[Practical approach of lymphomas: major role of general practitioner who has to face all these emerging drugs]. / Approche pratique des lymphomes : rôle majeur du médecin généraliste face à l'explosion des nouvelles thérapeutiques.

Malignant lymphoma and other lymphoproliferative disorders represent a group of malignant hemopathies where immunotherapy has allowed spectacular progresses over the last ten years. The recent W.H.O. classification, based upon tumor immunology, and cytogenetical anomalies, allows a better identification of each lymphoma and the comparison of homogeneous populations within various clinical studies. The increase in the incidence of non-Hodgkin lymphoma is related to the aging of the population as well as to other factors that are still to be analysed - a real challenge for the future. We have tried to offer an overview of the latest therapeutical advances while focusing on the major role of general practitioner. The most frequency askeed questions will be discussed.

Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer.

BACKGROUND: Molecular screening programs use next-generation sequencing (NGS) of cancer gene panels to analyze metastatic biopsies. We interrogated whether plasma could be used as an alternative to metastatic biopsies. PATIENTS AND METHODS: The Ion AmpliSeq™ Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze 69 tumor (primary/metastases) and 31 plasma samples from 17 metastatic breast cancer patients. The targeted coverage for tumor DNA was ×1000 and for plasma cell-free DNA ×25 000. Whole blood normal DNA was used to exclude germline variants. The Illumina technology was used to confirm observed mutations. RESULTS: Evaluable NGS results were obtained for 60 tumor and 31 plasma samples from 17 patients. When tumor samples were analyzed, 12 of 17 (71%, 95% confidence interval (CI) 44% to 90%) patients had ≥1 mutation (median 1 mutation per patient, range 0-2 mutations) in either p53, PIK3CA, PTEN, AKT1 or IDH2 gene. When plasma samples were analyzed, 12 of 17 (71%, 95% CI: 44-90%) patients had ≥1 mutation (median 1 mutation per patient, range 0-2 mutations) in either p53, PIK3CA, PTEN, AKT1, IDH2 and SMAD4. All mutations were confirmed. When we focused on tumor and plasma samples collected at the same time-point, we observed that, in four patients, no mutation was identified in either tumor or plasma; in nine patients, the same mutations was identified in tumor and plasma; in two patients, a mutation was identified in tumor but not in plasma; in two patients, a mutation was identified in plasma but not in tumor. Thus, in 13 of 17 (76%, 95% CI 50% to 93%) patients, tumor and plasma provided concordant results whereas in 4 of 17 (24%, 95% CI 7% to 50%) patients, the results were discordant, providing complementary information. CONCLUSION: Plasma can be prospectively tested as an alternative to metastatic biopsies in molecular screening programs.

[Non Hodgkin's lymphomas: a major breakthrough with immunotherapy]. / Les lymphomes non hodgkiniens: apports considérables de i'immunothérapie.

Non hodgkin's lymphomas are a group of haematological malignancies in which spectacular progress has been made over the last ten years thanks to immunotherapy. Furthermore, the new WHO classification, based upon tumour immunology, the degree of tumour differentiation and cytogenetic abnormalities, has finally improved identification of each lymphoma and has enabled comparison of homogeneous populations between different clinical studies. The increase in the incidence of non hodgkin's lymphoma is related to the aging of the population and to other factors that are yet to be elucidated--a real challenge for the future. We have tried to offer an overview of the latest therapeutic advances, with a focus on (radio-) immunotherapy and haemopoietic stem cell transplantation.

How should we treat mucinous appendiceal neoplasm? By laparoscopy or laparotomy? A case report.

Appendicular mucocele (AM) usually denotes a dilatation of the appendiceal lumen as a result of mucus accumulation that may be related to various neoplastic and non-neoplastic processes. Most of them are discovered incidentally. Treatment consists in complete resection avoiding rupture of the cyst in the peritoneal cavity. Indeed, rupture of such a cystic lesion in the peritoneal cavity can induce a catastrophic complication such as 'pseudomyxoma peritonei' (PMP). Therefore, some authors recommend an open surgical treatment. Currently, the debate concerning the best surgical technique to adopt for AM remains controversial. We report a case of AM found incidentally and treated by laparoscopy. The macroscopic aspect of the appendix suggested the diagnosis intra-operatively and every effort was made to avoid cystic rupture during appendicular resection. The histopathological diagnosis was mucinous cystadenoma. The patient is doing well at 2-year follow-up. The reported case and literature review show us that AM is not a contra-indication for laparoscopic surgery, but major concern resides in the early recognition of such a lesion at laparoscopy and in taking appropriate precautionary measures to avoid rupture in the peritoneal cavity.

