A case of Muir-Torre syndrome associated with mucinous hepatic cholangiocarcinoma and a novel germline mutation of the MSH2 gene.

Muir-Torre syndrome (MTS) is a rare cancer-predisposing syndrome that is autosomal dominantly inherited and characterized by the development of sebaceous skin lesions (adenomas, epitheliomas, basaliomas and carcinomas). These lesions are typically associated with tumors that belong to the spectrum of hereditary nonpolyposis colorectal cancer (HNPCC) (i.e., tumors of the colorectum, endometrium, stomach or ovary). Biliary malignancy in association with MTS has only rarely been reported. We report a case of Muir-Torre syndrome associated with intrahepatic cholangiocarcinoma, a location not previously described, and associated with a novel missense mutation of the MSH2 gene (c.2026T > C), predicted to disrupt the function of the gene.

[Treatment of bone metastases with bisphosphonates]. / Traitement des métastases osseuses par les bisphosphonates.

Bone metastasis are very common in many cancers; metastatic bone disease is the most common cause of cancer pain and also of serious complications, which reduce the quality of life of these patients. Management of skeletal cancer involves a multimodality approach who include bisphosphonates, which in association with anti-tumour treatments reduce the apparition of new skeletal-related events (SRE) and prolong the delay to first SRE. They although reduce the pain of bone metastasis. All this facts do the quality of life better.

Review of the pemetrexed and gemcitabine combination in patients with advanced-stage non-small cell lung cancer.

Pemetrexed is a new multitargeted antifolate that can be easily administered as a 10-min infusion every 3 weeks. The use of folic acid, vitamin B(12), and corticoid prophylaxis has significantly reduced pemetrexed-induced toxicity. Single-agent pemetrexed has shown antitumor activity in a wide range of solid tumors, including non-small cell lung cancer (NSCLC). Association with vinorelbine, cisplatin, carboplatin, and oxaliplatin have been tried, but the pemetrexed and gemcitabine combination, an easy to administer cisplatin-free doublet, has been documented in many phase 2 trials in the first-line treatment of advanced NSCLC. In vitro cytotoxic assays and phase I studies have defined several schedules of administration for pemetrexed and gemcitabine. The recommended dose is pemetrexed 500 mg/m(2) on day 1 or 8, and gemcitabine 1250 mg/m(2) on day 1 and 8, but it is unknown if pemetrexed should precede or follow gemcitabine and at what time interval. Published studies have failed to show significant differences in overall survival times despites response rates oscillating between 15% and 41%. The main toxicities are neutropenia, fatigue, skin rashes and elevated transaminases and seem to occur with similar rates in the many phase 2 trials. Hopes for the future are in tailored chemotherapy, since molecular markers of sensitivity are available for gemcitabine and pemetrexed, allowing to determinate in the future which patients will be most likely to benefit from the gemcitabine-pemetrexed doublet.

Nosocomial nontyphoidal salmonellosis after antineoplastic chemotherapy: reactivation of asymptomatic colonization?

An increased frequency of nontyphoidal salmonellosis is well established in cancer patients, but it is unclear whether this represents increased susceptibility to exogenous infection or opportunistic, endogenous reactivation of asymptomatic carriage. In a retrospective study, a simple case definition was used to identify the probable presence of reactivation salmonellosis in five cancer patients between 1996 and 2002. Reactivation salmonellosis was defined as the development of nosocomial diarrhea >72 h after admission and following the administration of antineoplastic chemotherapy in an HIV-seronegative cancer patient who was asymptomatic on admission, in the absence of epidemiological evidence of a nosocomial outbreak. Primary salmonellosis associated with unrecognized nosocomial transmission or community acquisition and an unusually prolonged incubation period could not entirely be ruled out. During the same time period, another opportunistic infection, Pneumocystis pneumonia, was diagnosed in six cancer patients. Presumably, asymptomatic intestinal Salmonella colonization was converted to invasive infection by chemotherapy-associated intestinal mucosal damage and altered innate immune mechanisms. According to published guidelines, stool specimens from patients hospitalized for longer than 72 h should be rejected unless the patient is neutropenic or >or=65 years old with significant comorbidity. However, in this study neutropenia was present in only one patient, and four patients were <65 years old. Guidelines should thus be revised in order not to reject stool culture specimens from such patients. In cancer patients, nosocomial salmonellosis can occur as a chemotherapy-triggered opportunistic reactivation infection that may be similar in frequency to Pneumocystis pneumonia.

Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer.

