Stefano Kim | University hospital of Besançon, Fr (original) (raw)
Papers by Stefano Kim
Clinical Medicine Insights. Oncology, 2013
Prostate cancer (PC) is one of the most common cancers and is a leading cause of death. Its initi... more Prostate cancer (PC) is one of the most common cancers and is a leading cause of death. Its initial growth is dependent on androgens; most patients show an initial response to hormonal therapy but will experience disease progression when PC becomes resistant to castration. In 2004, two key randomized controlled trials demonstrated a benefit for docetaxel-based regimens in the treatment of men with castration-resistant prostate cancer (CRPC). Cabazitaxel (XRP6258, TXD258, and RPR116258A), a tubulin-binding taxane drug as potent as docetaxel in cell lines, was the first treatment able to prolong survival for metastatic CRPC in the post-docetaxel setting. This review describes pharmacologic parameters of this agent followed by a review of clinical trials involving cabazitaxel. Other available treatments and the place of cabazitaxel in metastatic CRPC setting are discussed.
Journal of Hepatology, 2013
Hepatic epithelioid hemangioendothelioma is a rare liver mesenchymatous tumor with an epithelial ... more Hepatic epithelioid hemangioendothelioma is a rare liver mesenchymatous tumor with an epithelial aspect developed from endothelial cells with a lack of validated therapeutic options at metastatic stage. Metronomic chemotherapy has been described as an anti-angiogenic therapy leading to the depletion of circulating endothelial progenitors. We report the results of two patients treated for metastatic hemangioendothelioma with metronomic cyclophosphamide chemotherapy. Following initiation of metronomic cyclophosphamide chemotherapy (50 mg once a day continuously), the two patients exhibited significant clinical improvement and decrease in metastasis size without any clinically relevant side-effect. Metronomic cyclophosphamide could be proposed as a new therapeutic option to treat metastatic hepatic epithelioid hemangioendothelioma. Ó
Revue des Maladies Respiratoires, 2013
Lung cancer in nonsmoker: A separate entity Nous avons vécu cette dernière décennie de notables p... more Lung cancer in nonsmoker: A separate entity Nous avons vécu cette dernière décennie de notables progrès dans la prise en charge du cancer bronchopulmonaire. Ceux-ci sont issus en particulier d'une meilleure compréhension de la biologie, avec des conséquences thérapeutiques aboutissant à des traitements plus personnalisés qui nous ont permis de passer d'une monotonie léthargique à une stratégie innovante, basée non seulement sur l'histologie mais également sur des caractéristiques moléculaires. Ces progrès nous ont montré qu'il n'existe pas « un » mais « des » cancers du poumon. C'est ainsi que le cancer bronchopulmonaire du non-fumeur (CBNF) s'est imposé comme une entité à part, avec ses spécificités épidémiologiques, biologiques, cliniques et thérapeutiques .
Emerging Infectious Diseases, 2003
Clinical Medicine Insights: Oncology, 2015
Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignanc... more Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignancies both in the adjuvant and metastatic setting. Although myelosuppression is the most adverse event of this therapy, gemcitabine might induce severe pulmonary toxicities. We describe a case of pulmonary veno-occlusive disease (PVOD) related to gemcitabine. The patient was an 83-year-old man with a metastatic pancreatic cancer who was treated by gemcitabine as first-line therapy. He was in good health and received no other chemotherapy. A dose of 1000 mg/m(2) of gemcitabine was administered over a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. After a period of 6 months, a complete response was observed. Nevertheless, the patient developed a severe dyspnea, with arterial hypoxemia and very low lung diffusion for carbon monoxide. A CT scan showed diffuse ground glass opacities with septal lines, bilateral pleural effusion, and lymph node enlargement. On echocardiography, there was a suspicion of pulmonary hypertension with elevated systolic pulmonary artery pressure and normal left ventricular pressures. Right heart catheterization confirmed pulmonary hypertension and normal pulmonary artery occlusion pressure. Diagnosis of PVOD was made, and a gemcitabine-induced toxicity was suspected. A symptomatic treatment was started. At last follow-up, patient was in functional class I with near-normal of CT scan, arterial blood gases, and echocardiography. A gemcitabine-induced PVOD is the more likely diagnosis.
Références en gynécologie obstétrique
tion to conventional cancer therapy. The main knowledge drawn by these preliminary results might ... more tion to conventional cancer therapy. The main knowledge drawn by these preliminary results might be the potential of a new-targeted therapy directed towards metabolic pathways to promote the outcome of conventional cancer treatments.
Journal of Cancer Therapy, 2013
Background: metronomic chemotherapy is based on antiangiogenic and immunologic mechanisms obtaine... more Background: metronomic chemotherapy is based on antiangiogenic and immunologic mechanisms obtained by the administration of traditional cytotoxic drugs at lower concentration without rest periods. The low dosage induces fewer or no side effect compared to classic maximum tolerated dose administration (MTD). At present, no treatment related acute leukaemia was reported in cyclophosphamide-based metronomic chemotherapy (CMC). Case: We report the case of an 81-year-old man considered as having castration and chemo-refractory metastatic prostate cancer. CMC was started. Objective response was observed in this heavily pre-treated patient with progression free survival lasting more than 30 months. No toxicity was observed in this period and his autonomy was maintained. Finally, our patient developed a chemotherapy-induced acute myeloid leukaemia at 36th month of CMC. Conclusion: Even CMC is a well-tolerated treatment; secondary acute leukaemia is related to cumulative dose of cyclophosphamide. The benefit and the risk of long-term exposure to cyclophosphamide should be carefully balanced.
Bulletin du cancer, 2012
Castration resistant prostate cancer occurs when patients experience disease progression despite ... more Castration resistant prostate cancer occurs when patients experience disease progression despite appropriate hormonal manipulations. In these patients, chemotherapy remains standard treatment. Preclinical and clinical data have demonstrated the potential utility of an immunotherapy-based approach for the treatment of prostate cancer (PC). The phase III trial (IMPACT) has recently reported an advantage for Sipuleucel-T over placebo, with an overall survival 4.1 months superior to placebo. Sipuleucel-T is also the first FDA-approved immunotherapy for prostate cancer. These promising results need to be confirmed with other large studies and within previous step of PC. Neoplasic cells can escape immune responses by multiple mechanisms. A better knowledge of these mechanisms is of major concern for the future development of new immunotherapies approach.
Annals of Oncology, 2013
Background: Squamous cell carcinoma of the anal canal (SCCA) is a rare disease, mostly diagnosed ... more Background: Squamous cell carcinoma of the anal canal (SCCA) is a rare disease, mostly diagnosed at early stage.
The American journal of case reports, 2015
BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompa... more BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompanied by a delayed histopathological diagnosis, primarily due to submucosal disease. A concentric ring pattern or "target sign" on T2-weighted magnetic resonance imaging (MRI) has been proposed as being characteristic for early suspicion. Even though RLP is more aggressive and has poorer survival than other rectal adenocarcinomas, no specific treatment is recommended. In this case report of 3 patients, we challenge the sensitivity of the characteristic radiological pattern, and we review the existing data for a treatment strategy. CASE REPORT One patient presented classic clinical characteristics of RLP with young age and advanced stage at diagnosis, with chemo-refractory disease and rapid fatal evolution. Biopsies confirmed the RLP with the presence of signet-ring cells (SRC) in a strong desmoplastic stromal reaction. However, the characteristic concentric ring pattern was abse...
Bulletin du cancer, Jan 29, 2015
Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 a... more Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy...
Cancer Epidemiology Biomarkers & Prevention, 2015
Background: Baseline prognostic biomarkers stratifying treatment strategies in first-line metasta... more Background: Baseline prognostic biomarkers stratifying treatment strategies in first-line metastatic colorectal cancer (mCRC) are lacking. Angiopoietin-2 (Ang-2) is proposed as a potential biomarker in several cancers. We therefore decided to establish the additional prognostic value of Ang-2 for overall survival (OS) in patients with first-line mCRC.
Cancer Chemotherapy and Pharmacology, 2014
Perioperative chemotherapy improves the overall survival of resectable gastroesophageal adenocarc... more Perioperative chemotherapy improves the overall survival of resectable gastroesophageal adenocarcinoma (GEA) patients. However, more than 40 % of the patients are not healthy enough to complete their post-operative chemotherapy, and the progression-free survival rate is lower than 35 % at 5 years. In order to optimise neoadjuvant chemotherapy regimen, a pilot study of weekly dose-intensified cisplatin, epirubicin, and paclitaxel (PET) was conducted. The primary objective was a complete resection (R0) rate. Then, a R0 rate ≤80 % was considered as uninteresting, with an expected R0 rate of 92 %. Secondary objectives were the feasibility, safety, histological response rate (Becker score), and survival (Trial registration: NCT01830270). Patients with >T1N0M0 GEA were included. Treatment consisted of eight preoperative cycles of weekly PET regimen at 30/50/80 mg/m² of cisplatin, epirubicin, and paclitaxel, respectively. Primary prophylaxis by granulocyte colony-stimulating factor was administered. Surgery was performed 4-6 weeks following the last cycle of chemotherapy. Using Fleming two-step design with a unilateral alpha type one error of 5 % and a statistical power of 80 %, it would be required to include 68 patients. At planned interim analysis for futility, it was required to observe at least 25 of 29 patients with R0 resection to pursue inclusion. At the second step, it was required to observe at least 61 of 68 patients with R0 resection to conclude for promising activity of the dose-intensified chemotherapy. Between May 2011 and January 2013, 29 patients were enrolled. Median age was 62 years (range 39-83 years), and seven (24 %) patients presented signet-ring cell histology. Twenty-seven (93 %) patients underwent surgery. Pathological complete responses (Becker score 1a) were observed in four patients, and nearly complete responses (Becker score 1b) for additional three patients. A R0 rate was achieved for 24 of 29 (82.7 %; 95 % CI 64-94 %) patients. No Becker score 1a/1b response was observed among patients with signet-ring cell GEA. Twenty-one (72 %) patients completed all eight cycles, and 86 % received seven or more cycles. Sixteen (56 %) patients experienced grade 3-4 neutropenia, and five patients had febrile neutropenia. Among non-haematological toxicities, mucositis and fatigue were the most frequent ones. The median-delivered relative dose intensity (DI) was 80 % for cisplatin, 75 % for epirubicin, and 79 % for paclitaxel. However, only 45 % of the patients received at least 80 % of the planned median DI for all three drugs. Despite high R0 and pathological response rates, neoadjuvant PET chemotherapy did not meet the primary end-point and failed to show an acceptable relative DI. PET chemotherapy is not recommended in resectable GEA patients.
