Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy

in European Journal of Cancer (2010), 46

Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years.We hypothesized that SCLC chemotherapy could be improved by ... [more ▼]

Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years.We hypothesized that SCLC chemotherapy could be improved by using histone deacetylase (HDAC) inhibitors based on their ability to interfere with lysine acetylation and to alter gene expression. The goal of this study was to evaluate the anticancer efficacy of a HDAC inhibitor (valproate: VPA) on SCLC cells in combination with the standard chemotherapeutic first-line regimen (cisplatin + etoposide). We show that VPA induces apoptosis of small cell lung cancer cell lines and improves efficacy of cisplatin combined with etoposide. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. As expected for an HDAC inhibitor, VPA hyperacetylates histone H3. The mechanism of VPA pro-apoptotic activity involves induction of p21, inhibition of Bcl-xL, cleavage of Bid and phosphorylation of Erk and H2AX. In the presence of VPA, Bax is translocated from the cytoplasm to the mitochondria and cleaved in an 18 kDa isoform. Cytochrome c is released from the mitochondria into the cytosol. Transcriptomic analyses by microarray show that VPA modulates transcription of genes (Na+/ K+ ATPase, Bcl-xL) involved in chemoresistance to cisplatin and etoposide. Finally, the efficacy of VPA combined with cisplatin and etoposide is supported by preclinical models of SCLC cells engrafted into SCID mice. Together, these data demonstrate that VPA augments anticancer activity of cisplatin and etoposide, two components of the standard first-line chemotherapy of small cell lung cancer. [less ▲]

Profile of methylaion of tumour related genes in breast cancer in Tunisian women

in European Journal of Cancer (2008), 6(9), 195

Does a patient's self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer? (vol 42, pg 42, 2006)

in European Journal of Cancer (2007), 43(3), 633-633

Baseline health-related quality-of-life data as prognostic factors in a phase III multicentre study of women with metastatic breast cancer

in European Journal of Cancer (2004), 40(7), 1021-1030

The potential value of baseline health-related quality-of-life (HRQOL) and clinical factors in predicting prognosis was examined using data from an international randomised phase III trial which compared ... [more ▼]

The potential value of baseline health-related quality-of-life (HRQOL) and clinical factors in predicting prognosis was examined using data from an international randomised phase III trial which compared doxorubicin and paclitaxel with doxorubicin and cylophosphamide as first line chemotherapy in 275 women with metastatic breast cancer. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the related breast module (QLQ-BR23) were used to assess baseline HRQOL data. The Cox proportional-hazards regression model was used for both univariate and multivariate analyses of survival. In the univariate analyses, performance status (P < 0.001) and number of sites involved (P = 0.001) were the most important clinical prognostic factors. The HRQOL variables at baseline most strongly associated with longer survival were better appetite, physical and role functioning, as well as less fatigue (P < 0.001). The final multivariate model retained performance status (P < 0.001) and appetite loss (P = 0.005) as the variables best predicting survival. Substantial loss of appetite was the only independent HRQOL factor predicting poor survival and was strongly correlated (\r\ > 0.5) with fatigue, role and physical functioning. In addition to known clinical factors, appetite loss appears to be a significant prognostic factor for survival in women with metastatic breast cancer. However, the mechanism underlying this association remains to be precisely defined in future studies. (C) 2004 Elsevier Ltd. All rights reserved. [less ▲]

Shortened irradiation scheme, continuous infusion of 5-fluorouracil and fractionation of mitomycin C in locally advanced anal carcinomas. Results of a phase II study of the European Organization for Research and Treatment of Cancer. Radiotherapy and Gastrointestinal Cooperative Groups

in European Journal of Cancer (2003), 39

Abstract The European Organization for Research and Treatment of Cancer (EORTC) 22861 randomised trial established that combined radiochemotherapy is the standard treatment for locally advanced anal ... [more ▼]

