Primary extranodal non-Hodgkin lymphomas of the uterus and the breast: report of three cases

The authors describe one case of a rare primitive non-Hodgkin lymphoma of the uterus, and two cases of primary non-Hodgkin lymphoma of the breast. Histologically, the uterine lymphoma, although clinically confined to the uterus, was a diffuse large cell lymphoma, group G according to the Working formulation for Clinical Usage. The two cases of breast lymphoma were a centrocytic-centroblastic and a lymphoplasmocytoid non-Hodgkin lymphoma, respectively. All cases were initally treated with radical surgery plus radiotherapy, but the first patient showed an early recurrence at distant sites, which required systemic cytotoxic chemotherapy. The patient with uterine non-Hodgkin lymphoma received a very intense regimen-i.e. the ProMACE-Cytabom-because of the unfavourable histology, while the two patients with primary breast non-Hodgkin lymphoma received less aggressive CHOP and CVP chemotherapy. All patients are still alive and free of disease 3 to 6 years after initial diagnosis. These cases stress the systemic nature of non-Hodgkin lymphomas even if apparently localized to a single extranodal organ. Thus, although a definitive therapeutic strategy cannot be drawn from the rare and occasional reports in the medical literature, primary extranodal lymphomas require integrated multimodality therapy with radiotherapy and/or chemotherapy. © 1995 W.B. Saunders Company Limited

Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies.

Mutations in the Ki-ras and TP53 genes are the most frequently observed genetic alterations in colorectal cancer (CRC). Ki-ras mutations are mostly found in codons 12 and 13, and less in codon 61. The majority of the TP53 mutations occur in the core domain which contains the sequence-specific DNA binding activity of the protein, and they results in loss of DNA binding. Few centres have sufficient patients to collect detailed information in the large numbers required to determine the impact of individual ki-ras and TP53 genotypes on outcome. Moreover, it has been reported that specific genetic alterations, and not any mutation, might play a different biological role in cancer progression. For these principal reasons, two collaborative studies have been conducted (the RASCAL and the TP53-CRC Collaborative Studies) with the aim of investigating the prognostic role of any, and specific, Ki-ras and TP53 mutations in CRC progression. The results obtained from the RASCAL studies suggest that Ki-ras mutations might have an effect on the survival rate of CRC patients, and that the specific codon 12 glycine/valine mutation might play a role in the progression of this neoplasia. The results of the TP53-CRC International Collaborative Study demonstrate the importance of primary tumor site when analyzing the prognostic value of TP53 mutations in CRC. In addition, different types of TP53 mutation might play a pivotal role in determining the biological behavior of CRC from different sites and hence the prognosis of patients. This meta-analysis produced evidence for interesting tumor site differences in the predictive value of TP53 mutation for survival benefit from 5FU chemotherapy

Gemcitabine-based doublets versus single-agent therapy for elderly patients with advanced nonsmall cell lung cancer: a Literature-based Meta-analysis.

Although platinum-based combinations are considered the best option of care for patients with advanced nonsmall cell lung cancer (NSCLC), single-agent therapy is the preferred treatment for older patients. Since the late 1990s, various combinations of third-generation agents (gemcitabine [G], vinorel- bine, docetaxel, and paclitaxel) have been tested, yielding contradictory results. The authors of this report performed a literature-based meta-analysis to assess the efficacy and tolerability of G-based doublets compared with single-agent chemotherapy for elderly patients with NSCLC. METHODS: Data from all published, randomized, phase 3 trials that compared a G-based doublet with a third-generation single agent in elderly patients were collected from electronic databases (Medline and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. Pooled odds ratios (ORs) were calculated for the 1-year survival rate, the overall response rate (ORR), and grade 3 and 4 toxicities. RESULTS: Four eligible trials (1436 patients) were selected from 442 studies that initially were identified. A significant difference in ORR favoring G-based doublets over single agents was observed (OR, 0.65; 95% confidence interval [95% CI], 0.51-0.82 [P<.001]), whereas the trend toward an improved 1-year survival rate was not significant (OR, 0.78; 95% CI, 0.57-1.06 [P¼.169]). Grade 3 and 4 toxicities did not differ significantly except for thrombocytopenia (OR, 1.76; 95% CI, 1.12-2.76 [P¼.014]). CONCLUSIONS: G-based doublets appeared to be effective and feasible compared with single agents in the treatment of elderly patients with advanced NSCLC who were not suitable for full-dose, platinum-based chemotherapy. Further prospective, elderly specific, phase 3 trials will be necessary

