Protein expression of prognostic genes in primary melanoma and benign nevi.

PURPOSE: To evaluate the protein expression characteristics of genes employed in a recently introduced prognostic gene expression assay for patients with cutaneous melanoma (CM). METHODS: We studied 37 patients with CM and 10 with benign (melanocytic) nevi (BN). Immunohistochemistry of primary tumor tissue was performed for eight proteins: COL6A6, DCD, GBP4, KLHL41, KRT9, PIP, SCGB1D2, SCGB2A2. RESULTS: The protein expression of most markers investigated was relatively low (e.g., DCD, KRT9, SCGB1D2) and predominantly cytoplasmatic in melanocytes and keratinocytes. COL6A6, GBP4, and KLHL41 expression was significantly enhanced in CM when compared to BN. DCD protein expression was significantly correlated with COL6A6, GBP4, and KLHL41. GBP4 was positively correlated with KLHL41 and inversely correlated with SCGB2B2. The latter was also inversely correlated with serum S100B levels at time of initial diagnosis. The presence of SCGB1D2 expression was significantly associated with ulceration of the primary tumor. KRT9 protein expression was significantly more likely found in acral lentiginous melanoma. The presence of DCD expression was less likely associated with superficial spreading melanoma subtype but significantly associated with non-progressive disease. The absence of SCGB2A2 expression was significantly more often observed in patients who did not progress to stage III or IV. CONCLUSIONS: The expression levels observed were relatively low but differed in part with those found in BN. Even though we detected some significant correlations between the protein expression levels and clinical parameters (e.g., CM subtype, course of disease), there was no major concordance with the protective or risk-associated functions of the corresponding genes included in a recently introduced prognostic gene expression assay.

Carcinoma Seroso de alto grado de Trompa Uterina. Reporte de un caso / High-grade Serous Carcinoma of Uterine Tube. Case Report

Introducción: El cáncer primario de la Trompa de Falopio es una de los neoplasias más inusuales tratadas por los ginecólogos y rara vez se la diagnostica correctamente antes de la cirugía ya que su detección temprana y el diagnóstico preoperatorio son muy difíciles de ser realizados; a menudo la enfermedad se confunde con tumoraciones o cáncer de otro órgano y la laparotomía debe ser llevada a cabo invariablemente. Caso Clinico. Paciente de 62 años, conocida hipertensa y diabética. Acude al servicio por hemorragia de la postmenopausia, se le realiza ecografía que informa una tumoración anexial izquierda y endometrio engrosado de 6,1mm, se toma dosaje de marcadores tumorales cuyo resultados fueron normales (CEA: 1,67 U/mL; CA125 31,72 U/mL), se le practica una histeroscopía donde se observa un pólipo endometrial de 1 x 0.5cm, se procede a la realización de legrado biopsico con resultado anatomopatologico que informo endometrio atrófico y pólipo de glándulas ístmicas sin atipias. Sometida a una anexectomia vía laparotomica donde se llega al diagnostico por congelación intraoperatoria de carcinoma maligno de ovario no mucinoso. Se decide por lo tanto anexohisterectomía total, biopsias múltiples abdominales, omentectomia y linfadenectomia pélvica. El informe anatomopatológico final fue carcinoma infiltrante seroso de alto grado de trompa uterina izquierda de región ampular, el tumor compromete todas las capas de la trompa, ganglios pélvicos positivos. Trompa derecha, útero, ovarios, epiplón sin evidencia de neoplahipoecogesia, liquido peritoneal negativo correspondiente a la estadificación III-C de la FIGO. Actualmente la paciente está en tratamiento quimioterápico. Discusión. El diagnóstico preoperatorio de cáncer de la Trompa de Falopio es difícil debido a su rareza, síntomas y hallazgos inespecíficos de imágenes. En el estadio I el cáncer, que se limita a la Trompa de Falopio, es extremadamente difícil de ser precisado, por lo que es común que sea diagnosticado recién en estadios avanzados. No existe ningún síntoma característico del cáncer de la Trompa de Falopio, sin embargo el sangrado vaginal anormal ha sido reportado como el síntoma principal. Palabras Claves: Trompa de Falopio, carcinoma seroso, linfadenectomia

