Search

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.

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.

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 . 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potential in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5-year follow-up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser-microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (α-1,3-)-glycoprotein β-1,4-N-acetyl-glucosaminyl-transferase (GnT-IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT-IV upregulation was confirmed by RT-PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications. © 2005 Wiley-Liss, Inc.

The aim of this study was to evaluate factors associated with pathologic tumor response following preoperative chemoradiation therapy, and the prognostic impact of pathologic response on overall and disease-free survival. Between 1994 and 2002, 132 patients underwent chemoradiation therapy followed by surgery for middle to lower rectal cancer. After excluding 26 cases (metastatic cancer, n = 13; nonradical surgery, n = 6; local excision procedure, n = 4; non-5-fluorouracil-based chemotherapy, n = 2; incomplete data on preoperative chemoradiation therapy regimen used, n = 1), the remaining 106 patients were included in the study. Variables considered were the following: age, gender, tumor location, pretreatment T and N stage, modality of 5-fluorouracil administration, total radiotherapy dose delivered, chemoradiation therapy regimen used (Regimen A: chemotherapy (bolus of 5-fluorouracil and leucovorin, days 1–5 and 29–33) + radiotherapy (45 Gy/25 F/1.8 Gy/F); Regimen B: chemotherapy (5-fluorouracil continuous venous infusion ± weekly bolus of carboplatin or oxaliplatin) + radiotherapy (50.4 Gy/28 F/1.8 Gy/F)), time interval between completion of chemoradiation therapy and surgery, postoperative chemotherapy administration, surgical procedures, pT, pN, and pTNM stage, and response to chemoradiation therapy defined as tumor regression grade, scored from 1 (no tumor on surgical specimen) to 5 (absence of regressive changes). Statistical analysis was performed by means of logistic regression analysis (Cox’s model for overall and disease-free survival). Median age of the 106 patients was 60 (range, 31–79) years and the male:female ratio, 66:40. Median distance of tumor from the anal verge was 6 (range, 1–11) cm. Pretreatment TNM stage, available in 104 patients, was cT3–T4N0, n = 41; cT2N1, n = 9; cT3N1, n = 39; and cT4N1, n = 17. The median radiotherapy dose delivered was 50.4 (range, 40–56) Gy; 58 patients received 5-fluorouracil by continuous venous infusion, and carboplatin with oxaliplatin was added to the chemotherapy schedule in 71 cases. Patients were given Regimen A in 47 cases and Regimen B in 59. The median interval between chemoradiation therapy and surgery was 42.5 (range, 19–136) days, and 94 patients underwent a sphincter-saving procedure. Tumor regression grade, available in 104 cases, was 1, n = 19; 2, n = 18; 3, n = 15; 4, n = 13; and 5, n = 39. At a median follow-up of 42 (range, 1–110) months, 11 patients had died, and 95 were alive. None of the patients had local recurrences, but 13 had distant recurrences. At logistic regression analysis, the chemoradiation therapy regimen used was the only independent predictor of tumor response following preoperative chemoradiation therapy (odds ratio = 0.29, 95% confidence interval = 0.13–0.67, P = 0.003). At Cox’s regression analysis, pretreatment T stage was the only independent prognostic factor for both disease-free survival (relative risk = 7.13, 95% confidence interval = 2.3–21.8, P = 0.001) and overall survival (relative risk = 4.83, 95% confidence interval = 1.1–19.9, P = 0.029). Tumor response following preoperative chemoradiation therapy is mainly related to the preoperative regimen used. For patients receiving preoperative chemoradiation therapy, pretreatment T stage, but not tumor response to preoperative chemoradiation therapy, is prognostic for outcome (both disease-free and overall survival).

