Epigenetic therapy and cisplatin chemoradiation in FIGO stage IIIB cervical cancer.

INTRODUCTION: This trial aimed to evaluate the safety and efficacy of epigenetic therapy associated with cisplatin chemoradiation in FIGO Stage IIIB patients. METHODS: Hydralazine containing either 182 mg for rapid-, or 83 mg for slow acetylators and magnesium valproate were administered at 30 mg/kg tid. Both drugs were taken until intracavitary therapy was finished. Pelvic external beam radiation and low-dose rate brachytherapy were administered at a total cumulative dose to point A of at least 85 Gy. Weekly cisplatin at 40 mg/m2 was delivered for six cycles. RESULTS: Twenty-two patients were included and 18 (82%) patients completed treatment. Mean dose to point A was 84.6 + 2.2. Median number of cisplatin cycles was 5.5 (range, 1-6). Brachytherapy was delayed for technical reasons; the mean overall treatment time was 11.8 weeks. Grade 3 anemia, leucopenia, neutropenia, and thrombocytopenia were observed in 9%, 45%, 45%, and 9% of patients, respectively. CONCLUSIONS: Hydralazine and valproate are well-tolerated and safe when administered with cisplatin chemoradiation. Unfortunately, the suboptimal administration of brachytherapy for technical reasons in this study, precluded assessing the efficacy of epigenetic therapy. However, the tolerability of this regimen administered concurrent to radiation needs to be further tested.

Concurrent chemoradiation with carboplatin for elderly, diabetic and hypertensive patients with locally advanced cervical cancer.

INTRODUCTION: Chemoradiation based on cisplatin is the standard treatment of locally advanced cervical cancer, however, a subset of patients are either elderly and/or have comorbidities such as diabetes and hypertension. These conditions may compromise the administration of cisplatin. We report our Institution experience with weekly carboplatin as a radiosensitizer for the management of this subset of patients. PATIENTS AND METHODS: We reviewed the files of 59 patients with locally advanced cervical cancer who were treated with primary chemoradiation with weekly carboplatin. Response rate, toxicity and survival were analyzed. RESULTS: Mean age was 62 years (range, 36-83 years). The majority of cases were squamous cell carcinoma (88.14%), and distribution according to FIGO Stage was IB2 8.4%, IIA 13.5%, IIB 52.5%, IIIA 3.3% and IIIB 18.6%; Overall, 100% and 91% of patients completed external beam and intracavitary therapy. Seventy-nine percent received from five to six planned cycles of weekly carboplatin. Complete responses were achieved in 49 (83.05 %) patients, whereas ten patients (16.95%) had either persistent or progressive disease. The most common toxicities were grades 1 and 2 hematological and gastrointestinal. At median follow-up (20 months; range 2-48 months), 16 patients (32.65%) have relapsed. Estimated 30-month overall survival is 63%. CONCLUSIONS: Weekly carboplatin concurrent with pelvic radiation is well tolerated in patients with locally advanced carcinoma of the cervix who are older than 70 years and/or have diabetes mellitus and/or high blood pressure, however, the apparently slighty lower survival observed cautions against its routine use.

Comparison of histological results from the resection of residual masses at different sites after chemotherapy for metastatic non-seminomatous germ cell tumours.

Cisplatin-based combination chemotherapy is considered standard treatment for patients with metastatic testicular cancer. However, despite the normalisation of serum tumour markers, 25-50% of patients will demonstrate residual neoplastic masses on radiological examination after completion of chemotherapy. The management of patients presenting with multiple residual masses at different localisations remains particularly difficult. This report summarises the histological findings and the clinical outcome of 27 patients with metastatic non-seminomatous germ cell tumours who underwent multiple resections for residual masses at different localisations after first-line cisplatin-based chemotherapy at Hannover University Medical School between 1980 and 1995. Fifty-six resections were performed (27 retroperitoneal interventions, 21 thoracotomies, 4 resections of hepatic lesions, 3 neck dissections, 1 craniotomy). No surgery-related mortality was observed. 8 patients (30%) showed dissimilar histological findings at sequential or one-stage resections. 5 of these demonstrated less favourable pathological features (mature teratoma or undifferentiated tumour) at the second operation, while only necrosis (n = 3) or teratoma (n = 2) had been found following the first operation. Tumour necrosis was documented more frequently at thoracotomy (n = 15/21) compared to retroperitoneal lymph node excision (n = 17/27). By univariate analysis, completeness of surgery (R0 resection) and the histological finding of necrosis or differentiated teratoma were associated with improved relapse-free and overall survival. After a median follow-up period of 33 months (range 1-167), 19 of 26 (73%) evaluable patients are alive; 18 of 27 (67%) patients have continuous no evidence of disease (1 patient with recurrent disease was lost to follow-up). Since the histological findings in postchemotherapy residuals may vary between different anatomical sites and no prediction seems possible, patients are best managed by excision of all present tumour masses if technically feasible. Necrosis identified at thoractomy should not lead to omission of retroperitoneal lymph node resection since there was, in accordance to other authors, a trend that the retroperitoneum harbours unfavourable histological findings more frequently.