Introduction: Primary cancer of the Fallopian tube is ne of the mist unusual neoplasm treated by gynecologists and is rare this diagnosis before surgery, as early detection and pre-operative diagnosis are very difficult to make. Often times, this disease is mistaken as other tumors or cancer from other organs and a laparatomy has to be undertaken. Case: 62 years old female, with high blood pressure and diabetes. Came for an evaluation of post-menopausal hemorrhage, an ultrasound showed a tumor within the anexum of the left ovary and thickened endometrium of about 6.1 mm, tumor markers in blood were normal (CEA: 1,67 U/mL; CA125 31,72 U/mL). She underwent for a hysterectomy where a 1 x 0.5 cm endometrial polyp is found, curettage is performed and this showed atrophic endometrium with polyps of isthmic glands without atypical cells. An ovariectmy was performed by laparascopic surgery, and a diagnosis of serous carcinoma of the ovary by intra-operative histology was made. Because of this finding, a total resection of the uterus and ovaries was performed, with multiple abdominal biopsies and resection of the omentum and the pelvic lymphadenopathy. Final pathology report was of infiltrative, high grade serous carcinoma of the left uterine tube, ampular region, with compromise of all the layers of the Fallopian tube, and pelvic lymph nodes. Right uterine tube, ovaries and mesentery have no evidence of neoplasm, as well as the peritoneal fluid. This fits in grade III-C from FIGO. This patient is currently on chemotherapy. Discussion: The pre-operative diagnosis of cancer of the Fallopian tube is difficult because is rare and imaging studies are unspecific. In FIGO stage I, the cancer limits itself to the Fallopian tube and the diagnosis is extremely difficult to make, and it is quite common to diagnose this cancer in advance stages. There are no characteristic symptoms of this type of cancer, although vaginal bleeding has been described as the main symptom. Key words: Fallopian tube, serous carcinoma, lymphadenectomy

Síndrome de Herlyn Werner Wünderlich. Reporte de tres casos / Herlyn Wunderlich Werner Syndrome. Report of three cases

Caso Clínico 1. J.A, 21 años, nuligesta. Acude por hipermenorragia y síndrome doloroso abdominal. Ecografía informa útero didelfo, hematocolpo en hemivagina ciega, tumoraciones anexiales y agenesia renal derecha conformándose el diagnostico de HWW, es sometida a neosalpingostomia con fimbrioplastia por hematosalpinx derecho por vía laparoscópica. A quince días del postoperatorio presenta cuadro de abdomen agudo. Ecografía informa quiste de ovario con hemorragia intraquística y liquido libre abdominal. Se realiza histerectomía subtotal derecha y drilling del quiste por vía laparotómica. Caso Clínico 2. T.A, 53 años, diagnostico conocido de HWW, cirugías previas histerectomía subtotal y resección del tabique vaginal 38 años antes. Acude por hipermenorrea por miomatosis uterina. Se realiza histerectomía total con resección del 2º cérvix. Caso Clínico 3. S.S, 35 años, diagnostico conocido de HWW, cirugías previas anexectomía izquierda por endometrioma 14 años antes, e histerectomía subtotal, sin resección del tabique en otro hospital 6 años antes. Acude a la consulta donde se diagnostica cervicitis mucopurulenta. Actualmente en planes de resección del tabique vaginal que no se realizo por el cuadro infeccioso presente. Discusión: Hay aproximadamente 200 casos reportados de HWW. La clínica más frecuente es dolor por hematocolpo. Esta patología presenta estrecha relación con infertilidad y endometriosis. Palabras Claves: Síndrome de Herlyn Werner Wünderlich, útero didelfo, hemivagina, agenesia renal.