Prostate-specific antigen (PSA) is a serine-protease that, in addition to cleaving semenogelins in the seminal coagulum, is able to cleave extracellular matrix glycoproteins, thereby affecting cell migration and metastasis. We here report some new activities of PSA that deserve careful consideration in the cancer context: degradation of gelatin, degradation of type IV collagen in reconstituted basement membrane (Matrigel) and activation of progelatinase A (MMP-2), but not pro-MMP-9, in a cell-free system. Since consumption of green tea has been reported to lower the risk of prostate cancer, we investigated the effects of the major flavanol of green tea, (-)epigallocatechin-3-gallate (EGCG), on expression and activity of PSA by prostate carcinoma cells. In addition to restraint of PSA expression, EGCG was found to inhibit in a dose-dependent manner all the above PSA activities, at concentrations lower than the cytotoxic serine-protease inhibitor PMSF and close to levels measured in the serum following ingestion of green tea. The activity of PSA was suppressed also by the elastase released by the inflammatory leukocytes. These results highlight new PSA activities, suggest gelatin zymography as a new convenient assay for PSA, propose EGCG as natural inhibitor of prostate carcinoma aggressiveness, but also stimulate further investigation on the role of prostatic inflammation.

We investigated the relationship between pathologic T-stage and mesorectal metastases after preoperative chemoradiotherapy (CRT) for clinical stage II to III rectal carcinoma.The records of consecutive patients with clinical stage II to III carcinoma of the mid or low rectum who underwent surgery after CRT were reviewed. Indications for preoperative CRT were cancer up to 11 cm from the anal verge, Eastern Cooperative Oncology Group performance status of 0 to 2, age 18 to 75 years, and clinical tumor-node-metastasis stage II or III.The study group consisted of 235 patients (148 men and 87 women; median age, 61 years). The pretreatment tumor-node-metastasis stage was as follows: I, n = 1; II, n = 96; and III, n = 138. Radiotherapy was delivered at a median dose of 50.4 Gy. A pathologic complete response on the rectal wall was found in 24% of patients, and nodal metastases were found in 20% of patients. According to the pT stage, the rate of node positivity was 2% for pT0, 15% for pT1, 17% for pT2, 38% for pT3, and 33% for pT4 cases. At multivariate analysis, the best model for predicting pathologic node involvement included young age, positive pretreatment N status, and pT status. On considering pT stage alone, the odds ratio was in the region of 10 for pT1/2 and20 for pT3/4 patients.In patients with pT0 after preoperative CRT for clinical stage II to III mid or low rectal cancer, the risk of nodal metastases is very low. More conservative surgery (local excision) may be considered in these cases.

Stop-flow perfusion (SFP) is a recently implemented locoregional treatment based on the vascular isolation of the tumor bearing body district through a radiointerventistic technique. SFP is currently under investigation as a palliative therapeutic option for patients with locally advanced tumors. This paper reports on the results of our prospective study of limb and pelvic SFP. Thirty-seven patients were treated with SFP. No postoperative deaths occurred. Locoregional and systemic toxicity were observed after 22 and 31 treatments, respectively; complete and partial response after 3 (6%) and 24 (51%) SFPs, respectively. The pharmacokinetic study showed that pelvic SFP was associated with a leakage rate higher than femoral SFP (38% vs 28%). In conclusion, SFP is a feasible procedure. Toxicity and tumor response rates strictly depend upon drug leakage control.

BACKGROUND Abdominal sarcomatosis is a rare nosologic entity with a poor prognosis. After a Phase I study on cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy (HIIC), the authors reported the results of the treatment of 60 patients using this novel multimodal approach. METHODS Twenty-nine patients had multifocal primary disease and 31 patients had recurrent abdominal sarcoma. Tumor histology was represented by visceral (n = 26 [43%]) and retroperitoneal (n = 34 [57%]) sarcoma. All patients underwent cytoreductive surgery (with no or minimal residual disease) and 90-minute HIIC with doxorubicin (15.25 mg/L of perfusate) and cisplatin (43 mg/L). The clinical outcome and the prognostic value of 11 clinicopathologic variables were analyzed. RESULTS No postoperative deaths occurred. The morbidity rate was 33% and the moderate to severe locoregional toxicity rate was 15%. The median time to local disease progression and the median overall survival were 22 months and 34 months, respectively. Using multivariate analysis, histologic grading and completeness of surgical cytoreduction predicted patient prognosis, indicating that both local progression-free and overall survival were affected significantly by tumor aggressiveness and local disease control. CONCLUSIONS Although these results were encouraging, there was no definitive conclusion reached regarding the therapeutic activity of this locoregional treatment. In addition, the toxicity rate was substantial. In the absence of effective systemic agents, the therapeutic potential of cytoreductive surgery plus HIIC should be explored further in comparative trials. Cancer 2004. © 2004 American Cancer Society.