BACKGROUND: PKC412 (N-benzoyl-staurosporine), an oral inhibitor of protein kinase C, is capable of cell cycle inhibition and is endowed with anti-angiogenic properties. This dose-finding phase I study was designed to establish the maximum tolerated dose (MTD) of PKC412 when combined with cisplatin-gemcitabine. PATIENTS AND METHODS: Escalating doses of PKC412 were given every day of a 4 week cycle with cisplatin 100 mg/m2 on day 2 and gemcitabine 1000 mg/m2 on days 1, 8 and 15 in patients with non-small-cell lung cancer. Dose escalation was based on a modified continuous reassessment method. RESULTS: Twenty-three patients, assigned to four cohorts receiving PKC412 at a dose ranging from 25 to 150 mg/day were evaluable. Grade 3 diarrhea occurring in 3/4 patients at cycle 1 led us to define 150 mg/day as the MTD. The MTD based on multiple cycles was redefined as 100 mg/day, since prolonged grade 2-3 nausea/vomiting leading to treatment discontinuation occurred in 3/7 patients after repeated cycles. The next lower dose tested of 50 mg/day was therefore considered as the recommended dose for phase II trials. Among 33 cycles in eight patients, toxicity consisted of grade 1-2 diarrhea (12.5%) and asthenia (50%) with only one patient experiencing grade 3 headache at this dose level. A partial response was observed in three patients. CONCLUSIONS: The results of the present study indicate that PKC412 at a dose of 50 mg/day can be safely added to cisplatin and gemcitabine in patients with advanced non-small-cell lung cancer.

Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma.

BACKGROUND: The aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC). METHODS: Gemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m(2), respectively. RESULTS: Forty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m(2)) and oxaliplatin (85 mg/m(2)) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated (167 cycles) at that dose level. Thirteen cycles were associated with grade 3-4 non-febrile neutropenia in six patients, and eight cycles with grade 3-4 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m(2) experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70-100 mg/m(2). Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients. CONCLUSIONS: The combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m(2) and oxaliplatin 85 mg/m(2) every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.

End points for new agents in induction chemotherapy for locally advanced head and neck cancers.

More than 60% of patients diagnosed with squamous cell carcinoma of the head and neck present at a locally advanced stage. Although multimodality therapy has improved locoregional control, the 5-year survival rate of this population rarely exceeds 30%. In this review, we analyzed the impact of chemotherapy in the management of locally advanced head and neck cancer and we underline the potential benefit of induction chemotherapy. The Meta-Analysis of Chemotherapy in Head and Neck Cancer collaborative group has suggested a survival advantage of 5% at 5 years for platin-5-fluorouracil induction chemotherapy. We have analyzed cofactors that may affect the survival of head and neck patients and propose new end points for assessment of the efficacy of induction chemotherapy. The detrimental effect of second primary tumors on long-term results is stressed and we have suggested the use of overall 2-year survival as a surrogate end point for induction chemotherapy efficacy. Finally, we have examined the impact of new cytotoxic agents and present the promising results of new taxane-based combinations.

Phase I clinical and pharmacokinetic studies of the taxoid derivative RPR 109881A administered as a 1-hour or a 3-hour infusion in patients with advanced solid tumors.

PURPOSE: To define the maximum tolerated dose (MTD), the recommended phase II dose, the optimal infusion duration and pharmacokinetics of the semisynthetic taxoid derivative RPR 109881A, given as a 1-h or 3-h infusion every 3 weeks. PATIENTS AND METHODS: RPR109881A was administered as a 1-h i.v. infusion to 34 patients (study 1) with oral steroids as pre-medication. In a subsequent study, 29 patients were treated at the recommended dose or at the dose immediately below (study 2); the first 14 patients received RPR 109881A as a 3-h infusion, while the subsequent 15 were randomized to receive the drug as a 1-h or 3-h infusion. The pharmacokinetics of RPR109881A was studied in plasma and urine and for selected patients in some biological fluids (cerebrospinal fluid, pleural effusion, ascitis). RESULTS: In study 1, the dose was escalated from 15 to 105 mg/m(2), at which dose two of five patients presented dose-limiting toxicities with febrile neutropenia (FN) after the first cycle, thus defining the MTD. The dose of 90 mg/m(2), at which grade 3/4 neutropenia was almost universal with FN in 18%, was recommended for phase II. At 90 mg/m(2) the incidence of diarrhea, fatigue and alopecia were 59, 29 and 70%, respectively. The results of study 2 were comparable to those of study 1, thus recommending the 1-h infusion duration for phase II evaluation. RPR 109881A exhibited a high total body clearance, a large distribution volume and long terminal half-life of 20 h. RPR 109881A was detected in cerebrospinal fluid shortly after the end of 1-h infusion. Three objective responses were observed in non-small-cell lung cancer (NSCLC) patients, including a patient with brain metastases. CONCLUSIONS: The antitumor activity in NSCLC, the reproducible profile of toxicity and above all the ability to cross the blood-brain barrier make RPR 109881A worthy of further disease-oriented clinical development.

