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PurposeGermline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS).Experimental designAn APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated.ResultsComparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients.ConclusionsOur findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.

Purpose The treatment of unresectable liver-confined metastatic disease from colorectal cancer (CRC) is a challenging issue. Although locoregional treatments such as hepatic arterial infusion (HAI) claim the advantage of delivering higher doses of anticancer agents directly into the affected organ, the benefit in terms of overall survival (OS) is unclear. We quantitatively summarized the results of randomized controlled trials (RCT) comparing HAI with systemic chemotherapy (SCT). Methods To date, 10 RCTs have been published, for a total of 1,277 patients enrolled. For tumor response rates, relative risks (RR) and their 95% CIs were obtained from raw data; for OS, hazard ratios (HRs) and their 95% CIs were extrapolated from the Kaplan-Meier survival curves. Results HAI regimens were based on floxuridine (FUDR) in nine of 10 RCTs, whereas in one RCT, fluorouracil (FU) + leucovorin was used. SCT consisted of FUDR, FU, FU + leucovorin, or a miscellany of FU and best supportive care in three, one, four, and two studies, respectively. Pooling the data, tumor response rate was 42.9% and 18.4% for HAI and SCT, respectively (RR = 2.26; 95% CI, 1.80 to 2.84; P < .0001). Mean weighted median OS times were 15.9 and 12.4 months for HAI and SCT, respectively; the meta-risk of death was not statistically different between the two study groups (HR = 0.90; 95% CI, 0.76 to 1.07; P = .24). Conclusion Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy.

The incidence of most types of cancers is age-dependent and progressive ageing is rapidly increasing the number of elderly people who need treatment for cancer. It is an ethical dilemma how aggressive one should be when it comes to treating cancer in the older population. Presumed fear of increased postoperative morbidity and mortality often results in delivery of sub-optimal cancer surgery. A careful evaluation of the general and organ-related conditions of the patients is absolutely necessary for planning the right treatment. Nevertheless, preoperative removal of risk factors and postoperative rehabilitation are as important as the use of the best techniques of anaesthesia and surgery to achieve good postoperative outcomes in these patients. In this review article we take into consideration physiology of the aged and tools available to assess surgical risks in elderly patients, in the aim of increasing awareness on optimising surgical management of elderly patients with cancer. MEDLINE and EMBASE.com (search terms: "elderly", "preoperative", "surgery"), bibliographies of articles retrieved and the authors' reference files have been used as data sources. Independent extraction has been performed by the authors using predefined criteria, including study quality indicators.

To evaluate the toxicity and feasibility of pelvic radiotherapy (RT) and/or surgery in elderly patients with locally advanced low-lying rectal cancer.From November 1999 to November 2005, 51 patients agedor=70 years who underwent RT for locally advanced low-lying rectal cancer were retrospectively examined. Variables considered were age, co-morbidities (evaluated according to the Charlson score and the Cumulative Illness Rating Scale-Geriatric [CIRS-G] score) and surgery versus no surgery.The median age was 80 years (range 70-94 years) and the male : female ratio was 33 : 18. A total of 5.9% of patients were considered 'fit', 72.5% had one or more CIRS-G grade 1 or 2 co-morbidities and 21.6% had one or more CIRS-G grade 3 co-morbidities. 54.9% of patients underwent surgery and 45.1% underwent RT. Only 9 of 21 (42.8%) patients who underwent radical resection received the full course of adjuvant RT and only seven (50%) of all patients treated with RT alone received the full dose of therapy. Patients with one or more CIRS-G grade 3 co-morbidities reported similar numbers of grade 1-2 toxicities as patients with one or more CIRS-G grade 2 co-morbidities.Notwithstanding the small number of patients analysed, the findings of this study indicate that elderly patients with rectal cancer and mild co-morbidities could probably receive the same treatment as fit elderly patients, given that tolerability appeared to be similar in both categories of patients. Neither age nor co-morbidities should be considered reasons to deny the patient the possible benefits of receiving complete treatment. Moreover, Multidimensional Geriatric Assessment should always be undertaken to help clinicians make better decisions about treatment. Further prospective trials are needed to confirm these results.

In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity. Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement ≤50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC). Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3–4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1–6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028). Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.

BACKGROUND: Currently, approximately 80% of melanoma patients undergoing sentinel node biopsy (SNB) have negative sentinel lymph nodes (SLNs), and no prediction system is reliable enough to be implemented in the clinical setting to reduce the number of SNB procedures. In this study, the predictive power of support vector machine (SVM)-based statistical analysis was tested. METHODS: The clinical records of 246 patients who underwent SNB at our institution were used for this analysis. The following clinicopathologic variables were considered: the patient's age and sex and the tumor's histological subtype, Breslow thickness, Clark level, ulceration, mitotic index, lymphocyte infiltration, regression, angiolymphatic invasion, microsatellitosis, and growth phase. The results of SVM-based prediction of SLN status were compared with those achieved with logistic regression. RESULTS: The SLN positivity rate was 22% (52 of 234). When the accuracy was > or = 80%, the negative predictive value, positive predictive value, specificity, and sensitivity were 98%, 54%, 94%, and 77% and 82%, 41%, 69%, and 93% by using SVM and logistic regression, respectively. Moreover, SVM and logistic regression were associated with a diagnostic error and an SNB percentage reduction of (1) 1% and 60% and (2) 15% and 73%, respectively. CONCLUSIONS: The results from this pilot study suggest that SVM-based prediction of SLN status might be evaluated as a prognostic method to avoid the SNB procedure in 60% of patients currently eligible, with a very low error rate. If validated in larger series, this strategy would lead to obvious advantages in terms of both patient quality of life and costs for the health care system.

The aim of the present study was to identify the pattern of plasma protein species of interest as markers of colorectal cancer (CRC). Using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS), the plasma protein profile was determined in nine stage IV CRC patients (study group) and nine clean-colon healthy subjects (control group). Multivariate analysis methods were employed to identify distinctive disease patterns at protein spectrum. In the study and control groups, cluster analysis (CA) on the complete MALDI-MS spectra plasma protein profile showed a distinction between CRC patients and healthy subjects, thus allowing the identification of the most discriminating ionic species. Principal component analysis (PCA) and linear discriminant analysis (LDA) yielded similar grouping results. LDA with leave-one-out cross validation achieved a correct classification rate of 89% in both the patients and the healthy subjects.

