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Introduction: An in-patient clinical service has been set up in March 2016 in the Occupational Diseases Center of Brest University Hospital, France, to seek for work-relatedness of diseases in patients hospitalized into the oncology and hematology departments. We present here data after two years of existence., Methods: All cases of cancers or malignant hematological diseases (ICD-10 codes C00 to C97 and D37 to D48) seen between March 1, 2016, and March 1, 2018, have been identified. We present sociodemographic data, occupational exposures, occupation, business sector, and tobacco consumption. The causation level between the disease and each of the occupational exposures has been rated as strong, intermediate, weak or null by the occupational medicine specialist of the Occupational Diseases Center., Results: Among the 196 patients encountered, there are 127 work-related diseases and 82 of these had one occupational exposure rated as strong or intermediate. The most frequent occupational hazards were asbestos (48 cases) and ionizing radiation (23 cases). The most frequent business sectors were metallurgy, mechanical engineering, and agriculture. Lung cancer was the most frequently reported disease (49 cases)., Discussion: . We identified well-known couples with occupational exposures and diseases, such as asbestos and lung cancer. We also identified a link between pesticides and leukemias. This in-patient clinical service is helpful to identify work-related exposures and in helping patients to get compensated., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Cutaneous melanoma is a malignant tumor with a high metastatic potential. If an early treatment is associated with a favorable outcome, the prognosis of metastatic melanoma remains poor. Advances in molecular characterization of cancers, notably the discovery of BRAF gene mutations in metastatic melanoma, allowed to the recent development of targeted therapies against mutated BRAF protein. Despite high tumor response rates observed in clinical trials, these new drugs are associated with frequent secondary tumor resistance occurrence and paradoxical carcinogenic side effects. The cellular and molecular mechanisms of these carcinogenic side effects and secondary resistance are not yet fully elucidated and are actually intensely studied. This review of the literature focus on the mechanisms of these carcinogenic side effects and on the tumor resistance associated with anti-BRAF targeted therapies., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Polycythemia vera (PV) is a chronic myeloproliferative disorder due to a haematopoietic stem cell's clonal proliferation. PV is also characterized by independency or hyper sensibility of haematopoietic progenitors to several cytokine as erythropoietin. This acquired disorder is often associated with thrombocytosis, leukocytosis and splenomegaly. Generally, diagnosis remains easy, based on basic clinical and biological abnormalities. Sometimes, positive diagnosis required more sophisticated tests as assay of endogenous erythroid colony, erythropoietin blood level and bone marrow biopsy. Usually natural history of disease remains long with a good quality of life. In some cases complications occur: mainly thrombosis and late myeloid metaplasia with myelofibrosis and acute leukemia. Therapeutic approachs remain complex and difficult to optimize based up on age and disease severity. Treatment searchs for reducing hyper viscosity complications and for avoiding therapeutic induced leukemia.

Indirect standardisation or the standardised rate method, consists of a comparison of the number of observed and expected cases. This method could be applied in the field of pharmacovigilance in order to investigate the potential relationship between drug exposure and the occurrence of an adverse event. It consists of the calculation of an expected number of events obtained by multiplying the exposed population by the event rate in the reference population. The comparison is made by means of a standardised mortality or incidence ratio (SMR or SIR). Three examples of this method are presented. The first example concerns central nervous system demyelinating disorders and hepatitis B vaccine, where the SIR calculated from spontaneous reports was equal to 1.05 (95% CI [0.82-1.26]). In the second example, the SMR of cardiovascular deaths related to sildenafil was significantly different from 1 (0.69, [0.43-1.08]) using data from prescription-event monitoring. In the last example, a strong association between acute leukaemia and chemotherapy in breast cancer was found (SIR 28.5, [12.3-56.2]) using exhaustive data from cancer registries. This method allows a quick and cheap risk assessment, although the quality of available data may limit validity of results. In this case, the hypothesis need to be examined by further ad-hoc clinical and pharmacoepidemiological studies.