Attention to sex-related factors in the development of clinical practice guidelines.

BACKGROUND: Clinical practice guidelines describe optimal strategies for disease prevention, diagnosis, or treatment. Increasing evidence indicates that sex-related factors may have an impact on these strategies. We examined the way in which two Dutch guideline organizations address evidence on sex factors in their guideline development methodologies. We then determined whether attention to these factors could be improved and, if so, how this could be done. METHODS: We selected seven recent guidelines on four conditions: hypertension, depression, osteoporosis, and rheumatoid arthritis. We studied information obtained from interviews with members of the guideline committees and analyzed the content of the guideline documents themselves. Our findings were discussed at an expert meeting. RESULTS: We found that all the guideline committees concerned applied an internationally accepted framework for guideline development. The proportion of male members ranged from 67% to 100%. None of the guidelines included a question (or subquestion) focusing on sex-related factors. In the literature searches no sex-specific search terms were used. Critical appraisals did not include any systematic focus on sex-related factors or effects. The number of sex-specific recommendations (relative to the total number of recommendations) ranged from 0 of 82 and 0 of 148 in the guidelines on depression to 16 of 84 in one of the guidelines on osteoporosis. CONCLUSIONS: We found that when developing guidelines, none of the committees systematically focused on sex-related factors that might be relevant to the way in which evidence is identified, appraised, or described. A number of recommendations were made with the aim to facilitate greater attention to sex-related factors in the current methods of guideline development.

Gender equality in the work of local research ethics committees in Europe: a study of practice in five countries.

BACKGROUND: Funding organisations and research ethics committees (RECs) should play a part in strengthening attention to gender equality in clinical research. In the research policy of European Union (EU), funding measures have been taken to realise this, but such measures are lacking in the EU policy regarding RECs. OBJECTIVE: To explore how RECs in Austria, Germany, Ireland, The Netherlands and Sweden deal with gender equality issues by asking two questions: (1) Do existing procedures promote representation of women and gender expertise in the committee? (2) How are sex and gender issues dealt with in protocol evaluation? METHODS: Two RECs were selected from each country. Data were obtained through interviews with key informants and content analysis of relevant documents (regulations, guidelines and review tools in use in 2003). RESULTS: All countries have rules (mostly informal) to ensure the presence of women on RECs; gender expertise is not required. Drug study protocols are carefully evaluated, sometimes on a formal basis, as regards the inclusion of women of childbearing age. The reason for excluding either one of the sexes or including specific groups of women or making a gender-specific risk-benefit analysis are investigated by some RECs. Such measures are, however, neither defined in the regulations nor integrated in review tools. CONCLUSIONS: The RECs investigated in five European member states are found to pay limited attention to gender equality in their working methods and, in particular in protocol evaluation. Policy and regulations of EU are needed to strengthen attention to gender equality in the work of RECs.

Prolonged schedule of temozolomide (Temodal) plus liposomal doxorubicin (Caelyx) in advanced solid cancers.

Temozolomide (Temodal) is an oral imidazotetrazine. Increased temozolomide exposure and subsequent depletion of O-alkylguanine alkyltransferase may improve the activity of temozolomide. The rationale for investigating temozolomide plus Caelyx is based on their antitumor activity, their formulation and no significant overlapping toxicities. We conducted a study of a prolonged schedule of temozolomide (orally on days 1-7 and 15-21) plus Caelyx (day 1) every 28 days. Twenty-one patients (melanoma n=10, sarcoma n=7 and other n=4) were assigned to four dose levels (DL; temozolomide+Caelyx, mg/m): DL1: 100+30 (n=3 patients), DL2: 100+40 (n=6 patients), DL3: 125+40 (n=6 patients) and DL4: 150+40 (n=6 patients). Dose-limiting toxicities were noted after 2 or more cycles in one patient at DL3 (stomatitis) and one patient at DL4 (grade 4 ANC >/=7 days). Treatment delays and/or dose reductions (due to hematological toxicity) were necessary in five of six patients receiving DL4 compared with one of six patients at DL3, and one patient at DL1 and 2. Thus, the recommended dose was temozolomide 125 mg/m (daily for 7 days every other week) plus Caelyx 40 mg/m (day 1 every 4 weeks). Other toxicities were mild. Antitumor activity was observed in eight patients, including one complete response (melanoma), three partial responses (one melanoma, two sarcomas) and four patients with stable disease (three melanomas, one Ewing), with a duration lasting from 14 to 135+weeks. Two melanoma patients showed tumor stabilization in non-irradiated cerebral lesions. This schedule of temozolomide allowed higher dose intensity (1750 mg/m in 4 weeks) compared to the standard 5-day regimen (1000 mg/m in the same amount of time).