[Zd 1839 "Iressa"]. / Le ZD 1839: "Iressa".

ZD 1839 is a highly specific EGF receptor tyrosine kinase inhibitor. Inhibition of EGF receptor transphosphorylation by ZD 1839 blocks the signal transduction at the first step, thus providing antiproliferative effects. Preclinical studies demonstrated efficacy and good bioavailability. The terminal half-life of the compound in patients is ranging from 27 to 41 hours, allowing single oral dosing. Tolerance in healthy volunteers was excellent. In phase I studies, toxicity was manageable. Most common side effects were skin rash, nausea, vomiting, and diarrhea. During those studies, clinical responses were observed in patients with various malignant tumors, in particular non small cell lung cancer. Phase II and III studies are ongoing.

[Tumor anemia. Overview of the role of human recombinant erythropoietin (r-hu-EPO) in treatment of tumor anemia]. / Tumoranämie. Ubersicht über die Rolle des humanen rekombinanten Erythropoetins (r-hu-EPO) bei der Behandlung der Tumoranämie.

The prevalence of anaemia in patients with cancer lies between 10 and 40%, depending on the type of tumor and chemotherapy. Anaemia has a significant impact on the quality of life, along with pain or disease progression. There are multiple causes but the physiopathology resembles that of inflammatory anaemia. The following mechanisms can be distinguished: a resistance of the erythroid precursor cells (BFU-e, CFU-e) to erythropoietin, an inappropriately decreased renal erythropoietin secretion for a given haemoglobin value and alterations of the iron metabolism leading to a functional iron deficiency. Recombinant human erythropoietin (r-hu-EPO) is safe and efficient in the treatment of anaemia of chronic renal failure and rheumatoid arthritis. In oncology different phase I and II studies have demonstrated an efficacy (increase of haemoglobin, decrease of transfusion requirements) in about 50% of all adult patients. A response to a subcutaneous r-hu-EPO treatment with a relatively high posology of 150 U/kg three times a week can be expected after one to two months. No single reliable parameter will predict a response to the r-hu-EPO treatment. Several phase III studies confirm that anaemia in cancer patients undergoing chemotherapy (notably with cisplatin) can be corrected in 40 to 60% of all cases and that the haemoglobin increase improves the quality of life. Finally, recent clinical trials suggest that an early r-hu-EPO treatment might prevent the occurrence of anaemia secondary to chemotherapy. Several parameters will have to be specified such as the precise definition of the groups at risk, the appropriate haemoglobin level to initiate a r-hu-EPO treatment, its optimal posology, as well as the role of the iron substitution and its route of administration. The impact of the r-hu-EPO treatment on the quality of life of cancer patients constitutes a priority for future studies, which will have define the exact role of r-hu-EPO in oncology management.

[Homocysteine and venous thromboembolism]. / Homocystéine et maladie thrombo-embolique veineuse.

Congenital homocysteinuria is a rare inherited metabolic disorder with early onset atherosclerosis and arterial and venous trombosis. Moderate hyperhomocysteinemia is more frequently encountered and is recognized as an independent cardiovascular risk factor. Several case-control studies demonstrate an association between venous thromboembolism and moderate hyperhomocysteinemia. A patient with moderate hyperhomocysteinemia has a 2-3 relative risk of developing an episode of venous thromboembolism. The occurrence of mild hyperhomocysteinemia in heterozygotes for the mutation of Leiden factor V involves a 10-fold increase in the risk of venous thromboembolism. The biochemical mechanism by which homocysteine may promote thrombosis is not fully recognized. Homocysteine inhibits the expression of thrombomodulin, the thrombin cofactor responsible for protein C activation, and inhibits antithrombin-III binding. Treatment with folic acid reduces the plasma level of homocysteinemia, but no study has demonstrated its efficacy in reducing the incidence of venous thromboembolism or atherosclerosis. Hyperhomocysteinemia should be included in the screening of abnormalities of hemostasis and thrombosis in patients with idiopathic thromboembolism, and mild hyperhomocysteinemia may justify a trial of folic acid.