[Treatment modalities in patients with hepatocellular carcinoma: a retrospective series in a single institution in Mexico]. / Modalidades de tratamiento para pacientes con carcinoma hepatocelular: una serie retrospectiva de una sola institución en México.

BACKGROUND: To date, curative treatment options for hepatocellular carcinoma (HCC) include orthotopic liver transplantation or surgical resection. Most patients are detected with nonresectable or transplantable HCC due to disease extension or comorbid factors, and are therefore candidates for palliative treatments only. Few follow-up data are available in patients with HCC in Latin America. We therefore reviewed the experience of HCC treatment in a single institution over a 10-year period. PATIENTS AND METHOD: A total of 135 patients attending the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, a national referral center in Mexico, from January 1991 to December 2000 were included. In all patients etiology, stage, and diagnostic and therapeutic measures were documented. Survival time was calculated as a function of staging and therapy. RESULTS: Of 135 patients, 77 (57%) were men and 58 (43%) were women. The mean age at diagnosis was 59.17 years (range: 16-87 years). Cirrhosis was diagnosed in 89 patients (64.4%). The median overall survival for all patients with HCC was 7.9 months. Treatment included surgical resection (n=22), hepatic artery chemoembolization (n=10), percutaneous ethanol injection (n=6), systemic chemotherapy (n=5), tamoxifen (n=11), and thalidomide (n=1). Eighty patients received support measures. The median survival in the group of patients who underwent surgical resection (37.89 months) was significantly higher than that in the groups of patients who did not undergo resection. CONCLUSIONS: Patients with HCC who received no treatment had a median survival of 1.7 months. Hepatic resection offers the best chance of cure in patients with HCC. The strong association between HCC and cirrhotic liver disease makes surgical resection difficult in patients with low hepatic reserve.

Drug-induced agranulocytosis treated with granulocyte-macrophage colony stimulating factor.

Drug induced agranulocytosis (DIA) is a potentially lethal disorder characterized by selective neutropenia. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been utilized for its treatment. We report four cases of DIA treated with GM-CSF at the dose of 5 micrograms/kg/day. The patients presented infectious diseases at diagnosis. Median days to obtain 1 x 10(9)/L neutrophils and a normal neutrophil count (NNC), were 7(5-9) and 7.5 (6-10) days, respectively. The infectious disease at diagnosis improved and all patients are alive at the moment of this report. No other adverse effects than thrombocytosis (two cases) and thrombocytopenia (one case) were observed. We consider that GM-CSF could be a safe and effective alternative in the treatment of DIA.

[Elective endoscopic sclerotherapy in esophageal varices]. / Esclerosis endoscópica electiva de várices esofágicas.

We present our experience with elective sclerotherapy in ten years. 64 male and 57 females, median age 52.5 years, were treated. Post-necrosis cirrhosis was the primordial etiology in 44% followed by alcoholic in 40%. In regards to Child classification, 51% were "C"; 24% "B" and 25% "A". With variceal eradication we found no rebleeding, but in those without changes in variceal size, it was 82%. At six months, control of variceal hemorrhage was respectively to groups A, B, and C. 86%, 71% and 63%. The control at long follow-up were respectively 74%, 68% & 57%. Survival was directly related to the level of hepatic function instead of sclerosis. Complications were 2 to be 3% being the most severe: pleural effusion; mediastinitis and fiber. Mortality was 0.8% in one patient with esophageal perforation.

[Emergency endoscopic sclerosis in esophageal varices]. / Esclerosis endoscópica de urgencia en várices esofágicas.

In 52 patients we performed endoscopic sclerotherapy during active bleeding with good results in stopping hemorrhage in 93%. Most patients were Child "C" (66%) and postnecrotic cirrhosis was the commonest etiology (50%). Major complications were pleural effusion (2%) and mediastinal inflammation (2%), no mortality was found directly by this method. Conclusions are that endoscopic sclerosis of variceal hemorrhage have a special role in stopping bleeding but has no effect in one year survival.

Pharmacogenetics and pharmacoepigenetics of gemcitabine.