Detection of circulating tumor cells (CTCs) might improve current staging procedures by identifying a subgroup of patients with minimal residual disease and thus a higher risk of disease recurrence. Forty patients with > or =2-mm-thick cutaneous melanoma with or without lymph node metastasis were enrolled. After standard radical surgery and adjuvant therapy in case of lymph node metastasis, patients were followed up with routine physical and radiologic assessments as well as serial PCR-based analysis of CTCs using 2 melanoma markers (tyrosinase and Melan-A/Mart-1). After a median follow-up of 30 months, 18 patients had disease recurrence and 28 were PCR-positive before the disease became clinically evident. The sensitivity of the molecular test was 83%. Median time to PCR positivity and median PCR-to-relapse time were 12 and 8 months, respectively. At multivariate analysis, PCR positivity was an independent predictor of disease recurrence (hazard ratio=2.06, 95% CI 1.07-3.35; p=0.03). Among high-risk melanoma patients, serial PCR-based analysis of CTCs can identify a subgroup at higher risk of disease recurrence, with clinically significant advance. Therefore, CTC detection might be employed for the selection of patients for adjuvant treatment and during follow-up for early indication of therapeutic failure.

Hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) has been recently proposed to treat peritoneal carcinomatosis arising from colon adenocarcinoma, which is usually regarded as a lethal clinical entity. The purpose of this study was to evaluate the clinical outcome of this combined treatment.A retrospective study of 46 patients treated for peritoneal carcinomatosis from colon adenocarcinoma was performed. Thirty-four patients were treated with complete cytoreductive surgery immediately followed by intraoperative HIIC with mitomycin C and cisplatin. The clinical outcome of these 34 patients was analyzed; the median follow-up period was 14.5 months.No postoperative deaths were reported. The postoperative morbidity rate was 35%. No severe locoregional or systemic toxicity was observed. The 2-year overall survival was 31%, and the median survival time and the median time to local disease progression were 18 and 13 months, respectively. Survival and local disease control in patients with well- and moderately differentiated colon adenocarcinoma were significantly better than in those with poorly differentiated tumors.Considering the dismal prognosis of this condition, HIIC seems to achieve encouraging results in a selected group of patients affected with resectable peritoneal carcinomatosis arising from colon adenocarcinoma. These findings support the conduction of formal phase III randomized trials.

PURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites (≥ 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.

Isolation limb perfusion (ILP) is the treatment of choice for locally advanced limb melanoma. With melphalan, the referral drug, complete response (CR) is achieved in about 50% of patients, but significant local toxicity occurs in up to 30%. The aim of the present phase I-II study was to challenge fotemustine (F) in ILP after systemic chemosensitization with dacarbazine (DTIC), given its lower toxicity and greater efficacy, as reported in a previous pilot study. Eleven patients with locally advanced limb melanoma were subdivided into triplets, and given F ILP at escalating doses (starting from 25 mg/l) after intravenous administration of 500 mg/m2 DTIC. Acute and chronic locoregional and systemic toxicity, tumour response and clinical outcome were evaluated. Two patients in the first triplet had G3-G4 local toxicity, so that the scheduled F dosage was halved. At drug levels of 12.5, 15.6 and 18.2 mg/l, local toxicity decreased, but only one of eight patients showed CR. The trial was then interrupted due to the low tolerability and poor efficacy of this perfusion regimen. At present, F ILP after DTIC chemosensitization should not be recommended for the treatment of locally advanced limb melanoma.