Aims To investigate the survival benefit of extended lymphadenectomy (D2) in EGC patients in one European Institution. Methods A review was made of our prospective gastric database from January 1980 to December 2001. Of 527 patients with primary gastric adenocarcinoma, 119 with EGC underwent potentially curative resection (R0) with D2 lymphadenectomy. Results There were two post-operative deaths. Of the 117 evaluable cases, 96 were classified as N0 and 21 as N+, with metastases in the perigastric lymph nodes (level 1) in 13, and beyond this site (level 2) in eight. Five-year survival was 85.9 and 83.0% in N0 and N+ patients, respectively. During a median follow-up of 90 months, five of the eight patients with level 2 metastases died of recurrent disease and three were alive. The estimated survival benefit for 119 patients with EGC was 2.5% (3/119 cases). Conclusions In patients with EGC, metastases to level 2 are rare. Our results indicate that D2 lymphadenectomy has a limited survival benefit and that in these cases a less extensive lymphadenectomy (D1) could be performed.

In spite of the significant advances in conventional therapeutic approaches to colorectal cancer (CRC), most patients ultimately die of their disease. Dissecting the molecular mechanisms underlying CRC progression will not only accelerate the development of novel cancer-selective drugs but will also enable the therapeutic regimen to be personalized according to the molecular features of individual patients and tumors. Here, we report on the novel insights into CRC biology that are paving the way to the development of molecular therapies and summarize the results from recent clinical trials demonstrating that agents targeting tumor-specific molecular derangements can significantly improve the therapeutic efficacy of conventional chemotherapy. Only a broader clinical implementation of these concepts will provide patients with CRC the best chance of a cure.

Background: Oxaliplatin (OXA) significantly enhanced the antitumour activity of 5-fluorouracil (FUra) in patients with advanced colorectal cancer and displayed radiosensitising properties in preclinical studies. This study was thus performed to test the feasibility, identify the recommended doses (RDs) and explore preliminarily the clinical activity of weekly OXA and infused FUra combined with preoperative pelvic radiotherapy. Patients and methods: Forty-six patients with recurrent or locally advanced (cT3-4 and/or N+) adenocarcinomas of the mid-low rectum were treated with escalating doses of OXA (25, 35, 45, 60 mg/m2, weekly for 6 weeks) and FUra (200–225 mg/m2/day, 6-week infusion) concurrent to preoperative pelvic radiotherapy (50.4 Gy/28 fractions). The RDs for the phase II part of the study were immediately below the level resulting in dose-limiting toxicities in more than one third of the patients, or corresponded to the last planned dose level. Results: In the escalation phase, dose-limiting toxicities only occurred in one patient at the fourth level and one of six patients treated at the last planned dose level (grade III diarrhoea). OXA 60 mg/m2 and FUra 225 mg/m2/day are therefore the RDs for the regimen. Among 25 patients globally treated at these doses (phase II part), the incidence of grade III diarrhoea was 16% with no grade IV toxicity. Neurotoxicity did not exceed grade II (12%). All patients completed radiotherapy and were operated on as scheduled. Twenty-one of 25 patients had the tumour down-staged after chemoradiation with seven (28%) pathological complete responses and 12 (48%) residual tumours limited to ypT1-2N0. Conclusions: Weekly OXA, at doses potentially active systemically, can be combined with full-dose, infused FUra and radiotherapy. Given the low toxicity and promising activity, this regimen is being compared to standard FUra-based pelvic chemoradiation in a randomised study.

Fourteen blood samples from patients with melanomas and 11 blood samples from healthy subjects were analyzed by matrix-assisted laser desorption/ionization mass spectrometry. The study focussed on species of low molecular weight, in the 800–5000 Da range, present in plasma and sera. While for healthy subjects plasma samples lead to the production of a higher number of ionic species, for melanoma patients a high number of diagnostic ions, present with high frequency and with quite high relative abundance, are present, in particular, in serum samples and, to a lesser extent, also in plasma. Since plasma samples are obtained more easily in comparison to sera, it is possible to suggest that plasma can also be used for these studies.

Background and objectives. More than half of patients with positive sentinel node (SN) have no metastases in non-sentinel nodes (NSNs) on axillary lymph node dissection (ALND). The aim of this study was to investigate factors predictive of NSNs involvement, in order to identify patients with metastatic disease confined to the SN which might avoid ALND. Methods. ALND was performed in 167 patients with metastatic SN. Axillary NSNs status was correlated with the size of SN metastases, the size of the primary tumor and the occurrence of lymphovascular invasion. In 72 cases, the radiotracer (Tc-99m albumin colloid) marked multiple (in most cases 2 or 3) nodes. In this group, NSNs status was correlated with the number of metastatic radioactive nodes (1 or >1), and with the above mentioned histopathologic factors. Results. NSNs metastases were found in 57/167 cases (34.1%), the rate increasing proportionate to the size of both SN metastases (p < 0.0001) and primary tumor (p= 0.0075), while no significant correlation was found for lymphovascular invasion (p= 0.1769). At univariate and multivariate analysis of findings from the 72 cases with multiple probe-detected hot nodes, positivity in more than one hot node was the strongest predictor of NSN involvement (p= 0.0019). Conclusions. The identification and excision of multiple hot nodes can be useful in the prediction of NSNs involvement in patients with metastatic SN.

Background: The molecular mechanisms underlying tumor responsiveness to immunotherapeutic manipulations remain elusive. Investigators are therefore searching for new technologies to study immune-related events occurring in the tumor microenvironment. Aim: To validate the use of quantitative real-time PCR (qrt-PCR) for assessing immune cell density and cytokine (CK) gene profile in tumor biopsies obtained from patients treated with TNFα-based isolated limb perfusion. Materials and methods: We first assessed in vitro the ability of cell marker coding genes (CD4, CD8, CD14, CD56) to serve as housekeeping genes for helper and cytotoxic T-lymphocytes, macrophages and NK cells, respectively. Then, the correspondence between mRNA and protein levels of five CK (IL-2, IFNγ, IL-4, IL-10 and TGFβ1) expressed by stimulated PBMC was evaluated by means of qrt-PCR and ELISA, respectively. Finally, six patients affected with locally advanced soft tissue sarcomas underwent tumor biopsy before and after TNFα-based isolated limb perfusion. After RNA extraction and amplification, transcriptional levels of the above cell markers and CK were evaluated by qrt-PCR. Results: In vitro, leukocyte cell subsets constantly expressed the corresponding marker gene both under resting conditions and after cell stimulation. Cytokine mRNA levels expressed by stimulated PBMC corresponded significantly to supernatant protein concentrations. Compared to the pre-treatment gene profile, post-treatment gene expression showed higher levels of CD4 and IFNγ and a decreased abundance of the TGFβ1 transcript. Conclusion: In vitro we found that qrt-PCR can determine accurately immune cell density and CK gene profiles in tumor biopsies. In vivo findings support the hypothesis that, after TNFα-based treatment, a Th1-type shift occurs in the tumor microenvironment.

