A randomized phase II study evaluating different maintenance schedules of nab-paclitaxel in the first-line treatment of metastatic breast cancer: final results of the IBCSG 42-12/BIG 2-12 SNAP trial.

Background: The phase II SNAP trial was designed to evaluate the efficacy of alternative chemotherapy schedules for prolonged administration in HER2-negative metastatic breast cancer (MBC), after a short induction at conventional doses. Patients and methods: Between April 2013 and August 2015, 258 women untreated with chemotherapy for MBC were randomly assigned to receive three different maintenance chemotherapy schedules after three cycles of identical induction chemotherapy: arm A, nab-paclitaxel 150 mg/m2 days 1 and 15 Q28; arm B, nab-paclitaxel 100 mg/m2 days 1, 8 and 15 Q28; arm C, nab-paclitaxel 75 mg/m2 days 1, 8, 15 and 22 Q28. Induction was three cycles nab-paclitaxel 150/125 mg/m2, days 1, 8 and 15 Q28. The primary objective was to evaluate the efficacy of each maintenance schedule, in terms of progression-free survival (PFS), as compared with the historical reference of 7-month median PFS reported by previous studies with first-line docetaxel. One-sample, one-sided log-rank tests were utilized. Quality-of-life (QoL) evaluation was carried out, and the global indicator for physical well-being was defined as the primary QoL end point; completion rates of QoL forms were >90%. Results: In total, 255 patients were assessable for the primary end point. After 18.2-month median follow-up, 182 PFS events were observed. Median PFS was 7.9 months [90% confidence interval CI 6.8-8.4] in arm A, 9.0 months (90% CI 8.1-10.9) in arm B and 8.5 months (90% CI 6.7-9.5) in arm C. PFS in arm B was significantly longer than the historical reference of first-line docetaxel (P = 0.03). Grade ≥2 sensory neuropathy was reported in 37.9%, 36.1% and 31.2% of the patients in arm A, B and C, respectively (Grade ≥3 in 9.1%, 5.6% and 6.6% of the patients, respectively). Noteworthy, the QoL scores for sensory neuropathy did not worsen with prolonged nab-paclitaxel administration in any of the maintenance arms. Conclusion: The SNAP trial demonstrated that alternative nab-paclitaxel maintenance schedules with reduced dosages after a short induction at conventional doses are feasible and active in the first-line treatment of MBC. Registration: ClinicalTrials.gov NCT01746225.

Análisis de la distribución de tensiones en tres diseños de incrustaciones de cerómero y cerámica en primeros premolares superiores ante una carga axial de 200 y 400 N, mediante el MEF / Analysis of the distributions of tensions in three designs of ceromer and ceramic incrustations in first upper premolars with axial load of 200 and 400 N, by fem

El objetivo de este estudio fue comparar el estrés comprensivo en primeras premolares superiores, restauradas con tres diseños de incrustaciones de cerómero y cerámica por medio del análisis de elementos finitos. El grupo de estudio estuvo conformado por doce simulaciones en MEF, el diseño de una pieza dental (primera premolar superior), restaurada con 3 diversos diseños de incrustaciones: Inlay y dos distintos diseños de onlays (con y sin hombro); de dos materiales diferentes, cerómero y disilicato de litio aplicando diferentes niveles de fuerzas;200 N y 400 N en dirección vertical. Las restauraciones de cerómero en las diferentes intensidades de fuerzas, presentaron una mayor distribución de estrés dentario a diferencia del disilicato de litio. Las preparaciones inlays independientemente del material, producen mayor estrés comprensivo en la pieza dentaria a nivel cervical. El análisis fue mediante la estadística descriptiva que incluyó las medidas de dispersión básicamente máximo y mínimo para la variable estrés comprensivo en cada uno de los grupos evaluados, seguidamente se realizó el análisis gráfico mediante la escala de valores de Von Mises el cual es la magnitud física proporcional a la distorsión, se calcula a partir de las tensiones sobre un objeto. Se concluyó que las restauraciones de cerómero al poseer menor módulo de elasticidad y ser menos rígidas, absorben las fuerzas de la masticación y transmiten mayor estrés comprensivo a la estructura dentaria siendo éstas de forma homogénea a diferencia del disilicato de litio que transmite menor estrés comprensivo a la pieza dentaria pero en zonas más específicas, pudiendo ocasionar futuras fracturas. Las incrustaciones con cobertura de cúspides de cerómero y disilicato de litio protegen la estructura dentaria remanente permitiendo una adecuada distribución del estrés. (AU)

