Manejo de la neoplasia trofoblástica gestacional. A propósito de un caso

La enfermedad trofoblástica gestacional es definida como un grupo heterogéneo de lesiones, las cuales surgen a partir del epitelio trofoblástico de la placenta luego de una fertilización anormal. Se presenta el caso de una paciente de 35 años de edad, con diagnóstico de neoplasia trofoblástica gestacional posmolar en etapa I, que se detectó tras estudios imagenológicos de seguimiento y determinación de la hormona gonadotropina coriónica humana, para lo cual llevó tratamiento con quimioterapia y terapéutica de mantenimiento con metotrexato por 5 días o metotrexato/ácido folínico por 8 días, hasta la normalización de la gonadotropina coriónica humana. Lo más relevante es que, aunque estos tumores abarcan menos del 1 % de los tumores ginecológicos, representan una amenaza para la vida de las mujeres en edad reproductiva.

Gestational trophoblastic disease is defined as a heterogeneous group of lesions, which arise from the trophoblastic epithelium of the placenta after abnormal fertilization. The case of a 35-year-old female patient is presented with a diagnosis of posmolar gestational trophoblastic neoplasia in stage I, which was detected after follow-up imaging studies and determination of human chorionic gonadotropin, for which she underwent chemotherapy treatment and maintenance therapy with methotrexate for 5 days or methotrexate/folinic acid for 8 days, until normalization of human chorionic gonadotropin The most relevant thing is that, although these tumors comprise less than 1% of gynecological tumors, they represent a threat to the life of women of reproductive age.

Manifestaciones mucocutáneas de intoxicación por metotrexato / 4pp Mucocutaneous manifestations of methotrexate toxicity

El metotrexato es un antimetabolito análogo al ácido fólico que inhibe competitivamente la enzima dihidrofolato reductasa y timidilato sintetasa, indispensables para la síntesis de ADN y ARN. Se utiliza ampliamente en dermatología y sus efectos adversos en la piel y mucosas son variados, incluyendo reacciones leves y graves. Las erosiones y úlceras cutáneas como manifestación de citotoxicidad por metotrexato son infrecuentes y representarían un signo cutáneo temprano de pancitopenia por toxicidad medular secundaria a dicha droga. En la mayoría de los casos existen enfermedades cutáneas previas a la ulceración, principalmente psoriasis. En ausencia de dermatitis subyacente, la presencia de ulceraciones es excepcional. Se presentan ocho casos de pacientes con signos cutáneos de intoxicación por metotrexato, con y sin dermatosis previas. En la mayoría hubo asociación de mucositis y compromiso medular. Se recomiendan pautas de tratamiento.

Methotrexate is an antimetabolite analog to folic acid that competitively inhibits the enzyme dihydrofolate reductase and thymidylate synthetase, essential for the synthesis of DNA and RNA. It is widely used in dermatology and its adverse effects on the skin and mucous membranes are varied, including mild and severe reactions. The appearance of erosions and skin ulcers as a manifestation of methotrexate cytotoxicity are quite infrequent. These would represent an early cutaneous sign of pancytopenia due to marrow toxicity secondary to this drug. In most of the cases there are cutaneous diseases prior to ulceration, mainly psoriasis. In the absence of underlying dermatitis, the presence of ulcerations is very rare. We present eight cases of patients with cutaneous signs of methotrexate poisoning, with and without previous dermatoses. Most of them associated mucositis and bone marrow involvement. Treatment guidelines are recommended.

Can positron emission tomography-computed tomography predict response in locally advanced rectal cancer patients treated with induction folinic acid and 5-florouracil.

OBJECTIVE: The aim of this study was to determine the pathological complete response rates in a group of locally advanced rectal cancer patients who underwent chemoradiotherapy (CRT) after treatment with induction folinic acid and 5‑florouracil (FOLFOX) chemotherapy and the relationship between the complete response and positron emission tomography‑computed tomography (PET‑CT). MATERIALS AND METHODS: The files of 239 patients who were diagnosed with rectal cancer between January 2008 and January 2012 were evaluated retrospectively. Of these, there were 24 locally advanced rectal cancer patients who met the following criteria: They were administered CRT after receiving four courses induction oxaliplatin, FOLFOX and they underwent PET‑CT for staging and for the evaluation of their response to FOLFOX treatment. Of these 24 patients, 20 operable patients were included in the study. RESULTS: The pathological complete response was obtained in seven patients (35%) who were operated on and then given induction four courses FOLFOX chemotherapy and CRT. We determined that age, gender, clinical stage at diagnosis and PET‑CT before and after induction chemotherapy were not predictive of the pathological complete response to tumor fluorodeoxyglucose uptake activity. CONCLUSION: The rates of pathological complete response were increased in locally advanced rectal cancer patients who underwent short‑term induction chemotherapy. Although the PET‑CT has retained its importance in predicting pathological complete response, there is still a need for studies with a larger number of patients and long‑term follow‑ups.