Although surgery remains the mainstay for the treatment of most solid tumors, investigators are seeking complementary therapies to eradicate microscopic disease, which causes tumor relapse even after an apparently complete surgical excision. Although adjuvant chemotherapy has achieved some significant results, the control of minimal residual disease is still a challenge for clinicians. Among novel therapeutic approaches, immunotherapy holds promise. This anticancer strategy aims at triggering a highly specific endogenous killing machine against tumor cells. Recent progress in tumor immunology has improved our understanding of host-immune system interactions. In particular, new technologies have fostered the identification of potentially immunogenic tumor antigens that can be used as suitable targets for immune effector cells. After observing immunotherapy-mediated clinical responses in patients with metastatic disease, investigators have started evaluating this anticancer modality in the adjuvant setting. Here, we review the immunological strategies so far explored in humans and report worldwide results following the clinical application of adjuvant immunotherapy for solid tumors.

Background . Kupffer cells, monocytes and infiltrating T cells have been considered the major source of interleukin-1β and tumour necrosis factor-alpha in the liver. Aims . To explore the expression of interleukin-1β and tumour necrosis factor-alpha and to evaluate the density and the distribution of T lymphocytes and monocytes/macrophages in the liver of patients with primary and secondary tumours. Methods . Tumoural and peritumoural liver samples were examined from 21 patients with hepatocellular carcinoma, 1 D with hepatic metastases, 5 with benign focal liver lesions and 4 healthy adult livers. Interleukin-1β and tumour necrosis factor-alpha mPNAs were detected by a semiquantitative comparative reverse transcriptase polymerase chain reaction. T lymphocytes and monocytes/macrophages were detected by immunohistochemistry Results . Higher levels of interleukin-1β, tumour necrosis factor-alpha, CD3+ and CD68+ cells were found in the tissue surrounding hepato-cellular carcinoma and metastases than in the tumour itself. A strong expression of CD68+ and CD3+ cells was found mainly along the tumour-host interface but the highest expression of CD3+ cells was found at the metastasis interfaces. Interleukin-1β expression, CD3+ and CD68+ cell densities were higher in peritumoural samples than in so-called “normal” liver tissue. Conclusions . An increased production of interleukin-1β and, to a lesser extent, of tumour necrosis factor-alpha mRNA coincides with the presence of cancer, be it primary or secondary, both in healthy and cirrhotic livers. The presence of cancer, irrespective of the presence of underlying liver damage, appears to play the most important role.

Aims : The therapeutic approach for primary or recurrent advanced solid tumours, particularly when unresectable, is still one of the main medical challenges in the management of cancer patients. The stop-flow (SF) technique has been recently proposed as a semi-invasive drug delivery system based on the blood supply blockage of the tumour-bearing area. Here, we discuss the principles underlying the SF technique as well as the worldwide experience published so far. We also report on the results of our pilot study on pelvic and limb SF perfusion. Methods : We reviewed the worldwide experience on SF as reported by the literature published on PubMed from 1990 through 2001. In our series, we treated 20 patients affected with locally advanced melanoma, soft tissue sarcoma or colorectal cancer. Results : This therapeutic modality – at least for some tumours – can achieve encouraging results in terms of clinical response even after conventional therapies have failed. Moreover, as a safe and relatively simple procedure, SF can be applied to patients for whom traditional treatments (i.e. surgery, systemic chemotherapy) are contraindicated because of poor general conditions. Conclusions : At present, the SF technique should be considered an investigational approach to locally advanced cancers. The encouraging results obtained with this procedure should be validated by large phase III trials.

Isolated limb perfusion (ILP) is a well-established locoregional procedure to deliver high doses of cytostatics to an extremity with multiple in-transit lesions from cutaneous melanoma, with minimal systemic and mild local toxicity. This approach is quite sophisticated and requires accurate monitoring of systemic leakage and of the temperature of the affected limb in order to avoid major systemic and local side effects. Mephalan (L-PAM) is considered the reference drug, although complete responses are reported in only about 50% of patients. Since the early 1990s, tumor necrosis factor-alpha (TNF-alpha) was administered with melphalan in ILP aiming to improve the therapeutic index of this procedure. However, despite the impressive results reported, its role still remains controversial, seemingly confined to large tumor bulk. Fotemustine ILP was proposed as a less toxic alternative to L-PAM, after the results of a pilot experience claiming similar response rates with less local toxicity. A formal phase 1-2 study is now underway to confirm these findings. More straightforward procedures, such as isolated limb infusion, are appealing, as they seem capable of achieving good response rates, are easily repeatable, and are less costly. Larger series are required to validate such results. As potential agents to be delivered through ILP, new vasoactive drugs and agents with new mechanisms of action that interplay with chemotherapy, as well as virus-mediated gene therapy, are being developed.

BACKGROUND Hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) combined with cytoreductive surgery (CS) has been proposed as a new multimodal treatment mainly for carcinomatosis of gastrointestinal origin. To evaluate whether this regimen could be used for other tumor types, the authors conducted a Phase I study on HIIC with doxorubicin and cisplatin in patients with peritoneal carcinomatosis or sarcomatosis. PATIENTS AND METHODS Thirty-one patients with peritoneal carcinomatosis or sarcomatosis (PCS) were enrolled for the study. After completion of CS, HIIC was administered with drug doses that were increased for each consecutive cohort following a three-patient cohort scheme. Thereafter, the accrual was stopped when Grade 4 locoregional or systemic toxicity was observed. The maximum tolerated dose (MTD) was considered the dose in the previous triplet. Drug pharmacokinetics and procedure costs also were analyzed. RESULTS After CS, residual tumors were not present or measured less than or equal to 3 mm (in dimension) in all cases. Maximum tolerated dose was 15.25 and 43.00 mg L−1 for doxorubicin and cisplatin, respectively. The perfusate/plasma area under the curve ratios were favorable for both drugs, at 162 ± 113 and 20.6 ± 6.0, respectively, for doxorubicin and cisplatin. Doxorubicin levels in the peritoneum were higher than in tumor or normal tissue samples. There were no postoperative deaths. Surgery-related complications were observed in 25% of cases. Findings at cost analysis showed that the length of stay in the operation room and intensive care unit were the major cost drivers. CONCLUSIONS Cytoreductive surgery combined with HIIC is an expensive but feasible therapeutic approach for locally advanced abdominal tumors. Because our preliminary findings for local disease control are encouraging, a Phase II study is now advisable to verify the activity of this promising treatment. Cancer 2002;94:492–9. © 2002 American Cancer Society.