Postmenopausal hormone therapy: less favourable risk-benefit ratios in healthy Dutch women.

OBJECTIVES: To estimate the health effects of postmenopausal hormone therapy used for 10 or 20 years in a population of intermediate cardiovascular risk. DESIGN: Using existing estimates of the effect of hormone therapy on rates of myocardial infarction, hip fracture and breast cancer, a proportional multistage life table was generated to calculate the effects of use for 10 and 20 years in a synthetic cohort of Dutch women aged 55 with an average and a high-risk profile for cardiovascular disease. RESULTS: A woman of the general population who starts hormone therapy at age 55 for 10 years can prolong her life by 1 month and may postpone the occurrence of first incidence of one of the diseases under consideration by 2.4 months. One excess breast cancer case is likely to occur per 5-6 averted cases of first myocardial infarction or hip fracture. If she prolongs her use to 20 years, the gain of life expectancy and disease-free life expectancy is doubled. The risk-benefit ratio worsens to one extra breast cancer per 3-4 averted cases of the preventable diseases. For a woman with a high-risk profile, the gains in health are about twice as high as for her counterpart in the general population, and her risk-benefit ratio is also more favourable. Yet, the risk-benefit ratio still worsens for 20 as compared with 10 years of use. CONCLUSIONS: Women from the general population in the Netherlands and similar populations can achieve only a modest gain in life expectancy by using hormones during 10 or 20 years following menopause. This is a consequence of the low incidence of myocardial infarction and hip fracture and the relatively high incidence of breast cancer before the age of 75. Women at increased cardiovascular risk can benefit more from hormone therapy. But even amongst these women, the risk of breast cancer incurred with long-term use offsets much of the benefit that could accrue from changing the risk of heart disease and hip fracture.

The epidemiology of gallbladder cancer: lifestyle related risk factors and limited surgical possibilities for prevention.

Cancer of the gallbladder is a rare cancer with a poor prognosis. Most patients die within 1 year. The incidence shows large geographic variation and is higher in females and in certain ethnic groups. Gallstones are closely related to this type of cancer. Studying risk factors such as lifestyle is hampered by the generally small size of the case-series. Nevertheless, the studies conducted so far provide some indication that cigarette smoking, alcohol consumption, obesity and specific dietary habits might affect the risk. In women, reproductive history seems to affect the risk as well. Incidence may be lowered by identifying high risk groups and offering preventive measures. Although gallstones are associated with higher risk, most people with untreated gallstones are at low risk of developing the cancer. Moreover, the cancer occurs at such an old age that prophylactic removal of a stone-containing gallbladder is not an appropriate measure for the prevention of gallbladder cancer. Probably at a higher risk are those who are exposed to stones for longer periods. An indicator of duration of exposure is not presently available; whether stone size can be such an indicator in specific conditions and populations needs to be studied further.

Sex differences in illness beliefs and illness behavior in patients with suspected coronary artery disease.

The aim of this study was to explore sex differences in illness beliefs and behavior in patients with suspected coronary artery disease (CAD). Twenty-eight patients, 16 women and 12 men, were interviewed. The results show that both men and women think of CAD as a 'men's disease' and have equal knowledge of CAD risk factors. However, especially the men considered their own risk of developing CAD lower than their estimated probability of their own sex and as low as their estimated risk for women. Both men and women did not attribute their symptoms indicative of CAD to their heart. Women, especially those who did not attribute their symptoms to their heart, had a longer patient delay than men, although their symptoms were indicative of CAD. To conclude, men as well as women should be made more aware of their own risk of developing CAD and of the manifestation of CAD symptoms. Physicians could be encouraged to ask patients more explicitly and thoroughly about their illness beliefs, to check their knowledge and inform them about CAD.

Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer.