Objective: To report three cases of diagnosis of Werner Wünderlich Herlyn syndrome (HWWS) in the Central Hospital of Social Security Institute of Paraguay (HC-IPS). Materials and Methods: Data from the records of patients of the Gynecology Service of HC-IPS between January/2010 to enero/2012 diagnosed with HWW. Case 1. J.A., female, 21, nulígesta. Presents abdominal pain and hipermenorragia, ultrasound reports didelphys uterus, hematocolpo, adnexal tumors and right renal agenesia making the diagnosis of HWW, is treated by fimbrioplasty and neosalpingostomy for right hematosalpinx by laparoscopy. Postoperative presents acute abdominal pain, ultrasound reports intracystic hemorrhage and abdominal free fluid. Subtotal hysterectomy is done and drilling of right cyst by laparotomy. Case 2. TA, female, 53, HWW known diagnosis, previous surgery: subtotal hysterectomy and vaginal septum resection 38 years earlier. Presents menorrhagia for uterine fibroids. Total hysterectomy is performed with resection of the second cervix. Case 3. SS, female, 35, known diagnosis of HWW, previous surgeries: left adnexectomy for endometrioma 14 years earlier, and subtotal hysterectomy with out removal of the vaginal septum in another hospital 6 years earlier. Attending the clinic where they diagnosed mucopurulent cervicitis. Currently in plans of vaginal septum resection that was not performed by the infection present. Discussion: There are approximately 200 reported cases of HWW. The most frequent symptom is pain by hematocolopo. Keep in mind the strong association with infertility and endometriosis of this disease. Keywords: Werner Syndrome Wünderlich Herlyn, uterus didelphys, hemivagina, renal agenesis.

5 años de Experiencia en la Utilización del Dispositivo Intrauterino liberador de Levonorgestrel / 5 years of experience in the use of the levonorgestrel-releasing intrauterine device

Objetivo: Determinar el índice de éxito y los factores asociados en el uso del dispositivo intrauterino liberador de levonorgestrel (DIU-LVN). Materiales y Métodos: Estudio prospectivo, analítico experimental. Se recogieron datos de las pacientes ingresadas en el Servicio de Ginecología del HCIPS de febrero del 2007 a febrero del 2012 que se colocaron DIU-LVN y se realizo seguimientoa través del consultas ambulatorias. Resultados: Un total de 190 casos fueron seleccionados de forma aleatoria de 440. 60 casos fueron realizados en los años 2007 y 2008 sin evaluación histeroscopica de la cavidad endometrial 380 casos en los años 2009, 2010 y 2011 con evaluación histeroscopica, no considerando aptas para colocación pacientes con miomas submucosos irresecables. Edad de colocación: media de 42,9 años. Motivos: 92,6% HUA (61,6% miomas, 9,5% submucosos). Patologías asociadas: 31,1% HTA, 23,7% Diabetes Mellitus (DM), 34,2% Hipotiroidismo, 7,9% Hipotiroidismo y DM asociados 2,6% Anticoaguladas, 2,6% Endometriosis. Considerando la posición del útero, la situación de RVF resulto en un RR de 0,75, (IC: 0,41-1,38) y P: 0,33. La presencia de miomas en las pacientes que mantienen su SIU-LVN registró un RR de 1,26 (IC: 0,82-2,95) y una P: 0,28; comparando el IMC, las que presentaron IMC mayor a 25 obtuvo un RR 1,6 (IC: 0, 72-1,87) con P: 0,5. La presencia de hipertensión resulto un RR 1,14 (IC: 0,74-1,74) con P: 0,55. 37,4% con HSC previa. Hallazgos: 8,4% miomas submucosos y 3,7% pólipos endometriales. 76,8% tenían biopsia endometrial previa: 12,1% con hiperplasia endometrial simple sin atipias, 4,2% pólipo endometrial y el 60,5% normal. La histerometría a la colocación: promedio 9 cm. 70,6% mantienen su dispositivo, 3,2% con descenso y recolocación del mismo dispositivo por histeroscopía, 19,4% expulsó el dispositivo y 10% se retiró voluntariamente. De las que no mantienen su SIU-LVN 15,8% tuvieron una histerectomía, 2,6% se recoloco por segunda vez luego de una expulsión (todas mantienen su dispositivo), 2,6% fueron sometidas a una miomectomia por histeroscopía, 4,2% cambiaron a ACO, 3,7% entraron en menopausia, y 68,9% abandonaron tratamiento. Una tasa de éxito total del 76,3%, desglosada por año, éxito: 2007-2008 del 25%, 2009 del 69,5%, 2010 del 72% y 2011 Conclusión: Consideramos que estos dispositivos constituyen una opción más segura y de menor costo, con un buen índice de éxito, y una gran aceptación por parte de las pacientes y evita someterlas a procedimientos quirúrgicos mayores. Una evaluación histeroscópica previa a la colocación del dispositivo permite una mejor selección de las pacientes para colocación del dispositivo mejorando su tasa de éxito global. Aunque el dispositivo haya sido expulsado espontáneamente o se encuentre descendido, una segunda colocación o una reubicación por histeroscopía ha demostrado excelentes resultados. Palabras Claves: Dispositivo intrauterino, levonorgestrel, Mirena