Background and Objectives To evaluate the efficacy of preoperative ultrasound (US) scanning in identifying lymph node metastasis before sentinel node biopsy (SNB), we conducted a prospective study on 125 patients with primary cutaneous melanoma (CM). Methods We prospectively enrolled 125 patients with >1 mm thick CM and candidate for SNB. Preoperatively, patients underwent US scanning of regional lymphatic basins and FNA of suspected lymph nodes (LN). All patients underwent lymphatic mapping and SNB. Results Combined with fine-needle aspirate (FNA) of suspect LN, US scan allowed the correct preoperative detection of 12 out of 31 histologically positive lymphatic basins, specificity and sensitivity being 100 and 39%, respectively. The false negative rate (61%) was mainly linked to tumor deposits less than 2 mm in diameter, which can be considered the current spatial resolution limit of this technique. Conclusions Preoperative US scan could reduce the number of SNB, thus avoiding the stress of this surgical procedure in ∼10% of patients and reducing health care costs. As a non-invasive and relatively inexpensive technique, lymph node US scan can be part of the preoperative staging process of patients' candidate for SNB in order to avoid unnecessary surgical procedures. J. Surg. Oncol. 2003;83:80–84. © 2003 Wiley-Liss, Inc.

Background Auto-crosslinked polysaccharide hyaluronan-based solution (Hyalobarrier®-gel) prevents postoperative adhesions. However, its effect on tumour growth is still unknown. The aim of the present study was therefore to investigate the impact on survival of intra-abdominally administered Hyalobarrier®-gel, native hyaluronan (HA) and hyaluronan/carboxymethylcellulose (HA/CMC), after intraperitoneal tumour implantation. Methods After receiving an intraperitoneal inoculum of the human HT29 colorectal cell line, 615 athymic nude mice were assigned randomly to five groups: groups 1 and 2 received Hyalobarrier®-gel 20 mg/ml (n = 124) and 40 mg/ml (n = 126) respectively; groups 3 and 4 received HA (n = 120) and HA/CMC film (Seprafilm™) (n = 123) respectively. The survival of each treated group was compared with that of group 5, the control, which had no treatment (n = 122). Results As 34 of the 615 mice were not eligible, 581 animals were considered for the analysis. At 120 days, 136 animals (23·4 per cent) were still alive. At autopsy there was macroscopic absence of tumour in 75 cases (12·9 per cent). No statistically significant differences were found between the treatment and the control groups with respect to postoperative death and absence of tumour implantation. There was no difference in survival rate between the control group and groups treated with Hyalobarrier®-gel, HA or HA/CMC. Conclusion Hyalobarrier®-gel, HA and HA/CMC had no negative impact on the survival rate in mice that received an intraperitoneal implantation of HT29 colorectal human tumour cells.

Intraperitoneal chemotherapy, mainly when performed during HIIC after cytoreductive surgery, is considered potentially curative for the treatment of solid tumors with spread to the peritoneal surface. When selecting antiblastic agents to be administered intraperitoneally, it is important to bear in mind that a low lipophility and a high molecular weight are the ideal drug characteristics. Drugs with these features allow a favorable ratio to be achieved between peritoneal and plasma concentrations, due to the reduced tendency to diffuse through the plasma-peritoneal barrier, even after extensive removal of the peritoneum. Moreover, a low rate of diffusion through the tumor capillaries implies a low rate of drug clearance, with a higher intratumoral drug accumulation. Among the drugs used so far for intraperitoneal chemotherapy, the combination of CDDP and DXR appears to be one of the most effective available regimens with acceptable local-regional toxicity. CDDP has also been extensively employed as a single agent for ovarian and gastrointestinal cancers, under both normal and hyperthermic conditions, while intraperitoneally administered DXR appears to be of greater potential efficacy when associated with CDDP and hyperthermia (41.5 degrees C) following cytoreductive surgery. In our clinical experience with this drug combination, DXR showed a much more advantageous plasma/peritoneal AUC ratio than CDDP (162 +/- 113 and 20 +/- 6, respectively). On the other hand, it has been demonstrated that very high intraperitoneal concentrations of CDDP can be achieved without incurring significant systemic toxicity by using intravenous injection of sodium thiosulphate during HIIC. Penetration of the tumor mass by CDDP is greater than DXR. This phenomenon is enhanced by hyperthermia and by hypotonic solutions of sodium chloride used as the perfusate. Following experimental and clinical results of TNF alpha-based isolated limb perfusion for locally advanced soft tissue sarcoma or melanoma, greater efforts are being made to exploit the potential effect of this cytokine used in association with hyperthermia and other drugs (i.e., CDDP and DXR) suitable for intraperitoneal infusion/perfusion. However, it is not yet clear whether the observed effect of TNF alpha on the peritoneal-plasma barrier, which seems to favor the passage of both drugs into the systemic circulation, is overcome by the positive effect of this agent on drug penetration into tumor. Further pharmacologic studies should be undertaken to clarify whether or not these interactions will be of benefit to the patient. Likewise, liposomes, which in animal models seem to favor tumor uptake of encapsulated DXR, should now be tested in the clinical setting.