Revue Francophone des Laboratoires, 2014
ABSTRACT Numerous chemotherapies have been developed to treat cancers. Now, it is becoming clear ... more ABSTRACT Numerous chemotherapies have been developed to treat cancers. Now, it is becoming clear that cytotoxic agents not only have a direct effect on cancer cell death, but can also elicit tumour-specific immune responses. We recently showed that 8 patients treated with DCF for squamous cell carcinoma of the anal canal (SCCA) presented an overall survival rate of 62.5 % at 12 months. Half of the patients, with HPV16 positive SCCA, achieved a complete remission. To attempt to understand why such a good clinical response was obtained, we aimed to determine whether DCF regimen could increase antigenicity and immunogenicity in in vitro and in vivo models of HPV16 cancers. C57BL/6 mice were grafted subcutaneously with 3×105 TC1 cells (primary lung epithelial cells of C57BL/6 immortalized with E6 and E7 of HPV16 and transformed with c-Ha-ras). When the tumour size reached 100 mm2, mice were treated either with DCF or CF. The tumours were measured for 15 days and the number of Treg (CD4+ CD25+ FoxP3+) and Myeloid-Derived Suppressor Cells (MDSC, Gr1+, CD11b+) were assessed in the spleen after the sacrifice of the mice. Tumour specific immune responses against E7 and mTERT were analyzed by IFNg ELISPOT. In parallel in vitro studies were conducted with TC1 cells treated by DCF, CF or D. The analysis of calreticulin expression by flow cytometry, and the release of ATP and HMGB1 in the supernatant of treated cells were conducted to highlight the induction of an immunogenic cell death (ICD). The DCF regimen showed the best antitumor effect in TC1 grafted mice compared with CF. Furthermore a lower level of Treg and MDSC was observed in the spleen of mice treated with DCF compared to CF. Reduction of tumour size was linked to the induction of specific anti-E7 and anti-mTERT immune responses. As for the in vitro assessment of ICD, DCF increased the membrane expression of calreticulin and the release of HMGB1. As a whole our preliminary data indicate that the clinical response observed with DCF may be due to efficient modulation of tumour-specific immune responses by (i) inducing in mice a less immunosuppressive environment compared to CF, (ii) promoting the optimal release and presentation of tumour antigens through the induction of immunogenic cell death.
The American journal of case reports, 2015
BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompa... more BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompanied by a delayed histopathological diagnosis, primarily due to submucosal disease. A concentric ring pattern or "target sign" on T2-weighted magnetic resonance imaging (MRI) has been proposed as being characteristic for early suspicion. Even though RLP is more aggressive and has poorer survival than other rectal adenocarcinomas, no specific treatment is recommended. In this case report of 3 patients, we challenge the sensitivity of the characteristic radiological pattern, and we review the existing data for a treatment strategy. CASE REPORT One patient presented classic clinical characteristics of RLP with young age and advanced stage at diagnosis, with chemo-refractory disease and rapid fatal evolution. Biopsies confirmed the RLP with the presence of signet-ring cells (SRC) in a strong desmoplastic stromal reaction. However, the characteristic concentric ring pattern was abse...
Radiotherapy and Oncology, 2015
To retrospectively analyze the efficacy of 36Gy of elective node irradiation and report patterns ... more To retrospectively analyze the efficacy of 36Gy of elective node irradiation and report patterns of recurrence in patients with anal cancer treated by chemoradiation with the same radiotherapy (RT) treatment scheme. Between January1996 and December 2013, 142 patients with anal squamous cell cancer were scheduled to receive a dose of 36Gy of elective node irradiation (ENI) to the inguinal area and whole pelvis over 4weeks followed after a 2-week gap by a boost dose of 23.4Gy over 17days to the macroscopic disease. Mitomycin C combined with fluorouracil, capecitabin or cisplatin was given at day 1 of each sequence of RT. Disease stages were I: 3, II: 78, IIIA: 23, IIIB: 38. Compliance rates were 97.2% with RT and 87.9% with chemotherapy. After a median follow up of 48months [3.6-192], estimated 5-year overall survival and colostomy-free survival were 75.4% and 85.3% respectively. Eleven patients (7.7%) never achieved a complete response, 15 had a local component of recurrence and 5 a regional one. One patient had failure in the common iliac node area outside the treatment fields. The inguinal control rate was 98.5%. The 5-year tumor and nodal control rates were 81.5% and 96.0%, respectively. Chemoradiation with a dose of 36Gy ENI achieved excellent nodal control. However, it is necessary to improve the 5-year control rate of the primary tumor. Omitting the gap and using additional doses per fraction or hyper-fractionation are to be explored.
