Thèses sur le sujet « Pregnancy, Cancer, Chemotherapy, Outcome »

BACKGROUND The exact incidence of cancer during gestation is yet to be determined but it is estimated that cancer occurs in 1 in 1000 pregnancies. The most common cancers in pregnancy are those with a peak incidence during the woman‘s reproductive period such as cancer of the breast and cervix, lymphoma, leukemia and melanoma. Cancer during pregnancy is a challenge about assistance and therapy, the aim of therapy in pregnancy is to give optimal treatment to the mother without harm to the fetus. After cancer diagnosis there are following problems such as the difficulty to stage it according usual criteria, the need to planner differentiated treatment, the need to delay or modify treatment in order to preserve the fetus, the risk of teratogenic effects of chemotherapy, the risk of fetal prematurity and so on. The aim of this study was to analyze the pregnancy outcome in a group of patients whit diagnosis of several malignancies during pregnancy. METHODS We retrospectively analyzed 34 patients who have been treated during pregnancy or after delivery because of several malignancies. Cancer was diagnosed at the moment of obstetric visit and all the patients were staged according to standard criteria pregnancy permitting. Serial visits were done by Oncologist and Obstetrician at the same time to take the relationship between pregnant state, cancer and therapeutic choices into account. Chemotherapy, when useful, was started in the second trimester. In all cases were done fetal monitoring and prematurity complications prophylaxis at viability age. Gestational age at delivery was established according to disease state and fetal risk of prematurity. Was avoided the neonatal spinal marrow aplasia attending two weeks from last chemotherapy course. Placental histology was studied in all cases about the presence of cancer cell or chemotherapy effect. RESULTS Surgery during pregnancy was performed in 27% of cases. Chemotherapy during pregnancy was given in 48% of cases. There were not cases of preeclampsia or stillbirth. 73% of patients delivered before 37 weeks of gestation, of them 42% delivered before 34 weeks of gestation in order to begin a therapy not indicated in pregnancy. The incidence of cesarean section was 73%. The incidence of neonates small for gestational age was 12%. There were not cases of congenital malformations. There were not cases of metastatic involvement of placenta. The neonatal outcome evaluated within 1 year from birth was good in all cases. The maternal mortality was 33% between 3-5 years after delivery. CONCLUSIONS Our data are in conformity with the Literature about the possibility to continue the pregnancy when cancer diagnosis. The possibility to receive in pregnancy chemotherapy in selected cases as standard of care is the assumption to have the same survival between the patients that interrupt the pregnancy and who not. According to advancement of perinatal care is possible to do delivery early, treating the patient with the therapy controindicated in pregnancy, without important complications after 32 weeks of gestation. All neonates had good outcome and follow-up, however the prematurity (69% advanced stage vs 25% early stage) was conditioned by cancer stage at the moment of diagnosis. In conclusion, the most important thing is to follow these patients into Specialized Hospital, taking care the cancer and the pregnancy at the same time.

In this work, we found that proliferation-related prognostic gene signatures could aid treatment decision-making independent of age. This is clinically relevant for the younger breast cancer population given the potential long-term side effects of adjuvant systemic chemotherapy and hence the need to identify patients who are less likely to benefit adjuvant chemotherapy. In addition, it was clear that young age at diagnosis adds extra biological complexity, which is independent of differences in breast cancer subtype distribution. This includes enrichment with known breast cancer targets like RANKL. Whilst these results require further validation, either experimentally or in other clinical data sets, it suggests that separate therapeutic approaches may need to be specifically designed in order to improve outcomes for breast cancer arising in young women. In this regard, and based on our results and supportive evidence from other studies, we initiated a proof-of-concept prospective phase II neoadjuvant study investigating the role of denosumab, a RANKL inhibitor on modulating tumor biology in young premenopausal breast cancer patients.

We found that diagnosis during pregnancy does not significantly influence the classic pathological features or the prevalence of breast cancer subtypes. We also did not find obvious differences in the distribution of PIK3CA mutations. However, we found that tumors diagnosed during pregnancy have activated serotonin receptor signaling and high expression of potential breast cancer targets; of particular interest IGF1, and PDL1. Such differences appeared to be reflected in the normal pregnant breast underscoring the potential role of the pregnant breast microenvironment on the tumor transcriptome. We were not able to associate these genes with prognosis, which could be partly due to lack of statistical power. Of note, we cannot confirm whether any of these aberrations are key drivers of the biology of tumors diagnosed during pregnancy. Nevertheless, this remains the first study to look into the biology of this relatively rare disease and hence we believe it would serve as a very valuable resource for future research in this field. We are planning to perform targeted gene sequencing to further refine our understanding of the potential effect of pregnancy on the biology of these tumors.

In the last part of this work addressing the safety of pregnancy following breast cancer diagnosis, we identified that available studies suffered major limitations related to study design including selection bias and lack of information on patients with history of an ER-positive disease. This has resulted in advising against pregnancy in women with prior history of breast cancer. Our subsequent study has robustly addressed most of the limitations in older studies and clearly showed that pregnancy following breast cancer is safe even in women with a history of ER-positive disease. Hence, this study would provide a very important resource for the oncology community, which would aid adequate fertility counseling for young breast cancer survivors. This work is currently serving as the basis for a new prospective study by the IBCSG to test the safety of early interruption of tamoxifen in young women with early breast cancer seeking subsequent pregnancy.

Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

Background: HIV positive patients present a higher risk of cancer compared to the HIV-negative population. Three tumors, namely Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL) and invasive cervical cancer (ICC) occurs with particularly high incidence in HIV-positive patients, and have been classified as AIDS-defining malignancies (ADMs). However, a risk excess is observed for both ADMs and non-AIDS defining malignancies (NADMs). Beside co-infection with oncogenic virus, the pathogenic pathways underlying the development of infection-related and non infection-related cancer in PLWH are sustained by a complex network of interactions between various components of the immune system, with cytokines and other pro-inflammatory agents mediating those interactions. However, these mechanisms have not been fully characterized. Aim: To shed light on this topic, we conducted 3 studies with the following aims: - Natural Killer cell populations in HIV associated lymphoma: Natural Killer (NK, CD56+) cells exert anti-cancer and anti-viral actions and their number and function is impaired during HIV infection. In HIV-negative patients with Hodgkin Lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL), NK cell constitute a higher percentage of circulating lymphocytes and are associated with a better outcome. We aimed to evaluate the NK cell population in HIV-associated lymphomas. - Sex-based differences in factors associated with HPV infection and intraepithelial lesions in a cohort of HIV-positive patients: We aimed to assess the factors associated with HPV infection and with squamous intraepithelial lesions (SILs) in a cohort of HIV-positive patients with focus on gender differences, and possible factors linked with the capability to clear HPV infection, thus influencing the progression of SILs towards cancer. - Association of immune activation markers and CD4/CD8 ratio with the development of virus related and non-virus related cancers in HIV-positive patients: High levels of peripheral T-cells immune activation and low CD4/CD8 ratio in HIV-positive patients have been associated with comorbidities, increased risk of serious events and deaths, despite effective highly active antiretroviral therapy (HAART). Thus, we aimed to assess the association of peripheral immune activation markers (CD8+CD38+ T-lymphocytes) and CD4/CD8 ratio with the onset of infection-related and non-infection related cancers in a cohort of HIV-positive patients virological suppression. We further investigated possible association of CD8+CD38+ T-cells and CD4/CD8 ratio with overall survival of HIV-positive patients with virus-related cancer. Results: Association of immune activation markers and e CD4/CD8 ratio with the development of virus related and non-virus related cancer in HIV-positive patients: We collected clinico-pathologic and treatment data from a prospective series of HIV-positive patients with virus related and non-virus related cancers. We enrolled 140 HIV-positive patients, 115 with virus-related cancer and 25 with non-virus related cancers. We evaluated the association of CD4/CD8 ratio and CD8+CD38+ percentage at the time of first evaluation at our centre with the onset of virus ad non-virus related cancers in uni- and multivariable analyses, in relationship to other HIV-related criteria (CD4+ current and nadir, HIV-RNA, length of HIV infection, cART). Patients with virus-related cancer were more frequently males (p=0.002) and men who have sex with men (MSM) (p=0.003) compared to patients with non-virus related cancers. Further, at the time of cancer diagnosis, patients with virus-related disease were younger (p<0.0001), with a shorter time from HIV-diagnosis (p=0.04)and more frequently naïve to HAART (p=0.009); from an immunological perspective, pre-diagnostic levels of CD8+CD38+ T-cells were higher (p=0.05) and CD4/CD8 ratio was lower (p=0.01) in patients with virus related compared with non-virus related cancer. Natural Killer cell populations in HIV associated lymphoma: Clinical characteristics at lymphoma diagnosis have been prospectively collected at the National Centre for HIV Malignancy at Chelsea & Westminster Hospital, London, since 1986. We reviewed data of 615 HIV-positive patients including 360 lymphomas with full lymphocyte subset analysis at lymphoma diagnosis. The percentage of NK cells was significantly higher in patients with HL (median 9%) than in DLBCL (6%) and other NHL subtypes (p=0.009). The total NK cell count was significantly higher in patients with undetectable HIV-RNA(p<0.0001) but only weakly correlated with CD4 cell count (PearsonsR2 =0.11). For 156 patients with DLBCL, the 5-year OS was 64% (95%CI 56-72%) and in univariate analysis neither total NK-cell population (log rank p=0.14) not NK-cell % (log rank p=0.84) were prognostic variables for OS. In multivariate Cox model the only variable associated with OS was the International Prognostic Index (IPI) (log rank p<0.001). In conclusion, the percentage of NK-cells was reduced in HIV-associated NHL, in contrast with previous reports in HIV-negative patients, and this could contribute to lymphoma development in these patients. The NK-cell population was strongly influenced by effective ARV therapy but only marginally associated with CD4 counts. Nevertheless, NK-cell populations were not predictive of outcome in DLBCL. Sex-based differences in factors associated with HPV infection and intraepithelial lesions in a cohort of HIV-positive patients:We enrolled 472 patients. Anal/cervical brushing samples were collected for HPV-PCR detection/genotyping and cytologic abnormalities at baseline and follow-up visits. Viro-immunological data were recorded at the time of brushing. HPV infection(p<0.001), SIL (p<0.001), HPV persistence (p<0.001) and SIL progression (p=0.018) were all associated with male sex. Among females, HPV was associated with higher HIV-RNA (p=0.002) and SIL was independently associated with lower CD4+ count (AOR: 0.998; 95%CI: 0.997-1). In the males group, HPV was associated with MSM (AOR: 3.801, 95% CI: 1.82-7.95) while AIDS diagnosis (AOR: 0.387 95% CI:0.176-0.851) and older HIV infection (AOR: 0.996 95% CI:0.992-0.999) were negatively associated with HPV infection; males with SIL were younger (AOR 0.973, 95% CI 0.95-0,997), more MSMs (p=0.04) and with higher levels of immune-activation (CD38+CD8+%) (p=0.013) compared to SIL-negative males. In conclusion, the natural history of HPV and SIL is largely influenced by risky behaviors and immune-activation in males, particularly in recently HIV-infected patients, while it appears to be driven by immune-suppression in women. Given the high incidence of HPV infection in both men and women, we suggest that vaccination has to be strongly recommended to all HIV independently form the age and gender.