Gemcitabine (2',2'-difluoro 2'deoxycytidine, dFdC) is an analog of cytosine with distinctive pharmacological properties and a wide antitumor-activity spectrum. The pharmacological characteristics of gemcitabine are unique because two main classes of genes are essential for its antitumor effects: membrane transporter protein-coding genes, whose products are responsible for drug intracellular uptake, as well as enzyme-coding genes, which catalyze its activation and inactivation. The study of the pharmacogenetics and pharmacoepigenetics of these two gene classes is greatly required to optimize the drug's therapeutic use in cancer. This review aims to provide an update of genetic and epigenetic bases that may account for interindividual variation in therapeutic outcome exhibited by gemcitabine.

Comparison of the mineral and trace element concentrations between 'gazpacho' and the vegetables used in its elaboration.

Contents of moisture, ash and minerals and trace elements (sodium, potassium, calcium, magnesium, iron, copper, zinc and manganese) were determined in vegetable samples--garlic, tomato, white onion, cucumber, pepper--in 'gazpacho', which was elaborated using these vegetables. The mean sodium concentration in 'gazpacho' was much higher than those mean values observed in the fresh vegetables. The mean values of the minerals studied in the 'gazpacho', except sodium and calcium, tend to be lower than the mean values in the vegetables used. Garlic presented significantly higher mean contents of the trace elements than the rest of the vegetables and the 'gazpacho'. Many highly significant correlations between all the minerals analyzed, except calcium, were observed. Factor analysis makes it possible to differentiate the samples of garlic, onion, and 'gazpacho' from one another, and from the rest of the vegetables considered.

The prognostic significance of leukocytosis in cervical cancer.

Cervical cancer is a frequent tumor with established prognostic factors such as FIGO stage and hemoglobin levels among others. Despite the fact that paraneoplastic leukocytosis is relatively common in many solid tumors, only isolated cases of cervical cancer patients presenting this abnormality have been published; hence, the clinical significance of leukocytosis is unknown in this tumor type. Retrospective review on the medical records of 294 consecutive newly diagnosed and untreated locally advanced cervical cancer patients who received radiotherapy and concurrent cisplatin was conducted. Leukocytosis was defined as a persistent white blood cell count exceeding 10,800/microL, determined at least twice before commencing chemoradiation providing that patients were free of any active acute or chronic infection or any other condition known to elevate the leukocyte count. The frequency of leukocytosis and their correlation with clinicopathologic features were investigated, as well as their impact on tumor response and survival. Leukocytosis with a median value of 13,300/microL (11,100-28,800) was observed in 35 (11.9%) patients at diagnosis. Leukocytosis was statistically associated only with advanced stages. Clinical complete response was observed in 57% versus 86% of the patients with and without leukocytosis, respectively. In the univariate analysis, leukocytosis, stage, and hemoglobin levels were significant predictors of survival; however, only leukocytosis and the hemoglobin level remained significant predictors of survival in the multivariate analysis. Leukocytosis is common in cervical cancer patients and has a negative prognostic significance.

A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors.

BACKGROUND: Epigenetic aberrations lead to chemotherapy resistance; hence, their reversal by inhibitors of DNA methylation and histone deacetylases may overcome it. PATIENTS AND METHODS: Phase II, single-arm study of hydralazine and magnesium valproate added to the same schedule of chemotherapy on which patients were progressing. Schedules comprised cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, pemetrexed, topotecan, doxorubicin, cyclophosphamide, and anastrozole. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow, acetylators, and magnesium valproate at 40 mg/kg, beginning a week before chemotherapy. Response, toxicity, DNA methylation, histone deacetylase activity, plasma valproic acid, and hydralazine levels were evaluated. RESULTS: Seventeen patients were evaluable for toxicity and 15 for response. Primary sites included cervix (3), breast (3), lung (1), testis (1), and ovarian (7) carcinomas. A clinical benefit was observed in 12 (80%) patients: four PR, and eight SD. The most significant toxicity was hematologic. Reduction in global DNA methylation, histone deacetylase activity, and promoter demethylation were observed. CONCLUSIONS: The clinical benefit noted with the epigenetic agents hydralazine and valproate in this selected patient population progressing to chemotherapy' and re-challenged with the same chemotherapy schedule after initiating hydralazine and valproate' lends support to the epigenetic-driven tumor-cell chemoresistance hypothesis (ClinicalTrials.gov Identifier: NCT00404508).

A comparison of the radiation sensitivities of non-tumorigenic and tumorigenic human hybrid cell lines.

The radiation sensitivities of two related non-tumorigenic and two related tumorigenic human hybrid cell lines (HeLa x skin fibroblast) have been studied. The data show that the transformation from the non-tumorigenic to the tumorigenic state, which is accompanied by the loss of skin fibroblast chromosomes 11 and 14, is not associated with any major changes in radiation sensitivity. The data do indicate, however, a trend toward a steeper and longer initial slope to the cell survival curve for the tumorigenic cell lines, along with a subsequent reduced ability to accumulate sublethal radiation injury at low doses. Both nontumorigenic and tumorigenic cell lines have the capability of repairing sublethal injury.

Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular germ cell tumors.

PURPOSE: To analyse the frequencies of histological findings, predictive factors for the presence of undifferentiated tumor and variables influencing the survival of patients with non-seminomatous germ cell tumors who underwent secondary resection of residual masses after cisplatin-based combination chemotherapy. PATIENTS AND METHODS: 134 patients with a median age of 26 years (15-47) undergoing at least one surgical intervention at Hannover University Medical School were included. One hundred nine patients had received first-line chemotherapy and 25 underwent surgery after second-line chemotherapy. RESULTS: After first-line chemotherapy the distribution of histological findings was 52% necrosis, 27% differentiated teratoma and 21% undifferentiated tumor for 82 patients with marker negative PR (PRm-). Incompletely resected mass and failure to achieved complete tumor marker normalisation were significantly associated with the finding of undifferentiated tumor. Five-year progression-free survival rates according to histological findings were 78%, 67% and 66% for necrosis, differentiated teratoma and undifferentiated tumor. Patients with undifferentiated tumor in the resected specimen routinely received postoperative additional chemotherapy. Factors associated with a worse overall survival were progressive disease within three months, persistent AFP elevation prior to surgery, prechemotherapy elevated LDH levels or mediastinal lymph node involvement at primary diagnosis. In 8 of 27 patients (30%) undergoing multiple resections at different sites a dissimilar histology was found. In the 25 patients operated after salvage chemotherapy undifferentiated tumor was found in 80%. A five-year survival of 44% compared to 80% after first-line chemotherapy was achieved. CONCLUSIONS: Resection of residual tumors after first-line chemotherapy remains essential in the treatment of metastatic testicular cancer. Undifferentiated tumor may still be found in 20% of patients despite achieving PRm-after first-line chemotherapy. Necrosis is found in only 50% of marker normalized patients after first-line and approximately 30% after second-line chemotherapy. Future studies have to prove whether the combination of clinical prognostic factors and the use of PET-scanning will allow to spare subsets of patients from secondary resection.

rHuGM-CSF after high-dose chemotherapy in post-remission acute leukemia.

Post-remission high-dose chemotherapy has been an important advance in the treatment of adult acute leukemia (AAL). Without the use of colony-stimulating factors (CSFs) in this program, the mortality rate varies from 5 to 17%, and infectious complications arise in more than 50%. These findings limit the widespread use of such forms of therapy. The use of high-dose ara-C (HIDAC) alone or in combination with other drugs is the most common regimen studied, however neither other drug combinations nor the addition of supporting CSFs have been extensively explored. For this reason we studied the effect of high-dose cyclosphosphamide-etoposide (CECY) plus recombinant human granulocyte-macrophage (rHuGM)-CSF with the intention of decreasing morbimortality and prolonging disease-free survival (DFS). Since 1992 we have included 51 complete remission patients with AAL in the CECY plus rHuGM-CSF protocol. The maximal myelosuppression occurred in a mean of 6.4 days, and the mean days required for absolute neutrophil count recovery was 13 days and for platelets 21 days (p < 0.0001). No toxic deaths occurred and only two serious infectious complications were seen. After two years of follow-up, 50% of de novo acute myelogenous leukemia patients had relapsed at 13 months, and 50% of de novo adult acute lymphocytic leukemia patients had relapsed at 15 months. In a recent update, we have not seen a significant difference when compared to historic groups. The CECY protocol does not appear to be superior in prolonging DFS compared to HIDAC as a post-remission strategy for newly diagnosed AAL. The main difference was the absence of toxic deaths and minimal serious infectious complications in the CECY protocol. Therefore, we suggest that the use of rHuGM-CSF in post-remission programs should be included in future studies.

An unusual presentation of actinomycosis in a young woman, after surgery

Actinomycosis is an unusual, chronic granulomatous disease. Actinomyces israelli has been found to be related to infectious processes in those patients with affected skin integrity leading to abscess formation, fistulae or mass lesions. Actinomycosis mainly presents in three forms cervicofacial (50%), abdominal (20%) and thoracic (15%). Pelvic cases have been rarely reported and are usually associated with the use of intrauterine devices. We describe a case of a 23 y/o female without history of intrauterine device use, who was admitted with an ovarian cyst following an appendectomy. An ovarian abscess was drained. The pathology showed a granuloma and focal sulfur granules like particles compatible with Actinomyces. This is a case of pelvic Actinomyces, not related to the use of an intrauterine device