Long-term follow up for medicines used in children is necessary in some therapeutic areas. Long-term effects (e.g. in cancer) may be detected many years after the treatment period. Growth, development and maturation specific to children can make these effects particularly harmful. The development plan of a paediatric drug should include, long term follow up on the basis of pharmacological-toxicological and safety data. These aspects should be taken into account when modifying the protocol (lower dosage, withdrawal of some associations etc). The follow up period may be very long, as in cancer (e.g. second tumour after treatment for cancer). A cohort is the best choice for this follow up, but other alternatives may be useful, including a specific follow-up Unit. Long-term follow-up is nevertheless difficult and expensive, manpower-dependent and the risk of failure is great especially in the teenage years.

The frequent side effects of Hydroxy-Urea and the non-exceptional risk of leukemia and cancer in Polycythemia Vera treated for a long time by Hydroxy-Urea allow to conclude that Hydroxy-Urea is not an innocent drug. In a prospective trial of 150 patients with a median follow up of nine years, Hydroxy-Urea given alone induced side effects in 29% of patients necessitating to stop treatment in half of cases. The percentage of leukemia or myelodysplasia is 6.7% with an actuarial risk of leukemic transformation of 10% at 13 years. In an other prospective trial in 181 aged patients Hydroxy-Urea was given as maintenance therapy after 32P treatment. The median follow-up in that study is also of nine years. Side effects are observed in 13% of cases. A two fold increase of the leukemic risk was observed in the maintenance arm of the trial: 11 versus 19% at ten years, 14 vs 30% at 12 years, 16 vs 35% at 15 years because of the leukemogenic effect of Hydroxy-Urea in maintenance therapy we stopped including new patients in this arm of the trial.

Several publications have recently suggested a relationship between cannabis use and certain types of cancer. We gathered information on the latest findings on the subject. A manual and computerized bibliographic search on cannabis and cancer was conducted. In users under 40 years of age, cannabis is suspected to increase the risk of squamous-cell carcinoma of the upper aerodigestive tract, particularly of the tongue and larynx, and possibly of lung. Other tumours being suspected are non-lymphoblastic acute leukaemia and astrocytoma. In head and neck cancer, carcinogenicity was observed for regular (i.e. more than once a day for years) cannabis smokers. Moreover, cannabis increases the risk of head and neck cancer in a dose-response manner for frequency and duration of use. Interaction was observed with cigarette smoking and alcohol use. Delta9-THC seems to have a specific carcinogenic effect different from that of the pyrolysis products. Epidemiological studies are needed as soon as possible to provide data on the European and French situation. Information on the possible risks of a regular use of cannabis should be a priority.

Most chemical carcinogenic agents are industrial. About 4% of all cancers have an occupational origin, but the percentage is higher in exposed populations. Evidence of carcinogenicity is provided by epidemiological studies, animal experiments and other biological sources like experimental mutagenesis. The IARC (International Agency for Research on Cancer) classification and the European Union classification of carcinogenic agents for humans are useful for prevention and regulation. Some cancers are classified as occupational diseases but only a few persons receive compensation given the difficulties of aetiologic diagnosis and the frequent absence of declaration.