Thesis (Ph. D.)--University of Sydney, 2009.
Title from title screen (viewed Nov. 3, 2009) Includes tables and questionnaires. Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Public Health, Faculty of Medicine. Includes bibliography. Also available in print form.

PURPOSE: Pregnancy-associated breast cancer (PABC) is one of the most common malignancies during pregnancy (one in 3,000 pregnancies); up to 3% of breast cancers are diagnosed in pregnancy. Our objective is to verify if women with pregnancy-associated breast cancer (PABC) have poorer outcome than nonpregnant women with breast cancer. METHODS: We register in a Cancer and Pregnancy Registry the clinical course, treatment, and disease outcome of nonpregnant women with breast cancer and of women with PABC. In a retrospective control study (2:1) we compared the women with PABC (65 cases) with nonpregnant women with breast cancer (130 cases) matched for age at diagnosis, stage of disease and year of surgery. RESULTS: Of 65 cases diagnosed, 45 was early cancer and 20 was locally advanced or metastatic cancer. The pregnancy ended in a spontaneus miscarriage in 3 patients (5%), and 15 (23%) pregnancy were interrupted. The mean age at diagnosis was 36 ± 4.2 years. Treatment was started during pregnancy in 32 (49%) patients and after delivery in 33 (51%) patients. Of 65 cases, 49 (75%) women received chemotherapy, 52 (80%) women received radiotherapy and 46 (71%) women were diagnosed with an estrogen/progesterone receptors-positve tumor. The mean gestational age at delivery was 35.4 ± 2.1 weeks. Eleven women (17%) are deceased and 21 (32%) progressed with a median follow-up of 48 months. There are no difference between cases and control in term of biological features of cancer and treatment. CONCLUSIONS: The treatment of breast cancer in pregnancy should be executed by experienced specialists in a multidisciplinary setting and should adhere as closely as possible to standard protocols. As more women postpone child bearing until later in life, it is expected that PABC will become increasingly more common. The prognosis in pregnant women with breast cancer is worse than in nonpregnant women.

The description and interpretation of Latinas’ experience with chemotherapyinduced premature menopause from breast cancer treatment were explored in this study, which utilized an interpretive descriptive method from a feminist lens, and Knobf’s (1998, 2002) “Carrying on” theory. The specific aims of the study and the interview questions were guided by the state of the science literature. Overall, the impact of physiological effects, psychosocial effects, barriers, influencing factors that made their experience easier or harder, and how participants adjusted to a cancer diagnosis, treatment course, and menopause transition were described as bigger than the menopause experience alone. Participants also described a period of uncertainty or “ever-changing landscape” that began at the time of diagnosis and continued through survivorship. The impact of information, access to healthcare, acculturation levels, support, and a sense of control were elucidated as important factors in “working through” the experience. A range of collateral data sources were employed. Study limitations and future implications for practice, research, and health policy were demarcated.