The laparoscopic application of an adjustable silicone gastric band (Lap-Band System, Bioenterics, Carpinteria, CA) (Fig. 1), based on a similar device introduced by Kuzmak in 1986, is gaining widespread acceptance as a gastric restrictive procedure in treatment of morbid obesity. The advantage of an operation that does not open the gastrointestinal tract and can be performed laparoscopically is obvious. This procedure, using the laparoscopic approach , has been performed in our institutions since 1992. The goals of this article are to describe both our standardized surgical technique that minimized the morbidity rate and its results.

Background and Objectives Low tumor expression of the p27Kip1 protein, which is involved in cell cycle control and apoptosis, is considered a negative prognostic factor in different types of cancer. The aim of this study was to evaluate the clinical and pathological significance of low p27Kip1 protein expression in patients who had undergone resection for gastric adenocarcinoma. Methods p27Kip1 protein was studied by immunohistochemistry in formalin-fixed tumor sections from 95 patients who underwent resection for gastric adenocarcinoma between 1991 and 1996. Based on the median value of protein expression, p27Kip1 protein expression was classified as low or high. Results Low p27Kip1 protein expression was significantly associated with tumor de-differentiation, increased penetration through the gastric wall, lymph node metastasis, and advanced tumor stage. In the group of 84 patients who underwent curative surgery, 5-year survival was 74% in cases with high p27Kip1 protein expression and 38% in those with low p27Kip1 protein expression (P

Background: The authors investigated the outcome predictors in obese patients who underwent laparoscopic adjustable banding with the Lap-Band®. Methods:The 3-year excess weight loss (EWL) and rate of band-related complications (pouch dilatation and port leackage) were analyzed in 260 morbidly obese patients, according to several possible predictive characteristics. Success rate (EWL >50%), failure rate (EWL 10%EWL between 1 and 3 yrs) were considered. Results: The Lap-Band® produced a 43.0±22.3% EWL, corresponding to a BMI reduction from 46.6±7.0 to 36.8±6.6 kg/m2. Success rate was 35.7%, failure rate was 14.1% and weight regain rate was 20.7%. Pouch dilatation occurred in 32 patients (12.3%), band erosion in 2 (0.8%), port leakage in 74 (28.5%), and port twisting in 2 (0.8%). Major band-related surgery was requested in 11 patients (4.2%) and minor port-related surgery in 62 patients (23.9%). Significant success predictors were found to be age

Various series have reported similar survival and recurrence rates after resection of colorectal liver metastases (CRLM). If outcomes were predictable, indications for surgery could be improved. This hypothesis was tested in 135 consecutive patients with CRLM who underwent "curative" resection from 1977 to 1997. Among the 132 patients available for follow-up, three groups were identified on the basis of outcome: (1) survival of more than 5 years disease-free (n = 32; 24%); (2) diffuse recurrences within the first 6 months (n = 24; 18%); and (3) discrete recurrences for which reresection was performed (n = 16; 12%). As our results are similar to those reported in the literature, we assumed that about 50% of patients with resectable lesions have recognizable patterns of recurrence. At multivariate analysis, factors significant for disease-free survival (DFS) were the percentage of liver invasion, metastases to lymph nodes at the primary site, number of metastases, preoperative glutamic pyruvic transaminase (GPT) level, and type of liver resection. On the basis of the relative risk (RR) expressed by significant prognostic factors, a score model was developed, and three prognostic groups were defined: Group A, with the best prognostic score, included 23 of 32 (72%) patients who survived more than 5 years, and that with the worst prognostic score (group C) included 22 of 24 (92%) patients with early diffuse recurrences. Extreme (especially unfavorable) outcomes can therefore be predicted. By using improved models of outcome analysis, many patients could be spared surgery as first-line treatment, and stratification criteria could be worked out for future trials.

