Laurent Quero

miR-210 as a marker of chronic hypoxia, but not a therapeutic target in prostate cancer

INTRODUCTION Radiotherapy in combination with medical castration is the standard treatment for high-risk prostate cancer. Some relapses may be explained by the presence of radioresistant clones arising from hypoxic microenvironment. Since microRNAs (miR) are increased upon hypoxia, the aim of this study was to see whether miR-210 is a potential marker for hypoxia and/or a therapeutic target in prostate cancer. METHODS Human LNCaP, DU145 or PC3 prostate cancer cells were exposed to normoxia or hypoxia for several hours. Gene expression of miR-210, miR-373 and several hypoxia markers were analyzed by Taqman and SYBR green qRT-PCR, respectively. Clonogenic survival after LNA miR-210 inhibitor (78 nM) and concomitant irradiation were evaluated. RESULTS During anoxia, CAIX and VEGF expressions were dramatically increased. miR-210 expression increased during anoxia exposure, while basal miR-373 expression was low and remained stable upon anoxia. LNA miR-210 inhibitor decreased anoxic miR-210 expression by 90% and clonogenic survival under anoxia (p=0.01). However, no enhanced effect was observed when miR-210 inhibitor was combined with irradiation. CONCLUSION miR-210 could be an interesting marker of chronic hypoxia irrespective of the androgen dependency and should, therefore, be tested as a prognostic marker in high risk prostate cancer patients.

Anal carcinoma in HIV-infected patients in the era of antiretroviral therapy: a comparative study.

BACKGROUND: Before the introduction of highly active antiretroviral therapy, prognosis of anal squamous-cell carcinoma was worse when patients were infected with HIV. Since then, contradictory results have been reported. OBJECTIVE: To compare the results of chemoradiotherapy in HIV-infected and uninfected patients with anal carcinoma. DESIGN: Retrospective analysis of medical records. SETTING: Tertiary care center in France. PATIENTS: Patients with invasive anal carcinoma treated from 2001 through 2006. INTERVENTIONS: Chemoradiotherapy included 60 Gy pelvic irradiation and cisplatin-based chemotherapy. Surgery was performed for local failures or complications. MAIN OUTCOME MEASURES: Tolerance for chemoradiotherapy, tumor control, and survival were evaluated. RESULTS: A total of 46 patients (20 HIV-infected and 26 uninfected) were treated for nonmetastatic anal carcinoma. Median follow-up was 32.5 (range, 7–84) months. HIV-infected patients were more likely to be men (95% vs 23%, P < .001) and were younger (median age, 46 vs 62 years, P < .001) than uninfected patients. The viral load was less than 200 copies/mL in 15 (75%) of the HIV-infected patients. The duration of chemoradiotherapy was longer in HIV-infected than in uninfected patients (median, 103 vs 84 days, P = .027). Chemoradiotherapy failed to achieve local control in 10 (50%) HIV-infected and in 6 (23%) uninfected patients (P = .057). In HIV-infected patients, failure rates were higher in patients who required prolonged chemoradiotherapy than in those who received treatment as scheduled (7/11, 64% vs 1/7, 14%; P = .039). During follow-up, 7 (35%) of the HIV-infected and 3 (12%) of the uninfected patients died, all from anal carcinoma. The 5-year overall survival rate was 39% for HIV-infected and 84% for uninfected patients (P = .026); 5-year disease-free survival was 37% in HIV-infected and 75% in uninfected patients (P = .06). LIMITATIONS: Retrospective design, lack of data regarding precise toxicity grading, and use of cisplatin-based chemoradiotherapy. CONCLUSIONS: Even in the era of highly active antiretroviral therapy, HIV-infected patients with anal squamous-cell carcinoma show impaired tolerance to chemoradiotherapy, have a lower survival rate, and may have a higher rate of local failure compared with uninfected patients.

Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: a single institution experience

BackgroundTo assess the efficacy of salvage radiotherapy (RT) for persistent or rising PSA after radical prostatectomy and to determine prognostic factors identifying patients who may benefit from salvage RT.MethodsBetween 1990 and 2003, 59 patients underwent RT for PSA recurrence after radical prostatectomy. Patients received a median of 66 Gy to the prostate bed with 3D or 2D RT. The main end point was biochemical failure after salvage RT, defined as an increase of the serum PSA value >0.2 ng/ml confirmed by a second elevation.ResultsMedian follow-up was 38 months. The 3-year and 5-year bDFS rates were 56.1% and 41.2% respectively. According to multivariate analysis, only preRT PSA ≥1 ng/ml was associated with biochemical relapse.ConclusionWhen delivered early, RT is an effective treatment after radical prostatectomy. Only preRT PSA ≥1 ng/ml predicted relapse.

