Erythropoietin and erythropoietin receptor coexpression is associated with poor survival in stage I non-small cell lung cancer.

PURPOSE: This study was designed to evaluate the prognostic effect of erythropoietin (EPO) and EPO receptor (EPO-R) expression in stage I non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: EPO and EPO-R expression in 158 tumor samples from resected stage I NSCLC was evaluated using immunohistochemistry and tissue array technology. RESULTS: EPO-R and EPO were highly expressed in 20.9% and 35.4% of tumors, respectively. High EPO-R expression compared with negative or low-level expression was associated with a poor 5-year disease-specific survival (60.6% versus 80.8%; P = 0.01, log-rank test). High EPO expression compared with negative and low-level expression was associated with a trend toward a poor 5-year disease-specific survival (69.6% versus 80.4%; P = 0.13, log-rank test). A high level of EPO-R and EPO coexpression was associated with a poor 5-year disease-specific survival compared with other groups of patients (50.0% versus 80.0% survival at the end of follow-up; P = 0.005, log-rank test). In multivariate analysis for disease-specific survival, high-level EPO-R and EPO coexpression was an independent prognostic factor for disease-specific survival (hazard ratio, 2.214; 95% confidence interval, 1.012-4.848; P = 0.046). CONCLUSION: These results establish the pejorative prognostic value of EPO and EPO-R expression in early-stage resected NSCLC and suggest a potential paracrine and/or autocrine role of endogenous EPO in NSCLC aggressiveness.

Vascular endothelial growth factor-C and its receptor VEGFR-3 in non-small-cell lung cancer: concurrent expression in cancer cells from primary tumour and metastatic lymph node.

INTRODUCTION: Investigation of the role of vascular endothelial growth factor-C (VEGF-C) and VEGF receptor-3 (VEGFR-3) in non-small-cell lung cancer (NSCLC) has mainly focused on lymph node (LN) metastasis related to lymphangiogenesis. However, the coexpression of VEGF-C/VEGFR-3 by tumour cells can independently play an important role. The present study was therefore designed to evaluate VEGF-C/VEGFR-3 coexpression in tumour cells from the primary tumour and corresponding LN metastases. METHODS: VEGF-C and VEGFR-3 expression in cancer cells were evaluated by immunohistochemistry in 92 NSCLC samples and 45 metastatic LNs. Ki67 expression and mitotic index (MI) in tumours and clinicopathological data were analysed concurrently. RESULTS: VEGFR-3 and VEGF-C expression were observed in 42% and 74% of tumours, respectively. Concurrent expression of VEGF-C and VEGFR-3, observed in 39% of tumours, was significantly associated with a higher proliferation rate and a higher incidence of LN metastases. VEGF-C expression in tumour cells was observed in 100% of metastatic LN and VEGF-C/VEGFR-3 coexpression was observed in 71% of metastatic LN. Finally, concurrent expression of VEGF-C/VEGFR-3 in the primary tumour was associated with poor disease-free survival on univariate analysis. CONCLUSION: In NSCLC cancer cells, VEGF-C/VEGFR-3 coexpression suggests an autocrine/paracrine loop responsible for a high proliferation rate in tumour cells. As VEGF-C/VEGFR-3 coexpression is very frequent in metastatic LN tumour cells, it can be hypothesised that this coexpression participates in the growth of LN metastasis.

Is sentinel lymph node mapping in colorectal cancer a future prognostic factor? A meta-analysis.

The diagnostic value of sentinel lymph node mapping (SLNM) in patients with colorectal cancer (CRC) is controversial. Prognostic factors for CRC must be detected to improve its treatment. A PubMed query (key words: colorectal cancer, sentinel node) provided 182 studies on the sentinel lymph node (SLN) for CRC, the abstracts of which were reviewed. Altogether, 48 studies dealing with the diagnostic value of SLNM were selected from PubMed, and 6 other studies were retrieved from reviews. We compared the diagnostic value of SLNM with that of conventional histopathologic examination. We used the diagnostic accuracy odds ratio (DAOR) method. Because of significant heterogeneity, we chose the random effect model (Der Simonian and Laird). Statistics were performed on 33 studies, including 1794 patients (1201 colon and 332 rectum cancers). The mean SLNM failure rate was 10%. The global sensitivity and specificity of the SLNM were, respectively, 70% and 81%. The pooled DAOR was 10.7 (95% confidence interval 7.0-16.5). That means that a patient whose SLN is invaded has 10.7 times more risk to be node-positive than an SLN-negative patient. Lymphatic mapping appears to be readily applicable to CRC. One of the main reasons for the heterogeneity is the performance of the SLNM by Saha et al., whose data had better sensitivity (90%) than those in other studies. The SLNM technique should be better standardized in future studies. Understanding the cause of false-negative SLNs (9%) is a major issue to resolve before routinely using this technique in CRC management. The prognostic implication of micrometastases found in SLNs requires further evaluation.

Tumor lysis associated with sudden onset of syndrome of inappropriate antidiuretic hormone secretion.

Syndrome of inappropriate antidiuretic hormone secretion is frequent in small-cell lung carcinomas. We report on a case of syndrome of inappropriate antidiuretic hormone secretion after each of the first 2 cycles of chemotherapy for small-cell lung cancer. The association with chemotherapy-induced tumor lysis is proposed, particularly based on the course of antidiuretic hormone levels, and a review of the literature is presented. Syndrome of inappropriate antidiuretic hormone secretion can occur during tumor lysis syndrome.

Oxaliplatin combined with 5-FU in second line treatment of advanced pancreatic adenocarcinoma. Results of a phase II trial.

BACKGROUND: The efficacy and benefit of second-line chemotherapy in advanced pancreatic adenocarcinoma has never been demonstrated although it is regularly used. PATIENTS AND METHODS: A randomized phase II study evaluating oxaliplatin alone (OXA), infusional 5-fluorouracil alone (5-FU) and an oxaliplatin/infusional 5-FU combination (OXFU) in untreated advanced pancreatic adenocarcinoma has been conducted. In this trial, a second-line treatment with the OXFU regimen (OXA 130 mg/m2 2-h intravenous (i.v.) infusion combined with 5-FU (1000 mg/m2/day, continuous i.v., days 1-4), every 3 weeks) was offered to patients progressing after single agent treatment. RESULTS: Eighteen out of 32 patients (12 males, median age 57 years) treated in the single agent arms received the OXFU combination in second-line treatment. WHO performance status was at least 2 in 61% of the patients. There was no objective response and 3 patients (17%) had a disease stabilisation. Median time to progression from the start of second-line treatment was 0.9 months. Median overall survival was 4.9 months from the start of front-line therapy and 1.3 months from the start of second-line therapy. CONCLUSION: The results of this trial bring arguments to support a modest value of second-line chemotherapy for advanced pancreatic adenocarcinoma.

Real-time RT-PCR detection of CK19, CK7 and MUC1 mRNA for diagnosis of lymph node micrometastases in non small cell lung carcinoma.

Metastatic lymph nodes (LNs) are the major prognostic factor in resected non small cell lung carcinoma (NSCLC). However, almost 50% of pN0 patients relapse, suggesting metastatic cells undetected by current staging procedures. A combination of markers [cytokeratins 19 and 7 (CK19, CK7) and mucin type 1 (MUC1) mRNAs] was therefore evaluated by real-time RT-PCR in order to detect occult cancer cells. Forty-three NSCLC tumor samples, 4 micrometastatic, 6 metastatic and 84 histologically negative mediastinal LNs from 19 patients with NSCLC were evaluated as well as blood mononuclear cells from 29 healthy volunteers and 17 benign LNs. When tested on cell lines, RT-PCR was particularly efficient for evaluation of CK19, CK7 and MUC1 mRNA expression. All tumor samples were positive for at least 1 marker and 74% of samples were positive for all 3 markers. CK7 and CK19 mRNA were not detected in benign LN and blood cells from healthy donors in contrast with MUC1 mRNA. Only CK7 and CK19 mRNA were therefore used for evaluation of mediastinal LNs: the 6 histologically metastatic and the 4 micrometastatic LNs were positive for at least one marker. Among the 84 histologically negative LNs, 6 (7%) were positive for at least one marker, potentially changing the stage of 2 out of 19 patients. In conclusion, in our feasibility study, parallel molecular detection of CK19 and CK7 mRNA can be considered a specific diagnostic tool for the assessment of microscopic lymphatic spread. Its prognostic impact remains to be evaluated in a prospective study.

Lung cancer in patients with HIV Infection and review of the literature.

BACKGROUND: The improved survival of patients since the use of highly active antiretroviral treatments has lead to the reporting of non-AIDS defining tumors, such as lung cancer. METHODS: Analysis of the records of 22 HIV-infected patients with lung cancer (LC) diagnosed in three hospitals located in the Paris area (France). RESULTS: Twenty-one patients were smokers. The patients (86% male, 14% female) had a median age of 45 yr (range, 33-64 yr). Risk factors for HIV infection were intravenous drug use in 5 patients, homosexual transmission in 10 patients, and heterosexual transmission in 7 patients. At diagnosis of LC, seven patients had previously developed a CDC-defined AIDS manifestation, the median CD4 cell count was 364/mm3 (range 20-854/mm3) and median HIV1 RNA viral load was 3000 copies/mL. The most frequent histological subtype was squamous cell carcinoma (11 cases). A stage III-IV disease was observed in 75% of the patients. Only one patient had a small-cell lung carcinoma. Twenty-one patients received combined specific therapy, of which six patients underwent surgery for the LC. The median overall survival was 7 mo. No opportunistic infections occurred during LC therapy. CONCLUSIONS: LC occurs at a young age in HIV-infected smokers. LC is not associated with severe immunodeficiency. The prognosis is poor because of their initial extensive disease and a poor response to therapy. However, surgery appears to improve outcome in much the same way as in the general population.

Phase II study of paclitaxel combined with vinorelbine in patients with advanced breast cancer.

Paclitaxel and vinorelbine are two drugs active against breast cancer. A phase II study was initiated with the aim of assessing the efficacy and feasibility of the combination. Twenty-six patients presenting with advanced breast cancer with a taxane- and vinorelbine-free line of chemotherapy were included and treated with vinorelbine (20 mg/m2 on D1, D15), followed by paclitaxel (175 mg/m2 on D1), every 3 weeks. A 48% (95% CI: 35-61) response rate was obtained in the 23 patients evaluable for response. Vinorelbine was administered on D15, as scheduled, in 72% of cycles. The main toxicity observed was grade III to IV neutropenia in 73% of patients. Febrile neutropenia was reported in three patients. Disease-free survival was 118 days, and overall median survival was 361 days. This combination of paclitaxel and vinorelbine is feasible and effective in patients with early relapse or previously treated with first-line chemotherapy for metastatic disease.

[Dose density and dose intensity in the treatment of breast cancer]. / Densité de dose et intensité de dose dans le traitement du cancer du sein.

Since 10 years, high-dose chemotherapy has been evaluated for the treatment of breast cancer in numerous randomized clinical trials. Preliminary results of some of these studies have shown an advantage in relapse-free survival in both metastatic and high-risk breast cancer. Although follow-up is short in most of the studies, no impact on overall survival has been detected. Based on available results, high-dose chemotherapy cannot be proposed either in metastatic or in high-risk breast cancer patients outside a clinical trial. Conversely, two randomized trials have demonstrated that dose-dense scheduled chemotherapy with G-CSF support, containing an anthracycline, cyclophosphamide and paclitaxel, improves clinical outcomes compared with the same regimen administered every 3 weeks. These results establish dose-dense scheduled chemotherapy containing an anthracycline and paclitaxel as an option for the adjuvant treatment of positive lymph nodes breast cancer patients. Data are not sufficient to conclude in the neoadjuvant and metastatic setting. High-dose chemotherapy and dose-dense chemotherapy seem to increase the pathological complete response rate in inflammatory breast cancer. However, prospective and comparative survival data are lacking.

[Cardiovascular toxicity of some cancer agents (others than anthracyclines, fluoropyrimidines and trastuzumab)]. / Toxicités cardiaques de quelques agents anticancéreux (autres que anthracyclines, fluoropyrimidines et trastuzumab).

Many others cancer agents can lead to cardiovascular toxicity apart from anthracyclines, 5-fluorouracil, trastuzumab and ionizing radiations. Paclitaxel, high-dose cyclophosphamide and ifosfamide, mitomycin and irinotecan cardiotoxicity is unusual but for certain. Hormonal therapy is extensively used in breast and prostate cancers. Thromboembolic and cardiovascular events are increased by estrogens, synthetic progestatives and tamoxifene. Because of major toxicities related to intravenous interleukin-2, subcutaneous interleukin-2 regimens have been developed, allowing an improvement of cardiovascular tolerability. Interferon is less frequently associated with cardiotoxicity. Before treatment initiation, risk factors favouring cardiac toxicity should be evaluated. These risk factors can be related to the cancer agent, to the patient or to the tumour. Uncommon toxic events in general population can be more frequent in high risk patients. Therapeutic option can be influenced by these uncommon toxic events in high risk patients.

[Non-metastatic intrahepatic cholestasis associated with bronchial adenocarcinoma]. / Cholestase intra-hépatique non métastatique associée à un adénocarcinome bronchique.

In 1961, Stauffer first described a syndrome characterized by nonmetastatic intrahepatic cholestasis associated with undifferentiated renal adenocarcinoma. Since that time, this syndrome has been associated with other tumor diseases. We describe here a patient with lung adenocarcinoma which led to paraneoplastic cholestasis. We discuss the diagnosis and review the literature, emphasizing the pathophysiology of Stauffer's syndrome.

[The interest of radiotherapy in cancer of the rectum]. / Intérêt de la radiothérapie dans le cancer du rectum.

CONTEXT: Surgery remains the standard treatment of rectal cancer. The risk of local recurrence is still a serious problem with an incidence of between 15 and 45%. This depends on the initial TNM stage and the surgical technique. In order to optimally improve local control and survival of the patients, radiotherapy has become an unavoidable adjuvant treatment in specific situations. ISOLATED RADIOTHERAPY: For locally advanced cancers (T3 or T4), pre-surgical radiotherapy followed by curative surgery is the standard treatment because of the improvement in global survival and good local control that has recently been confirmed. With radiotherapy it is also possible to schedule conservative sphincter surgery in the case of low rectal lesions and permit surgery of initially inoperable lesions. THE CONCOMITANT ASSOCIATION OF RADIOTHERAPY AND CHEMOTHERAPY DURING THE PRE-SURGICAL PERIOD: In rare cases in which the tumour stage was underestimated in the pre-surgical controls, post-surgical concomitant radio-chemotherapy is required. In cases in which surgery was performed first line, in the presence of histological factors of poor prognosis, post-surgical radio-chemotherapy is warranted. In the United States, the reference chemotherapy used in this association is 5 FU in continuous intravenous infusion. In the rare cases of contraindication for surgery, exclusive concomitant radio-chemotherapy is an appropriate solution, even if no treatment has been validated in this indication. Palliative surgery can be proposed in supplement: usually a colostomy or, more rarely excision using the endorectal route. MEDICAL TREATMENT: Exclusive radio-chemotherapy has only demonstrated interest in the palliative treatment of inoperable loco-regional relapses that have already undergone radiation or in metastatic stages as in colon cancers. Currently post-surgical chemotherapy is recommended in stage III cancer of the rectum as in colon cancers at the same stage.

AIDS and non-AIDS-related malignancies: a new vexing challenge in HIV-positive patients. Part II. Cervical and anal squamous epithelial lesions, lung cancer, testicular germ cell cancers, and skin cancers.

As the AIDS epidemic progresses, more and more HIV-infected patients will develop malignancies. The natural history of a malignancy may change dramatically in the presence of HIV infection. Among the AIDS and non-AIDS malignancies, the most frequently reported solid tumors are cervical and anal cancer, testicular germ cell tumors, lung cancer, and skin cancer. Regardless of epidemiology and outcome, the natural history of the majority of non-AIDS-defining tumors changes in the setting of HIV infection. Physicians who treat patients with AIDS and non-AIDS-related cancers need to become familiar with antiretroviral agents, drug-drug interactions, and the prophylaxis and management of opportunistic infections.

Intrapleural infusion of activated macrophages and gamma-interferon in malignant pleural mesothelioma: a phase II study.

STUDY OBJECTIVES: Intrapleural immunotherapy has shown some activity in patients with malignant mesothelioma. We conducted a multicentric pilot phase II study to evaluate the tolerance and the activity of intrapleurally infused autologous human activated macrophages (AM Phi) in patients with stage IA, IB, and IIA malignant pleural mesothelioma (MPM). DESIGN: AM Phi derived from in vitro monocyte culture were infused into the pleura of patients every week for 8 consecutive weeks. Each infusion was followed 3 days later by an intrapleural injection of 9 millions units of gamma-interferon (gamma-IFN) in an attempt to prolong the in vivo activation of infused AM Phi. Response was assessed by CT scan and thoracoscopy when possible. If the patient's disease progressed after AM Phi treatment, an additional treatment was left to the choice of the investigator. PATIENTS: Nineteen patients with histologically proven stage IA, IB, or IIA MPM were enrolled. Two patients were excluded before any AM Phi infusion because of complications impeding infusion. Seventeen patients were actually treated. After completion of the AM Phi cellular therapy, 10 patients were treated with chemotherapy as their diseases progressed. RESULTS: The overall response rate of patients actually treated was 14%. When including the two patients enrolled but not treated, the overall response "in intention to treat" was 11%; two patients had a partial response, with a duration of response of 30 months and 3 months, respectively. One patient, who could not be evaluated by thoracoscopy because of pleural symphysis, is still alive without any clinical or radiologic sign of disease 69 months after treatment. No major adverse effects were observed during the infusion of either AM Phi or gamma-IFN, and there was no interruption of treatment because of toxicity. However, symphysis was observed in 7 of 14 patients who received the complete treatment. The median survival of patients actually treated, including those who received chemotherapy after AM Phi, was 29.2 months. CONCLUSION: Combined infusion of AM Phi and gamma-IFN was well tolerated in patients with MPM; however, it had limited antitumor activity.

AIDS and non-AIDS-related malignancies: a new vexing challenge in HIV-positive patients. Part I: Kaposi's sarcoma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

HIV-infected patients are at an increased risk for developing cancers. Three, in particular, are considered to be AIDS-defining malignancies: Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL), and cervical cancer. Other non-AIDS-defining malignancies have been reported in the setting of HIV infection as having an increased frequency compared with their incidence in the general population. One of those most frequently reported is Hodgkin's disease. As with KS and NHL, the problem of diagnosing and treating immunocompromised patients with cancer represents a formidable challenge. Moreover, a newly discovered human gamma-herpes virus, human herpes virus-8 (HHV-8), has been identified in over 90% of KS lesions from patients with and without AIDS, suggesting its etiological importance in the development of KS and new therapeutic approaches.