The purpose of this study was to compare the fracture of teeth has been described as a major problem in dentistry. It is important to know the mechanical properties of dental materials, and the effects they have on the remaining tooth structure, it is has to be taken into account a detailed evaluation to chosen the appropriate rehabilitation. For that reason, the aim of this study was to compare the compressive stress in first premolars restored with three different partial coverage restorations designs, using the finite element analysis. The study group consisted of forty-eight simulations in FEA, the design of a tooth (first premolar) restored with three different partial coverage restorations designs: inlay and two preparations of onlays (with or without bisel); of two different restorations materials; ceromer and lithium disilicato, applying different force levels; 200 N and 400N, in vertical direction. Ceromer restorations in different intensities and directions of forces had a greater distribution of stress unlike lithium disilicate ceramic. The inlays preparations, regardless of the material, produce greater compressive stress and the coverage of cusp protects the tooth. Analysis was by descriptive statitics including measures of dispersion essentially maximum and minimum for the compressive stress variable in each of the groups tested, then the graph analysis was performed using the scale values of Von Mises which is the physical quantity it proportional to the distortion, is calculated from the voltages on an object. It is concluded that ceromer by possess lower modulus of elasticity and being less rigid, absorbs forces of mastication and higher compressive stress in transmited homogeneously to the tooth structure, unlike lithium disilicate that transmitted lower compressive stress to the tooth but in more specific areas, which may cause fractures in the future. (AU)

Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial.

BACKGROUND: Fluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses. Perioperative chemotherapy in locally advanced resectable gastric cancer (RGC) has been reported improving survival by two large randomized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined. We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospective randomized phase III trial, of which we present the 10-year follow-up data. PATIENTS AND METHODS: Patients with cT3-4 anyN M0 or anyT cN1-3 M0 gastric carcinoma, staged with endoscopic ultrasound, computed tomography, bone scan, and laparoscopy, were assigned to receive four 21-day/cycles of docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2)/day over days 1-14, either before (arm A) or after (arm B) gastrectomy. Event-free survival was the primary end point, whereas secondary end points included overall survival, toxicity, down-staging, pathological response, quality of life, and feasibility of adjuvant chemotherapy. RESULTS: This trial was activated in November 1999 and closed in November 2005 due to insufficient accrual. Of the 70 enrolled patients, 69 were randomized, 34 to arm A and 35 to arm B. No difference in EFS (2.5 years in both arms) or OS (4.3 versus 3.7 years, in arms A and B, respectively) was found. A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy. A 12% pathological complete response was observed in arm A. CONCLUSION: Docetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC. The early stopping could mask the real effectiveness of neoadjuvant treatment. However, the complete pathological tumour responses, feasibility, and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting.

Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience.

PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.

Relapses in hepatoblastoma patients: clinical characteristics and outcome--experience of the International Childhood Liver Tumour Strategy Group (SIOPEL).

PURPOSE: To analyse the clinical characteristics and outcome of hepatoblastoma (HB) patients who relapsed after enrolment on SIOPEL studies 1-3. PATIENTS AND METHODS: Analysis of clinical data of all 59 patients (pts) registered in SIOPEL 1-3 studies, who relapsed after achieving complete remission (CR). RESULTS: The median time from the initial diagnosis to relapse was 12 months (4-115 m). The site of relapse was lung N=27, liver N=21, both liver and lung N=5 and other N=5 (missing data-MD: 1 patient). All but 9 pts had an alpha-fetoprotein level >10 ng/mL at the time of relapse. Treatment of the relapse included chemotherapy and surgery N=25, chemotherapy alone N=21, surgery alone N=7 and only palliative treatment N=5 (MD: 1 pt). Overall, 31 pts (52%) achieved a second CR. With a median follow-up of 83 months, 23 pts are alive, (18 in 2nd CR, 5 after a second relapse) and 36 pts have died (35 from disease and 1 from complications). Three-year event-free survival and overall survival are 34% and 43% respectively (95% confidence interval [CI] 0.28-0.69). The main factors associated with a good outcome were PRETEXT group I-III at diagnosis, a high AFP level at relapse and relapse treatment including both chemotherapy and surgery. CONCLUSION: Relapses in HB are rare events occurring in less than 12% of pts after CR. Combined treatment with chemotherapy and surgical removal of the tumour is essential for long-term survival.