Objective: To determine the success rate and associated factors in the use of levonorgestrel-releasing intrauterine system (LVN-RIS). Materials and Methods: Prospective study. 190 cases were selected at random for study from 440 to who the SIU-LVN where applied in the Gynecology Service of the HCIPS from February 2007 to February. Two groups where created: one with supposed high risk of failure of the treatment and one group with supposed high chances of success. The monitoring was done through the outpatient visits. Results: A total of 190 cases were selected at random from 440. 60 cases were performed in 2007 and 2008 without hysteroscopic evaluation of the endometrial cavity 380 cases in 2009, 2010 and 2011 with hysteroscopic evaluation, considered not suitable for LVN-RIS patients with unresectable submucosal fibroids. Placement age: mean 42.9 years. Diagnosis: HUA 92.6% (61.6% fibroids, submucosal 9.5%). Associated diseases: hypertension 31.1%, 23.7% diabetes mellitus (DM), hypothyroidism 34.2%, 7.9% hypothyroidism and 2.6% associated DM anticoagulated, 2.6% endometriosis. Considering the position of the uterus, the situation of RVF resulted in an RR of 0.75 (CI: 0.41 to 1.38) and P: 0.33. The presence of fibroids in patients who maintain their LVN-IUS showed a RR of 1.26 (CI: 0.82 to 2.95) and P: 0.28, comparing BMI, who had BMI greater than 25 RR was 1.6 (CI: 0, 72 to 1.87) with Q: 0.5. The presence of hypertension resulted RR 1.14 (CI: 0.74 to 1.74) with P = 0.55. 37.4% with previous HSC. Findings: 8.4% and 3.7% submucosal fibroids endometrial polyps. 76.8% had prior endometrial biopsy: 12.1% with simple endometrial hyperplasia without atypia, endometrial polyp 4.2% and 60.5% normal results. Hysterometry: mean of 9 cm. Patients who maintain their LVN-RIS: 70.6%, 3.2% with descended device and repositioning of the same by hysteroscopy, 19.4% expelled the device and 10% withdrew voluntarily. Of those who do not maintain their LVN-RIS 15.8% had a hysterectomy, 2.6% was repositioned for the second time after an expulsion (all keep their device), 2.6% underwent a myomectomy by hysteroscopy, 2% moved to oral contraceptives, 3.7% entered menopause, and 68.9% abandoned treatment. A total success rate of 76.3%. Success by year: 2007-2008: 25%; 2009: 69.5%; 2010: 72% and 2011: 83%. Conclusion: We believe that these devices are a safe and cheap treatment option, with a good success rate, and a high acceptance by patients, and avoid subjecting them to major surgical procedures. Hysteroscopic evaluation prior the placement of the device allows a better patient selection and improves its overall success rate. Even is this device descend or is expelled spontaneously, a second placement or relocation by hysteroscopy shows excellent results. Keywords: levonorgestrel releasing intrauterine system, Mirena

The model repository of the models of infectious disease agent study.

The model repository (MREP) is a relational database management system (RDBMS) developed under the auspices of models of infectious disease agent study (MIDAS). The purpose of the MREP is to organize and catalog the models, results, and suggestions for using the MIDAS and to store them in a way to allow users to run models from an access-controlled disease MREP. The MREP contains source and object code of disease models developed by infectious disease modelers and tested in a production environment. Different versions of models used to describe various aspects of the same disease are housed in the repository. Models are linked to their developers and different versions of the codes are tied to Subversion, a version control tool. An additional element of the MREP will be to house, manage, and control access to a disease model results warehouse, which consists of output generated by the models contained in the MREP. The result tables and files are linked to the version of the model and the input parameters that collectively generated the results. The result tables are warehoused in a relational database that permits them to be easily identified, categorized, and downloaded.

Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HD-FU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: randomized phase II trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft Internistische Onkologie.

PURPOSE: This multicentric, randomized, two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil (FU) or FU plus folinic acid (FA) and cisplatin (Cis) with the aim to select a regimen for future phase III trials. PATIENTS AND METHODS: A total of 145 patients with advanced gastric cancer where randomly assigned to weekly FU 3,000 mg/m2/24 hours (HD-FU), FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 (HD-FU/FA), or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2, each administered for 6 weeks with a 1-week rest. The primary end point was the response rate. RESULTS: Confirmed responses were observed in 6.1% (two of 33) of the eligible patients treated with HD-FU, in 25% (12 of 48, including one complete remission [CR]) with HD-FU/FA, and in 45.7% (21 of 46, including four CRs) with HD-FU/FA/Cis. The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met. The median progression-free survival of all patients in the HD-FU, HD-FU/FA, and HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1 months, respectively. The median overall survival was 7.1, 8.9, and 9.7 months, and the survival rate at 1 year was 24.3%, 30.3%, and 45.3%, respectively. Grade 4 toxicities were rare. The most relevant grade 3/4 toxicities were neutropenia in 1.9%, 5.4%, and 19.6%, and diarrhea in 2.7%, 1.9%, and 3.9% of the cycles in the HD-FU, HD-FU/FA, and HD-/FU/Cis arms, respectively. CONCLUSION: Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer.

Increased hepatic gluconeogenesis: the secret of Lance Armstrong's success.

Enormous amounts of lactic acid are produced during endurance sport by muscle cells. This metabolite is thought responsible for the muscle pain and the fatigue during sport. Its internal removal from the body by enzymatic conversion depends mainly on the capacity of the hepatic gluconeogenesis that converts lactic acid to glucose. The extraordinary sportive results of the racing cyclist Lance Armstrong did us realize that a high capacity of hepatic gluconeogenesis was the basis of his success, because it might have provided him with less pain complaints caused by lactic acid and with an extra source of energy from lactic acid. This enhanced gluconeogenesis can be due to his heavy training program. At the age of 12-13 years he daily swam 10,000m and cycled 32km. In later years as cyclist his training labour was also more than normal. A constitutional increased gluconeogenesis cannot be excluded, because as a boy of 12 years he became already fourth in 1500m free style swimming in a contest for swimmers from whole Texas. The last argument for an increased gluconeogenesis is that Armstrong in October 1996 suffered from an extensively disseminated testicular tumour. This large tumour load caused that in the tumour the oxidative (=aerobic) energy generation changed into a fermentative (=anaerobic) one. This resulted in a high increase of lactic acid that putted up the gluconeogenesis in the liver. We think that this stimulated, high level gluconeogenesis remained high in the following years, when Armstrong restarted cycling, that it provided him with extra energy from lactic acid and with fewer complaints due to the exercise, and that thus this was the basis of his success.

Prediction of chemotherapeutic response of colorectal liver metastases with dynamic gadolinium-DTPA-enhanced MRI and localized 19F MRS pharmacokinetic studies of 5-fluorouracil.

Systemic chemotherapy is effective in only a subset of patients with metastasized colorectal cancer. Therefore, early selection of patients who are most likely to benefit from chemotherapy is desirable. Response to treatment may be determined by the delivery of the drug to the tumor, retention of the drug in the tumor and by the amount of intracellular uptake, metabolic activation and catabolism, as well as other factors. The first aim of this study was to investigate the predictive value of DCE-MRI with the contrast agent Gd-DTPA for tumor response to first-line chemotherapy in patients with liver metastases of colorectal cancer. The second aim was to investigate the predictive value of 5-fluorouracil (FU) uptake, retention and catabolism as measured by localized (19)F MRS for tumor response to FU therapy. Since FU uptake, retention and metabolism may depend on tumor vascularization, the relationship between (19)F MRS and the DCE-MRI parameters k(ep), K(trans) and v(e) was also examined (1). In this study, 37 patients were included. The kinetic parameters of DCE-MRI, k(ep), K(trans) and v(e), before start of treatment did not predict tumor response after 2 months, suggesting that the delivery of chemotherapy by tumor vasculature is not a major factor determining response in first-line treatment. No evident correlations between (19)F MRS parameters and tumor response were found. This suggests that in liver metastases that are not selected on the basis of their tumor diameter, FU uptake and catabolism are not limiting factors for response. The transfer constant K(trans), as measured by DCE-MRI before start of treatment, was negatively correlated with FU half-life in the liver metastases, which suggests that, in metastases with a larger tumor blood flow or permeability surface area product, FU is rapidly washed out from the tumor.

Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism.

A review-based hypothesis is presented on the energy flow in cancer patients. This hypothesis centres on the hypoxic condition of tumours, the essential metabolic consequences, especially the gluconeogenesis, the adaptation of the body, and the pathogenesis of cancer cachexia. In growing tumours the O(2) concentration is critically low. Mammalian cells need O(2) for the efficient oxidative dissimilation of sugars and fatty acids, which gives 38 and 128 moles of ATP per mole glucose and palmitic acid, respectively. In the absence of sufficient O(2) they have to switch to anaerobic dissimilation, with only 2 moles of ATP and 2 moles of lactic acid from 1 mole of glucose. Since mammalian cells cannot ferment fatty acids, in vivo tumour cells completely depend on glucose fermentation. Therefore, growth of these tumour cells will require about 40 times more glucose than it should require in the presence of sufficient O(2). Since lactic acid lowers the intracellular pH, it decreases the activity of pyruvate dehydrogenase, stimulates fermentation, and thus amplifies its own fermentative production. Compensatory glucose is provided by hepatic gluconeogenesis from lactic acid. However, the liver must invest 3 times more energy to synthesize glucose than can be extracted by tumour cells in an anaerobic way. The liver extracts the required energy from amino acids and especially from fatty acids in an oxidative way. This may account for weight loss, even when food intake seems adequate. In the liver 6 moles of ATP are invested in the gluconeogenesis of one mole of glucose. The energy content of 4 out of these 6 moles of ATP is dissipated as heat. This may account for the elevated body temperature and sweating experience by cancer patients.

Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study.

BACKGROUND: CI-994, an oral histone deacetylase inhibitor, has antineoplastic activity and synergism with gemcitabine preclinically. This randomized phase II trial explored whether CI-994 plus gemcitabine improves overall survival, objective response, duration of response, time to treatment failure and change in quality of life (QoL) or pain compared with gemcitabine alone. PATIENTS AND METHODS: A total of 174 patients received CG (CI-994 6 mg/m(2)/day days 1-21 plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 each 28-day cycle) or PG (placebo plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 of each 28-day cycle days 1-21). RESULTS: Median survival was 194 days (CG) versus 214 days (PG) (P = 0.908). The objective response rate with CG was 12% versus 14% with PG when investigator-assessed and 1% versus 6%, respectively, when assessed centrally. Time to treatment failure did not differ between the two arms (P = 0.304). QoL scores at 2 months were worse with CG than with PG. Pain response rates were similar between the two groups. There was an increased incidence of neutropenia and thrombocytopenia with CG. CONCLUSIONS: Adding CI-994 to gemcitabine in advanced pancreatic carcinoma does not improve overall survival, response rate or time to progression; CG produced decreased QoL and increased hematological toxicity and appears inferior to single-agent gemcitabine.

Weekly high-dose 5-fluorouracil and folinic acid in metastatic pancreatic carcinoma: a phase II study of the EORTC GastroIntestinal Tract Cancer Cooperative Group.

The aim of the study was to assess the response rate and toxicity of high-dose 24 h infusion of 5-fluorouracil (5FU) in metastatic adenocarcinoma of the pancreas. Patients with measurable disease, performance status 0-2, and no prior chemotherapy were registered to receive cycles of leucovorin (LV) 500 mg/m2 (or l-LV 250 mg/m2 over 1 h followed by 5FU 2.6 g/m2 over 24 h, weekly for 6 weeks, followed by a 2-week rest. The main endpoints were the response rate and toxicity. From 37 patients, 36 were the analysed for toxicity, and 33 were eligible and analysed for response. The median age was 59 years (range 28-74 years), and the median performance status was 1. Partial response was observed in three patients (9%) (95% Confidential Interval (CI): [2-24]%). Main grade 3/4 National Cancer Institute (NCI) common toxicity criteria toxicities (patients) were diarrhoea (n = 3), vomiting (n = 2) and hand-foot syndrome (n = 5). Median time to progression was 7 weeks (95% CI: [6.4-11.7] weeks) and median survival 19 weeks (95% CI: [12-35] weeks). In conclusion, high-dose 5FU and folinic acid is well tolerated, but has only modest activity in pancreatic cancer.