Background: The p27Kip1 protein regulates the G1 to S phase transition of cell cycle by binding to and inhibiting the cyclin E/Cdk2 complex. This study explores the prognostic significance of the absence of the p27Kip1 protein in patients with colorectal cancer (CRC). Methods: Formalin-fixed tumor sections from 124 patients who underwent curative resection for stage I-III CRC were analyzed by immunohistochemistry using MoAb anti-p27Kip1. Results: Detectable levels of p27Kip1 protein were found in 86% of tumors. Median follow-up was 55 months. Actuarial 5-year disease-free survival (DFS) and overall survival (OS) were 76% and 85%, respectively, in patients with tumors with p27Kip1 protein expression and 34% and 40%, respectively, in those whose tumors lacked p27Kip1 protein expression (P < .001). At multivariate analysis, tumor stage (III vs. I-II) and p27Kip1 protein status (absence vs. presence) were found to be independent prognostic factors for DFS and OS. Conclusions: Lack of p27Kip1 protein expression in CRC is a negative prognostic marker and may therefore be useful in selecting early-stage patients more likely to benefit from adjuvant treatment.

BACKGROUND Of the different options for limb-sparing treatment for patients with soft tissue limb sarcomas (STLS), hyperthermic antiblastic perfusion (HAP) combined with surgery might be the most effective in terms of tumor resectability, local control, and aesthetic and functional results. The aim of this study was to identify the most safe, active, and effective perfusional regimen in order to improve multidisciplinary treatment for patients with advanced STLS. METHODS The first trial undertaken (which involved 18 patients) was a Phase I study to assess the maximum tolerable dose of doxorubicin, the second (with 29 patients) was a Phase II study of HAP with doxorubicin, and the third (with 20 patients) was a Phase I–II study to assess the maximum tolerable dose and tumor response to doxorubicin combined with tumor necrosis factor (TNF). Statistical tests were performed on the whole series to evaluate the factors influencing local toxicity, tumor response, and local disease free and overall survival. RESULTS Grade IV systemic toxicity was observed in only 2 cases (TNF >1 mg). Muscle temperature (>41.5 °C) was the limiting factor for locoregional toxicity. Limb-sparing surgery was feasible for 60 patients (92.3%). The highest tumor response was observed in the third trial, with complete histologic necrosis in 26.3% of cases. Muscle and tumor temperature (>41.5 °C) and the type of trial had a statistically significant influence on response. The local recurrence rate was influenced by tumor site, type of trial, maximum tumor temperature, and local toxicity, whereas the overall survival was influenced by the presence of metastasis, tumor grade, and response to treatment. CONCLUSIONS These findings show that HAP with doxorubicin and TNF (≤1 mg) at a muscle temperature of ≤41.5 °C is a safe, active, and effective perfusional regimen for the multidisciplinary treatment of patients with advanced STLS. Cancer 1999;86:1742–9. © 1999 American Cancer Society.