Cryptococcus gattii meningoencephalitis in an immunocompetent person 13 months after exposure.

A 53-year old immunocompetent Swiss female is described who developed severe meningoencephalitis due to infection with Cryptococcus gattii 13 months following exposure on Vancouver Island, Canada. Diagnosis was based on cerebrospinal fluid (CSF) examination, i.e., positive India-ink staining, positive latex particle agglutination, and positive culture. Species identification was performed by growth on L-canavanine-glycine-bromthymol blue medium and by sequencing of the intergenic and internal transcribed spacer regions of the rRNA genes. After initial therapy with fluconazole by which the patient did not improve, therapy was changed to amphotericin B and flucytosine and later to high-dose fluconazole and amphotericin B. Despite long-term treatment and external drainage of the CSF, the patient's condition improved only slowly. The patient was discharged after 132 days of hospitalization.

Adjuvant perioperative portal vein or peripheral intravenous chemotherapy for potentially curative colorectal cancer: long-term results of a randomized controlled trial.

BACKGROUND AND AIMS: The perioperative use of a single course adjuvant portal vein infusion chemotherapy in patients with potentially curable colorectal cancer has been shown to significantly improve overall survival but did not reduce the occurrence of liver metastases (SAKK 40/81) [Swiss Group for Clinical Cancer Research (SAKK) Lancet 345(8946):349-353, 1995]. The objective of the present prospective, three-arm randomized multicenter trial was to assess whether peripheral venous administration of adjuvant chemotherapy regimen based on 5-fluorouracil (5-FU) and mitomycin C decreases the occurrence of liver metastases as well as prolongs disease-free and overall survival. MATERIALS AND METHODS: Stages I-III colorectal cancer patients (n = 753) were randomized to receive either surgery alone (control arm), surgery plus postoperative portal venous infusion of 5-FU 500 mg/m(2) plus heparin given for 24 hours for seven consecutive days plus mitomycin C 10 mg/m(2) given on the first day (arm 2), or surgery and the same chemotherapy regimen administered by peripheral venous route (arm 3). RESULTS: The 5-year disease-free survival for the three treatment groups were 65% (control group), 60% (portal vein infusion, hazard ratio 1.18, p = 0.23), and 64% (intravenous infusion, hazard ratio 1.04, p = 0.76); the 5-year overall survival was 72% (control group), 69% (portal vein infusion, hazard ratio 1.21, p = 0.2), and 74% (intravenous infusion, hazard ratio 1.03, p = 0.86), respectively. A significant accumulation of early deaths were observed in the portal vein infusion group (p = 0.015). CONCLUSIONS: The present prospective randomized multicenter trial provides compelling evidence that short-term perioperative chemotherapy does not improve disease-free and overall survival in patients with potentially curative colorectal cancer. In contrary, the chemotherapy regimen administered in the present investigation seems to have potentially harmful effects, a finding which should be carefully considered in the planning of future trials. Postoperative short-term administration of 5-FU plus mitomycin C either through portal infusion or a central venous catheter is not recommended for routine use in patients with potentially curable colorectal cancer.

Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?

BACKGROUND: The role of chemotherapy in addition to combined endocrine therapy for premenopausal women with endocrine-responsive early breast cancer remains an open question, yet trials designed to answer it have repeatedly failed to adequately accrue. The International Breast Cancer Study Group initiated two concurrent trials in this population: in Premenopausal Endocrine Responsive Chemotherapy (PERCHE), chemotherapy use is determined by randomization and in Tamoxifen and Exemestane Trial (TEXT) by physician choice. PERCHE closed with inadequate accrual; TEXT accrued rapidly. METHODS: From 2003 to 2006, 1317 patients (890 with baseline data) were randomly assigned to receive ovarian function suppression (OFS) plus tamoxifen or OFS plus exemestane for 5 years in TEXT. We explore patient-related factors according to whether or not chemotherapy was given using descriptive statistics and classification and regression trees. RESULTS: Adjuvant chemotherapy was chosen for 64% of patients. Lymph node status was the predominant determinant of chemotherapy use (88% of node positive treated versus 46% of node negative). Geography, patient age, tumor size and grade were also determinants, but degree of receptor positivity and human epidermal growth factor receptor 2 status were not. CONCLUSIONS: The perceived estimation of increased risk of relapse is the primary determinant for using chemotherapy despite uncertainties regarding the degree of benefit it offers when added to combined endocrine therapy in this population.

Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL).

INTRODUCTION: Sequential high dose (SHiDo) chemotherapy with stem cell support has been shown to prolong the event-free survival in patients with diffuse large B-cell lymphoma. METHODS: To confirm this result in a multicenter trial, we randomized patients with aggressive NHL, to receive either eight cycles of CHOP or SHiDo. The primary endpoint was overall survival. RESULTS: 129 evaluable patients were randomized to receive either CHOP or SHiDo: median age, 48 years; 62% male; stage III+IV: 73%; age adjusted International Prognostic Index 1/2/3: 21%/52%/27%. Toxicity grades 3+4 were more pronounced in the SHiDo-arm with 13% versus 3% of patients with fever; 34% versus 13% with infections; 13% versus 2% with esophagitis/dysphagia/gastric ulcer. The remission rates were similar in SHiDo and CHOP arms with 34%/37% complete remissions and 31%/31% partial remissions, respectively. After a median observation time of 48 months, there was no difference in overall survival at 3 years, with 46% for SHiDo and 53% for CHOP (P = 0.48). CONCLUSION: In this multicenter trial, early intensification with SHiDo did not confer any survival benefit in previously untreated patients with aggressive NHL and was associated with a higher incidence of grades 3/4 toxicity.

5-Fluorouracil as protracted continuous intravenous infusion can be added to full-dose docetaxel (Taxotere)-cisplatin in advanced gastric carcinoma: a phase I-II trial.

BACKGROUND: A phase I-II multicenter trial was conducted to define the maximum tolerated dose (MTD) according to tolerance and toxicity (primary objective), as well as to describe the clinical activity, in terms of response and survival (secondary objectives), of a combination of 5-fluorouracil (5-FU) in protracted continuous intravenous infusion (p.i.v.) with docetaxel and cisplatin for patients with advanced gastric cancer. PATIENTS AND METHODS: Patients with measurable unresectable and/or metastatic gastric carcinoma, World Health Organization performance status < or =1, normal hematological and renal functions, adequate hepatic function and not pretreated for advanced disease by chemotherapy, received up to eight cycles of a combination of docetaxel on day 1, cisplatin on day 1 and 5-FU p.i.v. on days 1-14 (TCF) every 3 weeks, which was escalated up to the MTD, defined by the occurrence of dose-limiting toxicity in two patients in one dose level. RESULTS: Fifty-two patients were accrued and treated (43 in the phase I part of the trial and nine additional at the recommended dose level). A median of five cycles/patient was given. The recommended dose of TCF was docetaxel 85 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1 and 5-FU p.i.v. 300 mg/m(2)/day on days 1-14. Grade > or =3 toxicities were neutropenia 79%, alopecia 46%, fatigue 23%, mucositis 10%, diarrhea 19%, nausea/vomiting 13%, neurological 4% and palmar-plantar 2%. Ten non-fatal febrile neutropenia episodes were recorded in eight patients. There were no treatment-related deaths. Among 41 patients with measurable disease (79%), we observed one complete and 20 partial responses for an overall intent-to-treat response rate of 51% (95% confidence interval 35-67%). Five patients (20%) had stable disease for > or =12 weeks (four cycles). The median overall survival was 9.3 months. CONCLUSIONS: 5-FU p.i.v. at 300 mg/m(2)/day for 2 weeks out of three could be safely added to the docetaxel-cisplatin (TC) combination, but the dose of docetaxel had to be reduced to 75 mg/m(2) in a subsequent phase II trial. This drug regimen seems to be very active in advanced gastric cancer. Comparison with both TC and ECF in a randomized SAKK trial is ongoing.

Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2.