19F-magnetic resonance spectroscopy in patients with liver metastases of colorectal cancer treated with 5-fluorouracil.

The purpose of this study was to examine the uptake and metabolism of 5-fluorouracil (5-FU) in human liver metastases. Patients with liver metastases of colorectal cancer were treated with 5-FU (500/600 mg/m)+folinic acid with or without trimetrexate. The clinical application of F-magnetic resonance spectroscopy (MRS) of 5-FU in a random group of patients (n=17) was investigated. MR spectra of all patients showed 5-FU and catabolite resonances, and fluoronucleotides were also seen in seven patients. A correlation was found between maximum levels of 5-FU catabolites as measured by F-MRS and response in a group with larger metastases. However, such correlation was not observed in a group with smaller metastases, probably because of a significant contribution of normal liver tissue to the MR spectra.

Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model.

BACKGROUND: Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice. METHODS: Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1-11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated. RESULTS: Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss. CONCLUSION: Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.

Cancer cachexia: what is known about its etiology and what should be the current treatment approach?

Cancer cachexia, defined as involuntary weight loss and tissue wasting due to cancer, negatively influences physical condition, quality of life and prognosis. Well known causes, such as ileus or hypercalcemia, do not suffice to explain the entire phenomenon. Metabolic changes induced by the tumor and/or host are supposed to play a deciding role. In the present review current insights into the etiology and treatment are discussed.

An analysis of chemotherapy dose and dose-intensity in small-cell lung cancer: lessons to be drawn.

BACKGROUND: The survival in untreated small-cell lung cancer (SCLC) is <3 months. Prognosis has improved with chemotherapy, but remains poor. One of the issues concerning current chemotherapy is whether there is any benefit of increasing chemotherapy dose or dose intensity (DI). DESIGN: In the present review, 20 randomised studies, published in the period 1980-2001, in which dose or DI of chemotherapy in SCLC were the only variables tested, are analysed. The studies were categorised as follows: (i) number of cycles (treatment duration); (ii) dose per cycle; (iii) interval between cycles (dose densification); and (iv) a combination of these variables. RESULTS: (i) With treatment duration reduced to three to six cycles, median survival time (MST) was 2 months shorter, most evident in patients showing a (complete) response to initial chemotherapy. (ii) An improved survival was observed in two out of five high-dose studies. (iii) Survival was increased by 0.6 to 6.2 months in all four densification studies. (iv) Survival was not improved in studies that used dose-escalation and/or -densification in combination with a reduced number of cycles. The sample sizes were too small to be conclusive in most of the individual trials. The median of the MSTs in the 20 trials taken together was 9.8 months for the standard arms and 11.5 months for the intensified arms (i.e. more cycles, higher dose per cycle and/or shorter intervals). After omitting the two trials with reduced number of cycles in the so-called 'high-dose' arm, the median of MSTs was 8.7 and 11.5 months, respectively. There was only a slight improvement (1%) in 2-year survival for all trials taken together. However, when only taking high-dose and dose-densified chemotherapy trials into account, the difference in median 2-year survival became 19% (12% versus 31%). CONCLUSIONS: The above classification facilitates our understanding about doses of chemotherapy and it makes us appreciate the relevance of the individual determinants. It appears that the number of cycles, dose level, dose density, cumulative dose and DI are all important factors for improving survival. Intensification of chemotherapy still deserves further research in SCLC.

Vinorelbine and cisplatin in metastatic squamous cell carcinoma of the oesophagus: response, toxicity, quality of life and survival.

