Port-a-Cath-related complications in 252 patients with solid tissue tumours and the first report of heparin-induced delayed hypersensitivity after Port-a-Cath heparinisation.

The use of the subcutaneous Port-a-Catheters (Port-a-Caths) provides an important mean of venous access for oncological patients. The aim of our retrospective consecutive single-centre study was to investigate Port-a-Cath-related complications in 252 cancer patients. Overall period of Port-a-Caths maintenance was 25 months. The strategy of our centre is to keep Port-a-Caths in situ up to the end of follow-up in adjuvant cancer patients. A total of 22 complications were recorded (8.73%). Interventional complications occurred in four patients. The main complications during Port-a-Cath use included thrombosis (4 patients, 1.58%), infections (4 patients, 1.58%), persistent pain or discomfort (3 patients, 1.19%) and dislocations (2 patients, 0.79%). Median time to the occurrence of any type of complications was 4.5 months. Eleven Port-a-Caths were removed due to complications (4.36%). Similar rate of Port-a-Cath-related thrombosis/infection was seen in adjuvant and advanced cancer patients (no statistical significance). Continuous infusion of anticancer therapy via a Port-a-Cath system is a relatively safe procedure, although major complications might occur. We are first to describe heparin-induced delayed hypersensitivity after heparinisation of Port-a-Cath. This fact should influence the preference to keep the Port-a-Cath after completion of adjuvant anticancer treatment.

Molecular detection of epidermal growth factor receptor in colorectal cancer: does it still make sense?

AIM: The aim of the study was to detect and compare the epidermal growth factor receptor (EGFr) content using different methods, to establish whether the quantitative detection and functional study of EGFr in colorectal cancer, using methods other than immunohistochemistry (IHC), are appropriate. METHOD: Analysis of EGFr by IHC was performed in 230 colorectal cancer patients using monoclonal anti-EGFr. Total and activated EGFr (pY1068) contents were determined in 92 patients and real-time PCR, to determine the level of EGFr messenger RNA, was carried out in 60 patients. RESULTS: There was no association between EGFr IHC groups and the mean total EGFr levels measured using ELISA. CONCLUSION: The study shows that the results of different EGFr detection methods do not correlate with each other. Hence, the real role of EGFr in colorectal cancer remains unsettled. Clinically, the receptor itself does not seem to be important and it would be better to focus on EGFr signalling in downstream pathways.

Experimental results and related clinical implications of PET detection of epidermal growth factor receptor (EGFr) in cancer.

The epidermal growth factor receptor (EGFr) is one of the most studied molecules as a target for cancer therapy. Over these last few years, several studies attempting to identify predictive biomarkers of treatment response, such as the receptor status or other molecules related to the downstream signalling pathway, have been conducted. However, from a clinical point of view, the information obtained from ex vivo analyses still has various limitations that may be overcome by the combination with molecular imaging technologies which may provide a noninvasive, global, in vivo evaluation of the molecular tumour background. The aim of this review is to report the preclinical results of all positron emission tomography (PET) tracers synthesized until now for in vivo detection of EGFr in cancer. Two classes of PET compounds have been developed: labelled small molecules such as tyrosine kinase inhibitors and labelled monoclonal antibodies. The in vitro and in vivo results of these PET tracers are very different depending on the chemical properties, positron emission radionuclide, or animal models. As a consequence, various critical questions are still open, and the implications of a translation in the clinical setting for EGFr imaging in cancer patients is discussed.

Conventional and novel PET tracers for imaging in oncology in the era of molecular therapy.

In the last ten years, the development of several novel targeted drugs and the refinement of state of the art technologies such as the genomics and proteomics and their introduction to clinical practice have revolutionized the management of patients affected by cancer. However, everyday practice points out several clinical questions: the difficulty of response assessment to new drugs especially using standard RECIST criteria that do not provide information on biological, vascular or metabolic variations; the inadequate selection of patients who are likely to benefit from a targeted therapy excluding those with breast cancer and gastrointestinal stromal tumours; the need to know the global biological background of diseases especially in metastatic setting using repeatable non-invasive procedures. Molecular imaging could provide information on in vivo distribution of biological markers in response to targeted therapy and could improve the selection of patients before therapies. The aim of this review is to analyze the current role of conventional and innovative positron emission tomography (PET) radiotracers in clinical practice and to explore the promising perspectives of molecular imaging in cancer research.

Gene expression profiling of liver metastases from colorectal cancer as potential basis for treatment choice.

At present no reports on gene expression profiling of liver metastases from colorectal cancer are available. We identified two different signatures using Affymetrix platform: epidermal growth factor receptor pathway was upregulated in metachronous lesions, whereas the pathway mainly related to angiogenesis was in synchronous lesions. Synchronous or metachronous liver metastases could be treated differently on the basis of different molecular pathways.

Molecular imaging and targeted therapies in oncology: new concepts in treatment response assessment. a collection of cases.

The widespread use of several new non-cytotoxic drugs and the significant improvements in functional imaging highlights a number of difficulties in monitoring, interpreting and predicting treatment response in clinical practice. Certain guidelines for disease assessment after therapy are already available: the traditional Response Evaluation Criteria in Solid Tumours guidelines based on tumour size variations using conventional imaging technologies, the recent combined method developed by Choi and colleagues in gastrointestinal stromal tumour treated with tyrosine kinase inhibitors based on tumour density variations using computed tomography (CT), and the European Organization for Research and Treatment of Cancer criteria based on tumour glucose metabolism variations using fluorodeoxyglucose (FDG) positron emission tomography (PET). At the moment combined PET/CT response criteria are still not available. A number of new PET compounds other than FDG are also currently being developed to visualize specific cellular and molecular tumour pathways but their role in assessment and prediction of cancer treatment response has not yet been thoroughly investigated in a large series. However, in clinical practice many oncologists treat cancer patients with targeted therapies or chemotherapy and evaluate the response using conventional or functional imaging without appropriate and standardized guidelines. The aim of this study was to present a selection of clinical cases that illustrate the usefulness of new PET tracers and efficacy evaluation of new drugs. In the era of molecular imaging and molecular therapies, these cases highlight the urgency to develop new criteria for treatment assessment and the exigency of correctly interpreting the biological information obtained from new technologies, and introduce new concepts that require further investigation in clinical trials.

Surgical debulking of gastrointestinal stromal tumors: is it a reasonable option after second-line treatment with sunitinib?

INTRODUCTION: After imatinib treatment, the surgical management of patients affected by gastrointestinal stromal tumor (GIST) has been widely reported and often considered by many oncologists in clinical practice. Surgical results are correlated with disease responsiveness to tyrosine kinase inhibitors and with complete extirpation of all tumor sites. By now, no report specifically addressing surgical management after second-line treatment with sunitinib is still available. Most patients have an unresectable disease and do not have any other therapeutical options except for clinical trials. MATERIALS AND METHODS: We report two clinical cases of patients with metastatic GISTs, who underwent surgery after sunitinib, and discuss the surgical management option in this clinical setting. RESULTS: Both our patients had a long, durable stable disease on sunitinib, but one developed a chronic mild bleeding that does not call for emergency surgical interventions and the other one developed chronic heart toxicity. They were proposed to undergo surgery despite the unresectable diseases and received an incomplete resection because of residual metastatic lesions. They restarted sunitinib after surgery. CONCLUSIONS: The poor prognosis after sunitinib treatment and the absence of alternative validated options open the debate on the assessment of surgical management of metastatic GISTs in this setting. The role of surgery should be investigated in clinical trials; however, the enrollment may be difficult. In clinical practice and after a multidisciplinary case patient discussion, surgery could represent a reasonable choice for advanced GISTs especially if the risk of surgery-related death is not too high.

Molecular imaging suggests efficacy of bevacizumab beyond the second line in advanced colorectal cancer patients.

We report the clinical history of a female affected by advanced colorectal cancer (CRC). The patient was treated with five subsequent therapeutic schedules (FOLFIRI, FOLFOXIRI, FOLFIRI, FOLFOX4, FOLFOX4 plus cetuximab) because of the progression of the disease. The sixth treatment was bevacizumab in combination with 5-fluorouracil and irinotecan (FOLFIRI). The CT scan and the FDG-PET/CT performed 3 months after the beginning of the treatment showed that some, even if not all, lesions had a reduction of both size and metabolic activity. After the second revaluation the disease progressed. This short report suggests that the response of CRC to antiangiogenetic therapy may also occur after several unsuccessful antineoplastic treatments. Different biological features may explain the nonhomogeneous objective response of the metastatic lesions. Molecular imaging techniques seem to be mandatory in the era of tailored therapy since it is useful to have an in vivo 'biological picture' of the neoplastic disease.

Targeted therapies in solid tumours: results and promises.

In these last few years novel approaches to the treatment of solid tumours have been proposed. Therapeutic agents addressed to specific functions of the neoplastic cells seems to be very promising tools, with a low grade of toxicities. These agents are the basis of the so called targeted therapies. Small molecules inhibiting the proliferative cascade of the cancer cells and monoclonal specific antibodies against growth factor or vascular endothelial growth factor have been claimed as the promise in cancer therapy. Unfortunately, the very good results obtained in preclinical experiments have not been completely confirmed in the clinical practice. A selection of patients who could have beneficial effects from the novel agents is mandatory to avoid inappropriate therapies and also unjustified expenses.