The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment

PURPOSE: The aims of the TP53 Colorectal Cancer (CRC) International Collaborative Study were to evaluate the possible associations between specific TP53 mutations and tumor site, and to evaluate the prognostic and predictive significance of these mutations in different site, stage, and treatment subgroups. PATIENTS AND METHODS: A total of 3,583 CRC patients from 25 different research groups in 17 countries were recruited to the study. Patients were divided into three groups according to site of the primary tumor. TP53 mutational analyses spanned exons 4 to 8. RESULTS: TP53 mutations were found in 34% of the proximal colon tumors and in 45% of the distal colon and rectal tumors. They were associated with lymphatic invasion in proximal tumors. In distal colon tumors, deletions causing loss of amino acids were associated with worse survival. In proximal colon tumors, mutations in exon 5 showed a trend toward statistical significance (P < .05) when overall survival was considered. Dukes' C tumors with wild-type TP53 and those with mutated TP53 (proximal tumors) showed significantly better prognosis when treated with adjuvant chemotherapy. CONCLUSION: Analysis of TP53 mutations from a large cohort of CRC patients has identified tumor site, type of mutation, and adjuvant treatment as important factors in determining the prognostic significance of this genetic alteration

Activin A circulating levels in patients with bone metastasis from breast or prostate cancer

Recent studies have highlighted that Activin A, a member of the transforming growth factor-beta (TGF-beta) superfamily, may be involved in the regulation of osteoblastic activity and in osteoclast differentiation. Therefore, we have investigated the clinical significance of its circulating levels in patients with bone metastasis. Activin A serum concentrations were determined, by a commercially available enzyme-linked immunosorbent assay kit, in 72 patients with breast cancer (BC) or prostatic cancer (PC) with (BM+) or without (BM-) bone metastases, in 15 female patients with age-related osteoporosis (OP), in 20 patients with benign prostatic hypertrophy (BPH) and in 48 registered healthy blood donors (HS) of both sex (25 female and 23 male). Activin A serum concentrations were significantly increased in BC or PC patients as compared to OP (P < 0.0001) or BPH (P = 0.045), respectively, or to sex matched HS (P < 0.0001). Additionally, these levels resulted more elevated in PC patients as compared to BC patients (P = 0.032). Interestingly, Activin A was significantly higher in BM+ patients than in BM- patients (BC, P = 0.047; PC, P = 0.016). In BC patients, a significant correlation was observed only between Activin A and number of bone metastases (P = 0.0065) while, in PC patients, Activin A levels were strongly correlated with the Gleason score (P = 0.011) or PSA levels (P = 0.0001) and, to a lessen extent, with the number of bone metastases (P = 0.056). Receiver operating characteristic curve (ROC) analysis showed a fair diagnostic accuracy of Activin A to discriminate between BM+ and BM- patients (BC: AUC = 0.71 +/- 0.09, P = 0.03; PC: AUC = 0.73 +/- 0.081, P = 0.005). These findings indicate that Activin A may be implicated in the pathogenesis of bone metastasis. Therefore, this cytokine may be considered a novel potential target for a more selective therapeutic approach in the treatment of skeletal metastasis and may be also useful as additional biochemical marker of metastatic bone disease

Effects of zoledronic acid on proteinase plasma levels in patients with bone metastases.