Background. ACP gel is a new crosslinked derivative of hyaluronic acid (HA) that displays the biocompatibility properties of its original polymer but has a higher viscosity. It has been demonstrated in an animal model that the gel reduces adhesions after gynecological surgery. The aim of the present study was therefore to investigate the efficacy of ACP gel in increasing viscosity for the prevention of adhesions after abdominal surgery. Methods. The antiadhesive effect of ACP gel was tested in a controlled randomized study using a standardized animal model of abdominal surgery involving the creation of defects in the parietal peritoneum and muscular fascia and cecal abrasion. The animals (100 female New Zealand white rabbits) were randomly allocated into five treatment groups to receive: ACP gel (1, 2, 4, and 6%) on the injured area or no ACP gel (control). The incidence of adhesions and their grade (score 0–11) were blindly evaluated 10 weeks after surgery. Results. The percentages of adhesion-free animals were 60, 84, 90, and 84% in the 1, 2, 4, and 6% ACP gel concentration groups, respectively, versus 15% in the control group ( P = 0.001). The mean adhesion scores were 3.00 ± 0.91, 1.37 ± 0.75, 0.65 ± 0.45, and 1.16 ± 0.64 in the 1, 2, 4, and 6% ACP gel groups, respectively, versus 7.70 ± 0.83 in the control group ( P Conclusion. ACP gel prevents postsurgical abdominal adhesions even at a 1% concentration. This finding may be of clinical importance in situations in which large volumes of antiadhesive solution are required.

In this study we assessed whether the serum levels of the N-terminal peptide of type III collagen (PIIIP), an index of type III collagen synthesis, are influenced by colorectal cancer stage, and whether “in vitro” fibroblast growth and PIIIP production could be altered by tumor tissues obtained from metastatic and nonmetastatic colorectal cancer. 208 colorectal cancer patients (115 colon and 93 rectum) were studied; 54 were stage I, 62 stage II, 37 stage III and 55 stage IV. PIIIP serum levels were significantly higher in stage IV as compared to all other patient groups. The 5-year survival of stage I, stage II, stage III and stage IV patients were 87%, 88%, 32% and 20%, respectively. In the subgroup of stage I and stage II patients considered together, PIIIP (>0.5 U/ml), but not CEA (>5 μg/l) serum levels, were predictive for survival. Fibroblast growth was significantly inhibited, while PIIIP production was significantly enhanced, when these cells were conditioned with colorectal cancer homogenates obtained from patients with distant metastases, than from those without distant metastases. In conclusion, colorectal tumors, when metastatic, stimulate fibroblasts' PIIIP synthesis and the serum levels of this peptide might predict patients' outcome after radical surgery.

The distribution of the main prognostic factors in different age groups was evaluated in 1226 patients operated on for primary breast cancer, in order to identify those influenced by age and/or menopausal status. Patients were divided into the following groups: 1) 40 years of age and under; 2) premenopausal over 40 years of age; 3) postmenopausal under 75 years of age and 4) 75 years of age and over. Our findings showed that the youngest patients had the worst prognostic pattern, which improves as age increases and is the best in patients over 75 years of age. Some of the parameters investigated (tumour size, histologic and nuclear grade, tumour infiltrating lymphocytes, p53 and Ki 67) were found to be influenced by age, some (necrosis and oestrogen receptors) were influenced by menopausal status and/or age, some (vascular invasion, ploidy, S-phase and progesterone receptors) showed significant differences in different age groups but there was no consistent relation with patient age or menopausal status, and others (node status, ErbB2/Neu and Cathepsin D) were not influenced by age or menopause.

A moderate weight loss is known to improve the lipid levels in simple obesity. The extent of weight loss needed to achieve a clinically meaningful effect on lipid abnormalities in morbid obesity is little understood. We analyzed the effects of different levels of body weight loss on the lipid levels of morbidly obese patients operated with the LAP-BAND System.225 morbidly obese patients (172 F and 53 M) in which a complete lipid profile has been collected both before and 12-18 months after surgery were studied. The changes of the lipid profile were analyzed according to different levels of percent weight loss (%WL:10%, 10-20%, 20-30%,30%).Mean weight loss was 30.7+/-15.2 kg, corresponding to a 23.1+/-9.7% reduction of body weight. A large variability in the weight loss was observed. A significant difference in the change of the lipid parameters between the group with10%WL and the group with 10-20%WL was observed for total-cholesterol (+10.0+/-17.2% vs -0.7+/-14.7%; p0.05), for the LDL (+18.7+/-26.3% vs +3.1+/-22.9%; p0.05), and for the triglycerides (+7.7+/-26.3% vs -21.9+/-25.4%; p0.05). No further significant differences were found between the two groups with greater weight loss (20-30%WL and30%WL) and the group with 10-20%WL, the only exception being the percent change in triglycerides levels, i.e. higher in the group with %WL30 (-33.6+/-31.5% vs -21.9+/-25.4%; p0.05).A moderate weight loss of 10-20% of initial body weight produced the maximal effects on the lipid levels in morbid obesity.

The aim of this study was to discuss the role of preoperative ultrasound (US) scanning and sentinel node biopsy (SNB) in melanoma patients. 100 patients underwent SNB following preoperative US scan and lymphoscintigraphy; patent blue dye (PBD) was injected before biopsy. Intra-operative lymphoscintigraphy (IL) was performed in 51 basins. All nodes were examined with histology and immunohistochemistry. Sensitivity and specificity of US scanning was 33% and 100%, respectively; 7% were true positives. The low sensitivity was mainly due to the resolution power of the US scanner (2 mm) which was unable to identify all the patients with microdeposits. PBD associated with IL identified SNs in all cases. In all patients with Breslow >1.5 mm and in all cases with two metastatic SNs, further positive additional nodes were found. The mean counts per 10 s (CP10S) ratio for SN and non-SN values was 5.62 (1.29–23.51) and 3.09 (1.03–10.99) in the intra-operative and extra-operative phases, respectively. US scanning and preoperative lymphoscintigraphy associated with PBD allows preoperative patient selection and accurate SN(s) identification. Breslow thickness and the number of metastatic SN(s), but not their type, are correlated with disease spread; CP10S contributed to the differentiation amongst the nodes and the determining of procedure's completion.