Falla de la profilaxis con cotrimoxazol para la neumonía por Pneumocystis jiroveci con el uso concomitante de leucovorina: Reporte de un caso / Failure of cotrimoxazole prophylaxis for Pneumocystis jiroveci pneumonia with concomitant use of leucovorin: Case report

The concomitant use of leucovorin and cotrimoxazole in PCP can lead to therapeutic failure and increased risk of death due to antagonism. It is important to keep this possible antagonistic interaction in mind even during prophylaxis. This paper presents a case with this failure outcome.

A phase II study of oxaliplatin with 5-FU/folinic acid and concomitant radiotherapy as a preoperative treatment in patients with locally advanced rectal cancer

Objective: To evaluate the activity and safety of adding oxaliplatin to a standard chemoradiotherapy schema, including 5-fluorouracil (5-FU)/folinic acid (FA), in locally-advanced rectal cancer (LARC). Methods: Two cycles of oxaliplatin 130 mg/m2 plus FA 20 mg/m2 bolus for 5 days and 5-FU 350 mg/m2 continuous infusion for 5 days were given during week 1 and 4 of pelvic radiotherapy 46 Gy. Patients with a T3/4 and/or node-positive rectal tumour were eligible. Surgery was performed 4–6 weeks after radiotherapy. The primary endpoint was to determine the rate of pathological response. Secondary endpoints were to assess the rate of clinical response and the safety profile. Results: Between March 2005 and January 2009, a total of 35 patients were enrolled. The pathological downstaging rate was 79% with a pathological complete response rate of 17%. The overall clinical response rate (assessed by computed tomography or transrectal ultrasound) was 77%. Grade 3 diarrhoea and Grade 3 neutropaenia were reported in 14% and 11% of the patients, respectively. Eleven patients did not undergo surgery: four of them refused the operation, and seven patients were inoperable due to disease progression. In 24 patients who had surgery, a sphincter-preserving procedure could be performed in 29%. At the median follow-up time of 28.1 months, 25 patients (71%) survived with no evidence of disease. Conclusion: The promising results in terms of pathological response, and the associated good safety profile of a regimen of oxaliplatin plus 5-FU/FA with concomitant radiotherapy, suggest that the regimen could be used in LARC.

Oral Tegafur-uracil Plus Folinic Acid versus Intravenous 5-fluorouracil Plus Folinic Acid as Adjuvant Chemotherapy of Colon Cancer

To compare, in terms of compliance, toxicity, quality of life (QOL) and efficacy, intravenous 5-fluorouracil plus folinic acid with oral tegafur-uracil plus folinic acid as postoperative adjuvant chemotherapy after curative resection in patients with Dukes' stage B2 and C2 colon cancer. Among all patients with adenocarcinoma of the colon operated on between July 1997 and June 1999, 122 with Dukes' stage B2 or C2 colon cancer were enrolled in this study. Fifty-three patients were treated with intravenous 5-fluorouracil plus folinic acid (5-FU group) and 69 with oral tegafur-uracil plus folinic acid (UFT group). Compliance, toxicity, QOL and efficacy were evaluated. Compared with the 5-FU group, patients in the UFT group experienced a lower incidence of grade 1 toxicity. The incidences of grade 2-4 toxicity were similar in the two treatment groups. However, severe toxicity (grade 3 or 4) was rare in both groups. A steady and significant increase of the QOL score, both during and after therapy, was evident in both groups suggesting that chemotherapy is quite tolerable and does not deteriorate the patients' QOL. At the median follow-up duration of 28 months, the survival rate and disease free survival rate for the UFT and 5-FU groups were 94.9% vs. 92.5% and 87.5% vs. 84.1%, respectively (p > 0.05). These data suggest that oral tegafur-uracil modulated with oral folinic acid as an adjuvant chemotherapy in patients with Dukes' stage B2 and C2 colon cancer may be a good alternative to infusional 5- fluorouracil.