Background: The effects of the bisphosphonate derivative zoledronic acid (ZA) on the > circulating levels of matrix metalloproteinase-2 (MMP-2), matrix metallo-proteinases-9 > (MMP-9), cathepsin B (Cath B) and urokinase-type plasminogen activator (uPA) in > patients with bone metastasis (BMTS) and the possible correlation with the symptomatic > response induced by this drug in these patients were evaluated. Patients and Methods: > Proteinase levels were determined by enzyme-linked immunosorbent assay (ELISA) in the > plasma of 30 patients with painful bone metastases from breast or prostate cancer > undergoing multiple treatment with ZA (4 mg i.v., every 4 weeks). Healthy subjects > (HS) of both genders (12 female and 30 male) served as the control group. The > symptomatic response to ZA was assessed by the visual analog scale score (VAS). > Results: The median MMP-2 and MMP-9 pretreatment levels were more elevated in BMTS as > compared to HS (p¡Ü0.0001). Conversely, uPA levels were lower in BMTS p=0.0033; no > significant difference was observed for Cath B. ZA administration was associated with > a symptomatic response (VAS score¡Ü4) in 25/30 patients (83.3%) (p<0.0001). This > phenomenon paralleled a decrease of Cath B and MMP-2 plasma concentrations from > baseline values on week 12 (p=0.05). A similar trend, although not statistically > significant, was also noted for MMP-9 and uPA. However, no direct relationship was > observed between the analgesic effect induced by ZA and changes in the circulating > levels of these enzymes. Conclusion: These data show that ZA administration may > provide relief from bone pain in patients with diffuse skeletal metastases and confirm > a possible implication of cysteine proteinases and matrix metalloproteinases in bone > metastasis formation, but not in the pathogenesis of metastatic bone pain

Bisphosphonate-related osteonecrosis of the jaw (BRONJ): run dental management designs and issues in diagnosis.

Recently, jawbone osteonecrosis has been largely reported as a potential adverse effect of bisphosphonate (BP) administration. Because of the peculiar pharmacokinetic and pharmacodynamic features of the BF (mainly for i.v. administration), their efficacy and large use, some major issues have to be taken into account extendedly both by oncologists and by dentists: 1) therapeutic dental protocol for patients with diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ); 2) dental strategies for patients in former or current i.v. BF treatment and in absence of BRONJ signs; 3) strategies for patients before i.v. BF treatment. Clinical features and guidelines for the management of this condition have been investigated and reported, sometimes with unclear indications; hence, on the basis of the literature and our clinical experience, major end points of this paper are providing our run protocols for the issues above described and, finally, focusing on a crucial, but not extensively investigated point: the early and correct diagnosis of BRONJ versus metastatic jaw lesions in cancer patients

Clinical presentation and treatment of gastrointestinal stromal tumors.

AIMS AND BACKGROUND: Gastrointestinal stromal tumors (GISTs), although rare, are the most common mesenchymal neoplasms affecting the gastrointestinal tract. We present our experience in the treatment of localized and metastatic disease and a review of literature. PATIENTS AND METHODS: Nine patients were observed from April 2002 to July 2004. Eight tumors were in the gastric area and 1 was in the small bowel. In 5 cases, complete surgical removal was performed, and none of these patients underwent adjuvant therapy. The remaining 4 cases, with locally advanced or recurrent disease, were treated with imatinib. RESULTS: The patients with localized disease treated only by surgery did not relapse. In the patients with locally advanced or metastatic disease treated by imatinib, we observed 3 partial responses, and one case was not assessable because he had no measurable disease. In 2 of 3 responders, it was possible to perform a new radical surgery. CONCLUSIONS: Our series is too small to draw any conclusion. According to our review of the literature, surgery remains the standard treatment for non-metastatic GISTs. Imatinib mesylate represents a major breakthrough in the treatment of advanced GISTs and is the first effective systemic therapy for the disease

Aurora-A overexpression as an early marker of reflux-related columnar mucosa and Barrett's oesophagus.