SIOPEL 2 was a pilot study designed to test the efficacy and toxicity of two chemotherapy (CT) regimens, one for patients with hepatoblastoma (HB) confined to the liver and involving no more than three hepatic sectors ('standard-risk (SR) HB'), and one for those with HB extending into all four sectors and/or with lung metastases or intra-abdominal extra hepatic spread 'high-risk (HR) HB'. SR-HB patients were treated with four courses of cisplatin (CDDP), at a dose of 80 mg/m(2) every 14 days, delayed surgery, and then two more similar CDDP courses. HR-HB patients were given CDDP alternating every 14 days with carboplatin (CARBO), 500 mg/m(2), and doxorubicin (DOXO), 60 mg/m(2). Two courses of CARBO/DOXO and one of CDDP were given postoperatively. Between October 1995 and May 1998, 77 SR-HB (10 of whom were actually treated with the HR protocol) and 58 HR-HB patients were registered and all 135 could be evaluated. Response rates for the entire SR-HB and HR-HB groups were 90% (95% CI 80-96%) and 78% (95% CI 65-87%), and resection rates were 97% (95% CI 87-99%) and 67% (95% CI 54-79%) including several children undergoing liver transplantation. For SR-HB patients, 3-year overall and progression-free survivals were 91% (+/-7%) and 89% (+/-7%) and for the HR-HB group 53% (+/-13%) and 48% (+/-13%), respectively. The short-term toxicity of these regimens was acceptable, with no toxic deaths. A treatment strategy based on CDDP monotherapy and surgery thus appears effective in SR-HB but, despite CT intensification, only half of the HR-HB patients are long-term survivors. For SR-HB patients, the efficacy of CDDP monotherapy and the CDDP/DOXO ('PLADO') combination are now being compared in a prospective randomised trial (SIOPEL 3).

Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.

BACKGROUND: For hepatoblastoma (HB) that remains unresectable by partial hepatectomy after chemotherapy, total hepatectomy with orthotopic liver transplantation (LTX) has been advocated as the best treatment option. The role of LTX in the overall management of HB is still, however, unclear. PROCEDURE: The results of LTX from the first study of HB by the International Society of Pediatric Oncology, SIOPEL-1, were analyzed. In addition, the world experience of LTX for HB was extensively reviewed. Twelve patients in the SIOPEL-1 study underwent a LTX. Median (range) follow-up at Dec. 31, 2001 was 117 months (52-125) since LTX. RESULTS: Overall survival at 10 years post-LTX was 85% for the seven children who received a "primary LTX" and 40% for the 5 children who underwent a "rescue LTX" after previous partial hepatectomy. In the world experience (147 cases), the overall survival rate at 6 year post-LTX was 82% for 106 patients who received a "primary LTX" and 30% for 41 patients who underwent a "rescue LTX." Multivariate analysis of patients undergoing primary LTX showed that only macroscopic venous invasion had a significant impact (P-value: 0.045 with a hazard ratio of 2.96) on overall survival. CONCLUSIONS: Orthotopic LTX has added a new dimension to the treatment of HB unresectable by partial hepatectomy. Because of the rarity of the disease and to optimize results, children with extensive HB should be treated in centers with surgical expertise in pediatric major liver resection and LTX, in close collaboration with pediatric oncologists, radiologists, and histopathologists.

Spondylodiscitis as the first manifestation of Whipple's disease -a removal worker with chronic low back pain.

Whipple's disease is a rare systemic infectious disease caused by the actinobacterium Tropheryma whipplei. Spondylodiscitis is an extremely rare manifestation of the infection and has previously been described in only three case reports. We present a 55-year-old man with persistent lumbago and signs of systemic illness, but without any gastrointestinal symptoms or arthralgia. The signal response in the lumbar spine in magnetic resonance tomography, both native and after intravenous gadolinium administration, was compatible with spondylodiscitis at the L4/L5 level. Culture of a specimen obtained by radiographically guided disc puncture and repeated blood cultures remained sterile. Tropheryma whipplei was detected by PCR amplification in material obtained from the disc specimen, from a biopsy of the terminal ileum and from the stool. The histology of duodenum, terminal ileum, colon and disc material was normal and, in particular, showed no PAS-positive inclusions in macrophages. Long-term antibiotic treatment with sulphamethoxazole and trimethoprim was successful, with marked improvement of the low back pain and normalisation of the systemic inflammatory signs. The possibility of Whipple's disease must be suspected in the case of a 'culture-negative' spondylodiscitis even if there are no gastrointestinal symptoms and no arthralgia present.

Prevalence of Tropheryma whipplei DNA in patients with various gastrointestinal diseases and in healthy controls.