BACKGROUND: There are few previous epidemiologic studies of gallbladder cancer, a rare but nearly always lethal gastrointestinal cancer with a demonstrated greater frequency in adult women and older subjects of both sexes, and also in the members of populations throughout central and eastern Europe and certain racial groups such as native American Indians. Unfortunately, the prospects for the prevention of this form of cancer are poor. PURPOSE: Our purpose in conducting this study was to investigate possible new risk factors for gallbladder cancer and to strengthen our understanding of established causal agents that may be involved in this disease. METHODS: A large, collaborative, multicenter, case-control study of cancer of the gallbladder was conducted in five centers located in Australia (Adelaide), Canada (Montreal and Toronto), The Netherlands (Utrecht), and Poland (Opole) from January 1983 through July 1988. Case subjects with gallbladder cancer were accrued by the centers from hospital pathology records and from reports to regional cancer registries. Cancer diagnosis was confirmed by either biopsy, cholecystectomy, or at the time of autopsy. Control subjects were randomly assigned at each center from the population. The pooled analysis included 196 case subjects and 1515 control subjects (who did not report previous cholecystectomy). Ninety-eight percent of the subjects were white. Personal interviews of case subjects, control subjects, and surrogates (spouse or next of kin) were conducted by trained personnel. RESULTS: After adjusting for potential confounding factors (age, sex, center, type of interview, years of schooling, alcohol intake, and lifetime cigarette smoking), a history of gallbladder symptoms requiring medical attention (e.g., reduced bile secretion from the gallbladder into the small intestine due to obstructions of the common bile or cystic ducts) was the major risk factor associated with this form of cancer (odds ratio [OR] = 4.4; 95% confidence interval [CI] = 2.6-7.5). This association was present even in subjects who had their first gallbladder examination because of symptoms present more than 20 years earlier (OR = 6.2; 95% CI = 2.8-13.4). Other variables associated with gallbladder cancer risk included an elevated body mass index, high total energy intake, high carbohydrate intake (after adjustment for total energy intake), and chronic diarrhea. All of these risk factors have been previously associated with gallstone disease. CONCLUSIONS: These findings are consistent with a major role of gallstones, or risk factors for gallstones, in the cause of gallbladder cancer. Additional information on whether or not screening high-risk subjects for gallstones or gallbladder cancer is needed.

Cigarette smoking and pancreas cancer: a case control study of the search programme of the IARC.

A multi-centre case-control study of pancreas cancer, designed to be population-based, to use a random sample of local populations as controls and to use a common protocol and core questionnaire, was conducted as the first study of the SEARCH programme of the International Agency for Research on Cancer. "Ever-smokers" were found to be at increased risk for pancreas cancer compared with "never-smokers" consistently in all strata of gender, response status and centre. Risk of pancreas cancer was found to increase with increasing lifetime consumption of cigarettes, the relative risk rising to 2.70 (95% C.I. 1.95 to 3.74) in the highest intake category. The overall trend in risk was highly significant and the association was found consistently in each stratum of gender, response status and centre. Fifteen years had to pass from quitting cigarette smoking until the risk fell to a level compatible with that in never-smokers among the heaviest group of smokers; among the 2 lowest tertiles this happened within 5 years. Further, reported smoking habits more than 15 years before diagnosis appeared to have no influence on pancreas-cancer risk, irrespective of amount smoked. The results are consistent with a causal role for cigarette smoking in the aetiology of pancreas cancer and illustrate that ceasing to smoke cigarettes can lead to reductions in the elevated risk of pancreas cancer produced by this habit.

Consumption of foods and micronutrients and the risk of cancer of the biliary tract.

BACKGROUND: Gallstones and obesity have been suggested as risk factors for cancer of the biliary tract. Since both factors are related to diet, we studied the relationship between dietary intake and the cancer of interest in a population-based case-control study. METHODS: The study population comprised 111 patients and 480 controls. Food intake was assessed by means of a semiquantitative food frequency questionnaire. Estimates of the intake of foods and micronutrients were obtained from cases and controls themselves (direct respondents) or from relatives (indirect respondents). Participants were categorized into tertiles of intake. Risk ratios were estimated by logistic regression analysis. RESULTS: The major findings are a monotonic decrease in risk associated with the consumption of vegetables (ORs 1.0, 0.7, 0.4, P value trend < 0.01) and a monotonic increase in risk associated with sugar added to drinks and desserts (ORs 1.0, 1.3, 2.5; P value trend < 0.01). CONCLUSIONS: The finding on added sugar corresponds to our earlier report that the group monosaccharides and disaccharides is a potential risk factor for this cancer. Sugar may influence bile composition through lipoprotein metabolism. The protective effect of vegetables is in accordance with the reported inverse relationship between vegetables and many epithelial cancers of the alimentary tract.

Smoking, alcohol consumption and the risk of cancer of the biliary tract; a population-based case-control study in The Netherlands.