A Phase II Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in 5- Fluorouracil-Pretreated Metastatic Colorectal Cancer / 대한암학회지

PURPOSE: To evaluate antitumor response, time to progression, and toxicities of oxaliplatin, 5- fluorouracil (5-FU), and leucovorin (LV) continuous infusion in patients with metastatic colorectal cancer who progressed during or after treatment with a 5-FU-containing regimen. MATERIALS AND METHODS: Forty-eight patients with metastatic colorectal cancer, who progressed while receiving or after discontinuing palliative chemotherapy with 5- FU-based regimen, were enrolled in this study. Treatment consisted of oxaliplatin (85 mg/m2 on day 1) as a 2-hour infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 5-FU 48-hour infusion 2.4~3 g/m2 concurrently with LV 48-hour infusion 150 mg/m2, without mixing. Cycles were repeated at 2-week intervals. The dose of 5-FU was modified, depending on the hematologic toxicity profile. RESULTS: The objective response rate was 28% for 43 assessable patients (95% confidence interval, 14% to 42%), including one complete remission (2%). Seventeen additional patients (39%) had stable disease, and fourteen (33%) progressed. The median time to progression was 5.9 months and the median overall survival was 13.2 months from the start of the chemotherapy. From the 297 cycles analyzed, hematologic toxicities per course were: leukopenia; grade I 26.6%, grade II 3.4%, and grade III 0.3%, thrombocytopenia; grade I 10.8%, grade II 3.0%, grade III 1.0%, and grade IV 0.3%. The most frequent nonhematologic adverse reactions were nausea/vomiting and peripheral neuropathy, which were rated as WHO grade II in 13 patients (49%) and 11 patients (22%), respectively. CONCLUSION: This phase II study of oxaliplatin, 5-FU, and LV continuous infusion showed enhanced antitumor activity in patients with 5-FU-pretreated metastatic colorectal cancer. Overall toxicity was acceptable; neurotoxicity and bone marrow suppression constituted the dose-limiting side effects.

Treatment of advanced gastric cancer with the regimen of etoposide,folinic acid and fluorouracil / 中国癌症杂志

Purpose:To observe the response and tolerance to the regimen of etoposide,folinic acid and fluorouracil (ELF) in advanced gastric cancer. Methods:Thirty two patients with advanced gastric cancer received chemotherapy of ELF regimen(VP 16 100 mg iv d 1—3 ,CF 100—300 mg iv d 1—3,5 FU 750 1 000 mg iv d 1—3 Results:The overall response rate was 37.5% (12/32) and complete response rate was 3.1% (1/31), the partial response rate was 33.4% (11/32). The main toxicity was myelosuppression and alopecia. Leukopenia was observed in 81.6% of the patients, but grade 3 and 4 in only 12.5%. Anemia and throbopenia was observed in 21.8% and 35.1% of the patients respectively, alopecia in 100%. Other side effects were uncommon. Conclusions:This study shows that the regimen of ELF is effective and tolerable for treatment of advanced gastric cancer. [

Folinic Acid is an Active Chemosensitizer of 5-Fluorouracil in vivo against Human Transitional Cell Carcinoma / 대한비뇨기과학회지

While augmentation of 5-fluorouracil (5FU) cytotoxicity by folinic acid (FA) has clearly been demonstrated in vitro, its value in human is controversial. Unfortunately, essentially all tumors studied in vivo have been murine and none were transitional cell carcinoma (TCC); no in vivo studies of FA+5FU against TCC xenografts have been performed. The present study was initiated to test the effects of FA on 5FU induced cytotoxicity in two human bladder cancer xenografts, DU4184 and DU4284, and to further test the sequence dependence of FA+5FU synergism. To perform the in vivo chemosensitivity assay, we used modified nude mouse subrenal capsule assay. Before treatment, the mice were randomly allocated into four groups. Group A was given normal saline only as a control, group B was given 5FU (100 mg/kg i.p.) only, and group C was given FA (100 mg/kg i.p.) and 5FU simultaneously and group D was given FA and one hour later 5FU. Before treatment and after treatment tumor volumes were measured and tumor growth ratio (TGR) of each group was calculated. TGRs of group A, B, C, and D were 6.1+/-0.6, 3.8+/-0.3, 3.8+/-0.4, and 3.0+/-0.2, respectively.No difference in cytotoxicity was seen if 5FU was given simultaneously with FA (group C). However, pretreatment with FA one hour prior to 5FU resulted in statistically significant potentiation of 5FU efficacy (group D) (p<0.05). Using this preferred dose schedule, DU4184 vs. DU4284 (+/- FA) was evaluated. Comparative sensitivity of the two lines revealed that DU4284 is relatively resistant to 5FU. FA significantly enhanced the cytotoxicity of 5FU on both DU4184 and DU4284 xenografts (p<0.05, and p<0.01, respectively) and had a substantially greater impact in the intrinsically more 5FU-resistant tumor (DU4284). It is concluded that FA is an effective chemosensitizer of 5FU in vivo against human TCC. Nevertheless, dose schedule is critical; pre-loading of the tumor with FA prior to 5FU is essential. However, as yet undefined intrinsic biochemical differences between tumors [such as thymidine salvage pathways (not generally assessable by standard in vitro assays)] may modulate the extent of such efficacy. Further preclinical study with an expanded TCC xenograft battery is necessary and should be linked with a study of biochemical correlates to identify phenotypic differences in FA chemosensitivity of those benefiting from this regimen.

