Gemcitabine and oxaliplatin combination chemotherapy for metastatic well‐differentiated neuroendocrine carcinomas

BACKGROUND:

Beyond the usual regimens based on streptozocin and doxorubicin or 5‐fluorouracil, no second‐line therapy of metastatic neuroendocrine tumor has gained wide acceptance. Gemcitabine and oxaliplatin are generally well tolerated and have shown activity against a wide range of malignancies. The authors assessed the efficacy of gemcitabine‐oxaliplatin combination (GEMOX) in the treatment of patients with metastatic neuroendocrine tumors.

METHODS:

Twenty consecutive patients with progressive disease were treated with GEMOX, in most cases after failure of other chemotherapy regimens (median = 2). Patients were followed for evidence of toxicity, response, and survival. Two patients were chemotherapy‐naive at treatment initiation and were excluded from the efficacy analysis.

RESULTS:

Toxicity was manageable overall; however, 6 (30%) patients had to discontinue treatment because of oxaliplatin‐induced neurotoxicity (grade 2). Three (17%) of 18 patients had a partial response, median progression‐free survival was 7.0 months, and median overall survival was 23.4 months.

CONCLUSIONS:

Gemcitabine‐oxaliplatin combination shows interesting activity and is well tolerated in pretreated patients with neuroendocrine tumors. Cancer 2009. © 2009 American Cancer Society.     

CASP8 D302H and meningioma risk: an analysis of five case-control series

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.     

Is further screening of men with baseline PSA < 1 ng ml−1 worthwhile? The discussion continues—Results of the Swiss ERSPC (Aarau)

Recent studies indicate frequent early PSA retesting unrelated of men's baseline PSA, which increases the harms of early detection especially among men with low PSA. The current study investigates the PCa incidence among men with baseline PSA <1.0 ng ml^?1 in order to adjust retest intervals for more targeted early detection. Between 1998 and 2012, 2,416 men with baseline PSA <1.0 ng ml^?1 were prospectively observed. Primary endpoint was PCa diagnosis. Negative predictive value (NPV) and number needed to screen (NNS) to detect one PCa were calculated. During a median follow‐up time of 12.1 years, 54 (2.2%) PCa were diagnosed with n = 26 (48.1%) among men with baseline PSA of 0.75 ≤ 1.0 ng ml^?1 (upper baseline PSA quartile). The 10‐year probability of being diagnosed with PCa increased significantly from 0.19% (baseline PSA < 0.40 ng ml^?1) to 2.0% (baseline PSA 0.40 ≤ 0.56 ng ml^?1), 2.5% (baseline PSA 0.56 ≤ 0.75 ng ml^?1) over 4.4% (baseline PSA 0.75 ≤ 1.0 ng ml^?1) (all p values <0.0001), respectively. The frequency of Gleason ≥7 PCa increased from 1 (0.17%) to 8 (1.4%), 5 (0.8) over 11 (1.8%) in these groups. The 8‐year NPV for Gleason ≥ 7 PCa were 99.8 (baseline PSA < 0.40 ng ml^?1), 99.8 (baseline PSA 0.40 ≤ 0.56 ng ml^?1), 100 (baseline PSA 0.56 ≤ 0.75 ng ml^?1) and 99.5 (baseline PSA 0.75 ≤ 1.0 ng ml^?1), respectively. During 12 years, the numbers were 99.8, 98.6, 99.2, and 98.2, respectively. Therefore, due to the very low rate of Gleason ≥ 7 PCa, further screening might be omitted in men with baseline PSA < 0.4 ng ml^?1. Between 0.4 and 1.0 ng ml^?1, an 8‐year interval can be discussed.     

Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families

Introduction:

A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers.

Methods:

GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene.

Results:

The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer.

Conclusions:

Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.     

Tocotrienol inhibits proliferation of human Tenon’s fibroblasts in vitro: a comparative study with vitamin E forms and mitomycin C