BACKGROUND: Little is known about the epidemiology of Tropheryma whipplei and its prevalence in people without clinical signs of Whipple's disease. PATIENTS AND METHODS: We screened 239 patients with various gastrointestinal diseases for T. whipplei DNA and compared them with 215 healthy controls in order to check whether T. whipplei might be a risk factor for common gastrointestinal problems or diseases. We detected the 16S rDNA of T. whipplei in salivary and stool samples using a specific seminested PCR. RESULTS: The prevalence of T. whipplei DNA in patients and in controls was 4.2% (95% CI 2.0-7.6% ) and 7.0% (95% CI 4.0-11.3%), respectively. None of the different gastrointestinal diseases was associated with a higher rate of PCR-positive tests, except for the group of patients with reflux syndrome. Five out of 43 patients with reflux were found to be positive, with all five being positive in the salivary sample. This is in contrast to our findings in carriers without reflux with mainly positive stool samples (p < 0.01). CONCLUSION: We conclude that the asymptomatic carrier state of T. whipplei indeed exists and that it is much more frequent than the rare Whipple's disease. The higher prevalence of T. whipplei DNA in the saliva of patients with reflux syndrome suggests that the stomach might be the habitat of the organism.

A randomized double-blind trial to compare the clinical efficacy of granisetron with metoclopramide, both combined with dexamethasone in the prophylaxis of chemotherapy-induced delayed emesis.

BACKGROUND: The prophylactic use of 5-HT(3) receptor antagonists (setrons), after the first 24 h (acute phase) of exposure to emetic chemotherapy, to decrease the incidence of 'delayed phase' emesis increases costs. We designed a study to evaluate the efficacy of a setron (granisetron) in the delayed phase, compared with metoclopramide, each combined with a corticosteroid. PATIENTS AND METHODS: Patients on their first course of single-day emetic chemotherapy (cisplatin, carboplatin, doxorubicin, cyclophosphamide and others) received granisetron 2 mg p.o. and dexamethasone 8 mg p.o. on day 1, followed for 5 days by dexamethasone 4 mg p.o. od combined with either metoclopramide 20 mg p.o. tds or granisetron 1 mg bd in a double-blinded double-dummy protocol. Patients evaluated the results using a diary card. Randomization was stratified by institution, sex, emetic chemotherapy naïve versus previous, alcohol consumption and platinum versus non-platinum regimen. RESULTS: 131 evaluable patients received granisetron in the delayed phase, and 127 received metoclopramide. Control of acute emesis in both arms was similar (86% granisetron; 85% metoclopramide). The 35 patients experiencing acute emesis had poor control in the delayed phase, with only four granisetron and three metoclopramide patients having no or mild nausea and no vomiting. CONCLUSIONS: In daily practice, a combination of oral dexamethasone and oral granisetron achieves an extremely high control of acute emesis (86% protection). Our data suggest that routine prescription of setrons for delayed phase control is not advisable as it increases costs without any benefit for the majority of patients. Delayed emesis in the rare patients with acute phase emesis remains an unsolved problem.

Patients' estimation of overall treatment burden: why not ask the obvious?

PURPOSE: We investigated the clinical validity of patients' estimation of overall treatment burden. This measure was expected to be responsive to the wide spectrum of reactions on treatment and thus less precise for specific effects. PATIENTS AND METHODS: After the first chemotherapy within a randomized, double-blind trial of the prophylaxis for delayed emesis (SAKK 90/95), 249 patients documented nausea and vomiting daily for 6 days. Over the whole period, they estimated nausea/vomiting (N/V) burden and overall treatment burden by linear analog-self assessment (LASA) indicators and documented other side effects. RESULTS: At day 6, the two burden indicators were moderately correlated (r = 0.58) in accordance with their different concepts. No, partial, or total control of delayed emesis (days 2 to 6) was reflected in a consistent pattern by both indicators, with a stronger and more significant effect (P <.001) on changes in N/V burden than overall treatment burden. In contrast, toxicity other than N/V, assessed independently by patients and physicians, was mainly associated with overall treatment burden. Patients who indicated at least one other side effect rated their overall burden substantially higher than those with no indication of other toxicity (P <.0001). Physician-rated toxicity had a similar effect (P <.0001). CONCLUSION: A direct patient estimation of overall treatment burden by a LASA indicator may serve as an end point in clinical trials, particularly when treatments with different toxicity profiles are being compared. It is complementary to physicians' ratings of specific toxicities and a major component of patient-rated symptom checklists and quality-of-life measures.

Antibodies against recombinant heat shock protein 65 of Tropheryma whipplei in patients with and without Whipple's disease.