Folinic Acid Protection Against Hematopoietic Cell Depression Induced by Nitrous Oxide in Rats / 대한마취과학회지

The degree of hematopoietic depression and spontaneous recovery of depressed cells with 50% nitrous oxide inhalation for 6 or 12 hours were studied in 120 Sprague-Dawley rats. Immediately after, 1 day, 3 days and 1 week after nitrous oxide inhalation, precursor cells of granulocyte-monocyte and T lymphocyte in bone marrow and blood were sampled and cultured. After one week of culture period, the numbers of colony forming unit-granulocyte monocyte (CFU-GM) and colony forming unit-T lymphocyte (CFU-TL) were counted. There was no change in the number of colony immediately after inhalation of nitrous oxide, but was significant decrease in number of colony 1 day and 3 days after inhalation of nitrous oxide (p<0.001). One week after cessation of nitrous oxide inhalation, spontaneous recovery of number of colony developed without any treatment. To evaluate the protective effect of folinic acid (Rescuvolin) against hematopoietic depression, Rescuvolin 0.1 mg/0.3 ml were injected intraperitoneally at 12 hours and 1 hour before, 1 hour before and immediately after nitrous oxide inhalation, respectively. The data of each group were compared with that of the animals which have inhaled nitrous oxide for 6 hours without folinic acid. Folinic acid injected groups showed significant increase in numbers of colony (p<0.001) especially in 12 and 1 hour before nitrous oxide inhalation. In conclusion, the longer the duration of nitrous oxide inhalation, the faster and severer hematopoietic depression developed. The pretreatment of folinic acid may prevent the bone marrow depression by a long-term and repeated use of nitrous oxide. In clinical anesthesia, it is recommended to avoid to use nitrous oxide for the patients with bone marrow depressed disease such as leukemia and aplastic anemia.

Oxaliplatin combining fluorouracil and folinic acid in treatment of locally advanced and metastatic gastric cancer / 第二军医大学学报

To evaluate the efficacy and safety of an oxaliplatin, fluorouracil (5 FU), and folinic acid (FA) combination in treatment of patients with metastatic or advanced gastric cancer,we used oxaliplatin 130 mg/m 2 (2 hour intravenous infusion,1 d)and FA 200 mg/m 2 (2 hour intravenous infusion,1 to 5 d) followed by 5 FU 500 mg/m 2 (4 hour continuous infusion,1 to 5 d) every 3 weeks. Efficacy of treatment was evaluated after 3 cycles and the responders were confirmed 4 weeks later. In 26 case evaluated, patial release was achieved in 11 cases, stablized in 9 cases, progressed in 6 cases. The overall response rate was 42.3%. The main adverse effects were gastrointestinal tract toxicity, neurosensory toxicity and bone marrow suppression. This trail suggested that the short term curative effect of this regimen was similar to those of others and showed good efficacy and an acceptable safety profile. It is a new option for the treatment of metastatic and advanced gastric cancer.

Study on Toxicity of Nitroquine-Dapson Compound & Its Treatment with Folic Acid or Folinic Acid in Mice and Dogs / 第三军医大学学报

The toxic effects of nitroquine-dapson compound(NQD) per os in mice and dogs were studied. The therapeutic index of NQD in mice(1911) is the highest among the six antimalarial preparations studied. The toxic effects(50mg/kg/ day for 3 successive days per os) in dogs were similar to those of nitroquine. They manifested themselves as the injury on the adrenal cortex and on the intestinal epithelium. When folic acid (4 mg/kg/day for 4 successive days) or folinic acid(0.3 mg/kg/day for 4 successive days) was administered intramuscularly to the toxicated animals, both the death rate and the incidence of diarrhea were greatly reduced. Pathological study confirmed that the injury on the intestinal epithelium was much milder and the goblet cell was much more numerous in the treated than in the untreated. The results suggest that folic acid or folinic acid can protect the less differentiated cells in the intestinal crypts, so that the clinical manifestations of NQD toxicity are reduced after treatment.