[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.

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.

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.

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.

Gallstone size and the risk of gallbladder cancer.

The relation between gallstone size and gallbladder cancer was investigated in a matched hospital-based case-control study of surgical patients in a predominantly white population. Stone size was considered to be an indicator of the damaging effects of gallstones on gallbladder mucosa, which may enhance carcinogenesis. A radiologist determined the size of the largest gallstone within the gallbladder by reviewing hard copies of the ultrasonographic examinations of cases and controls. Between 1983 and 1989, 83 surgical patients with gallbladder cancer were identified in 18 participating hospitals. Hard copies were available for 72 patients and 208 matched controls. For 43 cancer patients and 98 matched controls stone size could be determined. In contrast to two other studies, no relation was found between stone size and gallbladder cancer. The reasons for this discrepancy are discussed.

Dietary sugar intake in the aetiology of biliary tract cancer.

Although gallstones and obesity are important risk factors for biliary tract cancer, the relation between diet and this type of cancer has not been studied in detail. Between 1984 and 1988 we conducted a case-control study of 111 cases of biliary tract cancer and 480 controls from the general population. Food intake was assessed by means of a semiquantitative food frequency questionnaire. Estimates of the total energy intake and the intake of macronutrients were obtained from the patients and controls themselves (direct respondents) or from relatives (indirect respondents). The major finding is that the risk associated with the intake of sugars (i.e. the combined intake of monosaccharides and disaccharides), independent of other sources of energy, is more than doubled for indirect respondents and for both respondent groups combined. A biological explanation for the fact that the intake of sugars may be a risk factor for biliary tract cancer might be based on the relationships between sugar, blood lipids and gallstone formation.

CT scan and testis tumors.

CT plays an important role in the management of testis tumors both in the initial staging and the follow-up of the patient after treatment. Abdominal CT for the search of lymph node metastases should be part of the initial evaluation but pathology remains necessary to validate the diagnosis.

Aspects of medical history and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands.

During 1984-88 a population-based case-control study was carried out in The Netherlands, in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between aspects of medical history and exocrine pancreatic carcinoma in 176 cases and 487 controls. About 58% of patients were interviewed directly. We observed an inverse relationship between medical treatment for allergy-related conditions and the development of pancreatic cancer (30 cases vs. 130 controls, OR 0.57, 95% CI 0.36 to 0.90). A history of gallbladder problems, gallstones, cholecystectomy, stomach or duodenal ulcer, pancreatitis, appendicitis, diabetes or tonsillectomy was not related to risk. In direct responses, compared with once daily, a positive relationship was seen for stool frequency, 10 years ago, of less than once daily (18 cases vs. 40 controls, OR 2.10, 95% CI 1.09 to 4.04). In men, diabetes treated with insulin and diagnosed more than 1 year previously was significantly and positively related to risk (5 cases vs. 1 control, OR 11.66, 95% 1.28 to 105.95). In brief, the results of the present study suggest that a history of allergy-related conditions may protect, whereas a past stool frequency of less than once daily may enhance the risk of cancer of the pancreas. Other elements of the medical history were not consistently related to risk.

Anthropometric and reproductive variables and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands.

During 1984-88 a population-based case-control study was carried out in The Netherlands, in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between aspects of medical history and exocrine pancreatic carcinoma in 176 cases and 487 controls. About 58% of patients were interviewed directly. In women, a significant, positive dose-response effect of height was seen (p-value trend less than 0.005). Compared with ages 14 or more, women with an early age at menarche, i.e., 11 years or less, had a 3-fold increase in risk (15 cases vs. 23 controls, OR 3.07, 95% CI 1.35 to 7.00). Other apsects of the reproductive history were not related to risk. In brief, the results of the present study support the hypothesis that, in women, early menarche and greater adult stature may be early predictors of the development of cancer of the pancreas later in life.

Lifetime consumption of alcoholic beverages, tea and coffee and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands.

From 1984 to 1988 a population-based case-control study was carried out in the Netherlands, in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between the habitual lifetime consumption of alcohol, coffee and tea and exocrine pancreatic carcinoma in 176 cases and 487 controls. An interviewer-administered questionnaire was used to ascertain major life events and obtain estimates of consumption (ever-never) and frequency of consumption throughout life. Logistic regression analyses yielded odds ratios adjusted for age, sex, response status, smoking, dietary intake of energy and vegetables and of alcoholic or non-alcoholic drinks. When compared with data from non-drinkers, the cumulative lifetime consumption of all types of alcohol in grams of ethanol (ORs 1.00, 0.97, 0.93, 1.25, p trend 0.55), beer, spirits, red wine and fortified wine was not related to risk. The consumption of white wine was inversely associated with risk (OR 0.41, 95% CI 0.24-0.70). The uniformly reduced risk estimates for the lifetime number of drinks of white wine were based on small numbers (ORs 1.00, 0.44, 0.25, 0.40, p trend 0.001). When compared with data from non-drinkers, our findings suggest an inverse dose-response relationship for the lifetime consumption of coffee (ORs 1.00, 0.72, 0.37, 0.58, p trend 0.06), whereas lifetime consumption of tea and of ground, instant and decaffeinated coffee was not associated with risk. The absence of an effect of lifetime consumption of decaffeinated coffee may be due to the small numbers of subjects. These results further strengthen existing evidence against a positive association between consumption as well as lifetime consumption of (sources of) alcohol, tea or coffee and the development of exocrine pancreatic cancer.