Biliary tract neoplasm is one of the most aggressive malignancies, with a very poor prognosis. Mo... more Biliary tract neoplasm is one of the most aggressive malignancies, with a very poor prognosis. Most cancers of the biliary tract will have grown beyond the limits of curative resection by the time they become clinically evident. This reality has fostered therapeutic nihilism, and most physicians and surgeons, in their pessimism, have to run ambitious trials evaluating new diagnostic tools and therapeutic techniques in this disease. Advances in imaging over the period of the last 5 years now allow for earlier diagnosis and better surgical planning. Recent improvements in operative technique have substantially improved the outlook of patients with this cancer. Palliative management of obstructive disease recently has been improved with the advent of photodynamic therapy. Among the different drugs tested in this disease, gemcitabine seems to have the best efficacy:toxicity ratio. However, efficacy results remain disappointing, and combination schedules need to be developed to improve the results. Among them, the gemcitabine-oxaliplatin combination seems to be one of the most promising schedules. Biological studies, especially those evaluating mutation-independent activation of the Hedgehog pathway, have provided interesting information on the carcinogenesis of this rare tumor. Furthermore, these results bring us the opportunity of development of future targeted therapies in biliary tract cancer. Biliary tract neoplasm remains one of the most aggressive malignancies. However, as for other gastrointestinal malignancies, biological studies and diagnostic and therapeutic improvements have provided interesting results that could lead to a major improvement in the prognosis of this disease.
The objective of our study was to compare the usefulness of contrast-enhanced sonography with bas... more The objective of our study was to compare the usefulness of contrast-enhanced sonography with baseline sonography in detecting malignant liver lesions.
Peritoneal carcinomatosis (PC) is a major disease, currently treated using complete cytoreductive... more Peritoneal carcinomatosis (PC) is a major disease, currently treated using complete cytoreductive surgery and intraperitoneal chemohyperthermia (IPCH). Morbidity is a significant limitation of this procedure, usually related to the extent of surgery, and hematological toxicity, which is considered as dependent upon the chemotherapy dosage alone. The aim of our study was to investigate whether surgery alone had an impact on the hematological toxicity associated with the standardized drug protocol that we routinely prescribed. Data were prospectively recorded from 83 consecutive patients who underwent complete cytoreductive surgery followed by IPCH with intraperitoneal oxaliplatin (360 mg/m(2)) and irinotecan (360 mg/m(2)), in 2 L/m(2) of dextrose over 30 min at 42-45 degrees C, using the Coliseum technique. Sixty minutes prior to IPCH, patients also received an intravenous perfusion of leucovorin (20 mg/m(2)) and 5-fluorouravyl (400 mg/m(2)). The doses and volume of IPCH were determined on the basis of the body surface area, so that all patients received the same concentration of drugs. Severe aplasia were defined as a leucocyte count of <500/ml, platelets <50,000/ml, and reticulocytes <6.5 g Hb/L. Postoperatively, severe aplasia was seen in 40 of the 83 patients (48%). There was no difference in the characteristics of patients with and without aplasia, other than the extent of surgery. The incidence of severe aplasia was only related to the duration of surgery (537 min in the aplastic group versus 444 min in the non aplastic group) (P = 0.002), and to the extent of the peritoneal disease (peritoneal index of 19.5 in the aplastic group, vs. 15.3 in the nonaplastic group) (P = 0.02). We report for the first time that the duration of surgery may increase the incidence of hematological toxicity following intraperitoneal chemotherapy. We also hypothesized that intra- and postoperative transient biochemical disorders, such as hypoalbuminemia, hemodilution, liver, and renal insufficiency and stress can be involved in this process. These hypotheses may allow improved postoperative care.