Abstract BACKGROUND: The development of oesophageal adenocarcinoma is generally closely associated with the presence of a specialised intestinal-type epithelium such as that found in Barrett's oesophagus (BO). A particular histological condition is when the distal oesophagus showing cardiac and/or fundic mucosa without intestinal metaplasia cannot be defined as 'Barrett's mucosa' [condition that we call 'columnar-lined oesophagus' (CLO)] and up till now, there has been no agreement in literature about the management of this condition. Aurora-A overexpression leads to centrosome amplification, chromosomal instability and aneuploidy in mammalian cells. PATIENTS AND METHODS: A prospective study was carried out on 28 consecutive patients who presented columnar mucosa above the gastro-oesophageal junction (GOJ) at endoscopy. As controls, two more biopsies were obtained, one on the normal-appearing squamous oesophagus above the GOJ, as far as possible from the columnar mucosa (controls A), and one taken 1 cm below the GOJ (controls B). The Aurora-A and p53 expression levels were analysed respectively by Quantitative Real Time PCR and immunohistochemistry. RESULTS: Twelve patients were affected by BO (43%) while the other 16 patients (57%) had a CLO. Nine of 28 (32%) cases were focally positive for p53 immunostaining. All the BO/CLO samples were positive for the Aurora-A transcript with regard to controls. Furthermore, 13 of 28 (46%) cases showed overexpression (above the median for the whole group). CONCLUSION: Due to the low number of cases, we are not at present able to state that statistically significant quantitative differences in Aurora-A messenger RNA expression exist between CLO and BO cases with and without dysplasia and p53-positive immunostaining. Further studies on a larger number of cases with a follow-up period are necessary in order to establish the risk of progression and the correct management of these subjects

MMP-2, MMP-9 and activin A blood levels in patients with breast cancer or prostate cancer metastatic to the bone.

Background: The clinical significance of the circulating levels of activin A and matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) was investigated in patients with breast cancer (BC) or prostate cancer (PC) with (M1) or without (M0) bone metastasis. Patients and Methods: MMP-2, MMP-9 and activin A blood concentrations were measured by enzyme immunoassays in 79 cancer patients and in 57 healthy blood donors (HS) who served as a control group. The diagnostic accuracy of these molecules to discriminate between M0 and M1 patients was evaluated by the receiver operating characteristic curve (ROC) and compared to that of tumor markers CA15.3 or prostate-specific antigen (PSA). Results: Activin A and MMP-2 were significantly increased in BC and PC patients as compared to sex-matched HS while MMP-9 levels were more elevated only in the PC patients. Interestingly, in the PC patients, activin A levels were significantly higher than those measured in the BC patients. In this latter group, activin A and CA15.3 but not MMP-2 or MMP-9 were increased in the M1 patients as compared to M0 patients. Furthermore, a significant relationship was also highlighted between activin A concentration and the number of bone metastases and tumor grade, between MMP-9 and tumor grade, and between MMP-2 and CA15.3. ROC curve analysis showed a good diagnostic accuracy for activin A and CA15.3 but a poor accuracy for MMP-2 and MMP-9 in discriminating between M0 and M1 patients. However, CA15.3 retained the best diagnostic accuracy in this respect. In the PC group, only activin A and PSA levels were significantly increased in the M1 patients as compared to the M0 patients. A similar although not statistically significant trend was noted for MMP-9. Interestingly, a significant correlation was observed between PSA and activin A and MMP-9, and between Activin A and Gleason score and the number of skeletal metastases. ROC curve analysis showed a good diagnostic accuracy for activin A, MMP-9 and PSA and a poor diagnostic accuracy for MMP-2 in detecting M1 patients. However, PSA showed the highest diagnostic accuracy. Conclusion: Activin A, MMP-2 and MMP-9 may be regarded as possible therapeutic targets in the treatment of metastatic bone disease. However, their usefulness as additional markers of bone metastasis remains to be better define