PURPOSE: It is not yet known whether preoperative combined radiotherapy and chemotherapy for rectal cancer affects postoperative mortality and morbidity. We therefore evaluated early postoperative complications in patients given adjuvant radiotherapy and chemotherapy before surgery for middle and lower rectal adenocarcinoma. METHODS: Between 1994 and 1998, 41 patients underwent combined preoperative pelvic radiotherapy and chemotherapy at our institution. Most of the patients had 45 Gy (1.8 Gy/day/25 fractions) during five weeks plus 5-fluorouracil (350 mg/m2/day) and low-dose leucovorin (10 mg/m2/day) bolus on Days 1 to 5 and 29 to 33. Surgery was performed four to six weeks after completion of adjuvant therapy. The 41 patients (Group A) were retrospectively compared with 30 patients (Group B) who, in the same period, underwent surgery without preoperative adjuvant therapy. The groups were homogeneous for age, gender, preoperative risk factors, operating surgeon, and pathologic stage. Mean distance of the tumor from the anal verge was shorter in Group A patients (P=0.031). RESULTS: There were seven major postoperative complications in each group. No significant differences were found between the groups for morbidity and mortality rates. Considering all patients, more postoperative complications were found in patients scored as American Society of Anesthesiologists 3, in those with a preoperative hemoglobin value

An association has been reported between nuclear p53 protein expression in tumour cells and a poor outcome in patients with colorectal cancer (CRC). In this study we investigated the prognostic significance of nuclear p53 protein expression in CRC liver metastases after curative hepatic resection. The study population consisted of 69 consecutive patients who underwent curative hepatic resection for metastases from CRC at our Institution between February 1987 and October 1993. Immunohistochemical expression of p53 protein was evaluated in formalin-fixed paraffin-embedded sections of CRC liver metastases using the monoclonal antibodies (MAbs) D01 and Pab 1801. The Cox proportional hazards model was used in forward stepwise regression to assess the relative influence of different prognostic factors. Forty-four (63.8%) CRC liver metastases were p53-positive. Kaplan-Meier survival curves demonstrated that patients with p53-positive metastases had a median survival of 27 months versus 93 months for patients with p53-negative metastases (P0.01). The 3 and 5 years survival rates were 31.5 and 21.0% in patients with p53-positive metastases and 71.8 and 53.1% in patients with p53-negative metastases. At multivariate analysis p53 protein status was the single best predictor of survival (P = 0.0079); the odds ratio of death among patients with p53-positive tumours was 2.53. Nuclear p53 protein expression in hepatic metastases from CRC is an independent prognostic factor of survival following liver resection. These findings may be of clinical importance in the selection of patients more likely to benefit from liver resection and could be used as criteria for stratification in trials on adjuvant therapy.

BACKGROUND Long term results after liver resection for hepatocellular carcinoma (HCC) are disappointing because the disease tends to recur. In this study, the authors assessed prognostic factors affecting long term outcome, in the hope that these factors might be used in selecting HCC patients for surgery. METHODS During the period 1977-1995, 100 consecutive patients underwent curative liver resection; 78 of 100 had HCC arising on preexisting cirrhosis (53 Child's Class A and 25 Child's Class B). Thirty-five prognostic factors were evaluated for their association with overall survival (OS) and disease free survival (DFS) in univariate and multivariate analysis (Cox proportional hazards model). RESULTS There were four postoperative deaths. Seven patients died in hospital of hepatorenal failure: six had Child's Class B cirrhosis and had undergone preoperative chemoembolization. Of the remaining 89 patients, 50 developed recurrence. All surviving Child's Class B patients had recurrence. Five-year OS, postoperative deaths included, was 38% (median, 36 months). Five-year DFS, postoperative deaths excluded, was 26% (median, 21 months). Independent prognostic factors for DFS were Child's class, glutamic-oxaloacetic transaminase, γ-glutamyltransferase, α-fetoprotein, number of tumor nodules, width of resection margins, preoperative chemoembolization, and experience of the team that performed the surgery. Factors with an independent effect on OS were Child's class and width of resection margins. CONCLUSIONS Liver resection can provide long term DFS in HCC patients with normal liver function. In patients with liver function impairment or an inadequate resection margin, recurrences are almost certain to occur. Preoperative chemoembolization significantly prolongs DFS but may increase the risk of postoperative liver failure in patients with liver function impairment. Cancer 1998;82:1028-36. © 1998 American Cancer Society.

Background: Sucrase-isomaltase (SI) is a tissue-based phenotypic marker that is an independent prognostic factor in colorectal cancer (CRC). DF3 and galectin 3 are two other tissue-based markers that are upregulated during neoplastic transformation. Because p53 mutations are acquired during neoplastic progression, we reasoned that alterations in SI and p53 may be associated despite an apparent lack of biological interaction. Methods: Paraffin sections from 183 patients who underwent surgery at New England Deaconess Hospital (NEDH) between 1965 and 1977 were analyzed first by immunohistochemistry (IHC) for the expression of the markers SI, DF3, and galectin 3, which were scored as absent or present. Paraffin sections from a second group of 59 patients who underwent surgery at NEDH between 1985 and 1992 were analyzed by IHC for the expression of p53 as well as SI, DF3, and galectin 3. p53 nuclear staining was scored as absent or present. Previous work has shown that p53 is mutated in all cells with nuclear staining and in 10% of tumors that are unstained. Results: SI expression was not associated with the expression of either DF3 or galectin 3, and neither DF3 nor galectin 3 were prognostic factors in CRC. None of the phenotypic markers were associated with any of the clinicopathologic variables. However, 21 of 24 p53-positive cases (88%) expressed SI, whereas 15 of 35 p53-negative cases (43%) were also SI negative (p = 0.02, Fisher exact test). p53 expression was not associated with expression of DF3 or galectin 3. Conclusions: SI expression and p53 mutation are associated significantly in CRC. Although the mechanism underlying such an association is presently unknown, the association may define a subset of patients with a worse prognosis. © 1997 The Society of Surgical Oncology, Inc.