To evaluate the role of hyperthermia combined with chemotherapy in the loco-regional treatment of tumors, a retrospective analysis was done with 228 limb melanoma patients treated with hyperthermic antiblastic perfusion (HAP). A series of treatment- and tumor-related prognostic factors was analyzed to establish their influence on tumor response, loco-regional control, and survival. Concerning tumor response, the logistic model showed that the number of lesions and the minimal tumor temperature (min T) maintained their individual predictive values (P < 0.000001 and P = 0.04, respectively). For loco-regional control, only the number of lesions had a significant predictive value. No direct correlation was found between the treatment-related variables and loco-regional control. However, the 5-year survival rate was significantly higher for patients who achieved a complete response (CR) (51.5%, P = 0.0033) as compared to those who did not (33.3%), providing indirect evidence of the role of the treatment. Multivariate analysis showed that both disease-free and overall survival are strongly influenced by numerous clinical variables and the min T always maintained its significance. When analyzing the subgroup of 119 patients evaluable for tumor response, the Cox model selected the tumor response as the dominant factor for both disease-free and overall survival. These data seem to demonstrate that the optimization of treatment parameters is crucial in determining the CR rate, which, in turn, positively affects the disease outcome. HAP is the treatment of choice for recurrent limb melanoma, and hyperthermia plays an important role in exploiting the efficacy of this technique. Semin. Surg. Oncol. 14:215–223, 1998. © 1998 Wiley-Liss, Inc.

BACKGROUND Several lines of evidence indicate that there is a close association between hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC). However, the role of the virus itself in the development of the disease is not yet well understood. METHODS In liver samples from 15 anti-HCV positive Caucasian patients with HCC, the authors searched for the presence and genomic characteristics of the infecting virus, and also analyzed the p53 gene by single strand conformation polymorphism and sequencing of abnormal bands. RESULTS In all cases but one, HCV RNA was detected in nonneoplastic liver tissue, whereas in neoplastic tissue, viral sequences were detected in 6 of 6 samples containing moderately differentiated HCC (Edmondson grades I-II) and in 2 of 9 containing poorly differentiated HCC (Edmondson grade III) (P = 0.007). Seventy-three percent of the cases were infected by genotype 1 and 20% by genotype 2, whereas the liver cells of 1 patient with a previous history of hepatitis B infection were HCV RNA negative. p53 mutations, observed in 2 patients, consisted of a G-to-A transition at codon 176 of exon 5 in 1 patient and a G-to-T transversion at codon 287 of exon 8 in the other. CONCLUSIONS The results of this study indicate that HCV may contribute to liver tumor development during the early stages of carcinogenesis, whereas p53 gene mutations were detected only in 2 of 15 patients in this cohort. Cancer 1998;83:1489-1494. © 1998 American Cancer Society.

A retrospective study was made on 22 patients who underwent surgery (28 operations) for lung metastases of colorectal origin from 1986 to 1995 at the Department of Surgery II, Padova University. The overall 5-year survival (OS) following pulmonary resection was 62% and the 5-year disease-free interval after metastasectomy (DFIM) 45%. The median survival was 23.6 months and the median DFIM 15.3 months. Univariate (Mantel Cox) and multivariate (Cox's model) analyses were used to identify any prognostic factors significant for OS and DFIM. Site and stage of primary colorectal carcinoma, number of pulmonary metastases at presentation, disease-free intervals between treatment of primary tumour and diagnosis of lung metastases (DFIP) appeared to have no influence on OS and DFIM. However, patients who underwent radical resection for metastases had a significantly longer DFIM than those who underwent ‘non-radical’ resections ( P =0.02), but radical resection had no significant positive effect on OS. A short DFIP, multiple and/or bilateral lesions, lung metastases occurring after liver resection with a curative aim are not contraindications to surgery in patients with pulmonary metastases from colorectal cancer, the main criterion for selection of patients being the possibility of performing ‘radical’ resection.

Kuzmak's gastric silicone banding technique is the least invasive operation for morbid obesity. The purpose of this study was to analyze the complications of this approach.Between September 1992 and March 1996, 185 patients underwent laparoscopic gastroplasty by the adjustable silicone band technique. A minimally invasive procedure using five trocars was performed.In 11 patients exposure of the hiatus was impeded because of hypertrophy of the left liver lobe which led to conversion in eight patients and abortion of the procedure in three other patients. Anatomical complications: We observed two gastric perforations and one band slippage at the early stage, one infection and three rotations of the access port. Functional complications: There were eight (4%) cases of irreversible total food intolerance resulting in pouch dilation and eight cases (4%) of esophagitis. One fatality on the 45th day in a patient with a Prader-Willi syndrome.The most disturbing complications of gastric banding technique are gastric perforation and pouch dilation. Their incidence may be reduced by improving the technique and by considering pitfalls of the procedure.