Background: Mutation and loss of TP53 function is one of the most frequent genetic abnormalities in ovarian cancer. TP53 genomic and functional status have been shown to provide potentially prognostic and predictive value in ovarian cancer; however, the results are controversial and evaluation in the context of a controlled clinical trial with single agent treatment have been lacking. Reactivation of p53 using MDM2-p53 antagonists is a promising therapeutic target for most patients with type I epithelial ovarian cancer and those left from type II harbouring wild-type TP53. BRCA1/2 mutations are present in 70-85% of germline mutations in patients with inherited ovarian cancer, and deficiencies in homologous recombination repair (HRR) account for up to 50% of epithelial ovarian cancer, indicating the possible sensitivity of ovarian cancer patients to PARP inhibitors. MDM2-p53 antagonists and PARP inhibitors are now undergoing clinical trials as targeted therapy for different types of cancer. The effect of RG7388 on its own and in combination with cisplatin, and combined treatment between MDM2-p53 antagonists and PARP inhibitors have not been investigated in ovarian cancer. Hypotheses: 1) Different genomic and functional status of p53 and some of its downstream targets such as p21WAF1, MDM2 and WIP1 can be used as prognostic and predictive biomarkers for the outcome of chemotherapy and overall survival in ovarian cancer. 2) Reactivation of p53 by inhibition of its negative regulator MDM2, using the MDM2-p53 antagonists Nutlin-3 and RG7388, will result in p53-mediated growth arrest and apoptosis in wild-type TP53 ovarian cancer cells, and combination of them with current therapeutic agents or rucaparib increases growth inhibition and/or apoptosis in ovarian cancer cell lines compared to either agent alone. Methods: TP53 was sequenced in 260 ovarian cancer samples from the ICON3 trial using Sanger sequencing and Next Generation Sequencing (NGS) methods. The prognostic value of the expression levels of p53, p21WAF1, MDM2 and WIP1 was investigated using immunohistochemistry (IHC). The effect of MDM2-p53 antagonists, Nutlin-3/RG7112/RG7388, and PARP inhibitor, rucaparib, as single agents and in combination with cisplatin or together were investigated on a panel of ovarian cancer cell lines. Sensitivity was measured by growth inhibition, clonogenic cell survival assay, apoptosis assays including caspase 3/7 activity and flow cytometry. The effect on the p53 molecular pathway and p53-regulated candidate gene expression were investigated by western blotting and Quantitative Reverse-Transcription Polymerase Chain Reaction (qRT-PCR) respectively. Results: Patients from the ICON3 clinical trial treated with carboplatin whose tumours harbour wild-type TP53 had a significantly better overall survival based on both univariate and multivariate analysis compared to those with mutant TP53 regardless of sequencing method. Adding paclitaxel to the platinum-based treatment showed a trend in favour of greater benefit for those with mutant TP53, although this failed to reach statistical significance (p > 0.05). Overexpression of p53 has potential prognostic value for overall survival of ovarian cancer patients. Ovarian cancer cell lines with wild-type TP53 were sensitive to MDM2-p53 antagonists, Nutlin-3/RG7112/RG7388, while those with mutant TP53 were resistant to MDM2 inhibitors. Among the individual cell lines, A2780 and MDAH-2774 were sensitive and other cell lines (IGROV-1, OAW42, CP70, MLH1-corrected CP70+ and SKOV-3) were resistant to rucaparib regardless of BRCA1/BRCA2 status or deficiencies in HRR reported for these cell lines. Combination of Nutlin-3/RG7388 with cisplatin or rucaparib has synergistic and/or dose reduction potential dependent on cell genotype and the type of MDM2-p53 antagonist. Combined treatments using Nutlin-3/RG7388 and cisplatin led to greater levels of p53 stabilisation and upregulation of p21WAF1 and MDM2, and higher expression of p21WAF1 was associated with a greater synergistic effect for growth inhibition. In combination treatment with rucaparib and Nutlin-3/RG7388, rucaparib showed no increase in the effect of MDM2 inhibitors on the p53 pathway, indicating that the mechanism of observed synergy does not involve enhancement of p53 pathway activation by MDM2 inhibitors. Nutlin-3/RG7388 in combination with cisplatin or rucaparib resulted in changes in cell cycle distribution, SubG1 events and caspase 3/7 activity in a cell type, time and compound-dependent manner. The fold changes in expression of candidate genes in response to MDM2 inhibitors were less in A2780 cells than IGROV-1 and OAW42. The balance of activity between growth inhibitory/pro-survival and pro-apoptotic genes dominates a small increase in the expression of several DNA repair genes as an explanation for the synergy observed for treatment with cisplatin and MDM2 inhibitors. Conclusions: The genomic and functional status of TP53 have potentially important prognostic and predictive values in ovarian cancer. Targeting the interaction between MDM2 and p53 using MDM2-p53 antagonists is a promising therapeutic strategy for ovarian cancer patients with wild-type TP53 tumours, and combination treatment with them and cisplatin or rucaparib.

Acute lymphoblastic leukemia (ALL) has poor prognosis in older/elderly adults and in high-risk/relapsed disease. Recommended treatment of ALL was evaluated (study I-IV). Data was obtained from the Swedish Acute Leukemia registries and from patient records. I. We assessed ALL relapse treatment and outcome in 76 patients aged 15-65 years (y). Complete remission (CR) was achieved in 50/71 patients (70%). Of them, 29 underwent allogeneic hematopoietic stem cell transplantation (hSCT). Five year overall survival (OS) was 15%, but close to 50% in 19 patients <35y after hSCT. II. We studied outcome of treatment with the Hyper-CVAD protocol in 19 of 24 patients with T-ALL aged 18-72y. CR was reached in 89%, but 5y leukemia-free survival was only 29%, and 20% in 15 patients not transplanted in CR1. Six patients received hSCT in CR2. Finally, 5y OS in all 19 patients was 47%. The only negative prognostic factor found was age ≥35y. III. We evaluated minimal residual disease (MRD) monitoring in 35 patients with Philadelphia (Ph) negative B-ALL aged 46-79y and treated with the ABCDV protocol. The CR rate was 91%. MRD was measured by flow cytometry in 73% in CR1 (MRD1) and omitted in those >70y or with high-risk ALL. Five patients received hSCT (only one due to MRD). Five year OS in the whole cohort was 47%. Continuous CR but not OS was improved in patients with MRD1 <0.1 %. IV. We studied 155 patients with ALL (Ph+ in 35%) aged 55-85y and treated with remission induction/palliation (124/31). Both, intensive, and palliative treatment resulted in the CR rates of 70/83/16% and 3y OS of 26/32/3%. OS was negatively influenced by age and platelet count ≤35×109/L (but not Ph+). OS was not enhanced by introduction of an age-adapted protocol. We concluded that intensive treatment with subsequent allogeneic hSCT is the most reasonable option in younger patients with ALL recurrence (I). Hyper-CVAD has low relapse-preventing efficacy (II). MRD guided intensification is probably feasible in only a minority of older patients (III). Prognosis in elderly ALL is poor, but no longer impaired by Ph+ (IV).

Besides exerting cytostatic or cytotoxic effects on tumor cells, some anti-cancer therapies (anthracyclines, oxaliplatin, X-Rays) could trigger an immunogenic cell death modality, releasing danger signals to alert immune system. We have shown that tumor-specific IFN- producing CD8+ T cells (Tc1) are mandatory for the success of chemotherapy to prevent tumor outgrowth. Priming of Tc1 response depends on IL-1β secretion by DC confronted with anthracycline-treated tumor cells releasing ATP. To identify the inflammatory components which link innate and cognate immune responses, we analyzed the influence of immunogenic chemotherapy on tumor microenvironment. We found an upregulated Th1- and Th17-related gene expression pattern in growth-retarded tumor after anthracycline treatment. By interfering with IFN- or IL-17A pathways, therapeutic effect of doxorubicin and oxaliplatin was abolished and dying tumor cell-based vaccine lost its efficacy to protect mice from live tumor cell rechallenge. Interestingly, we discovered that distinct subsets of  T lymphocytes (V4+ and V6+) colonized tumors shortly after chemotherapy, where they proliferated and became the dominant IL-17 producers within tumor beds. In three tumor models treated with chemotherapy or radiotherapy, a strong correlation between the presence of IL-17-producing  T ( T17) and IFN--producing CD8+ TIL (Tc1) was discovered. IL-17A signaling acts as upstream of IFN- since defect in IL-17RA led to complete loss of antigen specific Tc1 priming. The contribution of  T17 cells (V4+ and V6+) to chemotherapy is critical as V4/6-/- mice showed reduced sensitivity to chemotherapy and vaccination. Also, tumor infiltrating  T17 and Tc1 cells were reduced to basal level in this strain. IL-1β/IL-1R, but not IL-23/IL-23R, is pivotal for IL-17 production by  T cells and the success of chemotherapy. Importantly, adoptive transfer of  T cells could restore the efficacy of chemotherapy in IL-17A-/- mice and ameliorate the effect of chemotherapy in wild type host, provided that they retain the expression of IL-1R and IL-17A. Our research suggest a DC (IL-1β) →  T cells (IL-17) → Tc1 (IFN-) immune axis triggered by chemotherapy-induced dying tumor cells, which is critical for the favorable therapeutic response. To boost the immune system, we try to combine immunogenic chemotherapy with tumor vaccine in the presence of TLR3 agonist Poly (A:U). This sequential combined therapy, which we named VCT, could significantly retard tumor growth or even completely eradicate tumor and establish long-term protection against rechallenge in highly tumorigenic models. To dissect the effect of Poly (A:U) on immune system and that on TLR3 expressing-tumor cells, we performed VCT treatment in nude mice, TRIF-/- mice and with TRIF-silencing tumors. Interestingly, our results suggested that anti-tumor effect of VCT required T cells and intact TRIF signaling pathway at the level of the host and that of tumor cells. Poly (A:U) treatment could induce high level of CCL5 and CXCL10 production from tumor cells both in vitro and in vivo, which could negatively and positively influence the therapeutic outcome. By uncoupling the effect of CCL5 from that of CXCL10, the VCT treatment can be ameliorated. Our study emphasizes that both tumor and host derived inflammatory factors participate in regulating anti-tumor response. We also highlight that therapeutic application of TLR agonists can be optimized through regulating the profile of chemokines and their downstream signaling events.

Previously, peritoneal metastases(PM) from colorectal cancer(CRC) have been considered a terminal and generalised form of cancer. A new treatment strategy combining cytoreductive surgery(CRS) and intraperitoneal chemotherapy(IPC) has recently shown promising results. The aim of this thesis was to investigate different aspects of this treatment in order to optimise the treatment and to clarify its potential as a new treatment option. Treatment outcome, patient selection, method of IPC (hyperthermic intraperitoneal chemotherapy-HIPEC vs. sequential postoperative intraperitoneal chemotherapy-SPIC) and choice of drugs for IPC were the aspects covered in this thesis. The treatment outcome of CRS and IPC according to the median overall survival ranged from 24 to 34 months with 5-year overall survival ranging from 20 to 40% depending on the IPC treatment administered. Furthermore, the 5-year disease-free survival was impressive at 32% for patients receiving HIPEC. This establishes the curative potential of this treatment. Due to current inadequacies of radiological imaging, a score (Corep score) was developed for patient selection purposes. This score had a sensitivity of 80% and specificity of 100% in identifying patients with short cancer-specific survival after the treatment (<12 months). Further studies are needed to elucidate the clinical usefulness of the Corep score. HIPEC was associated with better survival than the SPIC method at similar morbidity and mortality rates, suggesting that HIPEC be the method of preference. Concerning the choice of drugs, the last study investigated the chemo-sensitivity of different PM tumour-types with a special focus on CRC. While CRC samples were generally more resistant, the ratio of the in vivo concentration compared to the ex vivo concentration giving a 50% tumour cell death showed that oxaliplatin had the best profile across all PM tumour types as well as for CRC. This needs further confirmation in a clinical trial.

Background: Omega-3 polyunsaturated fatty acids (PUFAs) have reported anti-cancer effects. Few studies have assessed oesophago-gastric cancer, either in vitro or in vivo. Aims: To evaluate whether addition of omega-3 PUFAs (Omegaven) to palliative chemotherapy would influence the clinical and biochemical outcome of patients with oesophago-gastric cancer, and to assess the response of oesophageal adenocarcinoma cell lines to omega-3 PUFAs compared to oxaliplatin. Methods: Participants in a phase II trial received palliative chemotherapy and Omegaven infusion. Clinical and radiological outcome were assessed. Comparison was made to historical patients who received chemotherapy alone. Serum cytokine concentrations and uptake of PUFAs in plasma and red cell membrane were assessed in trial patients. The in vitro response of cell lines to omega-3 PUFAs or oxaliplatin were evaluated. Results: Participants who received chemotherapy and Omegaven had a higher radiological response rate than those who received chemotherapy alone ((overall response: 73% (95% CI 51 to 95) vs 43% (95% CI 25 to 61), p=0.05; partial response 73% (95% CI 51 to 95) vs 39% (95% CI 21 to 57), p=0.03)). . Grade 3/4 toxicity was observed less frequently in those who received Omegaven (thromboembolism, gastrointestinal side-effects). This translated into fewer hospital admissions. There were significant reductions in the concentrations of TNF-α (p < 0.0001, 95% CI -0.0121 to -0.0046) & VEGF (p=0.002, 95% CI -0.0161 to -0.0034) following each treatment. Participants with low baseline IL-6 & TNF-α expression had a superior survival. Each infusion of Omegaven resulted in a short lived increase in plasma EPA and DHA. The serial infusions of Omegaven caused a sustained increase in the EPA content of the red cell membrane. DHA, EPA and oxaliplatin had an anti-proliferative effect on the oesophageal cancer cell lines at all concentrations. Omegaven had a more concentration dependent anti-proliferative effect. Reduction in VEGF expression was the most consistently observed cytokine effect. The anti-proliferative effect was associated with reduction in anti-apoptotic protein and an increase in pro-apoptotic protein. Conclusions: Infusion of omega-3 PUFAs resulted in a more favourable chemotherapy side-effect profile and an improved radiological response rate. Treatment resulted in a reduction in serum pro-inflammatory cytokines. Repeated Omegaven infusion resulted in a gradual and sustained uptake of EPA in the red cell membrane. The anti-proliferative effect of omega-3 PUFAs on oesophageal cancer was demonstrated in vitro.

En dehors des effets cytostatiques ou cytotoxiques sur les cellules tumorales, certaines thérapies anti-cancéreuses peuvent déclencher la mort cellulaire immunogénique, libérant les signaux de danger pour alerter le système immunitaire. Les cellules T CD8+ T (Tc1) productrices d’IFN- et spécifiques de la tumeur sont nécessaires pour le succès de la chimiothérapie et la diminution de la croissance tumorale. L’amorçage d’une réponse bénéfique Tc1 dépend de la sécrétion d'IL-1β par les cellules dendritiques confrontées à des cellules tumorales traitées avec de l’anthracycline libérant de l’ATP. Pour identifier les composants inflammatoires qui lient les réponses immunitaires innées et adaptatives, nous avons analysé l'influence de la chimiothérapie immunogène sur le microenvironnement de la tumeur. Nous avons identifié une up-régulation de gènes associés à la réponse Th1 et Th17 dans un modèle de tumeur répondant au traitement par les anthracyclines par un retard de croissance. En interférant avec les voies IFN- ou l'IL-17A, l'effet thérapeutique de la doxorubicine et l'oxaliplatine a été aboli et le vaccin à base de cellules tumorales mortes ne protège plus les souris de la réintroduction de cellules tumorales vivantes. Nous avons également découvert que des sous-populations distinctes de lymphocytes T  (V4+ et V6+) colonisent des tumeurs peu de temps après la chimiothérapie, où ils ont proliféré et sont devenus producteurs majeurs de l’IL-17 au sein de la tumeur. Nous avons constaté une forte corrélation entre la présence de lymphocytes T  producteurs d’IL-17 ( T17) et de TIL CD8+ (Tc1) dans trois modèles différents de tumeurs traitées par la chimiothérapie ou la radiothérapie. IL-17A agit sur la signalisation en amont de l'IFN- puisqu’un défaut d’expression d’IL-17RA conduit à la perte complète de la production des Tc1 spécifiques de l’antigène. La contribution des cellules  T17 (V4+ et V6+) dans l’effet bénéfique de la chimiothérapie est essentielle puisque les souris V4/6-/-. L’axe IL-1β/IL-1R, mais pas IL-23/IL-23R, est essentielle pour la production d'IL-17 par les cellules T et l’effet bénéfique de la chimiothérapie. Le transfert adoptif de lymphocytes  T peut rétablir l'efficacité de la chimiothérapie dans le modèle de souris IL-17A-/- et améliorer l'effet de la chimiothérapie chez la souris wt, s'ils conservent l'expression de l'IL-1R et de l'IL-17A. Nos résultats suggèrent l’existence d’un axe fonctionnel: DC (IL-1β) → cellules T (IL-17) → Tc1 (IFN-), déclenché par la chimiothérapie induisant la mort des cellules tumorales, phénomène essentiel pour une réponse thérapeutique favorable. Pour renforcer la réponse immunitaire, nous essayons de combiner la chimiothérapie « immunogène » avec le vaccin anti-tumoral en présence d’adjuvants (poly (A:U), l'agoniste de TLR3).Ce type de thérapie séquentielle combinée, appelé VCT, pourrait retarder considérablement la croissance des tumeurs, voire l’éradiquer complètement et établir une protection spécifique à long terme. Pour décortiquer l'effet de la poly (A:U) sur le système immunitaire et sur les cellules tumorales exprimant le TLR3, nous avons effectué un traitement VCT chez la souris nude, TRIF-/- et les souris présentant une diminution de l’expression de TRIF au niveau des cellules tumorales. Ainsi l'effet anti-tumoral de VCT requiert les lymphocytes T et la voie de signalisation TRIF intacte au niveau de l'hôte et des cellules tumorales. Le traitement poly (A:U) peut induire un niveau élevé de production de certaines chimiokines associées à la réponse de type Th1 (CCL5 et CXCL10 ) par les cellules tumorales in vitro et in vivo, ce qui peut influencer négativement et positivement les résultats thérapeutiques. Le découplage de l’action de CCL5 et de XCL10, pourrait améliorer le traitement par la VCT. Notre étude souligne ainsi le rôle des facteurs inflammatoires dérivés de la tumeur et de l’hôte dans la régulation de la réponse immunitaire anti-tumorale
Besides exerting cytostatic or cytotoxic effects on tumor cells, some anti-cancer therapies (anthracyclines, oxaliplatin, X-Rays) could trigger an immunogenic cell death modality, releasing danger signals to alert immune system. We have shown that tumor-specific IFN- producing CD8+ T cells (Tc1) are mandatory for the success of chemotherapy to prevent tumor outgrowth. Priming of Tc1 response depends on IL-1β secretion by DC confronted with anthracycline-treated tumor cells releasing ATP. To identify the inflammatory components which link innate and cognate immune responses, we analyzed the influence of immunogenic chemotherapy on tumor microenvironment. We found an upregulated Th1- and Th17-related gene expression pattern in growth-retarded tumor after anthracycline treatment. By interfering with IFN- or IL-17A pathways, therapeutic effect of doxorubicin and oxaliplatin was abolished and dying tumor cell-based vaccine lost its efficacy to protect mice from live tumor cell rechallenge. Interestingly, we discovered that distinct subsets of  T lymphocytes (V4+ and V6+) colonized tumors shortly after chemotherapy, where they proliferated and became the dominant IL-17 producers within tumor beds. In three tumor models treated with chemotherapy or radiotherapy, a strong correlation between the presence of IL-17-producing  T ( T17) and IFN--producing CD8+ TIL (Tc1) was discovered. IL-17A signaling acts as upstream of IFN- since defect in IL-17RA led to complete loss of antigen specific Tc1 priming. The contribution of  T17 cells (V4+ and V6+) to chemotherapy is critical as V4/6-/- mice showed reduced sensitivity to chemotherapy and vaccination. Also, tumor infiltrating  T17 and Tc1 cells were reduced to basal level in this strain. IL-1β/IL-1R, but not IL-23/IL-23R, is pivotal for IL-17 production by  T cells and the success of chemotherapy. Importantly, adoptive transfer of  T cells could restore the efficacy of chemotherapy in IL-17A-/- mice and ameliorate the effect of chemotherapy in wild type host, provided that they retain the expression of IL-1R and IL-17A. Our research suggest a DC (IL-1β) →  T cells (IL-17) → Tc1 (IFN-) immune axis triggered by chemotherapy-induced dying tumor cells, which is critical for the favorable therapeutic response. To boost the immune system, we try to combine immunogenic chemotherapy with tumor vaccine in the presence of TLR3 agonist Poly (A:U). This sequential combined therapy, which we named VCT, could significantly retard tumor growth or even completely eradicate tumor and establish long-term protection against rechallenge in highly tumorigenic models. To dissect the effect of Poly (A:U) on immune system and that on TLR3 expressing-tumor cells, we performed VCT treatment in nude mice, TRIF-/- mice and with TRIF-silencing tumors. Interestingly, our results suggested that anti-tumor effect of VCT required T cells and intact TRIF signaling pathway at the level of the host and that of tumor cells. Poly (A:U) treatment could induce high level of CCL5 and CXCL10 production from tumor cells both in vitro and in vivo, which could negatively and positively influence the therapeutic outcome. By uncoupling the effect of CCL5 from that of CXCL10, the VCT treatment can be ameliorated. Our study emphasizes that both tumor and host derived inflammatory factors participate in regulating anti-tumor response. We also highlight that therapeutic application of TLR agonists can be optimized through regulating the profile of chemokines and their downstream signaling events

La chimiothérapie néoadjuvante (CNA) est utilisée dans les cancers du sein agressifs ou localement avancés (CS). Au delà des bénéfices cliniques, elle représente une opportunité pour monitorer in vivo la sensibilité d’une tumeur à un traitement.A partir de l’analyse de sets de données de patients traités par CNA, nous souhaitons identifier des mécanismes associes à la résistance ou sensibilité au traitement. Dans la première partie, nous avons évalué des paramètres, cliniques, anatomopathologiques et transcriptomiques. Nous avons démontré que des éléments non explorés comme la présence d’embols après CNA revêtaient une information pronostique importante. Dans une 2ème partie, nous avons analysé l’impact de l’infiltrat immunitaire dans le cancer du sein, et avons décrit les changements observés entre des échantillons avant et après CNA. Nous avons montré que l’impact pronostique des TILs était différent avant et après CNA, et était opposé dans les CS triple négatif ou HER2-positif. Finalement, nous avons analysé l’impact des comédications pendant la CNA. Nous avons trouvé des effets positifs – via l’augmentation de l’infiltrat immunitaire et la réponse au traitement – et des effets négatifs avec des effets délétères dans certains sous groupes de patients. En conclusion, la situation néoadjuvante représente une plateforme pour générer et potentiellement valider des hypothèses de recherche. La mise à disposition de jeux de données de patients traités par chimiothérapie néoadjuvante constituerait une ressource majeure pour accélérer la recherche contre le cancer du sein
Neoadjuvant chemotherapy (NAC i.e. chemotherapy before surgery) is increasingly being used for aggressive or locally advanced breast cancer (BCs). Beyond clinical benefits, it represents an opportunity to monitor in vivo sensitivity to treatment. Based on the analysis of datasets of BCs patients treated with NAC, we aimed at identifying mechanisms associated with resistance or sensitivity to treatment.In the first part, we evaluated biological, clinical, pathological and transcriptomic patterns. We demonstrated that unexplored pathological features such as post-NAC lymphovascular invasion may carried an important prognostic information.In a second part, we analyzed impact of imune infiltration in BC and we described extensively the changes of tumor infiltrating lymphocytes (TILs) between pre and post-NAC samples. We showed that the prognostic impact of TILs was different before and after NAC, and was opposite in TNBC and HER2-positive BCs. Finally, we investigated the impact of comedications use during NAC. We found both positive effects - while enhancing immune infiltration and response to treatment - and negative effects with deleterisous oncologic outcomes in specific patients subgroups. In conclusion, the neoadjuvant setting represents a platform to both generate and potentially validate research hypotheses aiming at increasing the efficacy of treatment. The public release of real-life datasets of BC patients treated with NAC would represent a major resource to accelerate BC research

碩士
高雄醫學大學
藥學研究所碩士在職專班
101
Objective:Lung cancer is the leading cause of cancer mortality in the world. Majority of lung cancer death is mainly due to being diagnosed at an advanced stage, and hence, one cannot apply effective treatment to improve the survival rate of patients. The preferred treatment approach for advanced lung cancer patients is, a single chemotherapy drugs. The purpose of this study is to explore the association of chemical drugs and survival rates of lung cancer patients. Methods:The study adopts a retrospective cohort study design based on the National Health Insurance Research Database (NHIRD) from 2002 to 2011. Medical records of newly diagnosed lung cancer (ICD-9-CM 162.0-162.9) patients from 2003-2010 were extracted. Demographic characteristics, comorbidities, treatment patterns, and pattern of chemotherapy were analyzed. The total medical utilization was evaluated using descriptive statistics which incorporates sex, age and single agent therapy. Kaplan-Meier estimates were used to construct survival curves, and Cox proportional hazard model was used to evaluate hazard ratios. Results:There were 55,136 newly diagnosed lung cancer patients during 2003-2010 identified from NHIRD. Among them, 1,964 patients were treated by single therapy. There were 1,419 (72.3%) males and, 545 (27.7%) females. The average age was 71.1(?b10.4) years old. Treatment patterns are received chemotherapy only based. Chemotherapy prescriptions were divided into three groups, 375 patients in docetaxel, 1253 patients in gemcitabine, and 336 patients in vinorelbine group. Using vinorelbine group has higher average of survival time 31.4 (23.6-39.1) weeks than other groups. Elderly patients had a longer survival time than younger patients. Median and 1-year survival were 16.8 weeks and 34% in docetaxel group, 21.1 weeks and 31% in gemcitabine group, and 31.4 weeks and 37% in vinorelbine group. Conclusion:The study found that gender, age, treatment, and chemotherapy regimens are significant factors for the survival of NSCLC patients. Vinorelbine of three chemotherapy regimens offered a significant advantage over the others in the treatment of advanced lung cancer.