At present, limb-sparing surgery is the most appropriate and acceptable treatment available for sarcomas of the extremities, although the right balance between conservative therapy and maximum efficacy has yet to be found. A better knowledge of prognostic factors may help in planning the appropriate strategy for each case. Eighty patients underwent limb-sparing surgery for limb sarcomas (17 had surgery alone ; 19 had neo-adjuvant hyperthermic antiblastic perfusion combined or not with postoperative radiotherapy, and 44 had adjuvant radiotherapy). Univariate and multivariate analyses were made to detect statistically significant differences between subgroups and identify the more significant subset of prognostic factors. Only microscopically positive surgical margins were related to a greater risk of local recurrence, whereas overall survival was compromised by high grade and large tumor size.

Benign tumors of the liver are a heterogeneous group of lesions whose detection has greatly increased because of the widespread use of imaging techniques. Only a few types, such as cavernous hemangiomas, focal nodular hyperplasia (FNH), hepatic adenoma (HA), and cysts, are frequent enough to be of clinical importance. Although often asymptomatic, these tumors are sometimes associated with pain or digestive symptoms. In some of them, hormonal manipulation has a role in both the development and the course. Complications, such as spontaneous rupture or sudden increase in size, have been reported. Only in hepatic adenoma is malignant transformation considered possible. The clinical importance of these tumors lies mainly in making a correct diagnosis of the type of lesion, and in ruling out primary or metastatic tumors. Although most cases can now be identified through imaging techniques, in some, diagnosis remains uncertain even after percutaneous biopsy, making surgical exploration necessary. We here consider 104 patients with benign lesions: 60 underwent resection; the remaining 44 had follow up only. Of the former group, 35 had hemangiomas, 16 “cellular” tumors (either FNH or HA), and 9 cystic lesions. Forty-four were resected due to the presence of symptoms and 16 because of uncertain diagnosis. It is concluded that cavernous hemangioma, FNH, and most of the cysts have a favorable clinical evolution and, when the diagnosis is certain, resection is not indicated. Surgery can be considered for symptomatic or complicated cases and those in which the diagnosis remains uncertain with imaging work-up techniques. HA and cystic adenoma require surgical treatment even in asymptomatic patients.

The most common indications for percutaneous endoscopic gastrostomy (PEG) are neurologic deficits precluding adequate oral nutrition. The aim of this study was to ascertain whether PEG is as feasible, safe and effective in patients with advanced oropharyngeal, oesophageal and pulmonary carcinoma as it is in patients with neurologic deficit. PEG, attempted in 108 consecutive patients, was successful in 100 (overall success rate of 92%). On the basis of primary disease, the patients were subdivided into two groups: patients with neurologic diseases (group A, n = 50) and patients with oropharyngeal, oesophageal and lung carcinoma precluding adequate oral nutrition (group B, n = 50). No statistically significant difference was found between the PEG placement success rates of the two groups. Of the patients PEG placement 1 died and 2 had major complications. 15 out of 50 patients in group A and 11 out of 50 in group B had minor complications. No statistically significant differences were found between the mortality and morbidity rates of the two groups. Duration of nutrition was similar in both groups. In particular, 46% group A patients and 46% group B patients were PEG-fed for more than 3 months. A wider use of PEG is suggested in patients with advanced oropharyngeal, oesophageal and pulmonary carcinoma precluding adequate oral nutrition.

Vimentin and proliferating cell nuclear antigen (PCNA) immunohistochemical staining was performed in a series of 92 node-negative breast carcinomas and expression compared with tumour size, histological grade, nuclear grade, necrosis, lymphocytic infiltrate, oestrogen and progesterone receptors, and relapse rate. Vimentin was expressed in 13% of tumours and all positive cases were invasive ductal carcinomas. A strong relationship was noted between vimentin positivity, and both histological ( P = 0.01) and nuclear grade ( P = 0.02). The percentage of PCNA positive cells (PCNA index) varied from 0.2 to 70% (mean 27.45, median 28). PCNA index showed a significant correlation with histological ( P = 0.001) and nuclear grade ( P = 0.004). Furthermore vimentin positivity was significantly associated with high PCNA index ( P = 0.002). With univariate analysis vimentin positivity and high PCNA index (> 28) were both significantly correlated with shorter disease free survival ( P = 0.003 and P = 0.002 respectively) (median follow-up 84 months), while no other parameter reached significance. Using multivariate analysis PCNA index was statistically related to disease-free survival ( P = 0.05), whereas vimentin lost its significance. Our results suggest that PCNA may be useful in identifying node-negative breast cancer patients at risk of recurrence.

In order to ascertain whether plastic surgery for rectocele is of value in the treatment of outlet obstruction, a retrospective study was made of 21 women complaining of difficulty in expelling faeces: 13 patients (group A) underwent surgery with transanal longitudinal plication of the anterior rectal wall (Block's technique), and 8 patients (group B) had colpoperineoplasty which, in 2, was associated with bladder-neck suspension following the Raz-Peyrera technique for urinary incontinence. The mean follow-up was 24.2 +/- 18.7 and 36.8 +/- 17.8 months respectively. In 11 group A patients (80.9%) and 6 group B patients (75%) cure, or an improvement, was achieved. Of the remaining 4 patients (19%), recurrent rectocele was found in 2 (one group A and one group B) and intestinal transit time tests detected colonic constipation in one group A and in one group B patient. It is concluded that surgery can resolve outlet obstruction from rectocele, but Block's technique is preferable because it is more straight-forward and easier.

We here outline principles and trends in the treatment of soft tissue sarcomas without distant metastases (M0). Over the last 15 years significant advances have been made in the diagnostic imaging and histological classification of these tumors as well as in their treatment. Magnetic resonance imaging (MRI) has essentially replaced computerized tomography (CT) for the evaluation of the local growth pattern, although the latter is still preferred for the detection of pulmonary metastases. Immunohistochemistry techniques and electron microscopy have improved the histological diagnosis, although the results obtained should always be interpreted in the context of routine light microscopy. Adequate surgical resection and radiotherapy can reduce the incidence of local recurrence, which is still high for head-neck and retroperitoneal sarcomas. Limb-sparing surgery in combination with irradiation and/or intra-arterial or perfusion chemotherapy is considered the treatment of choice in 90% of limb sarcomas, with a local recurrence rate of less than 20%. New radiotherapeutical techniques and anti-neoplastic agents are now under investigation in an attempt to improve local control. There is also a need for a more effective adjuvant chemotherapy. Randomized clinical trials using doxorubicin/ifosfamide and growth factors are now underway.

