[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.

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.

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.

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.

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.

Exploring the aphasiac's naming disturbances; a new approach using the neighbourhood limited classification method.

The patterns of errors observed in eighteen patients with aphasia naming 42 different items presented 5 times in random succession were analyzed by the N.L.C. (Neighbourhood Limited Classification) method. The initial and last responses for each item were considered. The procedure allowed the computation of an improvement coefficient for each patient, illustrating the capacity to modify an initially erroneous response. For each type of response a cluster analysis was performed and a grouping of patients was obtained; in both cases some patients had close to normal scores. Clustering was chiefly a function of severity of word-finding disturbance. Phonemic paraphasias follow a more independent course, allowing additional clustering. In the future, more importance should be given to their discriminative value in the taxonomy of naming disturbances.

Aphasics' defective perception of connotative meaning of verbal items which have no denotative meaning.

This study deals with the question of whether in aphasic patients the grasping of connotative meaning is disturbed. The method used was the "maluma - takete" type (Koehler, 1947): matching of synthetic words to meaningless figures. It was proven that asphasics from different countries with different languages have a disturbed perception of connotative meaning. There was a correlation with the severity of language comprehension disturbance in aphasics.

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.

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.

A taxonomy of misnaming aphasiacs.

A cluster analysis, based upon the naming errors of 61 non-selected aphasiacs, was performed. Three clusters emerged; the first was marked by phonemic errors, the second by semantic ones and the third by the use of escape mechanisms. Subjects in the second cluster were less impaired; this could be a consequence of the disturbance type involved. Though many patients of first and third groups displayed a Wernicke aphasia, whereas Broca aphasia predominated in the second one, a concordance of clusters with aphasiologic diagnoses was far from excellent.

Towards a taxonomy of aphasic errors. A pilot study.

Error patterns occurring in an aphasic population performing a naming task were explored by factor analysis. This confirmed the existence of two error types: a phonemic and a semantic one. The latter was about twice as important as the former; as a consequence, a weighting system restoring the balance between both was required before submitting patients' scores to cluster analysis. Suitable weighting coefficients were computed according to data obtained by factor analysis. As defect severity interfered with the results of cluster analysis, scores were weighted in order to neutralize the severity dimension.

The background of aphasic misnamings. A factor analysis of visual naming errors.

A factor analysis of 4612 errors recorded among the 12 200 responses made by 61 non-selected aphasiacs, during a visual naming task, was performed; the 14 variables were mostly errors described by the neurologic terminology. The existence of a phonemic and a semantic articulation level was confirmed. A feedback system opening the way to alternative responses ("escape mechanisms") was disclosed. Phonemic paraphasias were the most specific errors at the phonemic level, whereas perseverations turned out to be the purest representative at the semantic one. Verbal semantic paraphasias were apparently not a lesser degree of verbal paraphasias but errors of a different nature (Acta neurol. belg., 1985, 85, 110-122).

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.