The frequency of leukemia and myelodysplasia following treatment with cytotoxic agents is increasing. Theses treatment-related leukemias raise both theoretical and practical concerns. On a theoretical basis, cytogenetic and molecular abnormalities described constitute useful models to study leukemogenesis. On a practical basis, prognosis of treatment related-leukemia is somehow unfavorable and implies to take in account this risk in the development of combination therapy for solid tumors or hematological malignancies. There are two distinctive types of treatment-induced leukemia: those secondary after alkylating agents and those secondary after topoisomerase-II- inhibitors. These two types of leukemia after regarding their clinical and their hematological characteristics, but also regarding their prognosis and their associated molecular abnormalities. Leukemias induced by alkylating agents occur generally 5 or 6 years after the beginning of the chemotherapy and are preceded by a more or less long phase of pancytopenia or myelodysplasia and according to their cytologic aspects are difficult to be classified within FAB classification. Their prognosis is pejorative. The most commonly found cytogenetic abnormalities associated with these types of induced leukemia are losses or deletions of chromosomes 5 and 7. Leukemias induced by topoisomerase-II-inhibitors occur shortly after the treatment (12 to 30 months), they begin generally suddenly without preleukemia prodom and their more frequent cytological aspects are M4 and M5 type. The prognosis is less severe than alkylating agent related forms with higher response rates and is dependant of discovered cytogenetic abnormalities. The more frequent molecular abnormalities are not chromosome deletions but balanced translocations. They affect particularly the MLL gene located at band 11q23. Other translocations have been described in this type of leukemia and are comparable to the one found in the de novo leukemia (t8;21, t15;17) for example. The evaluation of the risk of treatment-related leukemia for a given chemotherapeutic agent is difficult as for as current treatment use the combination of several agents potentially leukemogenic (chemotherapy and radiotherapy, combination chemotherapy). It is necessary to set up an up-dated data register in order to centralize all therapy-related myelodysplasia and leukemia within the treatment of a given type of cancer.

The rate of long lasting complete remissions in Hodgkin's disease is high and relapses are rare. Complications after treatment of the disease may be either non oncologic or oncologic. The second cancers observed are acute leukaemias, non Hodgkin's lymphomas and solid tumors. Details are given about these complications and new strategies in the treatment modalities are now proposed according to the observed cancers.

A hospital based case-control study was carried out in Lyon with the aim of assessing the association between haematologic malignancies and occupational exposures to 320 compounds. Job histories were obtained by questionnaire for 118 cases (52 non Hodgkin lymphomas, 48 acute myeloid leukemia, 18 others leukaemias), and 118 controls with diseases other than cancer from the same general hospital; controls were matched for sex, age and nationality. Systematic coding of exposures based on a blind analysis of job histories, was done by a team of experts in chemistry and occupational health. Mantel-Haenszel analysis was performed. Significantly elevated odds-ratio were observed for non Hodgkin lymphomas and exposure to mineral oils (14.86; 2.76-80.0), excavation dusts (3.91; 0.94-15.95), alkali compounds (2.90; 1.09-7.68), inks (2.47; 1.09-5.17). For inks, a dose-response relation was observed. Elevated odds-ratios appeared for acute myeloid leukaemias and arsenic compounds (3.02; 0.90-10.13) and lead compounds (3.70; 1.09-13.44). When regarding industrial activities, two of them are more frequently found: food industries (14 cases/5 controls), public works (12 cases/0 control). When regarding jobs, winding (6 cases/0 control), glass workers (8 cases/1 control) and warehousemen (10 cases and 4 controls) are more often seen among cases.

Potential hazards associated with the use of agricultural pesticides are a growing concern for society. We describe the relationships between the mortality data for cancers of the brain, the lymphatic tissues and leukemia, and the spatial distribution of agricultural pesticide use for 34 drainage basins in Quebec, from 1976-1985. The basins were grouped into three categories (low, intermediate, and high exposure) according to the level of sales of pesticides. For cancers of the lymphatic tissues among women 35 to 64 years of age, a high relative risk (RR) was observed (RR = 1.91, 95% Confidence Interval = 1.14, 3.18) in basins highly exposed to pesticides compared to those with low exposure. Analysis of correlation for this cancer at 34 basins showed significant associations between geographical distributions of the Standardized Mortality Ratio (SMR) and those of numerous variables indicative of pesticide use in agriculture. Agreement between the results for mortality data in this exploratory study and the results from another study on cancer incidence data for 1982-1983, supports the hypothesis of a potential relationship between the use of pesticides in agriculture and cancer of the lymphatic tissues.