Tumor necrosis factor (TNF)-alpha contributes to the development of acute pancreatitis. Because T... more Tumor necrosis factor (TNF)-alpha contributes to the development of acute pancreatitis. Because TNF-alpha is involved in the control of apoptosis, we studied its interaction with the pancreatic apoptotic pathway. Pancreatic acinar AR4-2J cells were used. Apoptosis was monitored by morphologic and biochemical criteria. TNF-alpha induced apoptosis in AR4-2J cells. Induction was strongly enhanced in cells treated with actinomycin D, suggesting that TNF-alpha activated concomitantly an antiapoptotic mechanism through newly synthesized proteins. This mechanism involved activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases because their inhibition worsened TNF-alpha-induced apoptosis. The antiapoptotic pancreatitis-associated protein (PAP) I is a candidate for mediating TNF-alpha activity. Its expression is induced by TNF-alpha, and cells overexpressing PAP I show significantly less apoptosis on exposure to TNF-alpha. We examined whether TNF-alpha ind...
ABSTRACT Le développement d’anticancéreux plus actifs (oxaliplatine, irinotécan) associés aux thé... more ABSTRACT Le développement d’anticancéreux plus actifs (oxaliplatine, irinotécan) associés aux thérapies ciblées ainsi que les avancées de la chirurgie ont allongé la survie des patients atteints de cancer colorectal métastatique (CCRm). Concernant les patients avec métastases considérées comme définitivement non résécables, le choix du traitement de première ligne est guidé par le bien-fondé et la faisabilité d’un traitement agressif, la notion d’une chimiothérapie antérieure par oxaliplatine, d’autant plus qu’elle est récente, et le statut tumoral RAS devenu désormais incontournable. Un facteur pronostique majeur est l’accès du patient à tous les anticancéreux, corrélé de façon linéaire à la survie. Il en est probablement de même avec les agents ciblés. Les combinaisons bithérapie-cytotoxique associée à un agent ciblé (bevacizumab ou anticorps anti-EGFR si RAS sauvage) constituent actuellement le traitement standard de première ligne chez les patients avec métastases sans espoir de résécabilité. En cas de maladie contrôlée après quatre à six mois de bithérapie cytotoxique, un traitement d’entretien par fluoropyrimidine (seule ou associée au bevacizumab) jusqu’à progression est devenu une option thérapeutique. Des données supplémentaires sont nécessaires pour identifier les sous-groupes de malades pouvant bénéficier d’une pause thérapeutique complète susceptible d’améliorer la qualité de vie des patients. En cas de maladie peu évolutive et/ou chez un patient « fragile », une fluoropyrimidine (seule ou associée au bevacizumab) peut constituer un traitement de première intention (ajout de l’oxaliplatine ou de l’irinotécan uniquement à la progression tumorale), sans détriment sur la survie comparé à une bithérapie cytotoxique d’emblée poursuivie jusqu’à progression ou toxicité limitante. Inversement, des survies jamais égalées ont été obtenues chez des malades sélectionnés recevant une trichimiothérapie cytotoxique d’induction (seule ou associée à une thérapie ciblée) suivie d’une désescalade thérapeutique. Ces stratégies méritent d’être comparées par des essais randomisés. Abstract The advent of more active cytotoxic drugs (oxaliplatin, irinotecan), combined with targeted therapies and advances in surgery, has increased the survival of patients with metastatic colorectal cancer. The choice of first-line chemotherapy in case of patients with definitely non-resectable metastasis is guided by the merits and feasibility of aggressive treatment, history of prior adjuvant oxaliplatin, and tumor RAS status that has become essential. A major prognostic factor is patient’s access to all anticancer drugs, which is linearly correlated to survival. The same is probably true regarding targeted agents. The combination of doublet chemotherapy (fluoropyrimidine combined with oxaliplatin or irinotecan) and a targeted agent (bevacizumab or anti-EGFR antibodies if wild-type RAS) is the first-line standard of care for patients with non-resectable metastasis. In case of disease control after a 4–6 month induction bitherapy, treatment maintenance with a fluoropyrimidine (alone or combined with bevacizumab) until disease progression is a therapeutic option. Supplementary data are warranted to select subgroups of patients that may benefit from intermittent treatment to improve quality of life. In case of slowly growing metastatic disease and/or in frail patients, fluoropyrimidine (alone or combined with bevacizumab) may also be a first-line treatment option (oxaliplatin or irinotecan being added at the time of disease progression), without damage to survival compared with a strategy based on immediate doublet chemotherapy continued until progression or dose-limiting toxicity. On the other hand, survival rates ever achieved were obtained in selected patients after tricytotoxic-induction therapy (alone or combined with targeted agent) followed by maintenance treatment. These strategies deserve to be compared through further randomized trials.
Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or ... more Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are non-informative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental param...
European journal of human genetics : EJHG, Jan 15, 2015
To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (C... more To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's χ(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0...
There is no standard for second line chemotherapy in poorly differentiated grade 3 neuroendocrine... more There is no standard for second line chemotherapy in poorly differentiated grade 3 neuroendocrine carcinoma (G3-NEC) patients. We analyzed the antitumor efficacy of 5-fluroruracil and Oxaliplatin (FOLFOX) chemotherapy in this population. A single center retrospective analysis of G3-NEC consecutive patients treated with FOLFOX chemotherapy after failure of cisplatinum-based regimen between December 2003 and June 2012 was performed. Progression-free survival, overall survival, response rate and safety were assessed according to RECIST 1.1 and NCI.CTC v4 criteria. Twenty consecutive patients were included (7 males, 13 females; median age 55; range 23-87 years) with a performance status of 0 to 1 in 75% of them. Primary location was gastro-enteropancreatic in 12, thoracic in 4, other in 2 and unknown in 2 patients. There were 12 (65%) large cell, 7 (30%) small cell grade 3 neuroendocrine carcinoma tumors and 1 (5%) unknown. All patients had distant metastases. Twelve (60%) patients rece...
European journal of cancer (Oxford, England : 1990), 2015
Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all can... more Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all cancer deaths globally each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Since the approval of sorafenib in advanced HCC, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting, and no agent has been shown to impact outcomes after sorafenib failure. This review will focus on the range of experimental therapeutics for patients with advanced HCC and highlight the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers ...
The aim of our study was to evaluate the prognostic role of immunological microenvironnement in s... more The aim of our study was to evaluate the prognostic role of immunological microenvironnement in stage II-III CRC patients. We constructed a tissue microarray from 196 consecutive patients with stage II-III CRC and compared CD3, CD4, CD8, CD57, CD68, CXCL9/MIG, CXCL13, and PPARγ immunoreactivity in tumour samples and their matched non-tumour tissue. We assessed their association with relapse-free survival (RFS; primary endpoint) and overall survival (OS) in multivariate Cox models. Low densities of CD57+ and CD68+ tumour-infiltrating cells (TIC) independently predicted worse outcomes. A prognostic score combining CD57 (+, > vs -, ≤2 cells per spot) and CD68 (+, >0 vs -, =0 cells per spot) TIC density discriminated CRC patients at low (CD68+/CD57+), intermediate (CD68+/CD57-), or high (CD68-/CD57-) risk, with hazard ratios for the intermediate-risk and high-risk groups of 2.7 (95% confidence interval (CI): 1.3-5.8) and 9.0 (3.2-25.4) for RFS, and 2.5 (1.2-5.1) and 10.6 (3.8-29.2...
Intraoperative sentinel lymph node (SLN) detection has been reported for colon cancer, but no stu... more Intraoperative sentinel lymph node (SLN) detection has been reported for colon cancer, but no study has focused on rectal cancer. Only an ex vivo technique can be performed easily in this location. We evaluated SLN detection using blue dye injection in patients with rectal adenocarcinoma. This prospective study included 31 patients. Preoperative radiotherapy (45 Gy) was done in 15 cases. After proctectomy the surgical specimen was examined in the operating room. Submucosal peritumoral injections were done. One to three SLNs were retrieved. The SLNs were sectioned at three levels and examined histologically and then, if negative by hematoxylin-eosin (H&E) staining and immunohistochemistry (IHC). There were 7 abdominoperineal resections, 12 colorectal anastomoses, 11 coloanal anastomoses, and 1 Hartmann procedure. The median number of lymph nodes harvested was 21 (7-38). A SLN was identified in 30 cases (feasibility 97%). The mean number of SLNs was 2 (0-3). A micrometastasis was disc...