Successful selective arterial embolizations for bone metastases in renal cell carcinoma integrated with systemic therapies: A case report.

Herein is described the case of a 64-year-old patient affected by metastatic clear-cell carcinoma, with exclusive bone disease, subjected after the initial cytoreductive nephrectomy to 3 successive lines of medical treatment (sunitinib, everolimus, and sorafenib) and multiple locoregional treatments (spinal surgery, radiation therapy, and selective arterial embolization), resulting in a surprisingly long survival of over 75 months. In the era of target therapy, integration strategies, including additional locoregional treatment to medical therapy, are essential to optimize the clinical benefit, to maximize treatment duration overcoming focal progressive disease, and to improve the quality of life. In this context, we would highlight that selective transcatheter embolization of bone metastases from renal cell carcinoma should be considered as an effective and safe option in the palliative setting for patients with bone metastasis, especially for pain relief.

Determination of Mammalian Target of Rapamycin Hyperactivation as Prognostic Factor in Well-Differentiated Neuroendocrine Tumors.

PURPOSE: To evaluate the role of the activation of mTOR (phosphorylated mTOR, p-mTOR) and the expression SSTR2A and IGF-1R as prognostic factor in well-differentiated neuroendocrine tumors. METHODS: A retrospective study was conducted on data from patients with diagnosis of neuroendocrine tumor originated from pancreas (pNET) or gastrointestinal tract (stomach, appendix, and ileus; GI-NET) made between January 2003 and December 2004 and followed up at our institution. Archival material should be available for revision according to WHO 2010 neuroendocrine tumor classification and for p-mTOR, SSTR2A, and IGF-1R immunostaining, calculating a quantitative score (QS). We evaluated clinical, pathological, and immunohistochemistry features for association with the presence of advanced disease at diagnosis and disease relapse in patients who have undergone radical surgery. RESULTS: Archival material from 64 patients was analyzed (37 pNETs and 27 GI-NETs). In these patients, G2 grading, low SSTR2A QS, and high p-mTOR QS were associated with advanced disease at diagnosis at multivariate analysis. Risk of recurrence in 49 patients with R0-resected tumors was higher for G2 grading, stage IIIB-IV, low IGF-1R QS, and high p-mTOR QS at univariate analysis. CONCLUSIONS: With the limits of retrospective data, activation of m-TOR is correlated with advanced disease at diagnosis and with shorter disease-free survival after R0 resection. Validation through prospective studies is needed.

Radiotherapy in the management of gist: state of the art and new potential scenarios.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. The main treatment for localized gastrointestinal stromal tumors is surgical resection. Unresectable or advanced GIST are poorly responsive to conventional cytotoxic chemotherapy but the introduction of tyrosine kinase inhibitors (TKIs) marked a revolutionary step in the treatment of these patients, radically improving prognosis and clinical benefit. Historically GIST has been considered radiation-resistant, and the role of radiotherapy in the management of patients with GIST is currently restricted to symptomatic palliation in current treatment guidelines. CASE PRESENTATION: Here we report two patients affected by metastatic GIST, treated with radiotherapy and radiosurgery in combination with TKIs, achieving an unexpected objective response in the first case and a significant clinical benefit associated with a local tumor control of several months in the second case. CONCLUSIONS: These and other successful experiences that are progressively accumulating, open up new scenarios of use of radiation therapy in various settings of treatment. GIST is not universally radioresistant and radiotherapy, especially if combined with molecularly targeted therapy, can improve the outcomes for patients diagnosed with GIST.

Treatment of hepatic metastases from colorectal cancer: many doubts, some certainties.

About 50% of patients with colorectal cancer (CCR) are destined to develop hepatic metastases during the course of the disease. Surgery is currently the only potentially curative treatment with a five year survival rate after hepatectomy from 26% to 49%. The criteria for resectability are now less rigid than in the past and the tendency to adopt a more aggressive treatment of metastatic lesions is the rule. Systemic infusion chemotherapies based on 5-fluorouracil (5-FU), oxaliplatin (OHP) and irinotecan (CPT-11) are well tolerated and have been shown to be effective in non-operable patients. These regimens allow surgery for patients who are initially not suitable for resection, giving them a probability of survival at five years similar to that of patients operated on at diagnosis. Intra-arterial infusion chemotherapy (HAI) is very effective in inducing objective responses, but is costly, difficult to manage and encumbered by major side effects, so that its application is necessarily limited to centres with specific experience. However, despite the broader criteria and recent advances of chemotherapy, surgery is not possible in most patients. The role of other local therapeutic techniques like cryosurgery (CS) and radiofrequency ablation (RF), alone or combined with surgery or chemotherapy, is not yet established in a multidisciplinary therapeutic approach. Roughly two thirds of patients relapse during the first two years after surgery suggesting appropriate post-operative chemotherapy treatment after hepatic resection may be indicated, but no randomised studies have been published to date. In case of relapse, another hepatectomy should be considered. The role of novel targeted therapies in pre-operative, post-operative and palliative management has yet to be evaluated.

Targeted therapy in colorectal cancer: do we know enough?

The present paper is a critical review about the recent development of new agents that have revolutioned the therapeutical approach of solid tumours with a particular focus on colorectal cancer. Until a few years ago, chemotherapy has been considered the only medical treatment for advanced disease. At the moment, new drugs blocking some cell functions, such as monoclonal antibodies or tyrosin kinase inhibitors are available for many oncologists, but their efficacy should be debated for several reasons. Despite having a strong biological and preclinical rationale, the clinical results of these agents are not comparable to the results obtained by imatinib in gastrointestinal stromal tumour or in chronic myeloid leukaemia even though superior to chemotherapy alone. Moreover, the efficacy does not show any correlation with the molecular expressions of the tumours. In this review, we considered different hypotheses in order to explain these results.

Effect of vitamin A, C, and E supplementation on rectal cell proliferation in patients with colorectal adenomas.

Studies suggest that cell proliferation abnormalities of the colorectal mucosa are associated with risk of neoplasia, and most cancers of the large bowel are thought to arise from adenomas. The results of other studies suggest that vitamins A, C, and E have chemopreventive efficacy against colon cancer in animal models. This study evaluates the effect of dietary vitamin supplementation on cell kinetics in uninvolved rectal mucosa in patients with colorectal adenomas. Twenty patients with colorectal adenomas were given vitamins A, C, and E for 6 months after complete polypectomy, and 21 patients with adenomas received placebo. In each patient, six biopsy specimens were taken from normal-appearing rectal mucosa before treatment and after 3 and 6 months of treatment and were incubated with tritiated thymidine ([3H]thymidine), and the [3H]thymidine-labeled cells were counted by use of autoradiography. Two parameters of cell proliferation were evaluated: 1) the ratio of the number of labeled cells to the total number of cells (thymidine labeling index) and 2) the ratio of the number of labeled cells in the upper 40% of the crypt to the total number of labeled cells in the crypt (phi h). The latter index reflects abnormal expansion of the proliferative compartment and is thought to be an intermediate biomarker of cancer risk. In patients receiving vitamins, phi h decreased progressively from baseline values, with increasing statistical significance (P less than .05 after 3 months, P less than .01 after 6 months). There was a statistically significant decrease in the thymidine labeling index in the 40% of the crypt near the mucosal surface, but the variation in the overall labeling index was not statistically significant. In the placebo group, we observed no statistically significant change in cell kinetics. These findings suggest that vitamin A, C, and E supplementation is effective in reducing abnormalities in cell kinetics that may indicate a precancerous condition. Before larger trials on chemoprevention of colorectal adenoma recurrence are conducted, additional studies are needed (a) to validate that cell kinetics is an intermediate biomarker, (b) to determine active agents, optimal dosage, and the relative efficacy of agents given alone and in combination, and (c) to test toxicity.

[Treatment of colorectal cancer liver metastases]. / Il trattamento delle metastasi epatiche da cancro del colon-retto.

Liver is the main target for colorectal cancer (CRC) metastases. About 50% of all patients affected by CRC develop liver metastases. Surgery remains the only potentially curative strategy and indications to surgery and resectability criteria are now less restrictive than before so that a more aggressive attitude in the treatment of metastatic lesions is the rule. However surgery is not possible in the majority of patients. For non resectable patients two options are available: local treatment strategies (Radio-frequency ablation and Cryosurgery: alone or in combination with surgery) and chemotherapy. High rates of objective response achieved with Fluoropyrimidines, Oxaliplatin (OHP) and Irinotecan (CPT-11) based chemo-therapy, enable initially unresectable patients to undergo surgery, with a 5-year survival rate comparable to that observed for primary resectable patients. Therefore chemotherapy has not only a palliative aim, but becomes a fundamental moment of a combined medical and surgical treatment with curative purpose. After surgery two-thirds of patients will relapse in first two years, so that adjuvant therapy has been investigated to reduce recurrence rates, mainly testing hepatic arterial infusion (HAI) schedules. So far no randomized trials have been published on the role of systemic intravenous adjuvant chemo-therapy. Finally we report the results of our monoinstitutional experience, suggesting a possible role of systemic adjuvant chemotherapy in reducing recurrence rates after liver metastasectomy. Probably in the next years new targeted drugs and locoregional therapies will contribute to further improve prognosis of such patients, in a neoadjuvant, adjuvant and palliative setting.

Epithelial cell kinetics in the remaining colorectal mucosa after surgery for cancer of the large bowel.

We used microautoradiography in order to evaluate cell replication of the remaining colorectal mucosa in 20 patients previously operated on for cancer of the large bowel. The results were compared to those of 24 controls without neoplasms or other relevant colorectal disease. Samples of colorectal mucosa were taken during endoscopy. At histological examination each labeled intestinal hemicrypt was divided into 5 longitudinal compartments, from the base to the surface, and S-phase cells in each compartment were counted. Total labeling index (LI, ratio of labeled to total cells x 100) and labeling index per crypt compartment were similar in surgical patients and in controls. In contrast, both total LI and labeling index in the upper portions of the crypt (compartments 3, 4, and 5) were significantly higher in the 9 patients who showed recurrence of polyps than in those (n = 11) without recurrence. The LI in compartments 4 and 5 (the "high crypt region") was 4.37 +/- 0.95 (SEM) in patients with recurrence versus 0.88 +/- 0.21 (P less than 0.001) in patients with negative endoscopy finding and 1.47 +/- 0.22 in controls. Moreover, the fifth compartment was labeled in 8 of 9 individuals in whom polyps recurred but in only 2 of 11 patients without recurrence and 3 of 24 controls. In conclusion, after resection for large bowel cancer colonic epithelial cell proliferation tends to become more quiescent and similar to that of controls. However, in the subgroup of patients in whom polyps reappear, the colorectal mucosa maintains a hyperproliferative state with an expansion of the replicative zone to the most superficial portions of the crypt. These findings support the sequence adenoma-carcinoma and suggest that the evaluation of cell proliferation might be useful in the identification of subjects at increased risk for multiple tumors of the large bowel.

Proliferative and antigenic properties of rectal cells in patients with chronic ulcerative colitis.

Two markers related to preneoplasia were studied simultaneously in ulcerative colitis (UC). The renewal of the rectal epithelial cells together with expression of second-trimester fetal antigen (STFA) were evaluated in nine patients with UC and four healthy subjects. Endoscopic biopsies were incubated with tritiated thymidine. Cell renewal was studied with microautoradiography, and the antigenic properties of the cells were evaluated by indirect immunofluorescence. At the time of the study, all the UC patients were in a mildly active or in a quiescent stage of the disease; their biopsies did not show dysplastic or neoplastic changes in epithelial cells. STFA was expressed in five UC patients. The analysis of cell renewal in this group revealed a shift of the proliferative compartment towards the luminal surface of the colonic crypts. By contrast, the patient group with STFA-negative reactions showed a pattern of cell proliferation similar to that observed in the controls. These results suggest that the expression of STFA in colonic mucosa is associated with an expansion of the epithelial stem cell population or with arrested cell differentiation, and it may represent a phenotypic marker of proneness of the mucosa toward neoplastic development.

Rectal cell proliferation and colon cancer risk in ulcerative colitis.

Cell proliferation kinetics of 30 patients affected by extensive ulcerative colitis in remission have been studied with autoradiography of rectal biopsies incubated with tritiated thymidine. The results have been compared with those of 20 control subjects without evidence of colonic diseases, and of 16 patients with multiple nonfamilial colonic adenomas. The labeling index was similar in the three groups (P = NS). On the contrary, the labeling frequency (SEM) in the upper 40% of the crypt (phi h value) was 0.04 +/- 0.01 in controls, 0.16 +/- 0.02 in ulcerative colitis, and 0.10 +/- 0.01 in adenoma patients (P less than 0.001 ulcerative colitis versus controls, P less than 0.01 adenomas versus controls, P = NS ulcerative colitis versus adenomas). The distribution of phi h values in ulcerative colitis showed a bimodal trend with 22 patients having mean phi h values similar to adenoma patients (0.10 +/- 0.01) and 8 with higher values (0.30 +/- 0.02). No relationship was found between phi h values and duration of colitis, age of patients, or age at onset of symptoms. These data show that cell kinetics studies can detect patients at particularly high risk of colon cancer, and that additional factors should determine colon cancer risk level in ulcerative colitis.