Tropheryma whipplei is the causative agent of Whipple's disease (WD), a chronic, life-threatening infection. Laboratory diagnosis is mainly based on PCR and histopathological analysis in duodenal biopsies and other specimens requiring invasive procedures. We have examined the presence of antibodies to recombinant heat shock protein (Hsp65) of T. whipplei in patients with Whipple's disease as well as in control subjects by Western blot and enzyme-linked immunosorbent assay (ELISA). A recombinant plasmid carrying the entire T. whipplei hsp65 gene was constructed, and the expression yielded a 65-kDa histidine-tagged protein. Among four patients with Whipple's disease, two showed an IgG- and one an IgA-response, respectively, when analyzed by Western blotting, whereas from 10 patients without Whipple's disease, only two patients showed a positive IgG-response. The differences between the sera from patients and controls were thus not significant. Successful purification of the protein was achieved by Ni-NTA affinity chromatography. Quantitative analysis of serum antibodies by ELISA demonstrated that antibody levels in the sera of 14 patients were not significantly higher than in those of 89 control subjects. The established ELISA test is not useful to clinical diagnostics.

Response shift in the perception of health for utility evaluation. an explorative investigation.

We previously showed that patients with newly diagnosed colon cancer change the internal standards on which they base their quality of life estimation. In the present investigation, we explored whether this response shift similarly affects the perception of health for utility evaluation in cancer clinical trials. After radical resection of adenocarcinoma of the colon (pT1-4 pN>0 M0 and pT3-4 pN0 M0) and perioperative chemotherapy, patients were randomised to three treatment arms: observation only (A), 5-fluorouracil (5-FU) 450 mg/m(2) plus levamisol (B), or 5-FU 600 mg/m(2) (C). Subjective health was assessed by a linear analogue self-assessment (LASA) scale anchored at 'perfect health-worst health' developed for serial assessment of utility values (Hürny C, van Wegberg B, Bacchi M, et al. Subjective health estimations (SHE) in patients with advanced breast cancer: an adapted utility concept for clinical trials. Br J Cancer 1998, 77, 985-991). Patients estimated their pre-surgery health among various quality of life indicators both before surgery and retrospectively thereafter, and their pre-adjuvant health both at the beginning of randomly assigned chemotherapy or observation and retrospectively approximately 2 months later. Thereafter, current subjective health was assessed. Paired t-tests were used to test the hypotheses of no change. Patients' estimated pre-surgery health was worse after surgery than before (n=127, mean change=-6.7, standard deviation (S.D.)=30, P=0.01), and their estimated pre-adjuvant health was worse under treatment or observation than at the beginning (n=132, mean change=-7.1, S.D.=23.8, P=0.001), in agreement with the quality of life indicators. Chemotherapy had no impact on these changes attributed to a response shift. Conventionally assessed changes between the beginning of adjuvant treatment or observation and 2 months later indicated no change in subjective health. Change scores relative to patients' retrospective estimation revealed an improvement (n=122, mean change=6.6, S.D.=24.8, P=0.004) in this period. Patients with colon cancer substantially reframe their internal standard of health as they do for quality of life. This explorative finding questions the assumption, generally made in decision models, that health estimates for utility evaluation are independent of time. Given that patients may change their standards, comparisons of health estimates across different populations and clinical situations are to be interpreted with caution.

Significantly different bcl-2 expression profiles in gastric and non-gastric primary extranodal high-grade B-cell lymphomas.

Fifty-five cases of primary extranodal high-grade B-cell non-Hodgkin's lymphoma were investigated for bcl-2 and p53 protein expression as well as for t(14;18) translocations and p53 mutations. Phenotypic and genotypic profiles were compared between tumours of gastric (27 cases) and non-gastric (28 cases) origin. bcl-2 protein expression was significantly lower in gastric (11/27) than in non-gastric (28/28) lymphomas (p<0.0001), while nuclear p53 protein expression did not differ significantly between these two groups. In the stomach, there were no significant differences in either bcl-2 or p53 expression profiles between high-grade lymphomas with (n=14) and without (n=13) evidence of a low-grade component of MALT type. However, secondary high-grade lymphomas showed a significant down-regulation of bcl-2 protein (p<0.0001) and, conversely, an up-regulation of p53 protein (p<0.0001) as compared with their low-grade tumour components. In extranodal high-grade B-cell lymphomas, bcl-2 protein expression was not associated with t(14;18) translocation. Only one gastric lymphoma had a p53 point mutation with potential alteration of the amino acid sequence. These findings indicate that primary gastric high-grade B-cell lymphomas are immunohistologically distinct from primary extranodal high-grade B-cell lymphomas of an origin other than in the stomach.