BACKGROUND: Vinorelbine and cisplatin are active against squamous cell oesophageal carcinoma. The purpose of this phase II study was to evaluate the efficacy and safety of vinorelbine plus cisplatin in previously untreated patients with metastatic squamous cell oesophageal carcinoma and to estimate the progression-free survival, overall survival and quality of life (QoL) of the patient population. PATIENTS AND METHODS: Seventy-one eligible patients were entered into a study of vinorelbine 25 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1, every 3 weeks. Degree of dysphagia relief was monitored and QoL was measured using the EORTC QLQ-C30. RESULTS: All eligible patients were assessed for response and 24 achieved a confirmed partial response (33.8%; 95% confidence interval 23-46); the median duration of response was 6.8 months, progression-free survival was 3.6 months and median survival of the whole group was 6.8 months. Toxicity was mainly related to neutropenia (grade 3/4 in 41% of patients). At cycle 2, 43% of the patients reported at least a moderate improvement in global health status/QoL and 25% experienced a large improvement. CONCLUSIONS: Vinorelbine plus cisplatin represents a well-tolerated active palliative regimen for patients with advanced squamous cell carcinoma of the oesophagus. This combination may offer a better therapeutic index than cisplatin-5-fluorouracil.

Results of a randomised phase II study of cisplatin plus 5-fluorouracil versus cisplatin plus 5-fluorouracil with alpha-interferon in metastatic pancreatic cancer: an EORTC gastrointestinal tract cancer group trial.

A randomised phase II study of 5-fluorouracil (5-FU) plus cisplatin (CDDP) with or without alpha-interferon 2b was performed in patients with pancreatic cancer with measurable metastatic disease outside the pancreas. The treatment in arm A consisted of cisplatin (100 mg/m(2)) on day 1, followed by a continuous infusion of 5-FU 1000 mg/m(2) for 4 days and in arm B the same treatment was given plus alpha-interferon 2b in a dose of 3 million Units/day subcutaneously (s.c.) from day 1 for 5 days. 36 patients were entered in the trial, 18 in each arm. In arm B only 15 patients were eligible. No responses were observed in the 5-FU/CDDP arm and only 2 partial responses were achieved in the interferon-arm, lasting 27 and 32 weeks, respectively. Both treatment arms showed considerable toxicity. It has to be concluded that both treatment regimens have little activity and cannot be recommended.

Progress in cancer screening over a decade: results of cancer screening from the 1987, 1992, and 1998 National Health Interview Surveys.

BACKGROUND: Screening to detect cancer early, an increasingly important cancer control activity, cannot be effective unless it is widely used. METHODS: Use of Pap smears, mammography, fecal occult blood tests (FOBTs), sigmoidoscopy, and digital rectal examination (DRE) was evaluated in the 1987, 1992, and 1998 National Health Interview Surveys. Levels and trends in screening use were examined by sex, age, and racial/ethnic group. The effects of income, educational level, and health care coverage were examined within age groups. Logistic regression analyses of 1998 data were used to develop a parsimonious, policy-relevant model. RESULTS: Use of all screening modalities increased over the period examined; for mammography and DRE, the increase was more rapid in the first half of the decade; for the Pap test and sigmoidoscopy, the increase was more rapid in the second half of the decade. Levels of colorectal cancer screening (both sigmoidoscopy and FOBTs) in 1998 were less than the level that prevailed a decade earlier for mammography. Patterns of change for all screening modalities differed between age, sex, and racial/ethnic groups, but prevalence of use during the study, within recommended time intervals, was consistently lower among groups with lower income and less education. Logistic regression analyses indicated that insurance coverage and, to a greater extent, usual source of care had strong independent associations with screening usage when age, sex, racial/ethnic group, and educational level were taken into account. CONCLUSIONS: While cancer screening is generally increasing in the United States, usage is relatively low for colorectal cancer screening and among groups that lack health insurance or a usual source of care.

Summary measures of population health: methods for calculating healthy life expectancy.

This report is one of several appearing as Healthy People Statistical Notes that evaluate methodological issues pertaining to summary measures. Summary measures of population health are statistics that combine mortality and morbidity to represent overall population health in a single number--in this report, health expectancy measures. This report presents a comprehensive discussion of the methods for calculation and methodologic issues related to the interpretation of healthy life expectancy. These measures combine both mortality and morbidity using an abridged life-table procedure. Data from the National Center for Health Statistics and other sources will be used to illustrate the calculation of the statistics and the associated statistical tests.