25 presumably induced leukemias, either following treatment (lymphoma, polycythemia vera, essential thrombocythemia, cancers) or after exposure to oncogenic agents have been studied cytogenetically and cytologically. Complex chromosomal abnormalities were associated with a difficult cytological classification. Complete monosomy 7 with presence of micromegacaryocytes and macroplatelets was observed in 7 cases. The findings observed in induced leukemias were compared with those found in "primitive" leukemias showing the same chromosomal patterns. The same relationships between cytology and cytogenetics have been observed.

In a retrospective study of 1 094 patients treated for Hodgkin's disease between 1963 and 1976, we have observed 65 malignant complications including 28 granulosis acute leukemias and 37 solid tumors. The actuarial 10 year risk of developing acute leukemia is 4.7 per cent; and 5.4 per cent for solid tumors. These figures vary according to the medications received. They are more important in the case of polychemotherapy, particularly for acute leukemia, thus confirming the specific role of alkyl agents. While the course of solid tumors does not seem to differ from that of identical primitive tumors; on the other hand, induced leukemia seems to have a more perjorative prognosis than spontaneous leukemia and they are often announced by cytopenia. The overall risk of developing secondary cancer is multiplied by 2.4 compared to the normal population; that of developing acute leukemia is multiplied by 9.3. In order to reduce this risk, active non alkyl agents of limited duration must be advocated. Irradiation fields must also be reduced.

Changes in mean corpuscular volume (MCV) were studied in cancer patients. Vitamin B12 or erythrocyte folate deficiencies were observed in only 9% of macrocytic patients (MCV greater than or equal to 100 fl). Bone marrow study in seven macrocytic patients with normal hemograms and normal levels of vitamin B12 and folic acid, on per os daily cyclophosphamide single agent therapy, showed myelodysplastic features. The highest MCV and MCV increases during therapy among 203 patients were observed in those cancers and cytotoxic therapies most commonly followed by secondary leukemia: Hodgkin's disease treated with MOPP and radiotherapy, and multiple myeloma and ovarian cancer treated with Melphalan. 21 patients who developed secondary leukemia had a higher MCV and a greater MCV increment than the control patients. Differences were significant in Hodgkin's disease. This preliminary report strongly supports monitoring MCV changes during cytotoxic therapy to attempt identification of patients at high risk of secondary leukemia.

Eighty-five patients with nodular lymphoma diagnosed between 1968 and 1975 were followed up for long periods and were treated by either conventional methods (local radiotherapy and single drug chemotherapy) or by more intensive therapeutic regimens, such as initial combined M.O.P.P. therapy and maintenance treatment with chlorambucil with or without further courses of M.O.P.P. Long-term follow-ups have brought to light some interesting points concerning the prognosis. Dissemination of the disease and large-cell histological pattern were, as already known, unfavourable factors. Neither age nor sex, nor bone-marrow involvement seemed to have any influence. Obtaining complete remissions improved the prognosis, but intensifying the initial and maintenance treatments proved disappointing: the survival rate remained the same, and the incidence of drug induced leukaemias was high. Indeed, relapses appeared to be less responsive to treatment when the patient had initially received multiple chemotherapy. However, in view of the high death rate of the disease (one-third of the patients in this series died within the first 5 years), trying new therapeutic regimens in the hope of obtaining better results, as has been done in Hodgkin's disease, would be fully justified.

A review of the literature upon 102 cases with cytogenetic study of preleukemic states (Prel.) and/or acute secondary leukemia (ASL) following chemotherapy and/or radiotherapy treatment has been made. The karyotype was almost always abnormal (91%) of cases). There was a predominance of hypodiploidy with abnormalities including chromosome number 5 (-5 ou 5q-) and/or number 7 (7- or 7q-) (chromosomes studied with banding). The abnormalities were present in preleukemia state. The pattern of the acute secondary leukemia was particularly different from that acute leukemia de novo: high frequency of preleukemia state, ANLL type of leukemia, very bad prognosis, importance of cytogenetic abnormalities. There was a great interest in the study of the karyotype for the previous detection in ASL: this allowed their discovery as soon as the preleukemia state.