Although cancer of the biliary tract is a highly fatal disease, the relationship with modifiable, life style-related factors is hardly studied. Between 1984 and 1987 we conducted a case-control study of 114 patients and 487 controls from the general population. An interviewer-administered questionnaire was used to collect information on life-time smoking habits and life-time alcohol consumption. The information was obtained either from the subjects themselves (direct response) of from relatives (indirect response). Results show that neither smoking at the time of interview (odds ratio (OR) 1.5; 95% confidence interval (CI) 0.9-2.4) nor smoking 2, 5 or 10 years before were associated significantly with the cancer. Alcohol consumption at the time of interview (OR 1.0; 95% CI 0.6-1.5) or drinking 2, 5 or 10 years before were not significantly associated either. Among current alcohol drinkers, long-term consumers had a reduced risk (duration of use > 38 years vs < 25 years: OR 0.4; 95% CI 0.1-0.9) and late starters an elevated risk (starting age > 38 years vs < 21 years: OR 2.7, 95% CI 1.0-7.5). A modifying effect of alcohol consumption on the smoking-cancer relationship was observed: the risk for current smokers was increased only when they did not drink alcohol at that point in time (OR 3.4, 95% CI 1.3-8.5). Our results indicate that long-term moderate alcohol use might be protective against cancer of the biliary tract, whereas smoking might be a risk factor for this cancer.

Regional fat distribution as risk factor for clinically diagnosed gallstones in middle-aged men: a 25-year follow-up study (the Zutphen Study).

Obesity is considered to be an important risk factor for the formation of gallstones. The relationship is well established for women but not for men. In a long-term follow-up study of middle-aged men the relationship between various markers of obesity and the incidence of clinically diagnosed gallstones during 25 years of follow-up was studied. Information on the presence of gallstones was obtained by self-report and verified through medical records after death. Of the 860 men who were between 40 and 59 years old at the start of the study, 54 developed gallstones, yielding an incidence rate of 3.1/1000 person-years. Cox proportional hazard models were used to examine the associations between the risk factors and newly diagnosed gallstones. Univariate analysis revealed that the subscapular-to-triceps skinfold thickness ratio (STR) yields a significant positive association (HR upper quartile: 2.5, 95% CI: 1.1-5.7). Subscapular skinfold thickness had a borderline significant, positive association, which became significant after exclusion of subjects who developed symptomatic gallstones within the first 3 years of follow-up (HR upper quartile: 2.5, 95% CI: 1.0-6.2). The multivariate model revealed that the association of STR with clinically diagnosed gallstones was independent of Body Mass Index. Our results indicate that regional fat distribution, as measured by the subscapular-to-triceps skinfold thickness ratio, may play an important role in the formation of gallstones in men, as was previously found for women in other studies.

Dietary risk factors for clinically diagnosed gallstones in middle-aged men. A 25-year follow-up study (the Zutphen Study).

In a long-term follow-up study of middle-aged men, the relation between the intake of energy, nutrients, and foods and the 25-year incidence of clinically diagnosed gallstones was studied. Information on the presence of gallstones was obtained by self-report and verified through medical records after death. Of 860 men, 54 developed symptomatic gallstones, yielding an incidence rate of 3.1/1000 person-years. The present study provides a comprehensive picture of dietary risk factors for clinically diagnosed gallstones based on a long-term follow-up. Calcium intake was inversely associated with gallstone incidence in the univariate and multivariate Cox proportional hazards analyses (hazard ratio (HR) upper tertile: 0.3; 95% CI: 0.1 to 0.7). A positive association with sugars (monosaccharides and disaccharides) appeared after the introduction of age, body mass index, calcium intake, and the intake of energy from nutrients other than sugars into the model (HR upper tertile: 2.3; 95% CI: 1.0 to 4.8). Calcium may alter the composition of bile by preventing the reabsorption of secondary bile acids in the colon, whereas sugars may influence bile composition through lipoprotein metabolism.

Reproductive history and cancer of the biliary tract in women.

Although reproductive factors have been shown to be related to the composition of bile and functioning of the biliary system, their relationship with biliary tract cancer has not been studied in detail. Between 1984 and 1987 we conducted a case-control study of 75 women with cancer of the biliary tract and 252 controls from the general population. An interviewer-administered questionnaire was used to collect information on reproductive history. The information was obtained from the responders themselves (direct response) or from relatives (indirect response). Our results indicate that younger age at menarche, early age at first pregnancy, higher number of pregnancies and prolonged fertility may enhance the risk of cancer of the biliary tract. Overall, increased exposure to endogenous oestrogens and progesterone constitutes a higher risk.