In 85 patients with intermediate to high risk cutaneous melanoma, concomitant palpation and ultrasound scanning (US) of the axillary and inguinal sites were performed in order to detect any locoregional lymph node metastases at pre-operative staging and postoperative monitoring. At 12 months follow-up, US identified 12 out of 13 (92%) histologically proven metastases, while palpation indicated metastatic disease in only 3 (23%) patients. Metastases were intranodal in 6 out of 12 cases detected with US, and extranodal in all the 3 cases identified by palpation, thus confirming that US is more effective than palpation in the early detection of lymph node metastases from melanoma. US was also more effective in discriminating all non-neoplastic lymph nodes: its overall specificity was 100% versus 85% for palpation. Thus, when carried out by well-trained radiologists, US is a very useful diagnostic tool for the surgical oncologist dealing with melanoma patients.

PURPOSE: This study was designed to determine the importance of innervation of striated anal sphincters, one of the most important structures in idiopathic fecal incontinence. METHODS: Forty-three idiopathic, fecally incontinent patients (40 women and 3 men; mean age, 57.2±11 (range, 33–77) years) underwent anorectal manometry and sphincteric electromyography. On the basis of electromyographic findings, patients were subdivided into three groups: Group A consisted of 21 patients with normal electromyography; Group B consisted of 14 patients with moderate denervation; Group C consisted of 8 patients with severe denervation. Manometric results from the patients were compared with those from 15 healthy subjects (8 women and 7 men; mean age, 35±12 (range, 15–55) years). RESULTS: Incontinent patients had a shorter anal canal (P=0.005), and anal canal pressure was lower at rest (P

A positive correlation between PCNA and the most important histoprognostic factors of cutaneous melanoma has been demonstrated. The aim of our work was to evaluate the efficacy of PCNA in predicting melanoma recurrence and to compare it with that of Breslow thickness. One-hundred and fifteen patients (75 women, 40 men; mean age 50 years) with primary cutaneous melanoma were retrieved. pTNM stages were as follows: stage I, 54 patients; stage II, 31 patients; stage III, 26 patients; and stage IV, four patients. The mean follow-up period was 55 months (range 2-260). Six patients developed lymph node metastases and 28 developed distant metastases; 27 patients died within 2-202 months from diagnosis. Tumour thickness was re-evaluated for each case. PCNA immunostaining was performed using the avidin-biotin complex method and the percentage of PCNA-positive tumour cells was indicated as the PCNA index. In order to evaluate and compare the PCNA index and Breslow thickness as predictors of recurrence, the receiver-operating characteristic (ROC) curve method, based on true-positive and false-positive rates was used. The PCNA index showed the highest true-positive rates and the lowest false-positive rates in the 5-30 interval. The PCNA index optimal cut-off is 20, characterized by 70% sensitivity and 80% specificity; Breslow thickness optimal cut-off is 3.5 mm, with 40% sensitivity and 90% specificity. Our results indicate that the PCNA index has a higher efficacy in predicting locoregional and distant recurrences in patients presenting primary cutaneous melanoma.

The authors report their experience of 30 patients with colorectal anastomotic stenosis treated by 62 dilatation sessions in order to evaluate which anastomotic characteristics could influence the success of dilatation therapy. Patients were subdivided into group A (dilatation successful) and group B (dilatation unsuccessful). Overall, dilatation was successful in 73.3% of cases, with only one important complication. The prognostic factors considered were anastomotic dehiscence, adjuvant radiotherapy, presence of colostomy at dilatation, site, morphology and length of the stenosis, presence of neoplastic recurrence, type of anastomosis and type of dilatation. Radiotherapy, local neoplastic recurrence and large anastomotic dehiscence were the more important independent prognostic factors. If present together, they were associated with an almost 100% probability of failure and, vice versa, if they were absent this probability was 5%.