To evaluate the impact on survival of primary tumour resection in patients with unresectable sync... more To evaluate the impact on survival of primary tumour resection in patients with unresectable synchronous metastases from colorectal cancer (CRC). Primary tumour resection in this setting remains controversial. We retrieved individual data of 1155 patients with metastatic CRC included in four first-line chemotherapy trials: Fédération Francophone de Cancérologie Digestive (FFCD)-9601, FFCD-2000-05, Actions Concertées dans les cancers COloRectaux et Digestifs (ACCORD)-13, and ML-16987. Patients with unresectable synchronous metastases were eligible for this study. We used univariate and multivariate analyses (Cox models stratified on the trial) to assess the impact of primary tumour resection and other potential prognostic variables on overall survival (OS) (the primary endpoint). Amongst the 1155 patients, 810 patients met the inclusion criteria and 59% (n = 478) underwent resection of their primary tumour, prior to trial entry (resection group). Compared to patients in the non-resection group (n =3 32 [41%]), those in the resection group were more likely to have a colonic primary, lower baseline carcinoembryonic antigen (CEA) and alkaline phosphatase levels, and normal white-blood-cell count (p < 0.001 each). Primary tumour resection was independently associated to better OS in multivariate analysis (hazard ratio (HR), 0.63 [0.53-0.75]; p < 0.001, with a more favourable impact of resection on OS in case of rectal primary and low CEA level. Primary tumour resection was also independently associated to a better progression-free survival in multivariate analysis (HR, 0.82 [0.70-0.95]; p < 0.001). Primary tumour resection was independently associated to a better OS in patients with CRC and unresectable synchronous metastases.
Transarterial chemoembolisation (TACE) is usually performed by injecting an emulsion of a drug an... more Transarterial chemoembolisation (TACE) is usually performed by injecting an emulsion of a drug and iodised oil. Drug-eluting beads (DEBs) have undeniable pharmacological advantages by offering simultaneous embolisation and sustained release of the drug to the tumour. No data are currently available on liver/biliary injury following DEB-TACE. This study describes and compares liver/biliary injuries encountered with TACE in tumours developed in cirrhotic (hepatocellular carcinoma (HCC)) and non-cirrhotic (endocrine tumours (NETs)) livers. In consecutive patients treated for a well-differentiated metastatic NET (n=120) or a HCC (n=88), 684 CT- and MR-scans were analysed. Liver/biliary injuries were classified as follows: dilated bile duct, portal vein narrowing, portal venous thrombosis and biloma/liver infarct. A generalised estimating equation logistic regression model was used. A liver/biliary injury followed 17.2% (82/476) of sessions in 30.8% (64/208) of patients. The occurrence of liver/biliary injury was associated with DEB-TACE (OR=6.63; p<0.001) irrespectively of the tumour type. Biloma/parenchymal infarct was strongly associated with both DEB-TACE (OR=9.78; p=0.002) and NETs (OR: 8.13; p=0.04). Biloma/liver infarcts were managed conservatively but were associated with an increase in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatases, and gamma glutamyl transpeptidase (p=0.005, p=0.005, p=0.012, and p=0.006, respectively). Liver/biliary injuries are independently associated with DEB-TACE. Biloma/liver infarct, the most serious injury, is independently associated with both DEB-TACE and NETs. The absence of such an association in TACE of HCC may be explained by the hypertrophied peribiliary plexus observed in cirrhosis, which protects against the ischemic/chemical insult of bile ducts. We suggest caution when using DEB-TACE in the non-cirrhotic liver.