Bulletin du cancer, Jan 29, 2015
Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 a... more Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy...
Clinical Medicine Insights. Oncology, 2013
Prostate cancer (PC) is one of the most common cancers and is a leading cause of death. Its initi... more Prostate cancer (PC) is one of the most common cancers and is a leading cause of death. Its initial growth is dependent on androgens; most patients show an initial response to hormonal therapy but will experience disease progression when PC becomes resistant to castration. In 2004, two key randomized controlled trials demonstrated a benefit for docetaxel-based regimens in the treatment of men with castration-resistant prostate cancer (CRPC). Cabazitaxel (XRP6258, TXD258, and RPR116258A), a tubulin-binding taxane drug as potent as docetaxel in cell lines, was the first treatment able to prolong survival for metastatic CRPC in the post-docetaxel setting. This review describes pharmacologic parameters of this agent followed by a review of clinical trials involving cabazitaxel. Other available treatments and the place of cabazitaxel in metastatic CRPC setting are discussed.
Journal of Hepatology, 2013
Hepatic epithelioid hemangioendothelioma is a rare liver mesenchymatous tumor with an epithelial ... more Hepatic epithelioid hemangioendothelioma is a rare liver mesenchymatous tumor with an epithelial aspect developed from endothelial cells with a lack of validated therapeutic options at metastatic stage. Metronomic chemotherapy has been described as an anti-angiogenic therapy leading to the depletion of circulating endothelial progenitors. We report the results of two patients treated for metastatic hemangioendothelioma with metronomic cyclophosphamide chemotherapy. Following initiation of metronomic cyclophosphamide chemotherapy (50 mg once a day continuously), the two patients exhibited significant clinical improvement and decrease in metastasis size without any clinically relevant side-effect. Metronomic cyclophosphamide could be proposed as a new therapeutic option to treat metastatic hepatic epithelioid hemangioendothelioma. Ó
Revue des Maladies Respiratoires, 2013
Lung cancer in nonsmoker: A separate entity Nous avons vécu cette dernière décennie de notables p... more Lung cancer in nonsmoker: A separate entity Nous avons vécu cette dernière décennie de notables progrès dans la prise en charge du cancer bronchopulmonaire. Ceux-ci sont issus en particulier d'une meilleure compréhension de la biologie, avec des conséquences thérapeutiques aboutissant à des traitements plus personnalisés qui nous ont permis de passer d'une monotonie léthargique à une stratégie innovante, basée non seulement sur l'histologie mais également sur des caractéristiques moléculaires. Ces progrès nous ont montré qu'il n'existe pas « un » mais « des » cancers du poumon. C'est ainsi que le cancer bronchopulmonaire du non-fumeur (CBNF) s'est imposé comme une entité à part, avec ses spécificités épidémiologiques, biologiques, cliniques et thérapeutiques .
Emerging Infectious Diseases, 2003
Clinical Medicine Insights: Oncology, 2015
Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignanc... more Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignancies both in the adjuvant and metastatic setting. Although myelosuppression is the most adverse event of this therapy, gemcitabine might induce severe pulmonary toxicities. We describe a case of pulmonary veno-occlusive disease (PVOD) related to gemcitabine. The patient was an 83-year-old man with a metastatic pancreatic cancer who was treated by gemcitabine as first-line therapy. He was in good health and received no other chemotherapy. A dose of 1000 mg/m(2) of gemcitabine was administered over a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. After a period of 6 months, a complete response was observed. Nevertheless, the patient developed a severe dyspnea, with arterial hypoxemia and very low lung diffusion for carbon monoxide. A CT scan showed diffuse ground glass opacities with septal lines, bilateral pleural effusion, and lymph node enlargement. On echocardiography, there was a suspicion of pulmonary hypertension with elevated systolic pulmonary artery pressure and normal left ventricular pressures. Right heart catheterization confirmed pulmonary hypertension and normal pulmonary artery occlusion pressure. Diagnosis of PVOD was made, and a gemcitabine-induced toxicity was suspected. A symptomatic treatment was started. At last follow-up, patient was in functional class I with near-normal of CT scan, arterial blood gases, and echocardiography. A gemcitabine-induced PVOD is the more likely diagnosis.