Prognostic and predictive factors of oesophageal carcinoma

Oesophageal carcinoma is a frequent disease, which incidence is high and stable (6,000 new cases per year in France). Its epidemiology has changed over the last three decades, adenocarcinoma becoming the most frequent histologic subtype. It is an aggressive disease with an early lymphatic spread. The prognosis of oesophageal carcinoma remains poor despite improved diagnosis and therapeutic strategies. The aim of this review is to describe the major prognostic and predictive factors of oesophageal carcinoma. These factors are mostly based on patient characteristics (performance status, weight loss, hemoglobin level), tumor spread (TNM stage, lymph node micrometastases, ratio of involved lymph nodes, extracapsular involvement), radicality of surgical resection (R0) or radiological and endoscopic response to chemoradiation therapy. Many molecular prognostic factors have also been described, among which the presence p53 mutations or high-levels of NF-kappaB are worth naming. An early decrease of tumoral glucose uptake measured by PET-CT appears to be a predictive factor of response to antitumor treatment. Genetic profiles of drug action pathways in oesophageal carcinoma have been described. They may provide additional information to predict tumor response to medical treatment.

Neoadjuvant or adjuvant therapy for gastric cancer

Currently, there is no international consensus on the best treatment regimen for patients with advanced resectable gastric carcinoma. In the United States, where a limited lymph-node dissection is frequently performed, adjuvant chemoradiotherapy after surgery is the standard treatment. In Europe, intensified perioperative chemotherapy is commonly administered. In Japan and South Korea, postoperative S-1-based adjuvant chemotherapy after surgery with D2 lymph-node dissection is the standard treatment. Several ongoing trials are currently evaluating the optimal sequence of chemotherapy, radiotherapy, and surgery, as well as the place of targeted therapeutic agents in the treatment of advanced gastric carcinoma.

Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy

BackgroundP53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti-p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma.MethodsSerum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted.ResultsTwenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression-free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT.ConclusionsAnti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population.

Colorectal cancer care in elderly patients: Unsolved issues

Colorectal cancers are common in elderly patients. However, cancer screening is poorly used after 75. Elderly patients form a heterogeneous population with specific characteristics. Standards of care cannot therefore be transposed from young to elderly patients. Tumour resection is frequently performed but adjuvant chemotherapy is rarely prescribed as there are no clearly established standards of care. In a metastatic setting, recent phase III studies have demonstrated that doublet front-line chemotherapy provided no survival benefit. Moreover, several studies have established the benefit of bevacizumab in association with chemotherapy. There is a lack of evidence for the efficacy of anti-epidermal growth factor antibodies in elderly patients. Geriatric assessments could help to select the adequate treatment strategy for individual patients. Geriatric oncology is now the challenge we have to face, and more specific trials are needed.

Exclusive moderate-dose radiotherapy in gastric marginal zone B-cell MALT lymphoma: Results of a prospective study with a long term follow-up

BACKGROUND In gastric MALT lymphomas persisting after Helicobacter pylori (H. pylori) eradication, a treatment by moderate-dose radiotherapy (RT) has been proposed but its efficacy has not been confirmed in large prospective series with long term endoscopic follow-up. METHOD Patients with localised gastric MALT lymphoma persisting after H. pylori eradication were offered moderate-dose RT (30Gy, 2Gy/fraction) and followed with annual endoscopies. All biopsies before and after RT were reviewed by a committee of pathologists. RESULTS From 1995 to 2011, out of the 232 patients followed prospectively, 53 received RT for persistence of lymphoma after H. pylori eradication: either macroscopic ulcer (n=31), or microscopic lymphomatous infiltrate (n=22), after a mean follow-up of 12 and 31months, respectively. All lymphomas were localised (45 stage IE and 8 stage IIE) and 38 (72%) were H. pylori-positive. The mean clinical and endoscopic follow-up from diagnosis was 7.6years (2.2-19.1). No acute or late toxicity occurred. A complete remission was achieved in all patients but one (98%) with no relapse after a median follow-up of 4.9years (1.3-16.6) after completion of RT. Overall survival and 5-year disease specific survival were 94% and 100%, respectively. One patient died of gastric adenocarcinoma. CONCLUSION Moderate-dose RT (30Gy) is effective and safe for localised gastric MALT lymphoma persisting after H. pylori eradication.

Réparation cellulaire et radiosensibilité tumorale : focus sur le gène ATM

Numerous parameters influenced tumour radiosensitivity. The number of clonogenic cells, growth fraction, hypoxia and intrinsic radiosensitivity are among the most important determinants of radiocurability. Detection of DNA damage and repair pathways are important components of intrinsic radiosensitivity. ATM plays a major role in the cellular response to ionizing radiation: it induced DNA repair, cell cycle arrest, and apoptosis via induction of p53. Analysis of single nucleotide polymorphisms could help us to predict normal tissue sensitivity on an individual basis. Mutations of ATM is probably involved in some cases of severe radiation-induced late effects. Measure of residual double-strand breaks by immunochemistry of H2AX, but also ATM or MRE11, is another way to evaluate tumour radiosensitivity. Integration of genomics and functional approach are needed to better predict what the best candidates for a curative radiotherapy are.

Antagonistic interaction between bicalutamide™ (Casodex®) and radiation in androgen-positive prostate cancer LNCaP cells

Bicalutamide™ (Casodex®) reportedly improves high‐risk prostate cancer survival as an adjuvant treatment following radiotherapy. However, biological data for the interaction between bicalutamide and ionizing radiation in concomitant association are lacking.