Biliary tract neoplasm is one of the most aggressive malignancies, with a very poor prognosis. Mo... more Biliary tract neoplasm is one of the most aggressive malignancies, with a very poor prognosis. Most cancers of the biliary tract will have grown beyond the limits of curative resection by the time they become clinically evident. This reality has fostered therapeutic nihilism, and most physicians and surgeons, in their pessimism, have to run ambitious trials evaluating new diagnostic tools and therapeutic techniques in this disease. Advances in imaging over the period of the last 5 years now allow for earlier diagnosis and better surgical planning. Recent improvements in operative technique have substantially improved the outlook of patients with this cancer. Palliative management of obstructive disease recently has been improved with the advent of photodynamic therapy. Among the different drugs tested in this disease, gemcitabine seems to have the best efficacy:toxicity ratio. However, efficacy results remain disappointing, and combination schedules need to be developed to improve the results. Among them, the gemcitabine-oxaliplatin combination seems to be one of the most promising schedules. Biological studies, especially those evaluating mutation-independent activation of the Hedgehog pathway, have provided interesting information on the carcinogenesis of this rare tumor. Furthermore, these results bring us the opportunity of development of future targeted therapies in biliary tract cancer. Biliary tract neoplasm remains one of the most aggressive malignancies. However, as for other gastrointestinal malignancies, biological studies and diagnostic and therapeutic improvements have provided interesting results that could lead to a major improvement in the prognosis of this disease.
The objective of our study was to compare the usefulness of contrast-enhanced sonography with bas... more The objective of our study was to compare the usefulness of contrast-enhanced sonography with baseline sonography in detecting malignant liver lesions.
Peritoneal carcinomatosis (PC) is a major disease, currently treated using complete cytoreductive... more Peritoneal carcinomatosis (PC) is a major disease, currently treated using complete cytoreductive surgery and intraperitoneal chemohyperthermia (IPCH). Morbidity is a significant limitation of this procedure, usually related to the extent of surgery, and hematological toxicity, which is considered as dependent upon the chemotherapy dosage alone. The aim of our study was to investigate whether surgery alone had an impact on the hematological toxicity associated with the standardized drug protocol that we routinely prescribed. Data were prospectively recorded from 83 consecutive patients who underwent complete cytoreductive surgery followed by IPCH with intraperitoneal oxaliplatin (360 mg/m(2)) and irinotecan (360 mg/m(2)), in 2 L/m(2) of dextrose over 30 min at 42-45 degrees C, using the Coliseum technique. Sixty minutes prior to IPCH, patients also received an intravenous perfusion of leucovorin (20 mg/m(2)) and 5-fluorouravyl (400 mg/m(2)). The doses and volume of IPCH were determined on the basis of the body surface area, so that all patients received the same concentration of drugs. Severe aplasia were defined as a leucocyte count of <500/ml, platelets <50,000/ml, and reticulocytes <6.5 g Hb/L. Postoperatively, severe aplasia was seen in 40 of the 83 patients (48%). There was no difference in the characteristics of patients with and without aplasia, other than the extent of surgery. The incidence of severe aplasia was only related to the duration of surgery (537 min in the aplastic group versus 444 min in the non aplastic group) (P = 0.002), and to the extent of the peritoneal disease (peritoneal index of 19.5 in the aplastic group, vs. 15.3 in the nonaplastic group) (P = 0.02). We report for the first time that the duration of surgery may increase the incidence of hematological toxicity following intraperitoneal chemotherapy. We also hypothesized that intra- and postoperative transient biochemical disorders, such as hypoalbuminemia, hemodilution, liver, and renal insufficiency and stress can be involved in this process. These hypotheses may allow improved postoperative care.