The authors undertook a retrospective study to determine the number of acute leukaemias developing amongst 2006 patients suffering from chronic inflammatory rheumatic conditions and connective tissue disorders, treated with cytotoxic agents. The follow-up period ranged from 1 to 13 years. Nineteen leukaemias were found, essentially granulocytic, with a latent period of 5.7 +/- 2, 8 years after the beginning of treatment. This incidence of almost 1% of leukaemias is probably less than the actual percentage since a number of patients were lost on follow up and since the period of observation is as yet too short. The majority of patients has been treated for more than one year. No cases were seen amongst patients treated for less than six months, or with less than 1g of chlorambucil or 50 g of cyclophosphamide. The risk would seem to be the same for both alkylating agents. No patients treated with azathioprine developed leukaemia, but few patients received this drug. Amongst 35 patients treated for severe psoriatic arthropathy with chlorambucil, 4 developed leukaemia. This particularly high percentage is such that all trials of alkylating agent in this condition should be stopped. The prevalence of leukaemia seen in the series as a whole is comparable to that found in mass studies carried out in various malignant diseases treated by cytotoxics. Awareness of this risk should, lead to even stricter limitations before the use of cytotoxic drugs in rheumatological conditions.

Medical, psychologic, socio-professional and economic side effects of adjuvant chemotherapy are frequent. Some of these are not easily recognized with accuracy. They influence directly the life of treated patients and perhaps later their medical future. They involve the quality of life for cancer patients, after initial curative treatments. Indications for adjuvant chemotherapy cannot be extended without comparative evaluation of their advantages and disadvantages. It is necessary to select patients with the highest probability of improvement in the duration and the quality of life and to give them so active but the least toxic treatments possible.

Among the neurological side-effects, peripheral neuropathy is a result of therapy with vindesine and above all vincristine. Although in most cases it is responsible only for paresthesias, it may cause extensive paralysis and requires that the drug be discontinued. These drugs may also affect the neurovegetative system. Ototoxicity may be seen with cis-platinum and vigilance disturbances with L-asparaginase. Genetic consequences are mainly due to alkylating agents. These agents almost constantly impair male and female fertility but recovery is possible. Libido is also affected with the attendant psychological consequences. The offspring of patients previously treated by chemotherapeutic agents are normal. Development of secondary carcinoma or leukemia is currently a major concern. Secondary malignant disease may develop after the treatment of any cancer, especially if radiotherapy was associated with alkylating agents. Leukemias are of the acute myeloid type and usually follow a preleukemic phase. A table summarizes the main toxicities of the most usual drugs.

On the basis of two personal cases of acute leukaemia occurring following immunosuppressive therapy for disseminated sclerosis and for Behçet's syndrome, the literature is reviewed. Thirty three similar detailed cases were collected. They are characterised in general by the prolonged use of immunosuppression. The acute leukaemia affected the granulocyte series in the majority of cases. In 30%; the leukaemia was preceded by a phase of several months of preleukaemic type dysmyelopoiesis. The mechanisms of action explaining this carcinogenic risk in a general way are multiple: the role of marrow aplasia, chromosomal abnormalities, the activation of a leukaemogenic virus, the role of immunodepression and that of repeated antigenic stimulation may all be discussed. The risks associated with such treatment should thus be borne in mind when evaluating its indications.