Abstract The European Organization for Research and Treatment of Cancer (EORTC) 22861 randomised trial established that combined radiochemotherapy is the standard treatment for locally advanced anal cancer. This EORTC phase II study (#22953) tests the feasibility of reducing the gap between sequences to 2 weeks, to deliver Mitomycin C (MMC) in each radiotherapy sequence and 5-FU continuously during the treatment. The first sequence consisted of 36 Gy over 4 weeks. 5-FU 200 mg/m2/days 1–26, MMC 10 mg/m2/day 1 gap 16 days. Then a second sequence of 23.4 Gy over 17 days, 5-FU 200 mg/m2/days 1–17 and, MMC 10 mg/m2/day 1 was given. 43 patients with a World Health Organization (WHO) status of 0 (n=27) or 1 (n=16) and with T2-T4, N0-3 tumours were included. Compliance with the planned treatment, doses and duration was 93%. The complete response rate was 90.7%. Grade 3 toxicities of 28, 12 and 2% were observed for skin, diarrhoea and haematological toxicities, respectively. The 3-year estimated rates for trials 22861 and 22953 are: 68 and 88% for local control; 72 and 81% for colostomy-free interval, 62 and 84% for severe late toxicity-free interval, and 70 and 81% for survival, respectively. The 22953 scheme is feasible and the results are promising. This is now considered as the new standard scheme by the EORTC. [less ▲]

Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis?

in European Journal of Cancer (2001), 37

Abstract To assess the prognostic factors and the outcome in patients with squamous-cell carcinoma of the penis, a retrospective review of 41 consecutive patients with non-metastatic invasive carcinoma of ... [more ▼]

Abstract To assess the prognostic factors and the outcome in patients with squamous-cell carcinoma of the penis, a retrospective review of 41 consecutive patients with non-metastatic invasive carcinoma of the penis, treated between 1962 and 1994, was performed. The median age was 59 years (range: 35±76 years). According to the International Union Against Cancer (UICC) 1997 classi®cation, there were 12 (29%) T1, 24 (59%) T2, 4 (10%) T3 and 1 TX (2%) tumours. The N-classi®cation was distributed as follows: 29 (71%) patients with N0, 8 (20%) with N1, 3 (7%) with N2 and 1 (2%) with N3. Forty-four per cent (n=18) of the patients underwent surgery: partial penectomy with (n=4) or without (n=12) lymph node dissection, or total penectomy with (n=1) or without (n=1) lymph node dissection. 23 patients were treated with radiation therapy alone, and all but 4 of the patients who were operated upon received postoperative radiation therapy (n=14). The median follow-up period was 70 months (range 20±331 months). In a median period of 12 months (range 5±139 months), 63% (n=26) of the patients relapsed (local in 18, locoregional in 2, regional in 3 and distant in 3). Local failure (stump in the operated patients, and the tumour bed in those treated with primary radiation therapy) was observed in 4 out of 16 (25%) patients treated with partial penectomy postoperative radiotherapy versus 14 out of 23 (61%) treated with primary radiotherapy (P=0.06). 15 (83%) out of 18 local failures were successfully salvaged with surgery. In all patients, 5- and 10-year survival rates were 57% (95% con®dence interval (CI), 41±73%) and 38% (95% CI, 21± 55%), respectively. The 5-year local and locoregional rates were 57% (95% CI, 41±73%) and 48% (95% CI, 32±64%), respectively. In patients treated with primary radiotherapy, 5- and 10-year probabilities of surviving with penis preservation were 36% (95% CI, 22±50%) and 18% (95% CI, 2±34%), respectively. In multivariate analyses, survival was signi®cantly in¯uenced by the N-classi®- cation, and surgery was the only independent factor predicting the locoregional control. We conclude that, in patients with squa- mous-cell carcinoma of the penis, local control is better in patients treated with surgery. However, there seems to be no di erence in terms of survival between patients treated by surgery and those treated by primary radiotherapy salvage surgery, with 39% having organ preservation. [less ▲]

Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis?

in European Journal of Cancer (2000), 37(2), 198203

To assess the prognostic factors and the outcome in patients with squamous-cell carcinoma of the penis, a retrospective review of 41 consecutive patients with non-metastatic invasive carcinoma of the ... [more ▼]

To assess the prognostic factors and the outcome in patients with squamous-cell carcinoma of the penis, a retrospective review of 41 consecutive patients with non-metastatic invasive carcinoma of the penis, treated between 1962 and 1994, was performed. The median age was 59 years (range: 35–76 years). According to the International Union Against Cancer (UICC) 1997 classification, there were 12 (29%) T1, 24 (59%) T2, 4 (10%) T3 and 1 TX (2%) tumours. The N-classification was distributed as follows: 29 (71%) patients with N0, 8 (20%) with N1, 3 (7%) with N2 and 1 (2%) with N3. Forty-four per cent (n=18) of the patients underwent surgery: partial penectomy with (n=4) or without (n=12) lymph node dissection, or total penectomy with (n=1) or without (n=1) lymph node dissection. 23 patients were treated with radiation therapy alone, and all but 4 of the patients who were operated upon received postoperative radiation therapy (n=14). The median follow-up period was 70 months (range 20–331 months). In a median period of 12 months (range 5–139 months), 63% (n=26) of the patients relapsed (local in 18, locoregional in 2, regional in 3 and distant in 3). Local failure (stump in the operated patients, and the tumour bed in those treated with primary radiation therapy) was observed in 4 out of 16 (25%) patients treated with partial penectomy ±postoperative radiotherapy versus 14 out of 23 (61%) treated with primary radiotherapy (P=0.06). 15 (83%) out of 18 local failures were successfully salvaged with surgery. In all patients, 5- and 10-year survival rates were 57% (95% confidence interval (CI), 41–73%) and 38% (95% CI, 21–55%), respectively. The 5-year local and locoregional rates were 57% (95% CI, 41–73%) and 48% (95% CI, 32–64%), respectively. In patients treated with primary radiotherapy, 5- and 10-year probabilities of surviving with penis preservation were 36% (95% CI, 22–50%) and 18% (95% CI, 2–34%), respectively. In multivariate analyses, survival was significantly influenced by the N-classification, and surgery was the only independent factor predicting the locoregional control. We conclude that, in patients with squamous-cell carcinoma of the penis, local control is better in patients treated with surgery. However, there seems to be no difference in terms of survival between patients treated by surgery and those treated by primary radiotherapy ±salvage surgery, with 39% having organ preservation. [less ▲]

Predicting response in head and neck cancer: The search for the holy grall

in European Journal of Cancer (1997), 33(supp 8), 289-290

Expression of the 67 Kd Laminin Receptor in Human Ovarian Carcinomas as Defined by a Monoclonal Antibody, Mluc5

in European Journal of Cancer (1996), 32A(9), 1598-602

Previous immunohistochemical data from our laboratory have demonstrated that expression of the 67 kD laminin receptor (67LR), a cancer-associated, high-affinity laminin-binding protein, is upregulated in ... [more ▼]

Previous immunohistochemical data from our laboratory have demonstrated that expression of the 67 kD laminin receptor (67LR), a cancer-associated, high-affinity laminin-binding protein, is upregulated in ovarian carcinoma cells compared with normal serosal cells, and that this increased expression in cancer cells could be related to patient outcome. The aim of this study was to validate MLuC5, a monoclonal antibody that recognises the 67LR, as a tool to perform future immunohistochemical studies on larger populations of ovarian carcinoma patients. Expression of the 67LR was determined in 51 primary human ovarian carcinoma samples using immunohistochemistry and MLuC5. The 67LR was detected in ovarian carcinoma cell clusters of variable extent. Analysis of the data determined that 67LR expression was significantly increased in the samples from patients with disease progression, compared with those with no evidence of disease after completion of primary therapy, and in pooled grade 2 and 3 tumours compared to borderline and grade 1 tumours (P < 0.05, chi-squared test). No other significant correlation between 67LR expression and other clinicopathological parameters could be established. These data suggest that the 67LR is correlated to ovarian tumour progression. Detection of the 67LR using this monoclonal antibody could constitute an interesting parameter in prognosis determination of ovarian cancer. [less ▲]

Effects of antimitotic agents bound to a macromolecular carrier in normal or cancer cells. Importance of the mode of binding of the agent to the carrier.

in European Journal of Cancer (1978), 14(9), 1005-11