Tumor necrosis factor (TNF)-alpha contributes to the development of acute pancreatitis. Because T... more Tumor necrosis factor (TNF)-alpha contributes to the development of acute pancreatitis. Because TNF-alpha is involved in the control of apoptosis, we studied its interaction with the pancreatic apoptotic pathway. Pancreatic acinar AR4-2J cells were used. Apoptosis was monitored by morphologic and biochemical criteria. TNF-alpha induced apoptosis in AR4-2J cells. Induction was strongly enhanced in cells treated with actinomycin D, suggesting that TNF-alpha activated concomitantly an antiapoptotic mechanism through newly synthesized proteins. This mechanism involved activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases because their inhibition worsened TNF-alpha-induced apoptosis. The antiapoptotic pancreatitis-associated protein (PAP) I is a candidate for mediating TNF-alpha activity. Its expression is induced by TNF-alpha, and cells overexpressing PAP I show significantly less apoptosis on exposure to TNF-alpha. We examined whether TNF-alpha ind...
ABSTRACT Le développement d’anticancéreux plus actifs (oxaliplatine, irinotécan) associés aux thé... more ABSTRACT Le développement d’anticancéreux plus actifs (oxaliplatine, irinotécan) associés aux thérapies ciblées ainsi que les avancées de la chirurgie ont allongé la survie des patients atteints de cancer colorectal métastatique (CCRm). Concernant les patients avec métastases considérées comme définitivement non résécables, le choix du traitement de première ligne est guidé par le bien-fondé et la faisabilité d’un traitement agressif, la notion d’une chimiothérapie antérieure par oxaliplatine, d’autant plus qu’elle est récente, et le statut tumoral RAS devenu désormais incontournable. Un facteur pronostique majeur est l’accès du patient à tous les anticancéreux, corrélé de façon linéaire à la survie. Il en est probablement de même avec les agents ciblés. Les combinaisons bithérapie-cytotoxique associée à un agent ciblé (bevacizumab ou anticorps anti-EGFR si RAS sauvage) constituent actuellement le traitement standard de première ligne chez les patients avec métastases sans espoir de résécabilité. En cas de maladie contrôlée après quatre à six mois de bithérapie cytotoxique, un traitement d’entretien par fluoropyrimidine (seule ou associée au bevacizumab) jusqu’à progression est devenu une option thérapeutique. Des données supplémentaires sont nécessaires pour identifier les sous-groupes de malades pouvant bénéficier d’une pause thérapeutique complète susceptible d’améliorer la qualité de vie des patients. En cas de maladie peu évolutive et/ou chez un patient « fragile », une fluoropyrimidine (seule ou associée au bevacizumab) peut constituer un traitement de première intention (ajout de l’oxaliplatine ou de l’irinotécan uniquement à la progression tumorale), sans détriment sur la survie comparé à une bithérapie cytotoxique d’emblée poursuivie jusqu’à progression ou toxicité limitante. Inversement, des survies jamais égalées ont été obtenues chez des malades sélectionnés recevant une trichimiothérapie cytotoxique d’induction (seule ou associée à une thérapie ciblée) suivie d’une désescalade thérapeutique. Ces stratégies méritent d’être comparées par des essais randomisés. Abstract The advent of more active cytotoxic drugs (oxaliplatin, irinotecan), combined with targeted therapies and advances in surgery, has increased the survival of patients with metastatic colorectal cancer. The choice of first-line chemotherapy in case of patients with definitely non-resectable metastasis is guided by the merits and feasibility of aggressive treatment, history of prior adjuvant oxaliplatin, and tumor RAS status that has become essential. A major prognostic factor is patient’s access to all anticancer drugs, which is linearly correlated to survival. The same is probably true regarding targeted agents. The combination of doublet chemotherapy (fluoropyrimidine combined with oxaliplatin or irinotecan) and a targeted agent (bevacizumab or anti-EGFR antibodies if wild-type RAS) is the first-line standard of care for patients with non-resectable metastasis. In case of disease control after a 4–6 month induction bitherapy, treatment maintenance with a fluoropyrimidine (alone or combined with bevacizumab) until disease progression is a therapeutic option. Supplementary data are warranted to select subgroups of patients that may benefit from intermittent treatment to improve quality of life. In case of slowly growing metastatic disease and/or in frail patients, fluoropyrimidine (alone or combined with bevacizumab) may also be a first-line treatment option (oxaliplatin or irinotecan being added at the time of disease progression), without damage to survival compared with a strategy based on immediate doublet chemotherapy continued until progression or dose-limiting toxicity. On the other hand, survival rates ever achieved were obtained in selected patients after tricytotoxic-induction therapy (alone or combined with targeted agent) followed by maintenance treatment. These strategies deserve to be compared through further randomized trials.
Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or ... more Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are non-informative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental param...
European journal of human genetics : EJHG, Jan 15, 2015
To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (C... more To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's χ(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0...
There is no standard for second line chemotherapy in poorly differentiated grade 3 neuroendocrine... more There is no standard for second line chemotherapy in poorly differentiated grade 3 neuroendocrine carcinoma (G3-NEC) patients. We analyzed the antitumor efficacy of 5-fluroruracil and Oxaliplatin (FOLFOX) chemotherapy in this population. A single center retrospective analysis of G3-NEC consecutive patients treated with FOLFOX chemotherapy after failure of cisplatinum-based regimen between December 2003 and June 2012 was performed. Progression-free survival, overall survival, response rate and safety were assessed according to RECIST 1.1 and NCI.CTC v4 criteria. Twenty consecutive patients were included (7 males, 13 females; median age 55; range 23-87 years) with a performance status of 0 to 1 in 75% of them. Primary location was gastro-enteropancreatic in 12, thoracic in 4, other in 2 and unknown in 2 patients. There were 12 (65%) large cell, 7 (30%) small cell grade 3 neuroendocrine carcinoma tumors and 1 (5%) unknown. All patients had distant metastases. Twelve (60%) patients rece...
European journal of cancer (Oxford, England : 1990), 2015
Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all can... more Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all cancer deaths globally each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Since the approval of sorafenib in advanced HCC, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting, and no agent has been shown to impact outcomes after sorafenib failure. This review will focus on the range of experimental therapeutics for patients with advanced HCC and highlight the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers ...
The aim of our study was to evaluate the prognostic role of immunological microenvironnement in s... more The aim of our study was to evaluate the prognostic role of immunological microenvironnement in stage II-III CRC patients. We constructed a tissue microarray from 196 consecutive patients with stage II-III CRC and compared CD3, CD4, CD8, CD57, CD68, CXCL9/MIG, CXCL13, and PPARγ immunoreactivity in tumour samples and their matched non-tumour tissue. We assessed their association with relapse-free survival (RFS; primary endpoint) and overall survival (OS) in multivariate Cox models. Low densities of CD57+ and CD68+ tumour-infiltrating cells (TIC) independently predicted worse outcomes. A prognostic score combining CD57 (+, > vs -, ≤2 cells per spot) and CD68 (+, >0 vs -, =0 cells per spot) TIC density discriminated CRC patients at low (CD68+/CD57+), intermediate (CD68+/CD57-), or high (CD68-/CD57-) risk, with hazard ratios for the intermediate-risk and high-risk groups of 2.7 (95% confidence interval (CI): 1.3-5.8) and 9.0 (3.2-25.4) for RFS, and 2.5 (1.2-5.1) and 10.6 (3.8-29.2...
Intraoperative sentinel lymph node (SLN) detection has been reported for colon cancer, but no stu... more Intraoperative sentinel lymph node (SLN) detection has been reported for colon cancer, but no study has focused on rectal cancer. Only an ex vivo technique can be performed easily in this location. We evaluated SLN detection using blue dye injection in patients with rectal adenocarcinoma. This prospective study included 31 patients. Preoperative radiotherapy (45 Gy) was done in 15 cases. After proctectomy the surgical specimen was examined in the operating room. Submucosal peritumoral injections were done. One to three SLNs were retrieved. The SLNs were sectioned at three levels and examined histologically and then, if negative by hematoxylin-eosin (H&E) staining and immunohistochemistry (IHC). There were 7 abdominoperineal resections, 12 colorectal anastomoses, 11 coloanal anastomoses, and 1 Hartmann procedure. The median number of lymph nodes harvested was 21 (7-38). A SLN was identified in 30 cases (feasibility 97%). The mean number of SLNs was 2 (0-3). A micrometastasis was disc...
To evaluate the impact on survival of primary tumour resection in patients with unresectable sync... more To evaluate the impact on survival of primary tumour resection in patients with unresectable synchronous metastases from colorectal cancer (CRC). Primary tumour resection in this setting remains controversial. We retrieved individual data of 1155 patients with metastatic CRC included in four first-line chemotherapy trials: Fédération Francophone de Cancérologie Digestive (FFCD)-9601, FFCD-2000-05, Actions Concertées dans les cancers COloRectaux et Digestifs (ACCORD)-13, and ML-16987. Patients with unresectable synchronous metastases were eligible for this study. We used univariate and multivariate analyses (Cox models stratified on the trial) to assess the impact of primary tumour resection and other potential prognostic variables on overall survival (OS) (the primary endpoint). Amongst the 1155 patients, 810 patients met the inclusion criteria and 59% (n = 478) underwent resection of their primary tumour, prior to trial entry (resection group). Compared to patients in the non-resection group (n =3 32 [41%]), those in the resection group were more likely to have a colonic primary, lower baseline carcinoembryonic antigen (CEA) and alkaline phosphatase levels, and normal white-blood-cell count (p < 0.001 each). Primary tumour resection was independently associated to better OS in multivariate analysis (hazard ratio (HR), 0.63 [0.53-0.75]; p < 0.001, with a more favourable impact of resection on OS in case of rectal primary and low CEA level. Primary tumour resection was also independently associated to a better progression-free survival in multivariate analysis (HR, 0.82 [0.70-0.95]; p < 0.001). Primary tumour resection was independently associated to a better OS in patients with CRC and unresectable synchronous metastases.
Transarterial chemoembolisation (TACE) is usually performed by injecting an emulsion of a drug an... more Transarterial chemoembolisation (TACE) is usually performed by injecting an emulsion of a drug and iodised oil. Drug-eluting beads (DEBs) have undeniable pharmacological advantages by offering simultaneous embolisation and sustained release of the drug to the tumour. No data are currently available on liver/biliary injury following DEB-TACE. This study describes and compares liver/biliary injuries encountered with TACE in tumours developed in cirrhotic (hepatocellular carcinoma (HCC)) and non-cirrhotic (endocrine tumours (NETs)) livers. In consecutive patients treated for a well-differentiated metastatic NET (n=120) or a HCC (n=88), 684 CT- and MR-scans were analysed. Liver/biliary injuries were classified as follows: dilated bile duct, portal vein narrowing, portal venous thrombosis and biloma/liver infarct. A generalised estimating equation logistic regression model was used. A liver/biliary injury followed 17.2% (82/476) of sessions in 30.8% (64/208) of patients. The occurrence of liver/biliary injury was associated with DEB-TACE (OR=6.63; p<0.001) irrespectively of the tumour type. Biloma/parenchymal infarct was strongly associated with both DEB-TACE (OR=9.78; p=0.002) and NETs (OR: 8.13; p=0.04). Biloma/liver infarcts were managed conservatively but were associated with an increase in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatases, and gamma glutamyl transpeptidase (p=0.005, p=0.005, p=0.012, and p=0.006, respectively). Liver/biliary injuries are independently associated with DEB-TACE. Biloma/liver infarct, the most serious injury, is independently associated with both DEB-TACE and NETs. The absence of such an association in TACE of HCC may be explained by the hypertrophied peribiliary plexus observed in cirrhosis, which protects against the ischemic/chemical insult of bile ducts. We suggest caution when using DEB-TACE in the non-cirrhotic liver.
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Papers by David Malka