The authors report 12 cases of acute leukemia observed after breast cancer. 4 patients received only adjuvant radiotherapy, whereas the other eight received both chemotherapy and radiotherapy. Acute leukemia appeared with a mean time of 5.5 years after the detection of breast cancer and was preceded in 7 cases by isolated pancytopenia during 4 months. Acute leukemias were always non lymphoblastic and myelofibrosis was very frequent. A complete remission was obtained at three patients out of the seven treated. The mean survival time was 5.6 months. The existence of acute leukemia after chemo-and/or radiotherapy poses several problems. The detection of patients with a high risk of leukemia by different methods such as cytogenetic, studies of dysmyelopoietic symptoms, is actually often too late occurring during preleukemia states of bad prognosis. We also need to know the exact incidence of secondary leukemia after treatment of breast carcinoma and the real benefit of such treatment.

The authors present 7 cases of preleukemic state and/or acute leukemia following the treatment of a first malignancy (3 malignant lymphomas, 3 epithelial cancers and one polycythemia vera). A preleukemic state was found in all patients. In 6 cases it was followed by an acute non-lymphoblastic leukemia which was rapidly fatal; in one case, death occurred during the preleukemic phase. A karyotype was prepared during the preleukemic phase in 6 out of 7 patients and in 4 out of 6 during the leukemia. Karyotypes prepared during the preleukemic state presented at least one of the abnormalities which are characteristic of secondary hematopoietic disorders: -5/5q; -7/7q; involvement of 17. The same major clone was found in 3 of the 6 patients who were karyotyped during the acute leukemic phase. These karyotype abnormalities are not only characteristic of secondary acute leukemias but also of secondary dysmyelopoietic syndromes.

From 1971 to 1980, 86 patients with polycythaemia (vera 69, undetermined 15 and respiratory 2) were treated with pipobroman (N,N' bis bromopropionyl piperazine). The initial treatment in doses of 75 mg/day resulted, within 45 days, in complete remission in 46/49 new patients (93.9%), and in 17/20 previously treated patients with polycythaemia vera (85%) and in 14/15 patients with apparently primary polycythaemia. The main duration of the first remission was 17.5 months. Relapses occurred in 30% of the cases but responded to pipobroman at the initial high dosage level. Low-dose maintenance treatment appears to be necessary. Adverse effects on the blood were rare; they included leucopenia (8%) and moderate thrombocytopenia (7%); macrocytosis was noted in 20% of the patients. Acute leukaemia (3 cases) and osteomyelofibrosis (3 cases) were only observed in patients previously treated with 32 P or busulfan. Pipobroman therefore appears to be much less toxic than other alkylating agents. Its is as effective as 32 P but acts more rapidly. It seems to have little oncogenic power, but a more prolonged study is required to ascertain this point.

Among 246 patients (49 with Hodgkin's disease, 29 with multiple myeloma, 75 with other lympho- and immunoproliferative syndromes, 70 with carcinomas and 23 with non-malignant affections) treated by cytostatic or immunosuppressive chemotherapy, 6 developed malignant hemopathy (acute myeloblastic leukemia, erythroleukemia and erythremia) apparently induced during the last 7 1/2 years. In addition, 2 carcinomas have been noted. All have received melphalan or chlorambucil, alone or associated with other cytostatic drugs. 5 out of these 6 patients also underwent radiotherapy. The lenght of chemotherapy ranged between 7 and 110 months and the latency between 45 and 110 months. A "preleukemic" cytopenia phase was observed in 4 out of 6 cases. An exceptional 45-month survival was secured in case 1 (acute myeloblastic leukemia in a patient probably cured of Hodgkin's disease IIIB). Observation 2 is the 3rd case ever published of induced acute leukemia in disseminated lupus erythematosus. All these observations are compared with the latest findings in the literature. To the very extent that the utilization of cytostatic drugs produces improvement in the prognosis of very serious diseases, their leukemogenic potential becomes more dangerous and demands limitation of their use.

Three children out of a total of 40 who had been treated with chlorambucil for juvenile rheumatoid arthritis developed acute leukaemia. No malignancy was detected in 160 patients in those treated with steroids and/or other anti-inflammatory drugs. Chlorambucil may have induced the malignancies and its use should be avoided in rheumatoid arthritis.