Eighteen patients, subdivided into groups of three, were perfused for 90 min with escalating doses of TNF-alpha (0.5-3.3 mg) and standard doses of doxorubicin (bolus 0.7-1.4 mg/kg) at a tumor temperature of at least 41 degrees C, with the aim to ascertain the maximum tolerable dose (MTD) and the activity of TNF-alpha combined with doxorubicin in hyperthermic antiblastic perfusion (HAP) for patients with limb sarcomas, candidates for amputation. Tumor response was assessed both pathologically and radiologically. Severe systemic toxicity (WHO) was observed in only 2 patients. Locoregional toxicity (Wieberdink's) was grade I in 3 patients, grade II or III in 10 and grade IV in 5. A strict correlation between the TNF dosage and the grade of limb reaction was found, grade IV being retrieved only with TNF dose >1 mg and/or muscular temperature >41.5 degrees C. Tumor necrosis was evaluated in 16 patients: in 11 (68.8%) it scored more than 75% while in 5 it was 25 to 75%. Four cases (25%) had 100% tumor histological necrosis. Limb sparing surgery was feasible in 13 (81%). Our findings suggest that this is a well-tolerated and highly active regimen in HAP.

Forty morbidly obese patients, scheduled for restrictive gastric surgery, were anaesthetized with two different techniques. In group A (20 patients) anaesthesia was induced and maintained with Propofol (total intravenous anesthesia, TIVA); in group B (20 patients) anaesthesia was induced with Thiopental and maintained with Isoflurane (balanced anaesthesia). At the end of surgery, recovery time (RT) and recovery score (RS) were assessed according to a modified Aldrete score. There was no difference of RS between group A and group B. RT was shorter (though not statistically significant) in group A than in group B. Our experience suggests that both techniques can be safely used in these patients, but with TIVA, patients appeared more awake and cooperative earlier. Such an advantage may be useful to prevent serious complications (thromboembolism and pulmonary failure) in the postoperative period.

p53 Gene variants BstUI RFLP at codon 72 in exon 4, 16bp tandem repeat in intron 3 and MspI RFLP in intron 6, which code for two functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms.p53 genotype was assessed in 90 CRC patients, 321 age-matched controls and 322 centenarians.The p53 codon 72 arginine, the p53 16bp deletion, and the MspI RFLP were significantly more frequent in CRC patients in comparison to the controls and to the centenarians (odd ratio 1.44 and 1.93). In the CRC group, the BstUI RFLP polymorphism was the more frequent combination (62.2%), and it was significantly associated with highly infiltrating (p0.01), poorly differentiated (p0.01), and metastatic (p0.05) tumours. Our findings indicate that the p53 codon 72 polymorphisms are associated with a higher risk of CRC and are associated with more advanced and undifferentiated tumours.

UNLABELLED Tumour microsatellite instability (MSI) is useful in identifying patients with hereditary non-polyposis colorectal cancer (HNPCC) with defective DNA mismatch repair (MMR) genes. A reference Bethesda panel has limitations resulting from the inclusion of dinucleotide markers, which are less sensitive and specific for detection of tumours with MMR deficiencies. We developed a multiplex PCR assay with additional four mononucleotide markers and one dinucleotide marker (NR-21, NR-24, BAT-40, TGF-BetaR and D18S58) for a rapid and proper classification of MSI-H, MSI-L and MSS colorectal cancers. Two tetranucleotide markers were added to identify sample mix-ups and/or contamination. RESULTS all the 44 cases test cases were in agreement with previous classification except for three cases: one case MSI-H-Bethesda unstable only for dinucleotides markers shifted to MSI-L category and two cases MSI-L-Bethesda unstable for mononucleotide markers shifted to MSI-H category. Immunohistochemistry analysis revealed that these two MSI-H cases did not expressed hMLH1 and they were found to be methylated at the MLH1 promoter, while the first one that shifted to MSI-L showed MMR protein expression. CONCLUSION a complete panel of ten markers including four dinucleotide and six mononucleotide microsatellites allows accurate evaluation of tumor MSI status.

The identification of prognostic determinants of colorectal cancer (CRC), including prediction of occult metastasis, is of urgent consideration, based on the tremendous differences in outcome and survival between patients who present with metastasis or develop metastasis versus those patients with organ-confined or nonrecurrent disease. Currently, a great deal of attention has been focused on using gene expression profiles of tumor specimens as a launch point for prognostic biomarker discovery. In our study, we chose to focus on functional protein-based pathway biomarkers as a new information archive because it is these proteins that form the functional signaling networks that control cell growth, motility, apoptosis, survival, and differentiation. We used reverse-phase protein microarray analysis of laser capture microdissected CRC tumor specimens to profile broad cell signaling pathways from patients who presented with liver metastasis versus patients who remained recurrence free after follow-up. Our results indicate that members of the EGFR and COX2 signaling pathways appear differentially activated in the primary tumors of patients with synchronous metastatic disease. If validated in larger study sets, this pathway defect might be useful as a prognostic clinical tool as well as a guide to potential therapeutic intervention strategies that target occult disease and/or preventative measure.

In recent years, wide agreement has been expressed on the value of surgical resection for liver metastases from colorectal cancer, while for unresectable patients different types of locoregional treatment have been attempted. One hundred seventy-one patients with hepatic metastases from colorectal cancer were treated by us over a period of 15 years. Sixty-four underwent hepatic resection, and 107 underwent various forms of locoregional treatment. Our experience confirms the opinion that hepatic resection can be performed with a "curative" aim in patients with colorectal liver metastases: a 5-year survival rate can be achieved in about 30% of resectable cases. Adjuvant chemotherapy after hepatic resection should be tested in prospective randomized trials. Patients with diffuse liver metastases can benefit from locoregional infusion chemotherapy. Symptoms improve in most patients and objective responses are higher than those reported for systemic chemotherapy. Survival benefit with respect to untreated patients, has not yet been demonstrated by prospective randomized studies. Future improvements may be achieved by using new treatment modalities, such as new drug combinations, repeat arterial ischemia, and local tumor destruction. As these types of treatment are still experimental they should be employed only in prospective clinical trials.

Tumor necrosis factor (TNF)-based isolated limb perfusion (ILP) yields high tumor response rates in patients with in-transit melanoma metastases. However, most patients will ultimately experience disease recurrence. The aim of this pilot study was to test the hypothesis that systemic low-dose interferon alpha-2b (LDI) might consolidate the therapeutic effect of ILP.A total of 12 patients with in-transit melanoma metastases not amenable to surgical excision were given LDI subcutaneously (3 million IU/day, 7 days/week for 12 months) after TNF-based ILP (TNF 1 mg + melphalan (L-PAM) 10 mg/L) (group A). The clinical outcome of these patients was historically compared with that of 19 patients with similar anthropometric and disease characteristics who underwent TNF-based ILP alone (group B).In group A, LDI was well tolerated, only grade 2 systemic toxicity being recorded in 50% of patients. The progression-free survival analysis showed a statistically significant advantage for group A patients as compared with group B (median time to progression: 26 and 17 months, respectively; log-rank test P-value: 0.037). This survival benefit was confirmed at multivariate analysis, where treatment was the only prognostic factor retained by the prediction model. The analysis of the risk of disease progression over time suggested that this survival benefit appears to vanish after LDI discontinuation, which further strengthens the hypothesis that LDI might consolidate the therapeutic effect of TNF-based ILP.These preliminary findings support the conduction of larger trials to formally assess the ability of LDI to improve the clinical outcome of melanoma patients with in-transit metastases undergoing TNF-based ILP.

Despite radical surgery, the prognosis of patients who have gastric carcinoma remains unsatisfactory because of the intrinsic but unpredictable aggressiveness of this malignancy. During the past decade an ever-growing list of molecular prognostic factors has been proposed based on the discovery of the mechanisms underlying gastric cancer aggressiveness. Studies performed in larger and more homogeneous series of patients and adequate statistical analysis are warranted before any of the candidate biomarkers can be implemented in the routine clinical setting for the identification of patients at higher risk and thus for the selection of candidates for adjuvant or more aggressive therapies.

As referred to in the literature, patients complaining of constipation may have a spastic or, in the case of chronic staining, weak pelvic floor. Twenty-two severely constipated patients who did not improve after a high fiber diet were submitted to whole gut transit time (TT), proctographic, and anorectal manometric studies. A control group consisting of five subjects for TT, five subjects for proctogram, and ten subjects for manometry was also studied. Transit time was delayed (P less than 0.001) in all patients. Manometry in the constipated group showed a high rectal threshold (64.1 vs. 17.1 ml of air, P less than 0.01), but no other significant difference. Proctograms in 10 of 22 patients (Group A) showed no differences in the anorectal angle (ARA) and in its distance from the pubococcygeal line (DLPC) in respect to the control group; 12 of 22 patients (Group B) had a paradoxical closure of the ARA at straining in respect to resting position (101.2 degrees vs. 120.1 degrees), and a higher DLPC than Group A and the control group in all positions studied. There was no difference in TT for rectal stasis of radiopaque markers between the two pathologic groups. Patients in Group B were older than patients in Group A (55.3 vs. 42.9 years, P less than 0.05). In conclusion, proctograms showed alterations of the pelvic floor, but there was no correlation between protographic data and rectal or colonic stasis of the radiopaque markers, or clinic severity of constipation, but a correlation between ages did exist.

Advances in tumor immunology are supporting the clinical implementation of several immunological approaches to cancer in the clinical setting. However, the alternate success of current immunotherapeutic regimens underscores the fact that the molecular mechanisms underlying immune-mediated tumor rejection are still poorly understood. Given the complexity of the immune system network and the multidimensionality of tumor/host interactions, the comprehension of tumor immunology might greatly benefit from high-throughput microarray analysis, which can portrait the molecular kinetics of immune response on a genome-wide scale, thus accelerating the discovery pace and ultimately catalyzing the development of new hypotheses in cell biology. Although in its infancy, the implementation of microarray technology in tumor immunology studies has already provided investigators with novel data and intriguing new hypotheses on the molecular cascade leading to an effective immune response against cancer. Although the general principles of microarray-based gene profiling have rapidly spread in the scientific community, the need for mastering this technique to produce meaningful data and correctly interpret the enormous output of information generated by this technology is critical and represents a tremendous challenge for investigators, as outlined in the first section of this book. In the present Chapter, we report on some of the most significant results obtained with the application of DNA microarray in this oncology field.

Mass spectrometry (MS)-based profiling was used to determine whether ion fingerprints could distinguish women with stage 1 breast cancer from women without breast cancer. The initial study population consisted of 310 subjects: 155 women with yearly negative breast examination and negative mammography findings for at least 4 years, and 155 women undergoing surgery for pathology-proven stage 1 invasive ductal carcinoma. High-resolution SELDI-TOF (surface-enhanced laser desorption ionization–time of flight) analysis was performed on serum obtained from blood samples collected before mammography in controls, and before surgery in patients with breast cancer. Samples were divided into a training (109 controls and 109 cancers) and blinded (46 controls and 46 cancers) testing set; each group had similar age demographics. In addition, an independent study set of 46 serum samples was analyzed 14 months after the initial study to validate the robustness of the classifier. A discriminatory profile consisting of seven ion peaks found in the training set, when applied to the blinded test set, achieved a sensitivity and specificity of 95.6% and 86.5%, respectively. This same seven-peak profile achieved a 96.5% sensitivity and 85.7% specificity, with correct identification of all of 17 T1a tumors when applied to the validation study set. Mass spectrometry profiling of human serum generated a robust classifier composed of seven low-molecular-weight ions that yielded a highly sensitive and specific diagnostic procedure for the discrimination of women with stage 1 breast cancer compared with women without breast cancer in this research study set.

BACKGROUND: The identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status. METHODS: The gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N-) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation. RESULTS: All patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N-). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value

OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.

Background: In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil + adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm. Patients and methods: This report is a prospective combined analysis of two randomized clinical trials conducted on patients who underwent radical resection for histologically proven adenocarcinoma of the stomach or esophagogastric junction. Three hundred and ninety-seven untreated patients, 206 from 23 European Organization for Research and Treatment of Cancer (EORTC) institutions and 191 from 16 International Collaborative Cancer Group (ICCG) institutions, were randomized. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method and the treatments were compared for these end-points by means of the log-rank test, retrospectively stratified by trial. Results: In a planned combined analysis of the two trials, no significant differences were found between the treatment and control arms for either DFS (hazards ratio: 0.98, P = 0.87) or OS (hazards ratio: 0.98, P = 0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively. Conclusion: Neither FAMTX nor FEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer.