma. Immunohistochemistry confirmed the diagnosis of B-immunoblastic lymphoma. Patient was treated with lomustine, and prednisolone with an overall survival time of 2.1 months. The aggressiveness of this feline lymphoma reinforces the need for further studies to understand better the disease progression and to establish improved therapeutic protocols that can increase survival time and improve quality of life of these patients.

RESUMEN El linfoma representa la enfermedad linfoproliferativa más frecuente en gatos. Sin embargo, el linfoma cutáneo es una rara forma de linfoma extranodal. Recientemente, el linfoma cutáneo se reportó localizado en el tarso. Tanto clínica como histopatológicamente, esta forma difiere de la forma cutánea típica, y se denominó linfoma tarsal felino. Este estudio describe el caso de un gato, doméstico de pelo largo, 13 años de edad con una masa subcutánea, de 30 días de evolución en la región tarsal del miembro pélvico derecho. La histopatologia reveló neoplasia de células redondas, sugestiva de linfoma de células grandes. La inmunohistoquímica confirmó el diagnóstico de linfoma imunoblástico de células B. El tratamiento realizado fue lomustina y prednisolona con tiempo de sobrevida de 2,1 meses. La agresividad de este linfoma, refuerza la necesidad de estudios para entender su curso y mejorar protocolos terapéuticos que incrementen tanto la sobrevida como la calidad de vida para estos pacientes.

Ciclooxygenase inhibitor and metronomic chemotherapy association for the treatment of metastatic anal sac carcinoma in dog: case report / Inibidor de ciclo-oxigenase associado à quimioterapia metronômica no tratamento de carcinoma de saco anal metastático canino: relato de caso

Metronomic chemotherapy consists of an anticancer modality treatment. It is applicable in patients at an advanced stage, with the objective of increasing overall survival. The aim of this study was to report an anal sac apocrine carcinoma case in a dog with lymph node metastasis treated with metronomic chemotherapy sequential to surgery and conventional chemotherapy using gemcitabine and carboplatin. Metronomic chemotherapy was associated with cyclooxygenase-2 (COX-2) inhibitors, due to strong tumor COX-2 immunohistochemistry expression. Metronomic chemotherapy was initiated with cyclophosphamide, but it was replaced by lomustine, also in metronomic dosage, due to adverse effects. Treatment showed effectiveness, since the patient's overall survival exceeded 1095 days (36 months), considerably higher than the mean overall survival expected for this pathology.(AU)

Quimioterapia metronômica consiste em uma modalidade de tratamento anticancerígeno, aplicável a pacientes em estadiamento avançado, com o objetivo de aumentar a sobrevida global. O objetivo deste trabalho foi relatar um caso de carcinoma apócrino do saco anal, em uma cadela, com metástase em linfonodo tratado com quimioterapia metronômica sequencial à cirurgia e quimioterapia convencional utilizando-se gencitabina e carboplatina. O tratamento metronômico foi associado ao uso de inibidores de ciclo-oxigenase-2 (COX-2), baseando-se na constatação de sua expressão tumoral. A terapia metronômica iniciou-se com ciclofosfamida, mas houve necessidade de substituição pela lomustina, também em dose metronômica, devido à ocorrência de efeitos adversos. O tratamento mostrou ser eficaz, pois a sobrevida do paciente ultrapassa 1095 dias (36 meses) desde a cirurgia, sendo consideravelmente maior que a média relatada para essa patologia.(AU)

Subtherapeutic INR in a Patient on Warfarin Therapy after Discontinuation of Lomustine.

Aims: To report a case of a potential drug interaction between warfarin and lomustine that may have led to a subtherapeutic International Normalized Ratio (INR) and to inform health care providers of a need for more frequent INR monitoring in this patient population. Presentation of Case: A 64 year-old Caucasian male previously stable on warfarin presented to an anticoagulation clinic with a subtherapeutic International Normalized Ratio (INR) of 1.6 after discontinuation of a six-month course of lomustine for glioblastoma three weeks prior. The patient had been on a stable warfarin dose of 42.5 milligrams (mg) weekly while using lomustine therapy for 6 months. After an 11.8% increase in the weekly dose of warfarin, the patient returned to a therapeutic INR. Discussion: Common drug interaction resources such as Micromedex®, Lexicomp® and Facts and Comparisons® do not consistently list an interaction with warfarin and lomustine.The mechanism of a lomustine and warfarin drug interaction is theorized to be related to decreased liver cytochrome P450 (CYP)-mediated enzyme activities as well as CYP 3A4 enzyme inhibition observed in previous studies. Due to the described effects of lomustine on the CYP enzyme activities and the possibility for pharmacokinetic interactions with a highly CYP metabolized drug like warfarin, there is a potential for prolonged warfarin activity when combined with lomustine therapy. For patients taking both medications, more frequent INR monitoring may be advised more than drug interaction references suggest.An objective causality assessment revealed that the interactionwas probable (Drug Interaction Probability Scale: 6-7). Conclusion: The interaction between lomustine and warfarin likely decreased the INR in this patient case report due to a reversal of decreased liver CYP 450-mediated enzyme activities and pharmacokinetic effects upon warfarin. Common drug-interaction references do not consistently list an interaction with warfarin and lomustine. Increased frequency of INR monitoring may be advised for patients taking both of these medications more than drug interaction references suggest.

The Role of Chemotherapy in Anaplastic Astrocytoma Patients

OBJECTIVE: This retrospective study was performed to evaluate the role of chemotherapy in the management of patients with anaplastic astrocytoma (AA). METHODS: We compared the survival outcome among the 3 different treatment protocol groups in a single institution. A total of 86 patients (39 men and 47 women) with newly diagnosed AA after surgery were analyzed. Among them, 31 patients (36.0%) were treated with radiotherapy only (RT Group), 30 patients (34.9%) were treated with nimustine-cisplatin chemotherapy before RT (ACNU-CDDP group), and 25 patients (29.1%) were treated with procarbazine, lomustine and vincristine (PCV) chemotherapy after radiotherapy (PCV group). RESULTS: The median survival was 14.0, 30.0 and 72.0 months in RT, ACNU-CDDP, and PCV group, respectively and showed significant differences (RT vs. ACNU-CDDP; p=0.039, RT vs. PCV; 0.002, ACNU-CDDP vs. PCV; 0.045). PCV group showed less toxicity rate (5 patients; 20%) than ACNU-CDDP group (12 patients; 40%), while only 3 patients (9.6%) in RT group experienced grade 3 or 4 toxicities. CONCLUSION: An application of chemotherapy before or after radiotherapy is beneficial in prolonging the survival of patients with AA. Adjuvant PCV chemotherapy after radiotherapy is recommendable.

The Role of Chemotherapy in Anaplastic Astrocytoma Patients

OBJECTIVE: This retrospective study was performed to evaluate the role of chemotherapy in the management of patients with anaplastic astrocytoma (AA). METHODS: We compared the survival outcome among the 3 different treatment protocol groups in a single institution. A total of 86 patients (39 men and 47 women) with newly diagnosed AA after surgery were analyzed. Among them, 31 patients (36.0%) were treated with radiotherapy only (RT Group), 30 patients (34.9%) were treated with nimustine-cisplatin chemotherapy before RT (ACNU-CDDP group), and 25 patients (29.1%) were treated with procarbazine, lomustine and vincristine (PCV) chemotherapy after radiotherapy (PCV group). RESULTS: The median survival was 14.0, 30.0 and 72.0 months in RT, ACNU-CDDP, and PCV group, respectively and showed significant differences (RT vs. ACNU-CDDP; p=0.039, RT vs. PCV; 0.002, ACNU-CDDP vs. PCV; 0.045). PCV group showed less toxicity rate (5 patients; 20%) than ACNU-CDDP group (12 patients; 40%), while only 3 patients (9.6%) in RT group experienced grade 3 or 4 toxicities. CONCLUSION: An application of chemotherapy before or after radiotherapy is beneficial in prolonging the survival of patients with AA. Adjuvant PCV chemotherapy after radiotherapy is recommendable.

Determination of the Content of Lomustine in Mouse Tumor Tissue by RP-HPLC / 中国药房

OBJECTIVE: To determine the content of lomustine in mouse tumor tissue. METHODS: Lomustine was separated and determined on a reverse-phase C18 5um column with a mobile phase of acetonitrile-H2O(54 : 46), detected at 254nm and no internal standard. RESULTS: The ca[ibration curve was 1ineaI(r = 0. 9 999) within the range of 0. 98- 15. 68ug/ml for lomus tine. The recovery ratio of lomustine was 68. 64% (n = 9). The relative standard deviation(RSD) was 0. 32%. CONCLUSION: This method is simple and accurate