Références en gynécologie obstétrique
tion to conventional cancer therapy. The main knowledge drawn by these preliminary results might ... more tion to conventional cancer therapy. The main knowledge drawn by these preliminary results might be the potential of a new-targeted therapy directed towards metabolic pathways to promote the outcome of conventional cancer treatments.
Journal of Cancer Therapy, 2013
Background: metronomic chemotherapy is based on antiangiogenic and immunologic mechanisms obtaine... more Background: metronomic chemotherapy is based on antiangiogenic and immunologic mechanisms obtained by the administration of traditional cytotoxic drugs at lower concentration without rest periods. The low dosage induces fewer or no side effect compared to classic maximum tolerated dose administration (MTD). At present, no treatment related acute leukaemia was reported in cyclophosphamide-based metronomic chemotherapy (CMC). Case: We report the case of an 81-year-old man considered as having castration and chemo-refractory metastatic prostate cancer. CMC was started. Objective response was observed in this heavily pre-treated patient with progression free survival lasting more than 30 months. No toxicity was observed in this period and his autonomy was maintained. Finally, our patient developed a chemotherapy-induced acute myeloid leukaemia at 36th month of CMC. Conclusion: Even CMC is a well-tolerated treatment; secondary acute leukaemia is related to cumulative dose of cyclophosphamide. The benefit and the risk of long-term exposure to cyclophosphamide should be carefully balanced.
Bulletin du cancer, 2012
Castration resistant prostate cancer occurs when patients experience disease progression despite ... more Castration resistant prostate cancer occurs when patients experience disease progression despite appropriate hormonal manipulations. In these patients, chemotherapy remains standard treatment. Preclinical and clinical data have demonstrated the potential utility of an immunotherapy-based approach for the treatment of prostate cancer (PC). The phase III trial (IMPACT) has recently reported an advantage for Sipuleucel-T over placebo, with an overall survival 4.1 months superior to placebo. Sipuleucel-T is also the first FDA-approved immunotherapy for prostate cancer. These promising results need to be confirmed with other large studies and within previous step of PC. Neoplasic cells can escape immune responses by multiple mechanisms. A better knowledge of these mechanisms is of major concern for the future development of new immunotherapies approach.
Annals of Oncology, 2013
Background: Squamous cell carcinoma of the anal canal (SCCA) is a rare disease, mostly diagnosed ... more Background: Squamous cell carcinoma of the anal canal (SCCA) is a rare disease, mostly diagnosed at early stage.
The American journal of case reports, 2015
BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompa... more BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompanied by a delayed histopathological diagnosis, primarily due to submucosal disease. A concentric ring pattern or "target sign" on T2-weighted magnetic resonance imaging (MRI) has been proposed as being characteristic for early suspicion. Even though RLP is more aggressive and has poorer survival than other rectal adenocarcinomas, no specific treatment is recommended. In this case report of 3 patients, we challenge the sensitivity of the characteristic radiological pattern, and we review the existing data for a treatment strategy. CASE REPORT One patient presented classic clinical characteristics of RLP with young age and advanced stage at diagnosis, with chemo-refractory disease and rapid fatal evolution. Biopsies confirmed the RLP with the presence of signet-ring cells (SRC) in a strong desmoplastic stromal reaction. However, the characteristic concentric ring pattern was abse...
Bulletin du cancer, Jan 29, 2015
Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 a... more Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy...
Cancer Epidemiology Biomarkers & Prevention, 2015
Background: Baseline prognostic biomarkers stratifying treatment strategies in first-line metasta... more Background: Baseline prognostic biomarkers stratifying treatment strategies in first-line metastatic colorectal cancer (mCRC) are lacking. Angiopoietin-2 (Ang-2) is proposed as a potential biomarker in several cancers. We therefore decided to establish the additional prognostic value of Ang-2 for overall survival (OS) in patients with first-line mCRC.
Cancer Chemotherapy and Pharmacology, 2014
Perioperative chemotherapy improves the overall survival of resectable gastroesophageal adenocarc... more Perioperative chemotherapy improves the overall survival of resectable gastroesophageal adenocarcinoma (GEA) patients. However, more than 40 % of the patients are not healthy enough to complete their post-operative chemotherapy, and the progression-free survival rate is lower than 35 % at 5 years. In order to optimise neoadjuvant chemotherapy regimen, a pilot study of weekly dose-intensified cisplatin, epirubicin, and paclitaxel (PET) was conducted. The primary objective was a complete resection (R0) rate. Then, a R0 rate ≤80 % was considered as uninteresting, with an expected R0 rate of 92 %. Secondary objectives were the feasibility, safety, histological response rate (Becker score), and survival (Trial registration: NCT01830270). Patients with >T1N0M0 GEA were included. Treatment consisted of eight preoperative cycles of weekly PET regimen at 30/50/80 mg/m² of cisplatin, epirubicin, and paclitaxel, respectively. Primary prophylaxis by granulocyte colony-stimulating factor was administered. Surgery was performed 4-6 weeks following the last cycle of chemotherapy. Using Fleming two-step design with a unilateral alpha type one error of 5 % and a statistical power of 80 %, it would be required to include 68 patients. At planned interim analysis for futility, it was required to observe at least 25 of 29 patients with R0 resection to pursue inclusion. At the second step, it was required to observe at least 61 of 68 patients with R0 resection to conclude for promising activity of the dose-intensified chemotherapy. Between May 2011 and January 2013, 29 patients were enrolled. Median age was 62 years (range 39-83 years), and seven (24 %) patients presented signet-ring cell histology. Twenty-seven (93 %) patients underwent surgery. Pathological complete responses (Becker score 1a) were observed in four patients, and nearly complete responses (Becker score 1b) for additional three patients. A R0 rate was achieved for 24 of 29 (82.7 %; 95 % CI 64-94 %) patients. No Becker score 1a/1b response was observed among patients with signet-ring cell GEA. Twenty-one (72 %) patients completed all eight cycles, and 86 % received seven or more cycles. Sixteen (56 %) patients experienced grade 3-4 neutropenia, and five patients had febrile neutropenia. Among non-haematological toxicities, mucositis and fatigue were the most frequent ones. The median-delivered relative dose intensity (DI) was 80 % for cisplatin, 75 % for epirubicin, and 79 % for paclitaxel. However, only 45 % of the patients received at least 80 % of the planned median DI for all three drugs. Despite high R0 and pathological response rates, neoadjuvant PET chemotherapy did not meet the primary end-point and failed to show an acceptable relative DI. PET chemotherapy is not recommended in resectable GEA patients.