Purpose To evaluate the potential of the vitamin E compound α-tocotrienol as antifibrotic agent in vitro. Methods Using human Tenon’s capsule fibroblast cultures, the antiproliferative and cytotoxic effects of the different vitamin E forms α-tocopherol, α-tocopheryl acetate, α-tocopheryl succinate and α-tocotrienol were compared with those of mitomycin C. To mimic subconjunctival and regular oral application in vivo, exposure time of serum-stimulated and serum-restimulated fibroblasts (SF and RF, respectively) to vitamin E forms was set at 6 days. Cultures were only exposed for 5 min to mitomycin C due to its known acute toxicity and to mimic the short-time intraoperative administration. Proliferation (expressed as % of control) was determined by DNA content quantification on days 2, 4 and 6, whereas cytotoxicity was assessed by cell morphology and glucose 6-phosphate dehydrogenase (G6PD) release after 24 h. Results α-Tocopherol and α-tocopheryl acetate stimulated growth of SF, but not RF. Reduction of fibroblast content by α-tocopheryl succinate was accompanied by increased G6PD release and necrosis. Contrary to α-tocopheryl succinate, 50 μM or repeatedly 20 μM of α-tocotrienol significantly inhibited proliferation without causing cellular toxicity (maximal effect: 46.8%). RF were more sensitive to this effect than SF. Mitomycin C 100–400 μg/ml showed a stronger antiproliferative effect than α-tocotrienol (maximal effect: 13.8%). Morphologic characteristics of apoptosis were more commonly found under treatment with mitomycin C. Conclusions Of the vitamin E forms tested, only α-tocotrienol significantly inhibited growth at non-toxic concentrations. In this in vitro study, antiproliferative effects of mitomycin C were stronger than those of α-tocotrienol.     

Adolescent dietary phytoestrogen intake and breast cancer risk (Canada)

Objective It has been suggested that dietary phytoestrogen intake during adolescence may reduce the risk of developing breast cancer. This population-based case–control study evaluated the association between adolescent dietary phytoestrogen intake and adult breast cancer risk among women in Ontario, Canada. Methods Pathology-confirmed, population-based breast cancer cases, aged 25–74 years, diagnosed between June 2002 and April 2003, were identified using the Ontario Cancer Registry. Population-based controls were recruited, and matched to cases within 5-year age groups. Adolescent phytoestrogen intake was obtained using a brief food frequency questionnaire (n = 3,024 cases, n = 3,420 controls). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results Higher phytoestrogen intake (both isoflavones and lignans) during adolescence was associated with a reduced breast cancer risk, and a monotonic trend was observed from the lowest to the highest quartile (OR [Q2] = 0.91, 95% CI 0.79–1.04, OR[Q3] = 0.86, 95% CI 0.75–0.98, and OR[Q4] = 0.71, 95% CI 0.62–0.82, p-trend < 0.001). Conclusion Adolescent dietary phytoestrogen intake may be associated with a decreased risk of adult breast cancer. If verified, this finding has important implications with regard to breast cancer prevention since diet is a potentially modifiable factor.     

Intratracheal exposure of the guinea pig lung to cadmium and/or selenium: a histological evaluation

Anesthetized male Hartley guinea pigs (350-410 g) (n=5) received intratracheally, saline; cadmium (Cd) (0.3 mg); selenium (Se) (0.3 or 0.06 mg); or Cd (0.3 mg) with Se (0.06 mg), per animal. Twenty-four hours later, lungs were evaluated. Bronchoalveolar-lavage fluid of Cd- and/or Se-treated animals varied in their total and differential leukocyte percent population from that of saline control (P<0.05). Cadmium alone or with Se caused high lung to body weight ratios (P<0.05). High lung wet-weight to dry-weight (W/D) ratios (P<0.05) suggestive of lung edema, were evident after Cd and/or Se exposure. Histological examination of Cd- and/or Se-exposed lungs revealed leukocytic infiltration. Results demonstrated that separate or concurrent exposure to noxious metal(s) such as Cd and Se provoke lung edema and injury. Low dose of Se which when instilled alone, although did not result in an increased W/D lung ratio, failed to subside concurrently administered Cd-inflicted damage.     

Induction chemotherapy with cisplatin and epirubicin followed by radiotherapy and concurrent cisplatin in locally advanced nasopharyngeal carcinoma observed in a non-endemic population

Background and purpose

Chemoradiotherapy (CRT) represents the main therapy choice in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). The aim of this study was the clinical evaluation of neoadjuvant chemotherapy (NACT) followed by CRT in a non-endemic population affected by advanced NPC.

Materials and methods

Patients with locoregionally advanced NPC were treated with three cycles of induction chemotherapy (CHT) with cisplatin (100 mg/m²) plus epirubicin (90 mg/m²), followed by cisplatin (100 mg/m²) and concomitant radiotherapy (70 Gy).

Results

In 40 patients treated with such protocol, after the completion of induction CHT and CRT we observed the objective response rates of 90% and 100%, respectively. Treatment tolerability and toxicity were easily controllable. With a median follow-up time of 54 months, 3- and 5-year disease-free survival was 75% and 65% and 3- and 5-year overall survival was 84% and 77%.Three- and 5-year locoregional control was 82% and 70%, and 5-year distant metastases free survival was 75%.

Conclusions

NACT with cisplatin and epirubicin followed by concomitant CRT represents a feasible, efficient treatment for patients with advanced NPC. This regimen ensures an excellent locoregional disease control and overall survival with a low incidence of distant metastases.