Revue Francophone des Laboratoires, 2014
ABSTRACT Numerous chemotherapies have been developed to treat cancers. Now, it is becoming clear ... more ABSTRACT Numerous chemotherapies have been developed to treat cancers. Now, it is becoming clear that cytotoxic agents not only have a direct effect on cancer cell death, but can also elicit tumour-specific immune responses. We recently showed that 8 patients treated with DCF for squamous cell carcinoma of the anal canal (SCCA) presented an overall survival rate of 62.5 % at 12 months. Half of the patients, with HPV16 positive SCCA, achieved a complete remission. To attempt to understand why such a good clinical response was obtained, we aimed to determine whether DCF regimen could increase antigenicity and immunogenicity in in vitro and in vivo models of HPV16 cancers. C57BL/6 mice were grafted subcutaneously with 3×105 TC1 cells (primary lung epithelial cells of C57BL/6 immortalized with E6 and E7 of HPV16 and transformed with c-Ha-ras). When the tumour size reached 100 mm2, mice were treated either with DCF or CF. The tumours were measured for 15 days and the number of Treg (CD4+ CD25+ FoxP3+) and Myeloid-Derived Suppressor Cells (MDSC, Gr1+, CD11b+) were assessed in the spleen after the sacrifice of the mice. Tumour specific immune responses against E7 and mTERT were analyzed by IFNg ELISPOT. In parallel in vitro studies were conducted with TC1 cells treated by DCF, CF or D. The analysis of calreticulin expression by flow cytometry, and the release of ATP and HMGB1 in the supernatant of treated cells were conducted to highlight the induction of an immunogenic cell death (ICD). The DCF regimen showed the best antitumor effect in TC1 grafted mice compared with CF. Furthermore a lower level of Treg and MDSC was observed in the spleen of mice treated with DCF compared to CF. Reduction of tumour size was linked to the induction of specific anti-E7 and anti-mTERT immune responses. As for the in vitro assessment of ICD, DCF increased the membrane expression of calreticulin and the release of HMGB1. As a whole our preliminary data indicate that the clinical response observed with DCF may be due to efficient modulation of tumour-specific immune responses by (i) inducing in mice a less immunosuppressive environment compared to CF, (ii) promoting the optimal release and presentation of tumour antigens through the induction of immunogenic cell death.
The American journal of case reports, 2015
BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompa... more BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompanied by a delayed histopathological diagnosis, primarily due to submucosal disease. A concentric ring pattern or "target sign" on T2-weighted magnetic resonance imaging (MRI) has been proposed as being characteristic for early suspicion. Even though RLP is more aggressive and has poorer survival than other rectal adenocarcinomas, no specific treatment is recommended. In this case report of 3 patients, we challenge the sensitivity of the characteristic radiological pattern, and we review the existing data for a treatment strategy. CASE REPORT One patient presented classic clinical characteristics of RLP with young age and advanced stage at diagnosis, with chemo-refractory disease and rapid fatal evolution. Biopsies confirmed the RLP with the presence of signet-ring cells (SRC) in a strong desmoplastic stromal reaction. However, the characteristic concentric ring pattern was abse...
Radiotherapy and Oncology, 2015
To retrospectively analyze the efficacy of 36Gy of elective node irradiation and report patterns ... more To retrospectively analyze the efficacy of 36Gy of elective node irradiation and report patterns of recurrence in patients with anal cancer treated by chemoradiation with the same radiotherapy (RT) treatment scheme. Between January1996 and December 2013, 142 patients with anal squamous cell cancer were scheduled to receive a dose of 36Gy of elective node irradiation (ENI) to the inguinal area and whole pelvis over 4weeks followed after a 2-week gap by a boost dose of 23.4Gy over 17days to the macroscopic disease. Mitomycin C combined with fluorouracil, capecitabin or cisplatin was given at day 1 of each sequence of RT. Disease stages were I: 3, II: 78, IIIA: 23, IIIB: 38. Compliance rates were 97.2% with RT and 87.9% with chemotherapy. After a median follow up of 48months [3.6-192], estimated 5-year overall survival and colostomy-free survival were 75.4% and 85.3% respectively. Eleven patients (7.7%) never achieved a complete response, 15 had a local component of recurrence and 5 a regional one. One patient had failure in the common iliac node area outside the treatment fields. The inguinal control rate was 98.5%. The 5-year tumor and nodal control rates were 81.5% and 96.0%, respectively. Chemoradiation with a dose of 36Gy ENI achieved excellent nodal control. However, it is necessary to improve the 5-year control rate of the primary tumor. Omitting the gap and using additional doses per fraction or hyper-fractionation are to be explored.
Bulletin du cancer, Jan 29, 2015
Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 a... more Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy...